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Chapter 6 Cornea

INTRODUCTION 168
Anatomy and physiology 168
Signs of corneal inflammation 168
Documentation of clinical signs 172
Specular microscopy 172
Principles of treatment 173
BACTERIAL KERATITIS 173
Pathogenesis 173
Clinical features 175
Investigations 175
Treatment 178
FUNGAL KERATITIS 180
Introduction 180
Candida and filamentous keratitis 180
Microsporidial keratitis 182
HERPES SIMPLEX KERATITIS 183
Introduction 183
Epithelial keratitis 183
Disciform keratitis 185
Necrotizing stromal keratitis 185
Neurotrophic ulceration 185
Other considerations 186
HERPES ZOSTER OPHTHALMICUS 187
Introduction 187
Acute shingles 188
Eye disease 188
Post-herpetic neuralgia 190
INTERSTITIAL KERATITIS 191
Pathogenesis 191
Syphilitic IK 192
Cogan syndrome 193
PROTOZOAN KERATITIS 194
Acanthamoeba 194
Onchocerciasis 196
BACTERIAL HYPERSENSITIVITY-MEDIATED CORNEAL DISEASE 196
Marginal keratitis 196
Phlyctenulosis 197
ROSACEA 197
SEVERE PERIPHERAL CORNEAL ULCERATION 199
Mooren ulcer 199
Peripheral ulcerative keratitis associated with systemic autoimmune disease 202
Terrien marginal degeneration 203
NEUROTROPHIC keratopathy 203
EXPOSURE keratopathy 204
MISCELLANEOUS keratopathy 206
Infectious crystalline keratopathy 206
Thygeson superficial punctate keratitis 206
Filamentary keratopathy 207
Recurrent corneal epithelial erosions 208
Xerophthalmia 209
CORNEAL ECTASIAS 210
Keratoconus 210
Pellucid marginal degeneration 210
Keratoglobus 212
CORNEAL DYSTROPHIES 212
Epithelial dystrophies 212
Bowman layer/anterior stromal dystrophies 216
Stromal dystrophies 218
Endothelial dystrophies 222
CORNEAL DEGENERATIONS 224
Age-related degenerations 224
Lipid keratopathy 224
Band keratopathy 227
Spheroidal degeneration 228
Salzmann nodular degeneration 228
METABOLIC KERATOPATHIES 228
Cystinosis 228
Mucopolysaccharidoses 229
Wilson disease 230
Lecithin-cholesterol-acyltransferase deficiency (Norum disease) 230
Immunoprotein deposits 230
Fabry disease (angiokeratoma corporis diffusum) 232
Tyrosinaemia type 2 (Richner–Hanhart syndrome) 232
CONTACT LENSES 232
Therapeutic uses 232
Complications 233
CONGENITAL ANOMALIES OF THE CORNEA AND GLOBE 235
Microcornea 235
Megalocornea 235
Sclerocornea 235
Cornea plana 235
Keratectasia 237
Posterior keratoconus 237
Microphthalmos 237
Anophthalmos 238
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Introduction

Anatomy and physiology

General aspects

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, with a downhill anterior–posterior oxygen gradient. The cornea is the most densely innervated tissue in the body, with a subepithelial and a deeper stromal plexus, both supplied by the 1st division of the trigeminal nerve. For this reason corneal abrasions and disease processes such as bullous keratopathy are associated with pain, photophobia and reflex lacrimation.

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 conventionally-measured intraocular pressure level.

Layers

The cornea consists of the following layers (Fig. 6.1), each of which is critical to normal function:

1 The epithelium is stratified squamous and non-keratinized, and is composed of the following:
• A single layer of columnar basal cells attached by hemidesmosomes to an underlying basement membrane.
• Two to three strata of ‘wing’ cells.
• Two layers of squamous surface cells.
• 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.
• Epithelial stem cells that are indispensable for the maintenance of a healthy corneal surface are located principally at the superior and inferior limbus, possibly in the palisades of Vogt. They also act as a junctional barrier, preventing conjunctival tissue from growing onto the cornea. Dysfunction or deficiency of limbal stem cells may result in chronic epithelial defects, overgrowth of conjunctival epithelium onto the cornea (‘conjunctivalization’) and vascularization.
2 Bowman layer is the acellular superficial layer of the stroma formed from collagen fibres.
3 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 cannot regenerate following damage.
4 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.
5 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 adult cell density is about 2500 cells/mm2. 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 cell density of about 500 cells/mm2 corneal oedema develops and transparency is reduced.
image

Fig. 6.1 Anatomy of the cornea

Signs of corneal inflammation

Superficial lesions

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1 Punctate epithelial erosions (PEE) are generally an early sign of epithelial compromise.
a Signs. Tiny epithelial defects that stain with fluorescein (Fig. 6.2A) and rose bengal.
b Causes include a wide variety of stimuli; the location of the lesions may give an indication of aetiology as follows:
• Superior – vernal disease, chlamydial conjunctivitis, superior limbic keratoconjunctivitis, floppy eyelid syndrome and mechanically-induced keratoconjunctivitis.
• Interpalpebral – dry eye (can also be inferior), reduced corneal sensation and ultraviolet keratopathy.
• Inferior – chronic blepharitis, lagophthalmos, eye drop toxicity, self-induced, aberrant eyelashes and entropion.
• Diffuse – some cases of viral and bacterial conjunctivitis, and toxicity to drops.
• Central – prolonged contact lens wear.
2 Punctate epithelial keratitis (PEK)
a Signs. Granular, opalescent, swollen epithelial cells, with focal intraepithelial infiltrates (Fig. 6.2B). They are visible unstained but stain well with rose bengal and variably with fluorescein.
b Causes
• Infection such as adenoviral, chlamydial, molluscum contagiosum, early herpes simplex and herpes zoster, and systemic viral infections (e.g. measles, varicella, rubella).
• Miscellaneous such as Thygeson superficial punctate keratitis and toxicity to drops.
3 Subepithelial infiltrates
a Signs. Tiny subsurface foci of non-staining inflammatory infiltrates.
b Causes include severe or prolonged adenoviral keratoconjunctivitis, herpes zoster keratitis, adult inclusion conjunctivitis, marginal keratitis, rosacea and Thygeson superficial punctate keratitis.
4 Superficial punctate keratitis is a non-specific term describing any corneal epithelial disturbance of dot-like morphology.
5 Filaments
a Signs. Strands of mucus admixed with epithelium, attached at one end to the corneal surface, that stain well with rose bengal (Fig. 6.2C). The unattached end moves with each blink. Grey subepithelial opacities may be seen at the site of attachment.
b Causes. Dry eye is by far the most common; others include superior limbic keratoconjunctivitis, neurotrophic keratitis, long-term ocular patching and essential blepharospasm.
7 Epithelial oedema
a Signs. Subtle cases may manifest with loss of normal corneal lustre, but more commonly by abundant tiny epithelial vesicles; bullae (Fig. 6.2D) are seen in moderate-severe cases.
b Causes. Endothelial decompensation, including that due to severe acute elevation of intraocular pressure.
8 Superficial neovascularization is a feature of chronic ocular surface irritation or hypoxia, as in contact lens wear (Fig. 6.2E).
9 Pannus describes superficial neovascularization accompanied by degenerative subepithelial change extending centrally from the limbus (Fig. 6.2F).
image

Fig. 6.2 Superficial corneal lesions. (A) Profuse punctate epithelial erosions stained with fluorescein; (B) punctate epithelial keratitis; (C) filaments stained with rose bengal; (D) corneal oedema with bullae; (E) superficial vascularization; (F) pannus

Deep lesions

1 Infiltrates are focal areas of acute stromal inflammation composed of inflammatory cells, and cellular and extracellular debris including necrosis. The key distinction of clinical importance is between sterile and infective lesions (Table 6.1); ‘PEDAL’ mnemonic: Pain, Epithelial defects, Discharge, Anterior chamber reaction, Location.
a Signs. Yellow- or grey-white opacities located initially within the anterior stroma (Fig. 6.3A) associated with limbal or conjunctival hyperaemia.
b Causes
• Suppurative keratitis is caused by active infection with bacteria, viruses, fungi or protozoa.
• Non-infectious ‘sterile keratitis’ is the result of an immunological hypersensitivity response to antigen as in marginal keratitis and with contact lens wear.
2 Ulceration refers to tissue excavation associated with an epithelial defect (Fig. 6.3B). Connective tissue ‘melting’ occurs in response to enzymatic activity, as in peripheral ulcerative keratitis.
3 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 (Fig. 6.3C).
4 Lipid deposition may follow chronic inflammation with leakage from corneal new vessels (Fig. 6.3D).
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5 Folds in Descemet membrane (striate keratopathy – Fig. 6.3E) may result from corneal oedema exceeding the capacity of the endothelium to maintain normal turgescence. Causes include inflammation, trauma (including surgery) and ocular hypotony.
6 Descemetocele is a bubble-like herniation of Descemet membrane into the cornea, plugging a defect which would otherwise be full-thickness.
7 Breaks in Descemet membrane may be due to corneal enlargement (Haab striae in infantile glaucoma) or deformation such as keratoconus and birth trauma (Fig. 6.3F). Acute influx of aqueous into the corneal stroma (acute hydrops) can occur.
8 Seidel test demonstrates aqueous leakage. A drop of 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 (Fig. 10.86A).

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 peripheral
Adjacent corneal reaction Extensive Limited
image

Fig. 6.3 Deep corneal lesions. (A) Infiltration; (B) ulceration; (C) vascularization; (D) lipid deposition; (E) folds in Descemet membrane; (F) traumatic breaks in Descemet membrane

(Courtesy of S Tuft – fig. D; R Curtis – fig. F)

Documentation of clinical signs

Clinical signs should be illustrated with a labelled diagram, particularly in order to facilitate monitoring. The dimensions of epithelial and stromal lesions, and the depth of new vessels, should all be recorded. Colour coding can be helpful (Fig. 6.4).

1 Opacities such as scars and degenerations are drawn in black.
2 Epithelial oedema is represented by fine blue circles, stromal oedema as blue shading and folds in Descemet membrane as wavy blue lines.
3 Hypopyon is shown in yellow.
4 Blood vessels are then added in red. Superficial vessels are wavy lines that begin outside the limbus and deep vessels are straight lines that begin at the limbus.
5 Pigmented lesions such as iron rings and Krukenberg spindles are shown in brown.
image

Fig. 6.4 Documentation of corneal lesions

Specular microscopy

Specular microscopy is the study of the changes in different layers of the cornea under very high magnification (100 times greater than slit-lamp biomicroscopy) that is mainly being used to assess the endothelium. The image is analyzed with respect to cellular size, shape, density and distribution. The normal endothelial cell is a regular hexagon (Fig. 6.5A) and the normal cell density in a young adult is about 3000 cells/mm2.

1 Physics. When a light beam of the specular photomicroscope passes through the cornea it encounters a series of interfaces between optically distinct regions. Some light is reflected specularly (i.e. like a mirror) back towards the photomicroscope when the angle of reflection is the same as the angle of incidence. This specular light is captured by the photomicroscope and forms an image which can be photographed and analyzed.
2 Indications
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a Prior to surgery. Evaluating the functional reserve of the corneal endothelium prior to intraocular surgery is the most important indication. A clear cornea with normal pachymetry (i.e. thickness) is not necessarily associated with normal endothelial morphology or cell density. Corneal oedema is considerably more likely to occur when pre-operative cell density is below 700 cells/mm2 but unlikely to occur when density is greater than 1000 cells/mm2.
b Donor cornea evaluation regarding suitability for penetrating keratoplasty.
c To demonstrate pathology, particularly cornea guttata (Fig. 6.5B), Descemet membrane irregularities and posterior polymorphous dystrophy.
image

Fig. 6.5 Specular micrograph. (A) Normal corneal endothelium; (B) cornea guttata with marked loss of endothelial mosaic

(Courtesy of T Casey and K Sharif, from A Colour Atlas of Corneal Dystrophies and Degenerations, Wolfe 1991 – fig. B)

Principles of treatment

Control of infection and inflammation

1 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.
2 Topical steroids should always be used with caution because they may promote replication of some forms of microorganism, notably herpes simplex virus and fungi. Steroids may also retard reparative processes such as re-epithelialization. Nevertheless, they are vital in a range of conditions for the suppression of destructive vision-compromising inflammation.
3 Systemic immunosuppressive agents are useful in certain local and systemic 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.

1 Reduction of exposure to toxic medications and preservatives wherever possible.
2 Lubrication with artificial tears (unpreserved if possible) and ointment. Taping the lids closed temporarily (Fig. 6.6A) is often used as a nocturnal adjunct.
3 Bandage soft contact lenses should be carefully supervised to exclude superinfection and their use kept to a minimum. Indications include:
• Promotion of healing by mechanically protecting regenerating corneal epithelium from the constant rubbing of the eyelids.
• To improve comfort, particularly in the presence of a large corneal abrasion.
• To seal a small perforation (Fig. 6.6B).
4 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 a poor visual prognosis in a highly uncooperative patient. Methods include:
• Botulinum toxin injection into the levator muscle to induce a temporary (2–3 months) ptosis.
• Temporary or permanent lateral tarsorrhaphy or medial canthoplasty, and occasionally a central tarsorrhaphy (Fig. 6.6C).
5 Amniotic membrane patch grafting (Fig. 6.6D) for persistent unresponsive epithelial defects.
6 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 (Fig. 6.6E) is inserted to aid retention of the patch.
7 Limbal stem cell transplantation 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.
8 Smoking should be discontinued.
image

Fig. 6.6 Methods of promoting epithelial healing. (A) Taping the lids temporarily; (B) bandage contact lens in an eye with a small perforation; (C) 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)

Bacterial keratitis

Pathogenesis

Pathogens

Bacterial keratitis usually only develops when the ocular defences have been compromised (see below). However, some bacteria, including N. gonorrhoeae, N. meningitidis, C. diphtheriae, and H. influenzae are able to penetrate a normal corneal epithelium, usually in association with severe conjunctivitis. It is important to remember that infections may be polymicrobial, including bacterial and fungal co-infection. The most common pathogens are the following:

1 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.
2 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.
3 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

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1 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 bacteria 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.
2 Trauma including refractive surgery (particularly LASIK), has been linked to bacterial infection, including with atypical mycobacteria.
3 Ocular surface diseases such as herpetic keratitis, bullous keratopathy, dry eye, chronic blepharitis, trichiasis and entropion, exposure, severe allergic eye disease and corneal anaesthesia.
4 Other factors include local or systemic immunosuppression, diabetes and vitamin A deficiency.

Clinical features

1 Presentation is with pain, photophobia, blurred vision and mucopurulent or purulent discharge.
2 Signs in chronological order:
• An epithelial defect associated with a larger infiltrate (Fig. 6.7A).
• Enlargement of the infiltrate (Fig. 6.7B) and the epithelial defect.
• Stromal oedema, folds in Descemet membrane and anterior uveitis.
• Chemosis and eyelid swelling in severe cases.
• Rapid progression of infiltration with an enlarging hypopyon (Fig. 6.7C and D).
• Severe ulceration may lead to descemetocele formation and perforation, particularly in Pseudomonas infection (Fig. 6.7E).
• Endophthalmitis is rare in the absence of perforation.
• Scarring, vascularization and opacification.
• Improvement is usually heralded by a reduction of eyelid oedema and chemosis, as well as shrinking of the epithelial defect and decreasing infiltrate density.
3 Reduced corneal sensation may suggest associated herpetic disease or neurotrophic keratopathy, particularly where there is no other evident major risk factor. Sensation may also be reduced in chronic surface disease and in contact lens wear.
4 Intraocular pressure should be monitored. Because applanation tonometry may be difficult an alternative method such as the Tono-Pen® may be used.
5 Differential diagnosis includes keratitis due to other micro-organisms (fungi, acanthamoeba, stromal herpes simplex keratitis and mycobacteria), marginal keratitis, sterile inflammatory corneal infiltrates associated with contact lens wear, peripheral ulcerative keratitis and toxic keratitis.
image

Fig. 6.7 Bacterial keratitis. (A) Epithelial defect with infiltration; (B) enlargement of the infiltrate; (C) hypopyon; (D) advanced disease; (E) perforation associated with Pseudomonas infection

(Courtesy of S Tuft – figs A and E)

Investigations

1 Corneal scraping
• They may not be required for a small infiltrate, particularly without an epithelial defect and away from the visual axis.
• Scraping may be delayed off treatment for 12 hours if antibiotics have previously been commenced.
• A non-preserved topical anaesthetic is instilled (preservatives may lower bacterial viability for culture); one drop of proxymetacaine 0.5% is usually sufficient.
• Scrapings are taken either with a disposable scalpel blade, the bent tip of a larger diameter hypodermic needle, or a sterile spatula (e.g. Kimura).
• The easiest way to ‘plate’ scrapings without breaking the gel surface is with a spatula. If a fresh spatula is not available for each sample a single instrument should be flame-sterilized between scrapes (heat for 5 seconds, cool for 20–30 seconds). Alternatively, a fresh scalpel blade or needle can be used for each pass.
• In scraping it is necessary to first carefully remove loose mucus and necrotic tissue from the surface of the ulcer.
• The margins and base (except if very thin) of the lesion are scraped (Fig. 6.8A).
• A thin smear is placed on one or two glass slides for microscopy, including Gram stain (see below). A surface is provided on one side of one end of the slide (conventionally ‘up’) for pencil labelling. The sample is allowed to dry in air at room temperature for several minutes then placed in a slide carrier.
• Rescraping is performed for each medium and samples are plated onto culture media (Fig 6.8B and Table 6.2), taking care not to break the surface of the gel.
• Routinely, blood, chocolate and Sabouraud media are used initially and the samples are placed in an incubator until transported to the laboratory.
• A blade or needle can be placed directly into bottled media such as brain-heart infusion (BHI). It has been suggested that a single scrape sent in BHI to the laboratory where it is subsequently homogenized and plated, provides similar results to the traditional multi-scrape method.
2 Conjunctival swabs may be worthwhile in addition to corneal scraping, particularly in severe cases, as occasionally an organism may be cultured when a corneal scrape is negative.
3 Contact lens cases, as well as bottles of solution and lenses themselves should be obtained when possible and sent to the laboratory for culture.
4 Gram staining
• Differentiates bacterial species into ‘Gram-positive’ and ‘Gram-negative’ based on the ability of the dye (crystal violet) to penetrate the cell wall.
• Bacteria that take up crystal violet are Gram-positive (Fig. 6.8C) and those that allow the dye to wash off are Gram-negative (Fig. 6.8D).
• Other stains, generally not requested at initial investigation, are given in Table 6.3.
image

Fig. 6.8 Bacteriology. (A) Corneal scraping; (B) culture media; (C) smear shows Gram-positive spherical cocci mostly arranged in clusters (S. aureus); (D) smear shows Gram-negative bacilli (P. aeruginosa); (E) S. aureus grown on blood agar forming golden colonies with a shiny surface; (F) N. gonorrhoeae grown on chocolate agar

(Courtesy of J Harry – fig. A; Emond, Welsby and Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – figs B–F)

Table 6.2 Culture media for corneal scrapings

Medium Notes Specificity
Blood agar (Fig. 6.8E) 5–10% sheep or horse blood Most bacteria and fungi except Neisseria, Haemophilus and Moraxella
Chocolate agar (Fig. 6.8F) Blood agar in which the cells have been lysed by heating. Does not contain chocolate! Fastidious bacteria, particularly H. Influenzae, Neisseria and Moraxella
Sabouraud dextrose agar Low pH and antibiotic (e.g. chloramphenicol) to deter bacterial growth Fungi
Non-nutrient agar seeded with E. coli E. coli is a food source for Acanthamoeba Acanthamoeba
Brain heart infusion Rich lightly buffered medium providing a wide range of substrates Difficult-to-culture organisms; particularly suitable for streptococci and meningococci. Supports yeast and fungal growth
Cooked meat broth Developed during the First World War for the growth of battlefield anaerobes Anaerobic (e.g. Propionibacterium acnes) as well as fastidious bacteria
Löwenstein-Jensen Contains various nutrients together with bacterial growth inhibitors Mycobacteria, Nocardia

Table 6.3 Stains for corneal and conjunctival scrapes

Stain Organism
Gram Bacteria, fungi, Microsporidia
Giemsa Bacteria, fungi, Acanthamoeba, Microsporidia
Calcofluor white (fluorescent microscope) Acanthamoeba, fungi, Microsporidia
Acid-fast stain (AFB)
e.g. Ziehl–Neelsen, Auramine O (fluorescent)		 Mycobacterium, Nocardia spp.
Grocott-Gömöri methenamine-silver Fungi, Acanthamoeba, Microsporidia
Periodic acid-Schiff (PAS) Fungi, Acanthamoeba

Refrigerated media should be gently warmed to room temperature prior to sample application.

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5 Sensitivity reports are sent out at 1 or 2 days, 7 days and 2 weeks. When determining drug sensitivity for an isolated organism, the results are reported as follows:
a Susceptible indicating that the organism is sensitive to a normal dose of the antimicrobial agent.
b Intermediate indicating that the organism is likely to be sensitive to a high dose of the antimicrobial agent.
c Resistant means that the organism is not sensitive to the antimicrobial agent at the tested dose.

Most laboratories test for antibiotic sensitivity using a disc diffusion (Kirby–Bauer) method. The relevance of this to topical antibiotic instillation, where very high tissue levels can be achieved, is uncertain.

Treatment

General considerations

1 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.
2 Discontinuation of contact lens wear is mandatory.
3 A clear plastic eye shield should be worn between eye drop instillation if significant thinning (or perforation) is present.
4 Decision to treat
• Intensive treatment may not be required for small infiltrates which are clinically sterile and may be treated by low-frequency topical antibiotic and/or steroid, and by temporary cessation of contact lens wear.
• The causative organism cannot be defined reliably from the appearance of the ulcer.
• Empirical broad-spectrum treatment may be initiated before microscopy results are available.

Local therapy

Topical therapy can achieve high tissue concentration and initially should consist of broad spectrum antibiotics which 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.

1 Antibiotic monotherapy has the major advantage over duotherapy of less surface toxicity, as well as being more convenient.
• 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.
• Moxifloxacin and gatifloxacin are new generation fluoroquinolones that may be indicated in cases resistant to earlier-generation drugs. Both have better activity against Gram-positive pathogens and moxifloxacin has superior ocular penetration.
• Ciprofloxacin instillation is associated with white corneal precipitates (Fig. 6.9) which may delay epithelial healing.
2 Antibiotic duotherapy may be preferred as first-line empirical treatment, particularly in aggressive disease or if microscopy suggests streptococci or a specific micro-organism which may be more effectively treated by a tailored regimen (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.
• Problems with fortified antibiotics include high cost, limited availability, contamination risk, short shelf-life and the need for refrigeration.
3 Subconjunctival antibiotics are only indicated if there is poor compliance with topical treatment.
4 Mydriatics (cyclopentolate 1%, homatropine 2% or atropine 1%) are used to prevent the formation of posterior synechiae and to reduce pain.
5 Steroids. The evidence for an optimal steroid regimen has yet to be established and practice varies.
• Proponents argue that steroids reduce host inflammation, improve comfort, and minimize corneal scarring. However, evidence that they improve the final visual outcome is limited.
• Steroids promote replication of some micro-organisms, 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).
• Epithelialization may be retarded by steroids and they should be avoided if there is significant thinning or delayed epithelial healing.
• Most authorities would not commence steroids until evidence of clinical improvement is seen with antibiotics alone, which may be as early as 24 hours after starting treatment. However, others feel that steroids should be delayed for considerably longer, at least until the sensitivity of the isolate to antibiotics has been demonstrated.
• Regimens vary from minimal strength preparations at low frequency to dexamethasone 0.1% every 2 hours; a reasonable regimen is prednisolone 0.5–1% q.i.d.
• Early discontinuation may lead to a recurrence of sterile inflammation.
image

Fig. 6.9 Ciprofloxacin corneal precipitates

Table 6.4 Antibiotics for treatment of keratitis

Isolate Antibiotic Concentration
Empirical treatment Fluoroquinolone monotherapy or 0.3%
Cefuroxime + 5%
Gentamicin duotherapy 1.5%
Gram-positive cocci Cefuroxime 0.3%
Vancomycin or Teicoplanin 5%
1%
Gram-negative rods Gentamicin or 1.5%
Fluoroquinolone or 0.3%
Ceftazidime 5%
Gram-negative cocci Fluoroquinolone 0.3%
Ceftriaxone 5%
Mycobacteria Amikacin or 2%
Clarithromycin 1%
Nocardia Amikacin or 2%
Trimethorim + Sulphamethoxazole 1.6%
8%

Table 6.5 Preparation of fortified antibiotics

image

Systemic antibiotics

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

1 Potential for systemic involvement such as the following:
• N. meningitidis, in which early systemic prophylaxis may be life-saving. Treatment is 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.
2 Severe corneal thinning with threatened or actual perforation requires:
• Ciprofloxacin for its antibacterial activity.
• A tetracycline (e.g. doxycycline 100 mg b.d.) for its anticollagenase effect.
3 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 lead to increasing discomfort, redness and discharge despite 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 (Table 6.2) and additional staining techniques requested (Table 6.3). High priority should be given to the possibility of a non-bacterial causative microorganism.
• If cultures remain negative, it may be necessary to perform 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).

Fungal keratitis

Introduction

Pathogenesis

Fungi are a group of microorganisms that have rigid walls and a distinct nucleus with multiple chromosomes containing both DNA and RNA. Fungal keratitis is rare in temperate countries but is a major cause of visual loss in tropical and developing countries. The two main types of fungi causing keratitis are:

1 Yeasts (e.g. genus Candida), ovoid unicellular organisms that reproduce by budding, are responsible for most cases of fungal keratitis in temperate climates.
2 Filamentous fungi (e.g. genera Fusarium and Aspergillus), multicellular organisms that produce tubular projections known as hyphae. They are the most common pathogens in tropical climates.

Predisposing factors

Common predisposing factors are chronic ocular surface disease, long-term use of topical steroids (often in conjunction with prior corneal transplantation), contact lens wear, systemic immunosuppression and diabetes. Filamentary keratitis may be associated with trauma, often relatively minor, involving plant matter or gardening/agricultural tools.

Candida and filamentous keratitis

Clinical features

The diagnosis is often delayed unless there is a high index of suspicion, and often infection will initially have been presumed to be bacterial.

1 Presentation is with a gradual onset of pain, grittiness, photophobia, blurred vision and watery or mucopurulent discharge.
2 Signs
a Candida keratitis
• Yellow-white densely suppurative infiltrate (Fig. 6.10A).
• A collar-stud morphology may be seen.
b Filamentous keratitis
• A grey or yellow-white stromal infiltrate with indistinct fluffy margins.
• Progressive infiltration, often with satellite lesions (Fig. 6.10B).
• Feathery branch-like extensions or a ring-shaped infiltrate may develop.
• Rapid progression with necrosis and thinning can occur.
• Penetration of an intact Descemet membrane may occur and lead to endophthalmitis without evident perforation.
c An epithelial defect is not invariable and is sometimes small when present.
d Other features include anterior uveitis, hypopyon, endothelial plaque, raised IOP, scleritis and sterile or infective endophthalmitis.
3 Differential diagnosis includes bacterial, herpetic and acanthamoebal keratitis. It should be remembered that bacterial infection may sometimes present subacutely, particularly when atypical organisms are responsible. It is important to beware of co-infection, including with an additional fungal species.
image

Fig. 6.10 Fungal keratitis. (A) Candida keratitis; (B) filamentous keratitis with satellite lesions and a small hypopyon; (C) Gram-stained Candida spp shows pseudohyphae; (D) corneal smear stained with Grocott hexamine silver shows Aspergillus spp.

(Courtesy of S Tuft – figs A and B; Hart and Shears – fig C; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. D)

Investigations

Samples for laboratory examination should be acquired before commencing antifungal therapy.

1 Staining
a Gram and Giemsa staining (Fig. 6.10C) are both about 50% sensitive.
b Periodic acid-Schiff (PAS) and Grocott–Gömöri methenamine-silver (GMS) stains may also be used (Fig. 6.10D), but are more commonly performed on histological sections.
2 Culture
• Corneal scrapes should be plated on Sabouraud dextrose agar, although most fungi will also grow on blood agar or in enrichment media.
• If applicable, contact lenses and cases should be sent for culture.
3 Corneal biopsy is indicated in the absence of clinical improvement after 3–4 days and if no growth develops from scrapings after a week. A 2–3 mm block should be taken, using a technique similar to the scleral block excision during trabeculectomy. The excised block is sent for culture and histopathological analysis.
4 Confocal microscopy is rarely available, but may permit identification of organisms in vivo.

Treatment

Improvement may be slow in comparison to bacterial infection.

1 General measures are as for bacterial keratitis although hospital admission is usually required.
2 Removal of the epithelium over the lesion may enhance penetration of antifungal agents. It may also be helpful to regularly remove mucus and necrotic tissue with a spatula.
3 Topical treatment should initially be given hourly for 48 hours and then reduced as signs permit. Because most antifungals are only fungistatic, treatment should be continued for at least 12 weeks.
a Candida is treated with amphotericin B 0.15% or econazole 1%; alternatives include natamycin 5%, fluconazole 2%, and clotrimazole 1%.
b Filamentous infection is treated with natamycin 5% or econazole 1%; alternatives are amphotericin B 0.15% and miconazole 1%.
c A broad-spectrum antibiotic should also be considered to address or prevent bacterial co-infection.
d Cycloplegia as for bacterial keratitis.
4 Subconjunctival fluconazole may be used in severe cases.
5 Systemic antifungals may be given in severe cases, when lesions are near the limbus, or for suspected endophthalmitis. Options include voriconazole 400 mg b.d. for one day then 200 mg b.d., itraconazole 200 mg daily, reduced to 100 mg daily, or fluconazole 200 mg b.d.
6 Tetracycline (e.g. doxycycline 100 mg b.d.) may be given for its anticollagenase effect when there is significant thinning.
7 IOP should be monitored using a Tono-Pen®.
8 Superficial keratectomy can be effective to de-bulk the lesion.
9 Therapeutic keratoplasty (penetrating or deep anterior lamellar) is considered when medical therapy is ineffective or following perforation.

Microsporidial keratitis

Pathogenesis

Microsporidia is a phylum of obligate intracellular one-celled parasites previously thought to be protozoa but recently reclassified as fungi. They rarely cause disease in the immunocompetent and until the advent of AIDS microsporidia were rarely pathogenic for humans. The most common general infection is enteritis and the most common ocular manifestation is keratoconjunctivitis.

Diagnosis

1 Signs
• Bilateral chronic diffuse punctate epithelial keratitis (Fig. 6.11A).
• Unilateral slowly progressive deep stromal keratitis may rarely affect immunocompetent patients (Fig. 6.11B).
• Sclerokeratitis and endophthalmitis are rare.
2 Biopsy and histology shows characteristic spores and intracellular parasites.
image

Fig. 6.11 Microsporidia keratitis. (A) Diffuse punctate epithelial keratitis; (B) deep stromal infiltrates

(Courtesy of S Tuft)

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Treatment

1 Medical therapy of epithelial disease is with topical fumagillin. Highly active antiretroviral therapy (HAART) for associated AIDS may also help resolution. Stromal disease is treated with a combination of topical fumagillin and oral albendazole 400 mg daily for 2 weeks, repeated 2 weeks later with a second course. Patients should be closely monitored for hepatic toxicity. Long term fumagillin treatment may be required and it is difficult to eradicate the parasites in immunocompromised patients.
2 Keratoplasty may be indicated although recurrence of disease can occur in the graft periphery; cryotherapy to the residual tissue may reduce this risk.

Herpes simplex keratitis

Introduction

Herpetic eye disease is the most common infectious cause of corneal blindness in developed countries. As many as 60% of corneal ulcers in developing countries may be the result of herpes simplex virus and 10 million people worldwide may have herpetic eye disease.

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 bestowed by maternal antibodies, it is uncommon during the first 6 months of life, though occasionally severe neonatal systemic disease may occur. Most primary infections 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.

Recurrent infection

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

1 After primary infection the virus is carried to the sensory ganglion for that dermatome (e.g. trigeminal ganglion) where a latent infection is established. Latent virus is incorporated in host DNA and cannot be eradicated.
2 Subclinical reactivation can periodically occur, during which HSV is shed and patients are contagious.
3 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.
4 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.
5 The rate for 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.
6 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).

Epithelial keratitis

Clinical features

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

1 Presentation may be at any age with mild discomfort, redness, photophobia, watering and blurred vision.
2 Signs in chronological order:
• Swollen opaque epithelial cells arranged in a coarse punctate or stellate pattern (Fig. 6.12A).
• Central desquamation results in a linear-branching (dendritic) ulcer, most frequent located centrally.
• The ends of the ulcer have characteristic terminal buds and the bed of the ulcer stains well with fluorescein (Fig. 6.12B).
• The virus-laden cells at the margin of the ulcer stain with rose bengal (Fig. 6.12C).
• 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.
• Elevated IOP may occur.
• Following healing, there may be persistent punctate epithelial erosions and irregular epithelium which settle spontaneously and should not be mistaken for persistent active infection. A whorled epithelial appearance can also result from assiduous, especially prolonged, topical antiviral instillation.
• Mild subepithelial scarring may develop after healing.
3 Differential diagnosis of dendritic ulceration includes herpes zoster keratitis, healing corneal abrasion (pseudodendrite), acanthamoeba keratitis, epithelial rejection in a corneal graft, tyrosinaemia type 2, use of soft contact lenses and toxic keratopathy secondary to topical medication.
image

Fig. 6.12 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

(Courtesy of S Tuft – fig. C)

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Treatment

Treatment of HSV disease is predominantly with nucleoside (purine or pyrimidine) analogues that are incorporated to form abnormal viral DNA. Aciclovir, ganciclovir and trifluridine have low toxicity and approximately equivalent effect. Idoxuridine and vidarabine are older drugs which are probably less effective and more toxic to the epithelium but are still used in regions where low cost is critical. The majority of dendritic ulcers will eventually heal spontaneously without treatment, though scarring and vascularization may be more significant with more prolonged disease.

1 Topical. The most frequently used drugs in Europe are aciclovir 3% ointment and ganciclovir 0.15% gel, each administered 5 times daily. Trifluridine is preferred in the United States and requires instillation up to nine times a day. The drugs are relatively non-toxic, even when given for up to 60 days, acting preferentially on virus-laden epithelial cells, and penetrating effectively into the stroma. On this treatment 99% of cases resolve by 2 weeks.
2 Debridement may be used for dendritic but not geographic ulcers. The corneal surface is wiped with a sterile cellulose sponge 2 mm beyond the edge of the ulcer, since pathology extends well beyond the visible dendrite. The removal of the virus-containing cells protects adjacent healthy epithelium from infection and also eliminates the antigenic stimulus to stromal inflammation. An antiviral agent must be used in conjunction.
3 Signs of treatment toxicity include superficial punctate erosions, waves of whorled epithelium, follicular conjunctivitis and, rarely, punctal occlusion.
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4 Oral antiviral therapy is probably indicated in most immunodeficient patients and may also be effective alternatives to topical treatment when the latter is poorly tolerated, or in resistant cases.
5 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.
6 Skin lesions may be treated with aciclovir cream five times daily, as for cold sores, and if extensive an oral antiviral may be given.
7 IOP control. If glaucoma treatment is necessary, prostaglandin derivatives should probably be avoided as they may promote herpes virus activity and inflammation generally.
9 Topical steroids are not used unless significant disciform keratitis is also present (see below).
10 Slow healing or frequent recurrence may indicate the presence of a resistant viral strain, and a combination of two topical agents with oral valaciclovir or famciclovir may be effective. A significant minority of cases are due to varicella-zoster virus (see below).

Disciform keratitis

The exact aetiology of disciform keratitis (endotheliitis) is controversial. It may be active HSV infection of keratocytes or endothelium, or a hypersensitivity reaction to viral antigen in the cornea. A clear past history of epithelial ulceration is not always present.

Clinical features

1 Presentation is with a gradual onset of blurred vision which may be associated with haloes around lights. Discomfort and redness are common, but tend to be milder than in purely epithelial disease.
2 Signs
• A central zone of stromal oedema often with overlying epithelial oedema (Fig. 6.13A); occasionally the lesion is eccentric.
• Keratic precipitates underlying the oedema (Fig. 6.13B).
• Folds in Descemet membrane in severe cases.
• A surrounding (Wessely) immune ring of stromal haze (Fig. 6.13C) signifies deposition of viral antigen and host antibody complexes.
• The IOP may be elevated.
• Reduced corneal sensation.
• Healed lesions often have a faint ring of stromal or subepithelial opacification and thinning.
• Consecutive episodes may be associated with gradually worsening subepithelial and/or stromal scarring and superficial or deep vascularization.
• Mid-stromal scarring can give the appearance of interstitial keratitis.
image

Fig. 6.13 Disciform herpes simplex keratitis. (A) Central epithelial and stromal oedema; (B) underlying keratic precipitates; (C) Wessely ring precipitates

Treatment

Treatment is set out below, but in practice the regimen should be tailored individually. Careful monitoring and adequate treatment, dependent on severity of inflammation, is critical to minimize progression of scarring. Patients should be cautioned to seek treatment at the first suggestion of recurrence, though minimal inflammation may not warrant treatment or can be addressed with cycloplegia alone.

1 Initial treatment is with topical steroids (prednisolone 1% or dexamethasone 0.1%) with antiviral cover, both q.i.d. As improvement occurs, the frequency of administration of both is reduced in parallel over not less than 4 weeks.
2 Subsequently prednisolone 0.5% once daily is usually a safe dose at which to stop topical antiviral cover. Some patients require a weaker steroid such as fluorometholone 0.1% or loteprednol 0.2% on alternate days for many months. Periodic attempts should be made to stop the steroid altogether.
3 With active epithelial ulceration it is reasonable to try to keep the steroid intensity as low as possible for adequate effect, with a more intensive antiviral regimen such as five times daily, with steroid b.d. or t.i.d., titrated according to the signs of activity.
4 Topical ciclosporin 0.05%may be useful, particularly in the presence of epithelial ulceration and to facilitate tapering of topical steroids such as in steroid-related IOP elevation.

Necrotizing stromal keratitis

This rare condition is thought to result from active viral replication within the stroma, though immune-mediated inflammation plays a significant role. It may be difficult to distinguish clinically from severe disciform keratitis and there may be a spectrum of disease, including overlap with neurotrophic keratopathy. One should be wary that a similar clinical picture may be caused by other infections.

1 Signs
• Stromal necrosis and melting, often with profound interstitial opacification (Fig. 6.14).
• Anterior uveitis with keratic precipitates underlying the area of active stromal infiltration.
• An epithelial defect may be present.
• Progression to scarring, vascularization and lipid deposition is common (see Fig. 6.62B).
2 Treatment is broadly similar to that of aggressive disciform keratitis, but oral antiviral supplementation, initially at the upper end of the dose range, may be beneficial. The restoration of epithelial integrity is critical.
image

Fig. 6.14 Necrotizing stromal herpes simplex keratitis

(Courtesy of S Tuft)

Neurotrophic ulceration

Neurotrophic ulceration is caused by failure of re-epithelialization resulting from corneal anaesthesia, often exacerbated by other factors such as drug toxicity.

1 Signs
• A non-healing epithelial defect, sometimes after prolonged topical treatment (Fig. 6.15).
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• The stroma beneath the defect is grey and opaque and may become thin.
• Secondary bacterial or fungal infection may occur.
2 Treatment is that of persistent epithelial defects; topical steroids to control any inflammatory component should be kept to a minimum.
image

Fig. 6.15 Neurotrophic ulceration stained with rose bengal

(Courtesy of S Tuft)

Other considerations

Prophylaxis

Long-term daily oral aciclovir reduces the rate of recurrence of epithelial and stromal keratitis by about 50% and is usually well tolerated. Prophylaxis should be considered in patients with frequent debilitating recurrences, particularly if bilateral or involving an only eye. The standard daily dose of aciclovir is 400 mg b.d. but if necessary a higher dose can be tried. Oral valaciclovir (500 mg once daily) or famciclovir are alternatives. The prophylactic effect decreases or disappears when the drug is stopped.

Complications

1 Secondary infection. Herpetic eye disease is a major predisposing factor for microbial keratitis.
2 Glaucoma secondary to inflammation or chronic steroid use may progress undetected, particularly if there is a poor view of the optic disc. Corneal thinning and distortion may give rise to an inaccurate reading on applanation and a Tono-Pen® may be superior in these cases.
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3 Cataract secondary to inflammation or prolonged steroid use.
4 Iris atrophy secondary to keratouveitis.

Keratoplasty

Recurrence of herpetic eye disease and rejection threaten the survival of corneal grafts. A trial of a rigid contact lens is often worthwhile prior to committing to surgery.

1 Topical antivirals given during a rejection episode may reduce epithelial viral reactivation but toxicity may delay re-epithelialization.
2 Prophylactic oral aciclovir (400 mg b.d.) improves graft survival and should be given to patients undergoing penetrating keratoplasty.

Herpes zoster ophthalmicus

Introduction

Pathogenesis

The varicella-zoster virus (VZV) causes both chickenpox (varicella) and shingles (herpes zoster). VZV belongs to the same subfamily of the herpes virus group as the HSV and the two viruses are morphologically identical but antigenically distinct. After an episode of chickenpox the VZV travels in a retrograde manner to the dorsal root and cranial nerve sensory ganglia, where it may remain dormant for decades, with reactivation thought to occur after VZV-specific cell-mediated immunity has faded. Herpes zoster ophthalmicus (HZO) describes shingles involving the dermatome supplied by the ophthalmic division of the 5th cranial (trigeminal) nerve. Mild ocular involvement can also occasionally occur when the disease affects the maxillary division alone.

Mechanisms of ocular involvement

1 Direct viral invasion may lead to conjunctivitis and epithelial keratitis.
2 Secondary inflammation and occlusive vasculitis may cause episcleritis, scleritis, keratitis, uveitis, optic neuritis and cranial nerve palsies. Inflammation and destruction of the peripheral nerves or central ganglia, or altered signal processing in the CNS may be responsible for postherpetic neuralgia. Cicatrizing complications may arise following severe eyelid, periocular skin and conjunctival involvement.
3 Reactivation causes necrosis and inflammation in the affected sensory ganglia, causing corneal anaesthesia that may result in neurotrophic keratitis.

Risk of ocular involvement

1 Hutchinson sign (Fig. 6.16A) describes involvement of the skin supplied by the external nasal nerve, a branch of the nasociliary nerve supplying the tip, side and root of the nose. The sign correlates strongly with ocular involvement although there is no correlation between the severity of the rash and the severity of ocular complications.
2 Age. HZO occurs most frequently in the 6th and 7th decades. In the elderly, signs and symptoms tend to be more severe and to be of longer duration.
3 AIDS patients tend to have more severe disease, and shingles can be an early indicator of HIV infection. The development of shingles in children (Fig. 6.16B) or young adults should also prompt a search for immunodeficiency or malignancy, though this will be found in only a minority.
image

Fig. 6.16 Herpes zoster ophthalmicus. (A) Hutchinson sign; (B) involvement in a child with AIDS

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Acute shingles

General features

1 A prodromal phase precedes the appearance of the rash. It lasts 3–5 days and is characterized by tiredness, fever, malaise and headache. Symptoms involving the affected dermatome vary from a superficial itching, tingling or burning sensation to a severe deep boring or lancing pain that is either constant or intermittent. Older patients with early severe pain and a larger area of involvement are at particular risk of postherpetic neuralgia.
2 Skin lesions
• The rash respects the midline, which may aid in distinguishing shingles from HSV infection.
• Erythematous areas with a maculopapular rash develop, and may also be confused with cellulitis or contact dermatitis.
• Within 24 hours, groups of vesicles appear and these become confluent over 2–4 days (Fig. 6.17A).
• Although the rash itself does not affect the lower lid in HZO, boggy oedema of upper and lower eyelids is common and may sometimes also involve the contralateral side of the face.
• The vesicles often pass through a pustular phase before they crust and dry after 2–3 weeks (6.17B).
• Large, deep haemorrhagic lesions are more common in immunodeficient patients (Fig. 6.17C).
• The lesions heal to leave residual skin destruction and depigmented scars (Fig. 6.17D).
• Rarely, no rash develops (zoster sine herpete)
3 Disseminated zoster may rarely develop in immunodeficiency or malignancy. The patient becomes severely ill and the rash progresses to involve multiple dermatomes and multiple organ systems.
image

Fig. 6.17 Herpes zoster ophthalmicus. (A) Vesicles; (B) confluent crusting; (C) haemorrhagic rash with involvement of both the ophthalmic and maxillary nerve; (D) residual scarring

(Courtesy of R Fogla – fig. A)

Treatment

1 Oral aciclovir 800 mg five times daily for 7–10 days, started within 72 hours of onset, is the treatment of choice. Patients presenting later than 72 hours at the vesicular stage should also be treated as this will still reduce the severity of the acute episode and the risk of postherpetic neuralgia. The incidence of late ophthalmic complications is also reduced by about 50%.
2 Intravenous aciclovir 5–10 mg/kg t.i.d. is indicated only for encephalitis.
3 Other oral antiviral agents such as valaciclovir 1 g t.i.d., famciclovir 500 mg t.i.d. and brivudine 125 mg once daily are more expensive than but have a more convenient regimen, are better tolerated, and are as effective as aciclovir.
4 Systemic steroids (prednisolone 40–60 mg daily) should be used only in conjunction with systemic antivirals. They have a moderate effect to reduce acute pain and accelerate skin healing but have no effect on the incidence or severity of postherpetic neuralgia.
5 Symptomatic treatment of skin lesions is by drying, antisepsis and cold compresses. The benefit of topical antibiotic-steroid combinations is uncertain.
6 Patients with shingles can transmit chickenpox so that contact with people not known to be immune (particularly pregnant women) and with immunodeficient individuals should be avoided at least until crusting is complete.

Eye disease

Acute eye disease

1 Acute epithelial keratitis develops in over 50% of patients within 2 days of the onset of the rash and usually resolves spontaneously within a few days. It is characterized by dendritic lesions which are smaller and finer than herpes simplex dendrites, and have tapered ends without terminal bulbs (Fig. 6.18A). The lesions stain better with rose Bengal than with fluorescein. Treatment, if required, is with a topical antiviral.
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2 Conjunctivitis (follicular and/or papillary) is common and typically associated with lid margin vesicles. Treatment is not required in the absence of corneal disease.
3 Episcleritis occurs at the onset of the rash and usually resolves spontaneously. A mild nonsteroidal anti-inflammatory may be used if necessary.
4 Scleritis and sclerokeratitis are uncommon and may develop at the end of the first week. Treatment of indolent lesions is with oral flurbiprofen (Froben) 100 mg t.i.d. Occasionally, oral steroids with antiviral cover may be required for severe involvement.
5 Nummular keratitis usually develops at the site of epithelial lesions about 10 days after the onset of the rash. It is characterized by fine granular subepithelial deposits surrounded by a halo of stromal haze (Fig. 6.18B). The lesions fade in response to topical steroids but recur if treatment is discontinued prematurely.
6 Stromal (interstitial) keratitis (Fig. 6.18C) develops in about 5% of cases three weeks after the onset of the rash. It responds to topical steroids but can become chronic and require slow tapering.
7 Disciform keratitis (immune-mediated endotheliitis) is less common than with herpes simplex infection but may lead to corneal decompensation. Treatment is with topical steroids.
8 Anterior uveitis affects at least a third of patients and can be associated with sectoral iris ischaemia and atrophy (see Fig. 11.44B).
9 IOP should be monitored as elevation is common, including steroid-induced. Prostaglandin derivatives should be avoided if treatment is necessary.
10 Neurological complications may require intravenous antivirals and systemic steroids.
• Cranial nerve palsies affecting the third (most common), 4th and 6th nerves usually recover within 6 months.
• Optic neuritis is rare.
• CNS manifestations are rare but include encephalitis, cranial arteritis, and Guillain-Barré syndrome.
image

Fig. 6.18 Acute lesions in herpes zoster ophthalmicus. (A) Dendritic epithelial lesions with tapered ends; (B) nummular keratitis; (C) stromal keratitis

(Courtesy of J Krachmer, M Mannis and E Holland, from Cornea, Elsevier 2005 – fig. A; C Barry – fig. C)

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Chronic eye disease

1 Neurotrophic keratitis develops in about 50% of cases, although it is usually relatively mild and settles over several months.
2 Scleritis may become chronic and lead to patchy scleral atrophy (Fig. 6.19A).
3 Mucous plaque keratitis develops in about 5% of patients, most commonly between the 3rd and 6th months. It is characterized by the sudden appearance of elevated mucous plaques that stain with rose bengal (Fig. 6.19B). Treatment involves a combination of topical steroid and acetylcysteine. Untreated, plaques resolve after a few months, leaving a faint diffuse corneal haze.
4 Lipid degeneration may develop in eyes with persistent severe nummular or disciform keratitis.
5 Lipid-filled granulomata may develop under the tarsal conjunctiva, together with subconjunctival scarring (Fig. 6.19C).
6 Eyelid scarring may result in ptosis, cicatricial entropion (Fig. 6.20A) and occasionally ectropion (Fig. 6.20B), trichiasis, lid notching and madarosis.
image

Fig. 6.19 Chronic lesions in herpes zoster ophthalmicus. (A) Scleral atrophy; (B) mucous plaque keratitis; (C) lipid-filled granulomas

(Courtesy of R Marsh – fig. B)

image

Fig. 6.20 Eyelid scarring in herpes zoster ophthalmicus. (A) Cicatricial entropion; (B) cicatricial ectropion

(Courtesy of D Meyer – fig. B)

Relapsing eye disease

In the relapsing phase lesions may reappear years after an acute episode, which may have been forgotten; eyelid scarring may be the only diagnostic clue. Reactivation of keratitis, episcleritis, scleritis or iritis can occur.

Post-herpetic neuralgia

Post-herpetic neuralgia is defined as pain that persists for more than one month after the rash has healed. It develops in up to 75% of patients over 70 years of age. Pain may be constant or intermittent, worse at night and aggravated by minor stimuli (allodynia), touch and heat. It generally improves slowly with time with only 2% of patients affected after 5 years. Neuralgia can impair the quality of life, and may lead to depression of sufficient severity to present the danger of suicide. Patients severely affected should be referred to a specialist pain clinic. Treatment involves the following:

1 Topical treatment with cold compresses, topical capsaicin 0.025% or 0.075% cream or local anaesthetic (lidocaine 5%) creams may be effective. Capsaicin takes up to 3 weeks to provide relief and may need to be continued long-term.
2 Systemic treatment should be increased in steps as follows:
• Simple analgesics such as paracetamol up to 4 g daily.
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• Stronger analgesics such as codeine up to about 240 mg daily.
• Amitriptyline 10–25 mg at night increasing gradually to 75 mg daily if appropriate.
• Carbamazepine 400 mg daily for lancinating pain.

Interstitial keratitis

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Pathogenesis

Interstitial keratitis (IK) is an inflammation of the corneal stroma without primary involvement of the epithelium or endothelium. In most cases, the inflammation is an immune-mediated process triggered by an appropriate antigen. Syphilis-related (usually congenital and sometimes acquired) IK is the archetype, but no longer the most common in developed countries. Others include herpetic keratitis (including chickenpox), other viral infections, tuberculosis, sarcoidosis, Cogan syndrome (see below), and a range of other infections.

Syphilitic IK

Syphilis is caused by the spirochaete Treponema pallidum. The organism is very fragile, easily eliminated by drying or heating, and does not survive in culture.

Acquired infection

1 The systemic features and investigations are described in Chapter 11.
2 Ocular manifestations include uveitis, IK, madarosis, optic neuritis, ocular motor nerve palsies and Argyll Robertson pupils.
3 Treatment is with procaine penicillin, (10 days in primary and secondary syphilis, 4 weeks in tertiary syphilis); alternatives in penicillin-allergic patients include doxycycline, tetracycline and erythromycin.

Congenital infection

Infection of the fetus can occur transplacentally. It may lead to stillbirth, be subclinical, or can result in a range of clinical features. It is important to diagnose and treat infants as early as possible.

1 Early systemic features include rhinitis and failure to thrive, maculopapular rash (especially on the buttocks and thighs), mucosal ulcers, fissures around the lips, nares and anus (rhagades), pneumonia, hepatosplenomegaly, lymphadenopathy and jaundice. Neurological and cardiovascular problems can also occur.
2 Late systemic features include sensorineural deafness, saddle-shaped nasal deformity (Fig. 6.21A), ‘sabre’ tibiae (Fig. 6.21B), bulldog jaw (mandibular prominence due to maxillary underdevelopment), malformed incisors, Hutchinson’s teeth (notched, small, widely spaced teeth – Fig. 6.21C), mulberry molars and Clutton joints (painless effusions in large joints, especially the knees).
3 Ocular features include anterior uveitis, IK, dislocated/subluxated lens, optic atrophy, ‘salt and pepper’ pigmentary retinopathy and Argyll Robertson pupils.
image

Fig. 6.21 Stigmata of congenital syphilis. (A) Saddle-shaped nasal deformity; (B) ‘sabre’ tibia; (C) Hutchinson teeth

(Courtesy of R Marsh and S Ford – fig. C)

Syphilitic IK

1 Presentation in congenital syphilis is between the ages of 5 and 25 years. The initial symptoms consist of those of acute anterior uveitis with severe blurring. Involvement is usually bilateral, although usually not simultaneous. In acquired disease IK is less common and usually unilateral, typically occurring years after the age at which the disease is contracted, although it can occur as part of primary infection.
2 Signs in chronological order:
• Limbitis associated with deep stromal vascularization, with cellular infiltration and clouding that may obscure the still-perfused vessels to give the characteristic ‘salmon-patch’ appearance (Fig. 6.22A).
• Granulomatous anterior uveitis which may be obscured by corneal clouding.
• After several months the cornea begins to clear and the vessels become non-perfused (ghost vessels – Fig. 6.22B).
• If the cornea later becomes inflamed, the vessels may re-fill with blood and, rarely, bleed into the stroma (Fig. 6.22C).
• The healed stage is characterized by ‘ghost vessels’, feathery deep stromal scarring (Fig. 6.22D), and sometimes thinning, astigmatism and band keratopathy.
3 Treatment of active IK is with systemic antibiotics, and topical steroids and cycloplegics. All patients with positive treponemal serology should be referred to a genitourinary medicine specialist for evaluation, treatment and screening of siblings, parents and partners.
image

Fig. 6.22 Syphilitic interstitial keratitis. (A) ‘Salmon patch’; (B) ‘ghost vessels’ in inactive disease; (C) intrastromal corneal haemorrhage from re-perfused vessels; (D) patchy residual scarring

(Courtesy of Krachmer, Mannis and Holland from Cornea, Mosby 2005 – fig. A)

Cogan syndrome

Cogan syndrome is a rare systemic autoimmune vasculitis characterized by intraocular inflammation and vestibuloauditory dysfunction (particularly neurosensory deafness but also tinnitus and vertigo) developing within months of each other. The disease primarily occurs in young adults, with both sexes affected equally.

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1 Systemic features include necrotizing vasculitis of the renal, gastrointestinal and cardiovascular systems that may be associated with polyarteritis nodosa in some patients.
2 Ocular signs
• Redness, pain, photophobia and blurred vision.
• Early faint bilateral peripheral anterior stromal opacities.
• Deeper opacities and corneal neovascularization then ensue that may remain peripheral (Fig. 6.23) or progress centrally.
• Uveitis, scleritis and retinal vasculitis may develop.
3 Treatment is with topical steroids for keratitis. Systemic steroids are usually required for scleritis or retinal vasculitis. Vestibuloauditory symptoms mandate immediate treatment with systemic steroids to prevent hearing loss; immunosuppressive therapy may also be required.
image

Fig. 6.23 Old peripheral interstitial keratitis in Cogan syndrome

(Courtesy of R Curtis)

Protozoan keratitis

Acanthamoeba

Pathogenesis

Acanthamoeba spp. are ubiquitous free-living protozoa commonly found in soil, fresh or brackish water and the upper respiratory tract. The cystic form (Fig. 6.24A) is highly resilient. Under appropriate environmental conditions, the cysts turn into trophozoites, which produce a variety of enzymes, leading to tissue penetration and destruction. In developed countries keratitis is most frequently associated with contact lens wear, especially if tap water is used for rinsing.

image

Fig. 6.24 Acanthamoeba keratitis. (A) Cysts in a corneal biopsy; (B) epithelial pseudodendrites; (C) focal anterior stromal infiltrates; (D) radial perineuritis; (E) ring abscess; (F) melting

(Courtesy of J Harry – fig. A; S Tuft – figs E and F)

Diagnosis

Early misdiagnosis as herpes simplex keratitis is relatively common. In advanced disease the possibility of fungal keratitis should be remembered.

1 Presentation is with blurred vision and pain, which may be severe and disproportionate to the clinical signs.
2 Signs
• In early disease the epithelial surface is irregular and greyish.
• Epithelial pseudodendrites (Fig. 6.24B) that may be mistaken for herpes simplex keratitis.
• Limbitis with diffuse or focal anterior stromal infiltrates (Fig. 6.24C).
• Perineural infiltrates (radial keratoneuritis – Fig. 6.24D) are seen during the first 1–4 weeks and are pathognomonic.
• Gradual enlargement and coalescence of the infiltrates to form a ring abscess (Fig. 6.24E).
• Scleritis may develop and is generally reactive rather than extension of infection.
• Slowly progressive stromal opacification and vascularization.
• Corneal melting (Fig. 6.24F) may occur at any stage when there is stromal disease. The melt often develops at the periphery of the area of infiltrate.
3 Investigations
a Staining of corneal scrapings using periodic acid-Schiff or calcofluor white (a fluorescent dye with an affinity for amoebic cysts and fungi). Gram and Giemsa stains may also demonstrate cysts.
b Cultures. Scrapings are plated on non-nutrient agar which is subsequently seeded with dead E. coli. Note that about 30% of patients are culture negative. Culture of the contact lens case will often yield both acanthamoeba and Gram-negative bacteria.
c Other investigations include immunohistochemistry, PCR and in vivo confocal microscopy. Corneal biopsy may be necessary for diagnosis.

Treatment

It is important to maintain a high index of suspicion for Acanthamoeba infection in any patient who responds incompletely to antibacterial therapy. The outcome is very much better if treatment is started within 4 weeks of onset of symptoms.

1 Debridement of infected epithelium to facilitate eye drop absorption is probably helpful, particularly in early disease.
2 Topical amoebicides
• Polyhexamethylene biguanide (PHMB) 0.02% and chlorhexidine digluconate (0.02%) are first-line agents that may be given as mono- or duo-therapy.
• Other agents are hexamidine di-isethionate, a propamidine homologue, and propamidine (Brolene®); the latter may also be an effective co-treatment with PHMB or chlorhexidine.
• Drops are given hourly at first and gradually reduced although a response may not be evident for as long as two weeks. Relapses are common as treatment is tapered, and it may be necessary to continue treatment for many months.
3 Topical steroids should be avoided if possible although low-dose therapy may be useful for persistent inflammation.
4 Pain control is with an oral NSAID such as flurbiprofen 100 mg t.i.d.
5 Keratoplasty may be necessary for residual scarring.

Onchocerciasis

Onchocerciasis (‘river blindness’) is caused by infestation with the parasitic helminth Onchocerca volvulus. It is the second most common infectious cause of blindness in the world and is endemic in areas of Africa, with foci elsewhere.

1 Systemic features – see Chapter 11.
2 Ocular features
• Live microfilariae may be seen in the cornea, aqueous and vitreous in up to 50% of patients.
• Anterior uveitis.
• Punctate keratitis affects a third of patients and consists of infiltrates surrounding dead microfilariae. The lesions are most commonly located at the 3 and 9 o’clock position in the anterior third of the stroma.
• Sclerosing keratitis starts at the 3 and 9 o’clock positions (Fig. 6.25A) and progresses slowly (Fig. 6.25B) to involve the entire cornea.
• Full thickness scarring has superficial and deep vessels with pigment migration over the surface (Fig. 6.25C).
• Chorioretinitis (see Fig. 11.33).
3 Treatment with systemic ivermectin has a beneficial effect on at least the anterior segment ocular features. Treatment of acute inflammation such as keratitis is with topical steroids.
image

Fig. 6.25 Sclerosing onchocercal keratitis; (A) Early peripheral involvement; (B) progressive opacification; (C) advanced disease

(Courtesy of S Tuft)

Bacterial hypersensitivity-mediated corneal disease

Marginal keratitis

Pathogenesis

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Marginal keratitis is probably caused by a hypersensitivity reaction against staphylococcal exotoxins and cell wall proteins with deposition of antigen-antibody complexes in the peripheral cornea (antigen diffusing from the tear film, antibody from the blood vessels) with a secondary lymphocytic infiltration. The lesions are culture negative but S. aureus can frequently be isolated from the lid margins.

Diagnosis

1 Symptoms are mild discomfort, redness and lacrimation that may be bilateral.
2 Signs
• Chronic marginal blepharitis is common.
• Subepithelial marginal infiltrates separated from the limbus by a clear zone, often associated with a focal adjacent area of conjunctival hyperaemia (Fig. 6.26A).
• Characteristically, any epithelial defect will be considerably smaller than the area of infiltrate.
• Coalescence and circumferential spread (Fig. 6.26B).
• Without treatment resolution occurs in 3–4 weeks. Sometimes there may be residual superficial scarring and slight thinning with mild pannus.
• Gross corneal infiltration can occur in the presence of modifying factors such as recurrent epithelial erosion or recent LASIK surgery.
image

Fig. 6.26 Marginal keratitis. (A) Marginal infiltrates; (B) coalescence and circumferential spread

Treatment

Coexisting chronic blepharitis should be treated if troublesome, or if marginal keratitis is frequently recurrent. Treatment of symptomatic disease is with a weak topical steroid such as prednisolone 0.5% q.i.d. for 1 week, sometimes combined (often in a fixed combination) with a topical antibiotic. An extended course of an oral tetracycline (erythromycin in children) may rarely be required for troublesome recurrent disease.

Phlyctenulosis

Pathogenesis

Phlyctenulosis is usually a self-limiting disease although rarely it may be severe and even blinding. Most cases seen in developed countries are the result of a presumed delayed hypersensitivity reaction to staphylococcal antigen; the most common systemic association is rosacea. However, in developing countries the majority are associated with tuberculosis or helminthic infestation.

Diagnosis

1 Presentation is usually in children or young adults with photophobia, lacrimation and blepharospasm.
2 Signs
• A small white nodule associated with intense local hyperaemia on the conjunctiva or limbus (Fig. 6.27A).
• A limbal phlycten may then extend progressively onto the cornea (Fig. 6.27B).
• A healed corneal phlycten usually leaves a triangular limbal-based scar associated with superficial vascularization and thinning (Fig. 6.27C).
• Spontaneous resolution usually occurs within 2–3 weeks, but occasionally severe thinning and even perforation can occur.
3 Investigations for tuberculosis are generally only indicated in endemic areas or in the presence of specific risk factors.
image

Fig. 6.27 Phlyctenulosis. (A) Limbal phlycten; (B) corneal phlycten; (C) healed phlycten

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2002 – fig. A; S Tuft – fig. B; Krachmer, Mannis and Holland, from Cornea, Mosby 2005 – fig. C)

Treatment

A short course of topical steroid accelerates healing. Recurrent troublesome disease may require an oral tetracycline. It is also important to treat associated chronic blepharitis.

Rosacea

Pathogenesis

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Rosacea is a common, idiopathic, chronic dermatosis involving the sun-exposed skin of the face and upper neck. Ocular complications develop in 6–18% of patients. The aetiology of rosacea is uncertain, and it is likely that there is interaction of several different factors. Vascular factors, including the vasodilatation response, are thought to be important. Papule and pustule formation may be precipitated by lipases secreted by S. epidermidis. Lipases break down the wax and sterol esters secreted by the meibomian glands to release inflammatory free fatty acids. Follicular infection with Demodex mites may have an aetiological role, although these are almost universally present in healthy older adults.

General features

1 Presentation is in adult life with symptoms depending on disease subtype.
2 Clinical types
a Erythematotelangiectatic is characterized by facial flushing (Fig. 6.28A).
b Papulopustular rosacea (Fig. 6.28B) is classical.
c Phymatous is characterized by focal thickenings of the skin that may evolve into rhinophyma (Fig. 6.28C).
image

Fig. 6.28 Acne rosacea. (A) Erythematotelangiectatic; (B) papulopustular; (C) phymatous

In contrast to acne vulgaris comedones (blackheads or whiteheads) are absent.

3 Treatment depends on subtype and severity.
• Avoidance of trigger factors such as alcohol, hot drinks or spicy food may be helpful.
• Topical metronidazole gel, azelaic acid cream and oral isotretinoin (retinoids are strictly contraindicated in pregnancy).
• Oral tetracycline may be effective by reducing the bacterial flora on the lids and thereby lowering lipase production, as well as exerting a direct anti-inflammatory effect and perhaps by altering meibomian gland function. It should be emphasized that systemic tetracyclines should not be used in children under the age of 12 years or in pregnant or breast-feeding women because the antibiotic binds to calcium and is deposited in teeth, and may cause dental hypoplasia and discoloration. Erythromycin can be used in children.
• Other measures include laser therapy to telangiectatic vessels, and surgical treatment of rhinophyma.

Ocular rosacea

1 Symptoms are non-specific irritation, burning and lacrimation.
2 Lid signs include margin telangiectasia and posterior blepharitis, often associated with recurrent meibomian cyst formation.
3 Conjunctiva
• Conjunctival hyperaemia, especially bulbar.
• Rarely, cicatricial conjunctivitis, conjunctival granulomas and phlyctenulosis may occur.
4 Cornea
• Inferior punctate epithelial erosions.
• Peripheral vascularization (Fig. 6.29A)
• Marginal keratitis, especially involving the inferonasal and inferotemporal cornea (Fig. 6.29B).
• Circumferential spread.
• Corneal thinning, usually located inferiorly, in severe cases (Fig. 6.29C).
• Perforation may occur as a result of severe peripheral or central melting, which may be precipitated by secondary bacterial infection.
• Corneal scarring and vascularization (Fig. 6.29D).
5 Topical treatment
• Lubricants alone for mild symptoms.
• Hot compresses and lid hygiene.
• Topical antibiotics such as fusidic acid ointment to the lid margins at bedtime for 4 weeks.
• Steroids (fluorometholone 0.1%, loteprednol 0.2% or 0.5%, or prednisolone 0.5% q.i.d.) are helpful for exacerbations.
6 Systemic therapy
• Tetracyclines (doxycycline, tetracycline or oxytetracycline), used in relatively low dose but extended duration (e.g. doxycycline 100 mg once daily for 4 weeks) may result in improvement lasting for several months but if necessary treatment can be continued long-term.
• Clarithromycin, metronidazole and clarithromycin may be effective alternatives.
• Severe disease with corneal melting may require immunosuppression. Azathioprine has demonstrated useful effect.
image

Fig. 6.29 Rosacea keratitis. (A) Peripheral vascularization; (B) marginal keratitis; (C) thinning; (D) scarring and vascularization

(Courtesy of S Tuft – fig. D)

Severe peripheral corneal ulceration

Mooren ulcer

Pathogenesis

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Mooren ulcer is a rare, idiopathic disease characterized by progressive circumferential peripheral, stromal ulceration with later central spread. There are two types: the first affects predominantly older patients, often in only one eye, and usually responds well to medical therapy; the second is more aggressive and less responsive to treatment. The latter may be bilateral and associated with severe pain, and tends to occur in younger patients, including widespread reports in young men from the Indian subcontinent. An autoimmune mechanism is thought to be responsible for Mooren ulcer, and in at least some (secondary) cases, there is an evident history of a corneal insult such as surgery, trauma or infection which is presumed to act as a trigger in susceptible individuals. These secondary cases tend to fall within the ‘limited’ category. It is critical to attempt to rule out associated systemic autoimmune disease (see below) before concluding the diagnosis to be Mooren ulcer.

Diagnosis

1 Symptoms include moderate-severe pain, photophobia and blurred vision (mainly due to astigmatism).
2 Signs in chronological order:
• Peripheral ulceration involving the superficial one-third of the stroma (Fig. 6.30A) associated with variable epithelial loss.
• Progressive circumferential and central stromal thinning with an undermined and infiltrated leading edge (Fig. 6.30B).
• Vascularization involving the bed of the ulcer up to its leading edge but not beyond (Fig. 6.30C).
• The healing stage is characterized by thinning, vascularization and scarring (Fig. 6.30D).
3 FA shows initially shows capillary closure at the limbus and then leakage from vascularization extending into the base of the ulcer.
4 Complications include severe astigmatism, perforation following minor trauma (spontaneous perforation is rare), secondary bacterial infection, cataract and glaucoma.
image

Fig. 6.30 Mooren ulcer. (A) Local peripheral ulceration; (B) circumferential and central spread; (C) advanced disease; (D) healed stage

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Treatment

The clinical course varies dependent on whether the patient appears to fall within the ‘limited’ or ‘relentless’ categories. In the second group, the outlook for vision tends to be very poor even with treatment.

1 Topical steroids as frequently as hourly are combined with a low-frequency prophylactic topical antibiotic. If an effective response is seen, treatment is tapered over several months.
2 Ciclosporin (up to 2%) may be effective, but may take weeks to exert a significant effect.
3 Adjunctive topical therapy includes artificial tears and collagenase inhibitors such as acetylcysteine 10%.
4 Conjunctival resection, which may be combined with excision of necrotic tissue, is performed if there is no response to topical steroids. The excised area should extend 4 mm back from the limbus and 2 mm beyond the margins of the lesion. Resection may be combined with keratoepithelioplasty to produce a physical barrier against conjunctival regrowth and further melting. Steroids are continued postoperatively.
5 Systemic immunosuppression should be instituted earlier for bilateral disease, or if involvement is advanced at first examination. Options include ciclosporin (5 mg/kg), prednisolone, methotrexate and azathioprine.
6 Systemic collagenase inhibitors such as doxycycline may be beneficial.
7 Lamellar keratectomy involving dissection of the residual central island in advanced disease may remove the stimulus for further inflammation.
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8 Visual rehabilitation involving deep anterior lamellar or penetrating keratoplasty may be considered once inflammation has settled. Surgery is covered with systemic immunosuppression to reduce the risk of recurrence.
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Peripheral ulcerative keratitis associated with systemic autoimmune disease

Pathogenesis

Peripheral ulcerative keratitis (PUK) may precede or follow the onset of systemic disease. Severe peripheral corneal infiltration, ulceration or thinning unexplained by evident ocular disease should prompt a search for an associated systemic collagen vascular disorder (see below). In patients with an underlying autoimmune disease there is immune complex deposition in peripheral cornea. Diseased epithelium, keratocytes and recruited inflammatory cells may result in the release of matrix metalloproteinases that degrade collagen and the extracellular matrix. Autoantibodies may target sites in the corneal epithelium.

Clinical features

• Crescentic ulceration and stromal infiltration at the limbus (Fig. 6.31A).
• Limbitis, episcleritis or scleritis are usually present.
• Circumferentially and occasionally central spread; in contrast to Mooren ulcer the process may also extend into the sclera.
• End-stage disease may result in a ‘contact lens’ cornea (Fig. 6.31B).
image

Fig. 6.31 Keratitis in systemic collagen vascular disease. (A) Early peripheral ulcerative keratitis; (B) ‘contact-lens’ cornea; (C) peripheral melting with perforation and iris prolapse; (D) sclerosing keratitis

Associated systemic disease

1 Rheumatoid arthritis is the commonest systemic association. PUK involves both eyes in 30% of cases and tends to affect patients during the late and advanced vasculitic phase. Patients with rheumatoid arthritis may also develop the following non-ulcerative types of keratitis:
a Peripheral stromal thinning is characterized by gradual resorption of peripheral stroma leaving the epithelium intact. Perforation may occur in advanced cases (Fig. 6.31C).
b Sclerosing keratitis is characterized by gradual thickening and opacification of the corneal stroma adjacent to a site of scleritis (Fig. 6.31D).
c Acute central corneal melting may occur in association with inflammation or severe dry eye (see Fig. 4.5A).
2 Wegener granulomatosis is the second most common systemic association of PUK. In contrast with rheumatoid arthritis ocular complications are the initial presentation in 50% of cases.
3 Relapsing polychondritis is more commonly associated with episcleritis or scleritis than with PUK.
4 Systemic lupus erythematosus is a rare association.

Treatment

PUK associated with a potentially life-threatening systemic vasculitis must be treated with systemic immunosuppressive agents in collaboration with a rheumatologist.

1 Systemic high dose steroids are used to control acute disease and cytotoxic therapy is required for longer-term management to obviate the side effects of steroids. Cyclophosphamide is especially useful for Wegener granulomatosis; other options include azathioprine, mycophenolate mofetil and methotrexate.
2 Topical lubricants (preservative-free).
3 Topical antibiotics may be considered as prophylaxis against infection if an epithelial defect is present.
4 Oral tetracycline such as doxycycline 100 mg b.d. may retard thinning due to an anticollagenase effect.
5 Topical steroids are generally avoided as they may worsen thinning, although relapsing polychondritis may be an exception when frequent steroid instillation seems to be helpful.
6 Conjunctival excision may be considered if medical treatment is ineffective.
7 Corneal gluing or amniotic membrane patching for perforation.
8 Keratoplasty. Emergency keratoplasty (preferably lamellar) may be required for peripheral corneal perforation. Elective keratoplasty (lamellar or penetrating) may be performed subsequently to restore vision.

Terrien marginal degeneration

Terrien disease is an uncommon idiopathic thinning of the peripheral cornea. Although usually categorized as a degeneration, some cases are associated with episodes of episcleritis or scleritis. About 75% of affected patients are male and the condition is usually bilateral although involvement may be symmetrical.

Diagnosis

1 Presentation is usually after the 4th decade with initially asymptomatic peripheral corneal lesions.
2 Signs
• Fine, yellow-white, punctate stromal opacities frequently associated with mild superficial vascularization, usually start superiorly, spread circumferentially and are separated from the limbus by a clear zone (Fig. 6.32A). On cursory examination they may resemble arcus senilis.
• Slowly progressive circumferential thinning results in a peripheral gutter, the outer slope of which shelves gradually, while the central part rises sharply (Fig. 6.32B).
• Perforation may rarely occur either spontaneously or following blunt trauma.
• Gradual visual deterioration occurs as a result of increasing corneal astigmatism.
• A few patients develop recurrent episodes of disabling pain and inflammation.
• Pseudopterygia may develop in long-standing cases at positions other than the 9 o’clock and 3 o’clock meridian (Fig. 6.32C).
image

Fig. 6.32 Terrien marginal degeneration. (A) Peripheral stromal opacification; (B) circumferential thinning; (C) pseudopterygia

Treatment

• Safety spectacle lenses (polycarbonate as a minimum) if thinning is significant.
• Contact lenses for astigmatism. Scleral lenses, or even soft lenses with rigid gas permeable ‘piggybacking’, are likely to be necessary.
• Surgery, involving either crescent-shaped excision of the gutter with suturing of the margins or peripheral lamellar transplantation, gives variable results.
• ’Tectonic’ corneal grafting for perforation or threatened perforation.
• Topical lubricants or weak topical steroids for inflammatory episodes, the latter with caution because of the risk of promoting thinning.

Neurotrophic keratopathy

Pathogenesis

Neurotrophic keratopathy occurs when there is loss of the trigeminal innervation to the cornea resulting in partial or complete anaesthesia.

The loss of neural influences results in intracellular oedema, exfoliation of epithelial cells, impairment of epithelial healing and loss of goblet cells, culminating in epithelial breakdown and persistent ulceration. Loss of acetylcholine, substance P, and growth factors from the epithelium appear to be important.

Causes

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1 Acquired damage to the 5th cranial nerve or trigeminal ganglion following surgical ablation for trigeminal neuralgia (tic doloureux), stroke, aneurysm, multiple sclerosis or tumour (acoustic neuroma or neurofibroma).
2 Systemic disease such as diabetes and leprosy.
3 Ocular disease such as herpes simplex and herpes zoster keratitis, abuse of topical anaesthetic, chemical burn and refractive corneal surgery.
4 Congenital causes include familial dysautonomia (Riley–Day syndrome), Möbius syndrome, Goldenhar syndrome, anhidrotic ectodermal dysplasia and hereditary sensory neuropathy.

Diagnosis

The severity of signs can vary during the course of disease. Some patients develop serious lesions early while others only develop problems after many years.

1 Corneal sensation is tested with a wisp of cotton or an anasthesiometer (<5 mm is clinically significant).
2 Signs
• Interpalpebral punctate keratopathy in which the epithelium appears irregular (Fig. 6.33A).
• Slightly epithelial opacification, oedema and small defects (Fig. 6.33B).
• Persistent epithelial defect in which the epithelium at the edge of the lesion appears rolled and thickened, and is poorly attached (Fig. 6.33C).
• Enlargement of epithelial defect with stromal oedema and infiltration.
• Stromal corneal melting (Fig. 6.33D) that may be virtually asymptomatic.
• Perforation is uncommon but can occur rapidly, especially if there is secondary infection.
image

Fig. 6.33 Neurotrophic keratopathy. (A) Early central epithelial changes; (B) small epithelial defect and stromal oedema; (C) large epithelial defect; (D) stromal infiltration and melting

(Courtesy of S Tuft – fig. C; S Bonini – fig. D)

Treatment

1 Discontinuation, if possible, of potentially toxic medications already in use.
2 Topical lubricants (non-preserved) for associated dry eye or corneal exposure. Topical insulin-like growth factor-1, substance P, and neurogenic growth factor have been evaluated but are not commercially available.
3 Protection of the ocular surface by the following:
a Simple taping of the lids, particularly at night, may provide temporary protection.
b Botulinum toxin injection to induce a protective ptosis.
c Tarsorrhaphy may be temporary or permanent, and lateral or central, according to the underlying pathology and visual potential.
d Therapeutic silicone contact lenses may be fitted provided the eye is carefully monitored for infection.
e Amniotic membrane patch with temporary central tarsorrhaphy.

Exposure keratopathy

Pathogenesis

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Exposure keratopathy is the result of incomplete lid closure (lagophthalmos). Lagophthalmos may only be present on blinking or gentle lid closure, but absent on forced lid closure. The result is drying of the cornea despite normal tear production.

Causes

1 Neuroparalytic, especially facial nerve palsy which may be idiopathic or the result of surgery for an acoustic neuroma or parotid tumour.
2 Reduced muscle tone as in coma or parkinsonism.
3 Mechanical
• Eyelid scarring associated with cicatricial pemphigoid, burns and trauma.
• Tight facial skin due to eczema, solar keratosis, xeroderma pigmentosum and following blepharoplasty.
4 Abnormality of globe position
• Severe proptosis due to thyroid eye disease or orbital tumour.
• Severe enophthalmos.

Diagnosis

1 Symptoms are those of a dry eye.
2 Signs
• Mild punctate epithelial changes involving the inferior third of the cornea, particularly with nocturnal lagophthalmos.
• Epithelial breakdown (Fig. 6.34A).
• Stromal melting (Fig. 6.34B), which may result in perforation.
• Secondary infection may supervene (Fig. 6.34C).
• Inferior fibrovascular change with Salzmann degeneration may develop over time.
image

Fig. 6.34 Exposure keratopathy. (A) Inferior epithelial defect; (B) stromal melting; (C) secondary bacterial infection

(Courtesy of S Tuft – fig. C)

Treatment

Treatment depends on the severity of exposure and whether recovery is anticipated.

1 Reversible exposure
• Artificial tears during the day and ointment at night.
• Taping the lid closed at night may be an alternative to ointment.
• Bandage silicone rubber or scleral contact lenses.
• Temporary tarsorrhaphy or Frost suture.
2 Permanent exposure
• Permanent tarsorrhaphy.
• Gold weights inserted in the upper lid for facial nerve palsy.
• Permanent central tarsorrhaphy and conjunctival flap may be required for severe cases.
• Management of proptosis by orbital decompression if necessary.

Miscellaneous keratopathy

Infectious crystalline keratopathy

Pathogenesis

Infectious crystalline keratopathy is a rare, indolent infection usually associated with long-term topical steroid therapy where there has been an epithelial defect, most frequently following penetrating keratoplasty. S. viridans is most commonly isolated, although numerous other bacteria and fungi have been implicated.

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Diagnosis

1 Signs
• Slowly progressive, grey-white, branching stromal opacities (Fig. 6.35A and B).
• Minimal inflammation and usually intact overlying epithelium.
2 Culture or biopsy to determine the organism.
image

Fig. 6.35 (A) Infectious crystalline keratitis; (B) crystalline keratitis on a graft

(Courtesy of M Kerr-Muir – fig. A)

Treatment

Treatment is with topical antibiotics for several weeks. Stopping topical steroid without adequate antibiotic cover can precipitate a rapid increase in inflammation and even suppuration.

Thygeson superficial punctate keratitis

Thygeson superficial punctate keratitis is an uncommon, usually bilateral, idiopathic condition characterized by exacerbations and remissions. It most commonly affects young adults but may occur at any age and recurrences can continue for decades.

Diagnosis

1 Symptoms consist of recurrent attacks of irritation, photophobia, blurred vision and watering.
2 Signs
• Mainly central, coarse, distinct, granular, greyish, slightly elevated epithelial lesions (Fig. 6.36A) that stain with fluorescein.
• A mild subepithelial haze may be present (Fig. 6.36B), especially if topical antivirals have been used.
• The conjunctiva is uninvolved and the eye is not hyperaemic.
3 Differential diagnosis includes post-adenoviral keratitis.
image

Fig. 6.36 (A) Thygeson superficial punctate keratitis; (B) associated subepithelial haze

(Courtesy of R Curtis – fig. B)

Treatment

1 Topical
• Lubricants may suffice in mild cases.
• Steroids (fluorometholone 0.1% or loteprednol 0.2–0.5% b.d.) initially with gradual tapering. In some cases higher intensity treatment may be needed.
• Ciclosporin 0.05% is a good alternative to steroids, particularly in patients requiring long-term therapy.
2 Contact lenses (extended wear or daily disposable soft) may be considered if steroids are contraindicated or as an alternative.
3 Phototherapeutic keratectomy brings short term relief but recurrence is likely.

Filamentary keratopathy

Pathogenesis

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Filamentary keratopathy is a common condition that can cause considerable discomfort. It is thought that a loose area of epithelium acts as a focus for deposition of mucus and cellular debris. The causes are shown in Table 6.6.

Table 6.6 Causes of filamentary keratopathy

• Aqueous deficiency (keratoconjunctivitis sicca)
• Excessive contact lens wear
• Corneal epithelial instability (recurrent erosion syndrome, corneal graft, cataract surgery, refractive surgery and drug toxicity)
• Superior limbic keratoconjunctivitis
• Bullous keratopathy
• Neurotrophic keratopathy
• Prolonged or frequent eye closure

Diagnosis

1 Symptoms consist of discomfort with foreign body sensation, redness and sometimes photophobia.
2 Signs
• Strands of degenerated epithelial cells and mucus (Fig. 6.37 and see Figs. 4.4B and C) that move with blinking, attached at one end to the cornea.
• Filaments stain well with rose bengal and to a lesser extent with fluorescein.
• A small epithelial defect may be present at the base of a filament.
• Chronic filaments may form plaques.
image

Fig. 6.37 Corneal filaments

(Courtesy of S Tuft)

Management

1 General
• Any underlying cause such as dry eye should be treated (see Ch. 4).
• All unnecessary medications should be stopped.
2 Specific treatment for filaments.
• Mechanical removal for short-term symptomatic relief.
• Mucolytic agents such as 5% or 10% acetylcysteine drops.
• Non-steroidal anti-inflammatory drops such as diclofenac.
• Hypertonic 5% saline (drops q.i.d., ointment at bedtime) to encourage adhesion of loose epithelium.
• Bandage soft contact lenses of high oxygen permeability to protect the cornea from the shearing action of the lids.

Recurrent corneal epithelial erosions

Pathogenesis

Recurrent corneal epithelial erosion is the tendency for minor trauma to precipitate significant corneal epithelial disturbances. The condition is caused by an abnormally weak attachment between the basal cells of the corneal epithelium and their basement membrane. Minor trauma, such as eyelid-corneal interaction during sleep, can be sufficient to detach the epithelium. Erosions may be associated with previous trauma or corneal surgery, and with certain corneal dystrophies (see below).

Diagnosis

1 Presentation is with severe pain, photophobia, redness, blepharospasm, and watering waking the patient during the night or present on awaking in the morning. There is usually (but not invariably) a prior history of corneal abrasion, sometimes years previously, and this may have been minor compared to the recurrent symptoms.
2 Signs
• An epithelial defect may be present, usually in the inferior interpalpebral zone (Fig. 6.38).
• Healing of a defect can often be very rapid (hours), but the extent of loose epithelium may be highlighted by areas of pooling of fluorescein and rapid tear film breakup.
image

Fig. 6.38 Corneal erosion

Treatment

1 Acute symptoms
• Antibiotic ointment q.i.d. and cyclopentolate 1% b.d.
• Pressure patching should not be used as it may impair healing and does not improve comfort.
• In severe cases a bandage contact lens alleviates pain but may not improve healing.
• Debridement of heaped/scrolled areas of epithelium with a cellulose sponge may enhance healing.
• Topical diclofenac 0.1% reduces pain.
• Topical anaesthetic dramatically relieves pain but should not be dispensed for patient use.
• Hypertonic sodium chloride 5% drops q.i.d. and ointment at bedtime may improve epithelial adhesion.
• Following resolution, some authorities advise using a prophylactic topical lubricant such as carbomer gel q.i.d. for several months.
2 Recurrent symptoms
• Topical lubricant gel or ointment instilled at bedtime used long-term may be sufficient.
• Simple debridement of epithelium of involved areas which may be followed by smoothing of Bowman layer with a diamond burr or an excimer laser.
• Long-term extended-wear bandage contact lenses.
• Anterior stromal puncture for localized areas off the visual axis may reduce the recurrence rate; it may not be necessary to remove the epithelium prior to the procedure.

Xerophthalmia

Pathogenesis

Vitamin A is essential for the maintenance of the body’s epithelial surfaces, for immune function and for the synthesis of retinal photoreceptor proteins. Xerophthalmia refers to the spectrum of ocular disease caused by lack of vitamin A, and is a late manifestation of severe deficiency. Lack of vitamin A in the diet may be caused by malnutrition, malabsorption, chronic alcoholism or by highly selective dieting. The risk in infants is increased if their mothers are malnourished and by coexisting diarrhoea or measles.

Diagnosis

1 Symptoms are night blindness (nyctalopia), discomfort and loss of vision.
2 Conjunctiva
• Xerosis is characterized by dryness of the conjunctiva in the interpalpebral zone with loss of goblet cells, squamous metaplasia and keratinization.
• Bitot spots are triangular patches of foamy keratinized epithelium in the interpalpebral zone (Fig. 6.39A) thought to be caused by Corynebacterium xerosis.
3 Cornea
• Lustreless appearance due to secondary xerosis.
• Bilateral punctate corneal epithelial erosions in the interpalpebral zone can progress to epithelial defects but are reversible with treatment.
• Keratinization.
• Sterile corneal melting by liquefactive necrosis (keratomalacia) which may result in perforation (Fig. 6.39B).
4 Retinopathy, characterized by yellowish peripheral dots, may occur in advanced cases and is associated with decreased electroretinogram amplitude.
image

Fig. 6.39 Xerophthalmia. (A) Bitot spot; (B) keratomalacia and perforation

(Courtesy of N Rogers – fig. A; S Kumar Puri – fig. B)

Table 6.7 WHO grading of Xerophthalmia

XN = night blindness
X1 = conjunctival xerosis (X1A) with Bitot spot (X1B)
X2 = corneal xerosis
X3 = corneal ulceration, less than one-third (X3A); more than one-third (X3B)
XS = corneal scar
XF = xerophthalmic fundus

Treatment

Keratomalacia is an indicator of very severe vitamin A deficiency and should be treated as a medical emergency due to the risk of death, particularly in infants.

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1 Systemic treatment involves oral (oil-based 200 000 IU) or intramuscular vitamin A (aqueous-based 100 000 IU) for keratomalacia. Multivitamin supplements and dietary sources of vitamin A are also administered.
2 Local
• Intense lubrication.
• Topical retinoic acid may promote healing but is not sufficient without systemic supplements.
• Corneal perforation is addressed surgically as necessary.

Corneal ectasias

Keratoconus

Pathogenesis

Keratoconus is a progressive disorder in which the cornea assumes a conical shape secondary to stromal thinning and protrusion (Fig. 6.40A). Both eyes are affected, at least on topographical imaging, in almost all cases. The role of heredity has not been clearly defined and most patients do not have a positive family history. Offspring appear to be affected in only about 10% of cases and autosomal dominant transmission with incomplete penetrance has been proposed.

image

Fig. 6.40 Keratoconus. (A) Histology shows central stromal thinning; (B) ‘oil-droplet’ red reflex; (C) Vogt striae; (D) Fleischer ring; (E) advanced thinning; (F) Munson sign

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; M Leyland – fig. C; S Fogla – fig. D; R Bates – fig. E)

Presentation

Presentation is typically during puberty with unilateral impairment of vision due to progressive myopia and astigmatism, which subsequently becomes irregular. As a result of the asymmetrical nature of the condition, the fellow eye usually has normal vision with negligible astigmatism at presentation. Approximately 50% of normal fellow eyes will progress to keratoconus within 16 years; the greatest risk is during the first 6 years of onset.

Diagnosis

The hallmark of keratoconus is central or paracentral stromal thinning, accompanied by apical protrusion and irregular astigmatism. It can be graded by keratometry according to severity as mild (<48 D), moderate (48–54 D) and severe (>54 D).

1 Signs
• Direct ophthalmoscopy from a distance of one foot shows a fairly well delineated ‘oil droplet’ reflex (Fig. 6.40B).
• Retinoscopy shows an irregular ‘scissoring’ reflex.
• Slit-lamp biomicroscopy shows very fine, vertical, deep stromal stress lines (Vogt striae – Fig. 6.40C) which disappear with pressure on the globe.
• Epithelial iron deposits may surround the base of the cone (Fleischer ring) and are best seen with a cobalt blue filter (Fig. 6.40D).
• Progressive corneal thinning (maximal at the apical zone) (Fig. 6.40E) associated with poor visual acuity resulting from marked irregular myopic astigmatism with steep keratometry (K) readings.
• Bulging of the lower lid in downgaze (Munson sign – Fig. 6.40F).
2 Corneal topography shows irregular astigmatism and is the most sensitive method of detecting early keratoconus and for monitoring progression (Fig. 6.41).
image

Fig. 6.41 Relative scale corneal maps showing advanced keratoconus in the right eye and an early paracentral cone in the left

(Courtesy of E Morris)

Acute hydrops

Acute hydrops is caused by a rupture in Descemet membrane that allows an influx of aqueous into the cornea (Fig. 6.42A and B). Although the break usually heals within 6–10 weeks and the corneal oedema clears, a variable amount of stromal scarring may develop (Fig. 6.42C). Acute episodes are initially treated with cycloplegia, hypertonic (5%) saline ointment and patching or a soft bandage contact lens. Healing may sometimes result in improved visual acuity as a result of scarring and flattening of the cornea.

image

Fig. 6.42 Advanced keratoconus. (A) Histology shows oedema of basal epithelial cells and partial loss of Bowman layer; (B) severe corneal oedema; (C) apical scarring

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – figs A and C)

Associations

1 Systemic disorders include Down, Turner, Ehlers–Danlos and Marfan syndromes, atopy, osteogenesis imperfecta, mitral valve prolapse and mental retardation.
2 Ocular associations include vernal keratoconjunctivitis, blue sclera, aniridia, ectopia lentis, Leber congenital amaurosis, retinitis pigmentosa and persistent eye rubbing.

Treatment

1 Spectacles or soft contact lenses are generally sufficient in early cases.
2 Rigid contact lenses are required for higher degrees of astigmatism to provide a regular refracting surface. Advances in both lens design and material have increased the proportion of keratoconus patients who can satisfactorily use contact lenses.
3 Keratoplasty, either penetrating or deep anterior lamellar (DALK), may be necessary in patients with advanced disease, especially those with significant corneal scarring. Prior hydrops indicates the presence of a Descemet membrane discontinuity which is a contraindication to DALK. Although clear grafts are obtained in around 90% of cases, optical outcomes may be compromised by residual astigmatism and anisometropia, necessitating contact lens correction for best acuity.
4 Intracorneal ring segment (Intacs) implantation using laser or mechanical channel creation is relatively safe, and typically provides at least a moderate visual improvement, facilitating contact lens tolerance in advanced cases.
5 Corneal collagen cross-linking, using riboflavin drops to photosensitize the eye followed by exposure to ultraviolet-A light, is a newer treatment which offers promise of stabilization or reversal of ectasia in at least some patients. It can be combined with Intacs insertion.

Pellucid marginal degeneration

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Pellucid marginal degeneration is a rare progressive peripheral corneal thinning disorder, typically involving the inferior cornea. Occasionally it may co-exist with keratoconus and keratoglobus (see below). Like keratoconus, pellucid marginal degeneration is bilateral, although often asymmetrical.

Diagnosis

1 Presentation is in the 4th–5th decades with reduced visual acuity due to increasing astigmatism.
2 Signs
• A bilateral, slowly progressive, crescentic 1–2 mm band of inferior corneal thinning extending from 4–8 o’clock, 1 mm from the limbus (Fig. 6.43A).
• The epithelium is intact, and the cornea above the thinned area is ectatic and flattened.
• In contrast to keratoconus, Fleischer rings and Vogt striae do not occur and acute hydrops is rare.
3 Corneal topography shows a ‘butterfly’ pattern, with severe astigmatism and diffuse steepening of the inferior cornea (Fig. 6.43B).
image

Fig. 6.43 (A) Pellucid marginal degeneration; (B) topography shows severe astigmatism and diffuse steepening of the inferior cornea

(Courtesy of R Visser – fig. A; S Fogla – fig. B)

Treatment

1 Spectacles usually fail early as irregular astigmatism increases.
2 Contact lenses. In early disease soft toric lenses are adequate but more advanced cases require rigid gas permeable lenses.
3 Surgical options, none of which are ideal, in patients intolerant to contact lenses include large eccentric penetrating keratoplasty, thermocauterization, crescentic lamellar keratoplasty, wedge resection of diseased tissue, epikeratoplasty and intracorneal ring implantation. Results of collagen cross-linking are encouraging.

Keratoglobus

Keratoglobus is an extremely rare congenital condition in which the entire cornea is abnormally thin. Possibly genetically related to keratoconus, it may be associated with Leber congenital amaurosis and blue sclera.

1 Onset is at birth.
2 Signs
• In contrast to keratoconus the cornea develops globular rather than conical ectasia.
• Corneal thinning is generalized rather than at the apex of the protrusion (Fig. 6.44A).
• Acute hydrops (Fig. 6.44B) occurs less commonly than in either keratoconus or pellucid marginal degeneration but the cornea is more prone to rupture on relatively mild trauma.
3 Corneal topography shows generalized steepening (Fig. 6.44C).
4 Differential diagnosis is from congenital glaucoma (oedematous cornea) and megalocornea (not thinned). The corneal diameter is normal in keratoglobus.
5 Treatment is with scleral contact lenses because the results of surgery are poor, though large-diameter grafting can be attempted. Special care should be taken, particularly in childhood, to protect the eyes from trauma.
image

Fig. 6.44 (A) Keratoglobus; (B) acute hydrops; (C) topography shows generalized steepening

(Courtesy of S Fogla – fig. C)

Corneal dystrophies

The corneal dystrophies are a group of progressive, usually bilateral, mostly genetically determined, non-inflammatory opacifying disorders. Based on biomicroscopical and histopathological features corneal dystrophies are classified into (a) epithelial, (b) Bowman layer, (c) stromal and (d) endothelial. Recent advances in molecular genetics have identified the responsible gene defects for most.

Epithelial dystrophies

Cogan epithelial basement membrane dystrophy

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Epithelial basement membrane dystrophy is the most common dystrophy seen in clinical practice. Despite this it is frequently misdiagnosed, principally due to its variable appearance.

1 Inheritance. The condition is usually sporadic, and rarely autosomal dominant (AD) with incomplete penetrance.
2 Histology shows thickening of the basement membrane with deposition of fibrillary protein between the basement membrane and Bowman layer (Fig. 6.45A). There is also absence of hemidesmosomes of the basal epithelial cells, which is responsible for the typical recurrent corneal erosions.
3 Onset is in the 2nd decade. About 10% of patients develop recurrent corneal erosions in the 3rd decade and the remainder are asymptomatic throughout life. Simultaneous bilateral recurrent erosions suggest epithelial basement membrane dystrophy.
4 Signs. The following lesions may be seen in isolation or combination and are best visualized by retroillumination or scleral scatter. Over time one pattern frequently changes to another; the distribution of the lesions may also vary. Features may be variable, absent or only subtle in a fellow asymptomatic eye.
• Dot-like opacities (Fig. 6.45B).
• Epithelial microcysts (Fig. 6.45C).
• Subepithelial map-like patterns surrounded by a faint haze (Fig. 6.45D).
• Whorled fingerprint-like lines (Fig. 6.45D).
• Similar features can be seen in an eye suffering recurrent erosions from any cause.
5 Treatment is that of recurrent corneal erosions as described above.
image

Fig. 6.45 Cogan epithelial basement membrane dystrophy. (A) Histology shows intraepithelial extension of the basement membrane above the intraepithelial cyst – toluidine blue stain; (B) dots; (C) microcysts; (D) map-like pattern; (E) fingerprint lines seen on retroillumination

(Courtesy of Krachmer, Mannis and Holland, from Cornea, Mosby 2005 – fig. E; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A)

Meesmann epithelial dystrophy

Meesmann dystrophy is a very rare non-progressive abnormality of corneal epithelial metabolism, underlying which mutations in the genes encoding corneal epithelial keratins have been reported.

1 Inheritance is AD.
2 Histology shows irregular thickening of the epithelial basement membrane and intraepithelial cysts (Fig. 6.46A).
3 Symptoms are variable. Patients may be asymptomatic, or ocular irritation may begin in the first few months of life.
4 Signs
• Myriad tiny intraepithelial cysts of uniform size but variable density are maximal centrally and extend towards but do not reach the limbus (Fig. 6.46B).
• The cornea may be slightly thinned and sensation reduced.
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5 Treatment other than lubrication is not normally required.
image

Fig. 6.46 Meesmann dystrophy. (A) Histology shows thickening of the epithelial basement membrane and intraepithelial cysts – PAS stain; (B) myriad of intraepithelial cysts

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; S Fogla – fig. B)

Lisch epithelial dystrophy

Lisch dystrophy was previously suspected to be a variant of Meesmann, but is now believed to be genetically distinct.

1 Inheritance is AD or X-linked dominant (XLD) with the gene locus on Xp22.3 in the latter in at least some patients.
2 Signs
• Grey bands with a whorled configuration (Fig. 6.47A).
• Retroillumination shows densely packed microcysts (Fig. 6.47B).
image

Fig. 6.47 Lisch dystrophy. (A) Grey, bands with a whorled configuration; (B) retroillumination shows clear, densely crowded microcysts

(Courtesy of W Lisch)

Bowman layer/anterior stromal dystrophies

Reis–Bücklers dystrophy (corneal dystrophy of Bowman layer, type I, CDB1, GCD type III)

This so-called ‘true’ form of Reis–Bücklers dystrophy may also be categorized as a form of granular stromal dystrophy (GCD type III).

1 Inheritance is AD with the gene locus on 5q31 (gene TGFB1).
2 Histology shows replacement of Bowman layer and the epithelial basement membrane with fibrous tissue (Fig. 6.48A).
3 Onset is in the 1st or 2nd decade with severe recurrent corneal erosions.
4 Signs
• Grey-white, fine, round and polygonal subepithelial opacities similar to those of granular dystrophy type I, most dense centrally (Fig. 6.48B).
• The changes increase in density with age resulting in a reticular pattern due to the laying down of irregular bands of collagen replacing Bowman layer.
• Corneal sensation is reduced and visual impairment may occur due to scarring at the level of Bowman layer.
5 Treatment is directed at the recurrent erosions. Excimer laser keratectomy achieves satisfactory control in some patients.
image

Fig. 6.48 Reis–Bücklers dystrophy. (A) Histology shows replacement of Bowman layer and epithelial basement membrane by fibrous tissue; (B) clinical appearance

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A)

Thiel–Behnke dystrophy (corneal dystrophy of Bowman layer, type II, CDB2, honeycomb-shaped corneal dystrophy)

1 Inheritance is AD with gene loci on 10q24 and 5q31 (gene TGFB1).
2 Histology shows ‘curly fibres’ in Bowman layer on electron microscopy.
3 Onset is at the end of the 1st decade with recurrent erosions.
4 Signs. Subepithelial opacities in a honeycomb morphology involving the central cornea (Fig. 6.49).
5 Treatment may not be necessary because visual impairment is less than in Reis–Bücklers dystrophy.
image

Fig. 6.49 Thiel–Behnke dystrophy

Schnyder central crystalline dystrophy

Crystalline dystrophy is a disorder of corneal lipid metabolism which is associated with raised serum cholesterol in approximately 50% of patients.

1 Inheritance is AD with the gene locus at 1p36.
2 Histology shows deposits of phospholipids and cholesterol.
3 Onset is in the 2nd decade with visual impairment and glare.
4 Signs
• Central, oval, subepithelial ‘crystalline’ opacity (Fig. 6.50A).
• Diffuse corneal haze (Fig. 6.50B) and prominent corneal arcus develop by the 3rd decade.
5 Treatment is by excimer laser keratectomy.
image

Fig. 6.50 Schnyder crystalline dystrophy. (A) Early lesion; (B) late diffuse haze.

(Courtesy of K Nischal – fig. A)

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Stromal dystrophies

Lattice corneal dystrophy type I (LCD1, Biber–Haab–Dimmer)

1 Inheritance is AD with the locus at 5q31 (gene TGFB1).
2 Histology shows amyloid, staining with Congo red (Fig. 6.51A) and exhibiting characteristic green birefringence when viewed with a polarizing filter (Fig. 6.51B).
3 Onset is at the end of the 1st decade with recurrent erosions which precede typical stromal changes.
4 Signs in chronological order:
• Anterior stromal, glassy, refractile dots (Fig. 6.51C).
• Coalescence into fine lattice lines, best seen on retroillumination (Fig. 6.51D).
• Deep and outward spread sparing the periphery.
• Generalized stromal haze that progressively impairs vision and may obscure some of the lattice lines (Fig. 6.51E).
• Corneal sensation is reduced.
5 Treatment by penetrating or deep lamellar keratoplasty is frequently required. Recurrence in the graft may occur.
image

Fig. 6.51 Lattice dystrophy type 1. (A) Histology shows amyloid staining with Congo red; (B) green birefringence of amyloid when viewed with polarized light; (C) glassy dots in the anterior stroma; (D) fine lattice lines; (E) stromal haze

(Courtesy of J Harry – fig. A; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. B; D Smerdon – fig. D).

Lattice corneal dystrophy type II (LCD2, Finnish type amyloidosis, Meretoja syndrome, amyloid cranial neuropathy with lattice corneal dystrophy)

1 Inheritance is AD with a gene locus at 9q34.
2 Histology shows amyloid deposits in the corneal stroma and other involved sites.
3 Onset is in the 2nd decade; erosions are rare.
4 Signs
• Randomly scattered, short, fine lattice lines which are sparse, more delicate, more radially orientated and more peripherally located than in LCD1.
• Corneal sensation is impaired.
5 Treatment by keratoplasty may rarely be required in later life to improve vision.
6 Systemic features include progressive bilateral cranial and peripheral neuropathy, dysarthria, dry and extremely lax itchy skin, a characteristic ‘mask-like’ facial expression due to bilateral facial palsy, protruding lips and pendulous ears. Amyloidosis may also involve the kidneys and heart.

Lattice corneal dystrophy type IIIA

Lattice type IIIA is characterized by thick rope-like bands of deposited amyloid (Fig. 6.52). The age of onset is late (70–90 years) and inheritance AD (gene TGFB1).

image

Fig. 6.52 Lattice dystrophy type IIIa

Gelatinous drop-like dystrophy (Japanese type amyloid corneal dystrophy)

This is a rare disorder mainly affecting Japanese patients.

1 Inheritance is autosomal recessive (AR) with the gene locus at 1p32.
2 Histology shows subepithelial and anterior stromal accumulation of amyloid (Fig. 6.53A).
3 Onset is within the 1st and 2nd decades with severe photophobia, watering and visual impairment.
4 Signs in chronological order:
• Grey subepithelial nodules.
• Gradual confluence, stromal involvement and increase in size giving rise to a mulberry-like appearance (Fig. 6.53B).
5 Treatment is with repeated superficial keratectomy because of early recurrences on corneal grafts.
image

Fig. 6.53 Gelatinous drop-like dystrophy; (A) Histology shows irregular anterior stromal amyloid deposits; (B) clinical appearance

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; Krachmer, Mannis and Holland, from Cornea, Mosby 2005 – fig. B)

Granular corneal dystrophy type I (GCD1, Groenouw type I)

1 Inheritance is AD with the gene locus at 5q31 (gene TGFB1).
2 Histology shows amorphous hyaline deposits which stain bright red with Masson trichrome (Fig. 6.54A).
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3 Onset is in the 1st decade but vision is usually not affected in the early stage of the disease. Recurrent erosions are uncommon.
4 Signs in chronological order:
• Small, white, sharply demarcated deposits resembling crumbs, sugar granules, rings or snowflakes in the central anterior stroma (Fig. 6.54B).
• The overall pattern of deposition is radial or disc shaped, or may be in the form of a Christmas tree.
• Initially the stroma between the opacities is clear (Fig. 6.54C).
• Gradual increase in number and size of the deposits with deeper and outward spread but not reaching the limbus.
• Gradual confluence and diffuse haze of intervening stroma (Fig. 6.54D) causes visual impairment.
• Corneal sensation is impaired.
5 Treatment by penetrating or deep lamellar keratoplasty is usually required by the 5th decade. Superficial recurrences may require repeated excimer laser keratectomy.
image

Fig. 6.54 Granular dystrophy type 1. (A) Histology shows red-staining material with Masson trichrome; (B) sharply demarcated crumbs; (C) increase in number and outward spread; (D) confluence

(Courtesy of J Harry – fig. A)

Granular corneal dystrophy type II (GCD2, Avellino, combined granular-lattice dystrophy)

1 Inheritance is AD with the gene locus at 5q31 (gene TGFB1).
2 Histology shows both hyaline and amyloid in the stroma that stains with Masson trichrome and Congo red.
3 Onset is in the 2nd decade. Recurrent erosions are rare, and if present, mild so that some patients may be unaware of their disease.
4 Signs. Superficial, fine, opacities that resemble rings, discs, stars or snowflakes, most dense centrally (resembling those seen in granular dystrophy type I) associated with deeper linear opacities reminiscent of lattice dystrophy (Fig. 6.55).
5 Treatment is usually not required.
image

Fig. 6.55 Granular dystrophy type 2 (Avellino)

(Courtesy of W Lisch)

Macular dystrophy (Groenouw type II)

Macular dystrophy is the least common stromal dystrophy, in which a systemic inborn error of keratan sulphate metabolism seems to have only corneal manifestations. It has been divided into clinically indistinguishable types I, IA and II depending on the presence or absence of antigenic keratan sulphate in the serum and cornea; these have been shown to be due to mutations in the same sulfotransferase gene (CHST6).

1 Inheritance is AR with the gene locus at 16q22.
2 Histology shows abnormally close packing of collagen in the corneal lamellae and abnormal aggregations of glycosaminoglycans which stain with Prussian blue and colloidal iron (Fig. 6.56A).
3 Onset is towards the end of the 1st decade with visual deterioration.
4 Signs in chronological order:
• Anterior stromal haze, initially involving the central cornea.
• Greyish-white, dense, focal, poorly delineated spots in the anterior stroma centrally and posterior stroma in the periphery (Fig. 6.56B).
• Superficial deposits may produce an irregularity of the corneal surface, although recurrent erosions are unusual.
• Increase in size and stromal haze (Fig. 6.56C).
• Increasing opacification with eventual involvement of full-thickness stroma up to the limbus, associated with corneal thinning (Fig. 6.56D).
5 Treatment by penetrating keratoplasty is generally successful but late recurrence on the graft may occur.
image

Fig. 6.56 Macular dystrophy. (A) Histology shows deposits of abnormal glycosaminoglycans that appear blue with colloidal iron stain; (B) poorly delineated deposits; (C) increase in size and stromal haze; (D) extensive involvement

(Courtesy of R Ridgway – figs. B, C and D; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann, 2001 – fig. A)

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François central cloudy dystrophy

1 Inheritance is AD.
2 Signs
• Polygonal, cloudy grey opacities separated by relatively clear spaces, in the posterior stroma most prominent centrally, creating a leather-like appearance (Fig. 6.57).
• The signs are similar to posterior crocodile shagreen but it is differentiated by its central, posterior location and mode of inheritance.
3 Treatment is not required.
image

Fig. 6.57 François central cloudy dystrophy

(Courtesy of W Lisch)

Endothelial dystrophies

Fuchs endothelial dystrophy

Fuchs endothelial dystrophy (FED) is characterized by bilateral accelerated endothelial cell loss. It is more common in women and is associated with a slightly increased prevalence of open-angle glaucoma.

1 Inheritance may occasionally be AD although the majority are sporadic.
2 Onset of this slowly progressive disease is commonly in old age, although earlier onset can occur.
3 Signs
• Cornea guttata refers to irregular warts or ‘excrescences’ of Descemet membrane secreted by abnormal endothelial cells (Fig. 6.58A).
• Specular reflection shows tiny dark spots caused by disruption of the regular endothelial mosaic (Fig. 6.58B).
• Progression occurs to a ‘beaten metal’ appearance which may be associated with melanin deposition (Fig. 6.58C).
• Endothelial decompensation gradually leads to central stromal oedema and blurred vision, worse in the morning and clearing later in the day.
• Epithelial oedema develops when stromal thickness has increased by about 30%.
• Persistent epithelial oedema results in the formation of microcysts and bullae (bullous keratopathy – Fig. 6.58D and E) which causes pain and discomfort on rupture, thought to be due to exposure of naked nerve endings.
4 Treatment
a Conservative options include topical sodium chloride 5% drops or ointment, reduction of intraocular pressure and using a hair dryer to speed corneal dehydration in the morning.
b Bandage contact lenses provide comfort by protecting exposed nerve endings and flattening bullae.
c Penetrating or deep lamellar endothelial keratoplasty has a high success rate and should not be delayed.
d Other options in eyes with poor visual potential include conjunctival flaps and amniotic membrane transplants.
5 Cataract surgery may accelerate endothelial cell loss and result in decompensation. A ‘triple procedure’ (cataract surgery, lens implantation and keratoplasty) should be considered in eyes with corneal epithelial oedema or when preoperative pachymetry measurement is greater than 640 µm. If corneal thickness is less than 640 µm, a good visual outcome is to be expected.
image

Fig. 6.58 Fuchs endothelial dystrophy. (A) Histology of cornea guttata shows irregular excrescences of Descemet membrane – PAS stain; (B) cornea guttata seen on specular reflection; (C) ‘beaten-bronze’ endothelium; (D) bullous keratopathy; (E) histology shows severe epithelial oedema with surface bullae – PAS stain

(Courtesy of J Harry – figs A and E; W Lisch – fig. D)

Posterior polymorphous dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is a rare, innocuous and asymptomatic condition in which corneal endothelial cells display characteristics similar to epithelium. There are three forms, PPCD1-3, each caused by mutations in different genes.

1 Inheritance is usually AD.
2 Onset is at birth or soon thereafter, although it is most frequently identified by chance in later life.
3 Signs consist of subtle vesicular endothelial lesions (Fig. 6.59A) that may become confluent (Fig. 6.59B), band-like lesions (Fig. 6.59C) or diffuse opacities which may be asymmetrical.
4 Ocular associations include iris abnormalities, glaucoma and Alport syndrome.
5 Treatment is not required.
image

Fig. 6.59 Posterior polymorphous dystrophy. (A) Vesicles; (B) confluent vesicles; (C) band-like lesions

(Courtesy of W Lisch – figs B and C)

Congenital hereditary endothelial dystrophy

Congenital hereditary endothelial dystrophy (CHED) is a rare dystrophy in which there is focal or generalized absence of corneal endothelium. There are two main forms, CHED1 and CHED2, the latter being more severe.

1 Inheritance of CHED1 is AD with the gene locus on 20p11.2-q11.2. CHED2 is AR with the gene locus on 20p13.
2 Onset is perinatal (Fig. 6.60A).
3 Signs
• Bilateral, symmetrical, diffuse corneal oedema resulting in a blue-grey, ground-glass appearance (Fig. 6.60B) to total opacification (Fig. 6.60C).
• Visual impairment is variable and visual acuity may surpass that expected from the corneal appearance.
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4 Treatment by penetrating keratoplasty has a reasonable chance of success when performed early but is risky and technically more difficult than in adults. Undue delay in surgical intervention carries the risk of dense amblyopia.
5 Differential diagnosis includes other causes of neonatal corneal opacification such as congenital glaucoma, mucopolysaccharidoses, birth trauma, rubella keratitis and sclerocornea.
image

Fig. 6.60 Congenital hereditary endothelial dystrophy. (A) Bilateral perinatal corneal opacification; (B) mild; (C) very severe

(Courtesy of K Nischal – figs A and C; Krachmer, Mannis and Holland, from Cornea, Mosby 2005 – fig. B)

Corneal degenerations

Age-related degenerations

Arcus senilis

1 Systemic implications. Arcus senilis is the most common peripheral corneal opacity; it frequently occurs without predisposing systemic conditions in elderly individuals. Occasionally arcus may be associated with familial and non-familial dyslipoproteinaemias. Arcus has also been noted in patients with Schnyder crystalline corneal dystrophy.
2 Signs (Fig. 6.61A)
• Stromal lipid deposition which starts in the superior and inferior perilimbal cornea and then progresses circumferentially to form a band about 1 mm wide.
• The band is usually wider in the vertical than horizontal meridian.
• The central border is diffuse and the peripheral edge is sharp and separated from the limbus by a clear zone.
• This lucid interval may occasionally undergo mild thinning (senile furrow).
image

Fig. 6.61 Age-related degenerations. (A) Arcus senilis; (B) Vogt limbal girdle; (C) cornea farinata; (D) crocodile shagreen

Vogt limbal girdle

Vogt limbal girdle is a common innocuous condition which is more common in women and is present in up to 60% of individuals over 40 years of age.

1 Signs
• Bilateral, arc-like, whitish crescentic lines composed of chalk-like flecks located at the limbus at 9 and/or 3 o’clock, more common nasally (Fig. 6.61B).
• There may be irregular central extensions.
2 Classification
a Type I may be closely related to band keratopathy, featuring a ‘Swiss cheese’ hole pattern and a clear area separating the lesion from the scleral margin.
b Type II is distinguished from type I by the absence of holes and sometimes also absence of a juxtalimbal clear zone.

Cornea farinata

Cornea farinata is a visually insignificant condition characterized by bilateral, minute, flour-like deposits in the deep stroma, most prominent centrally (Fig. 6.61C).

Crocodile shagreen

Crocodile shagreen is characterized by asymptomatic, greyish-white, polygonal stromal opacities separated by relatively clear spaces (Fig. 6.61D). The opacities most frequently involve the anterior two-thirds of the stroma (anterior crocodile shagreen), although on occasion they may be found more posteriorly (posterior crocodile shagreen). It resembles the central cloudy dystrophy of François (see Fig. 6.57).

Lipid keratopathy

1 Primary lipid keratopathy is rare and occurs spontaneously. It is characterized by white or yellowish stromal deposits consisting of cholesterol, fats and phospholipids and is not associated with vascularization (Fig. 6.62A).
2 Secondary lipid keratopathy is much more common and is associated with previous ocular injury or disease which has resulted in corneal vascularization (Fig. 6.62B). The most common causes are herpes simplex and herpes zoster disciform keratitis.
3 Treatment is primarily aimed at medical control of the underlying inflammatory disease. Other treatment options include:
a Argon laser photocoagulation to the arterial ‘feeder’ vessels may induce resorption of the lipid infiltrate provided the vessels can be identified by fluorescein angiography.
b Needle point cautery is performed by grasping a 6 mm or similar suture needle in thermal cautery forceps and applying the hot needle tip to the feeder vessels at the limbus under microscopic control.
c Penetrating keratoplasty may be required in advanced but quiescent disease, although vascularization, thinning and hypoaesthesia may prejudice the outcome.
image

Fig. 6.62 Lipid keratopathy. (A) Primary; (B) secondary to vascularization

(Courtesy of S Tuft – fig. B)

Band keratopathy

1 Histology shows deposition of calcium salts in Bowman layer, epithelial basement membrane and anterior stroma (Fig. 6.63A).
2 Causes
a Ocular. Chronic anterior uveitis (particularly in children), phthisis bulbi, silicone oil in the anterior chamber, chronic corneal oedema and severe chronic keratitis.
b Age-related affects otherwise healthy individuals.
c Metabolic (metastatic calcification). This is rare and includes increased serum calcium and phosphorus, hyperuricaemia and chronic renal failure.
d Hereditary causes include familial cases and ichthyosis.
3 Signs
• Peripheral interpalpebral calcification with clear cornea separating the sharp peripheral margins of the band from the limbus (Fig. 6.63B).
• Gradual central spread to form a band-like chalky plaque containing transparent small holes and occasionally clefts (Fig. 6.63C).
• Advanced lesions may become nodular and elevated with considerable discomfort due to epithelial breakdown.
4 Treatment is indicated if vision is threatened or if the eye is uncomfortable. It is important to recognize and treat any underlying condition.
a Chelation is simple and effective for relatively mild cases and is performed under the microscope.
• Large chips of calcium can be scraped off the cornea with forceps.
• The corneal epithelium overlying the opacity and any solid layer of calcification is scraped off with a number 15 blade.
• The cornea is rubbed with a cotton-tipped bud (Fig. 6.63D) dipped in a solution of ethylenediaminetetraacetic acid (EDTA) 1.5–3.0% until all calcium has been removed (Fig. 9.60D); allow adequate time (15–20 minutes) for chelation to occur.
• Re-epithelialization can take many days.
• Recurrence is not uncommon, particularly in patients with an underlying systemic condition or persistent uveitis.
b Other modalities include the use of a diamond burr, excimer laser keratectomy and lamellar keratoplasty.
image

Fig. 6.63 Band keratopathy. (A) Histology shows black calcium deposits – von Kossa stain; (B) early involvement; (C) advanced; (D) chelation

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A)

Spheroidal degeneration

1 Pathogenesis. Spheroidal degeneration (corneal elastosis, Labrador keratopathy, climatic droplet keratopathy and Bietti nodular dystrophy) is a bilateral, degenerative condition of unknown cause which typically occurs in men whose working lives are spent outdoors. The main postulated predisposing factor is ultraviolet exposure, since severity correlates closely with the length of time spent outdoors. The condition is relatively innocuous although visual impairment may occur rarely.
2 Histology shows irregular protein deposits in the anterior stroma that replace Bowman layer (Fig. 6.64A).
3 Signs
• Amber-coloured granules in the superficial stroma of the peripheral interpalpebral cornea.
• Increasing opacification, coalescence and central spread.
• Advanced lesions are nodular and the surrounding stroma often hazy (Fig. 6.64B).
4 Treatment options include protection against ultraviolet damage with sunglasses, and superficial keratectomy or lamellar keratoplasty to improve vision.
image

Fig. 6.64 Spheroidal degeneration. (A) Histology shows dark red proteinaceous deposits in the anterior stroma that replace Bowman layer; (B) advanced involvement

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; R Fogla – fig. B)

Salzmann nodular degeneration

1 Pathogenesis. Salzmann nodular degeneration can occur in any form of chronic corneal irritation or inflammation, especially trachoma.
2 Signs
• Discrete, elevated grey or blue-grey, nodular, superficial stromal opacities (Fig. 6.65).
• The lesions are located in scarred cornea or at the edges of transparent cornea.
• The base of a nodule may be surrounded by epithelial iron deposits.
• Recurrent epithelial erosions may occur.
3 Treatment is similar to that of spheroidal degeneration.
image

Fig. 6.65 Salzmann nodular degeneration

(Courtesy of R Bates)

Metabolic keratopathies

Cystinosis

1 Pathogenesis. Cystinosis is a rare AR disorder characterized by widespread tissue deposition of non-protein cystine crystals as a result of a defect in lysosomal transport.
2 Systemic features include severe growth retardation, early-onset renal failure, hepatosplenomegaly and hypothyroidism. Patients with the most severe nephropathic form usually succumb before the 2nd decade. Treatment with systemic cysteamine may forestall renal disease. Non-nephropathic (‘ocular’) cystinosis is characterized by absence of renal disease.
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3 Keratopathy may present by 1 year of age and is characterized by progressive deposition of cystine crystals in the conjunctiva and cornea which cause intense photophobia, blepharospasm, epithelial erosions and visual disability by the end of the 1st decade. Peripherally, crystals involve the entire stromal thickness, whereas centrally only the anterior two-thirds are affected (Fig. 6.64A). Later, involvement of the iris, lens capsule and retina further affects vision.
4 Treatment with topical cysteamine 0.2% for several weeks can reverse corneal crystal deposition.

Mucopolysaccharidoses

1 Pathogenesis. The mucopolysaccharidoses (MPS) comprise a group of inherited deficiencies of catabolic glycosidase necessary for hydrolysis of mucopolysaccharides. The altered metabolite accumulates in intracellular vacuoles in various tissues and organs and may also be detected in the urine.
2 Inheritance is mainly AR, although the two subtypes of Hunter syndrome are X-linked recessive.
3 Systemic features, which vary with the type of MPS, include facial coarseness, skeletal anomalies, mental retardation and heart disease.
4 Keratopathy is characterized by punctate corneal opacification and diffuse stromal haze (Fig. 6.66B). It occurs in all MPS except Hunter and Sanfilippo. In Hurler and Scheie syndromes corneal deposits are most severe and are present at birth. Corneal clouding in this setting should be differentiated from that secondary to congenital glaucoma, rubella keratopathy, congenital hereditary endothelial dystrophy and birth trauma.
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5 Other ocular features
a Pigmentary retinopathy occurs in all except Morquio and Maroteaux–Lamy.
b Optic atrophy occurs in all six MPS and is most severe in Hurler.
c Glaucoma is uncommon.
image

Fig. 6.66 Metabolic keratopathies. (A) Cystinosis; (B) mucopolysaccharidoses; (C) Wilson disease; (D) Norum disease; (E) immunoprotein deposits

(Courtesy of L Merin – fig. A; W Lisch – fig. D)

Wilson disease

1 Pathogenesis. Wilson disease (hepatolenticular degeneration) is a rare condition caused by deficiency of caeruloplasmin resulting in widespread deposition of copper in the tissues.
2 Presentation is with liver disease, basal ganglia dysfunction or psychiatric disturbances.
3 Keratopathy is present in nearly all patients and is characterized by a zone of copper granules in the peripheral part of Descemet membrane (Kayser–Fleischer ring, best detected on gonioscopy when subtle) which change colour under different types of illumination (Fig. 6.66C). The deposits are preferentially distributed in the vertical meridian and may disappear with penicillamine therapy.
4 Anterior capsular ‘sunflower’ cataract is seen in some patients.

Lecithin-cholesterol-acyltransferase deficiency (Norum disease)

This is an AR disease characterized by hyperlipidaemia, early atheroma, anaemia and renal disease. Keratopathy is characterized by numerous minute greyish dots throughout the stroma, often concentrated in the periphery in an arcus-like configuration (Fig. 6.66D).

Immunoprotein deposits

1 Pathogenesis. Diffuse or focal immunoprotein deposition is a relatively uncommon manifestation of several systemic diseases, including multiple myeloma, Waldenström’s macroglobulinaemia, monoclonal gammopathy of unknown cause, certain lymphoproliferative disorders and leukaemia. Corneal involvement may be the earliest manifestation.
2 Signs. Gradual development of bilateral bands of multiple punctate flake-like opacities, mostly at the level of the posterior stroma (Fig. 6.66E).
3 Treatment should address the underlying systemic disease with cytotoxic chemotherapy or steroids. Severe corneal involvement may require penetrating keratoplasty.
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Fabry disease (angiokeratoma corporis diffusum)

1 Pathogenesis. Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A.
2 Systemic features include periodic burning pain in the extremities, purple cutaneous telangiectasis (angiokeratoma corporis diffusum; Fig. 6.67A), hypertrophic cardiomyopathy and renal disease.
3 Keratopathy is characterized by faint but extensive vortex changes (Fig. 6.67B) similar to those seen with chloroquine.
4 Other ocular manifestations include wedge-shaped cataract, conjunctival vascular tortuosity and aneurysm formation (Fig. 6.67C), retinal vascular tortuosity (especially venous), 3rd nerve palsy and nystagmus.
image

Fig. 6.67 Fabry disease. (A) Angiokeratoma corporis diffusum; (B) vortex keratopathy; (C) conjunctival tortuosity and aneurysms

Tyrosinaemia type 2 (Richner–Hanhart syndrome)

1 Pathogenesis. Tyrosinaemia type 2 is a rare AR disease in which there is deficiency of hepatic cytosolic tyrosine aminotransferase with resultant increase in plasma tyrosine levels. Ocular involvement may occasionally be the presenting feature.
2 Systemic features include painful, palmar and plantar hyperkeratotic lesions (Fig. 6.68), and variable central nervous system involvement which may cause mental retardation, nystagmus, tremor, ataxia and convulsions.
3 Keratopathy is characterized by recalcitrant pseudodendritic keratitis with crystalline edges. In contrast to true herpetic ulcers the lesions are usually bilateral and inferotemporal, corneal sensation is normal, there is lack of response to antiviral therapy, typical terminal bulbs are absent and staining with fluorescein is limited.
image

Fig. 6.68 Plantar hyperkeratotic lesions in tyrosinaemia type 2

(Courtesy of D Taylor and C Hoyt, from Pediatric Ophthalmology and Strabismus, Elsevier 2005)

Contact lenses

Therapeutic uses

The risks of fitting a contact lens to an already compromised eye are greater than with lens wear for cosmetic reasons. The balance between benefit and risk should therefore be carefully considered, and close monitoring is vital to ensure early diagnosis and treatment of complications. The choice of lens type is dictated by the nature of ocular pathology.

Optical

Optical indications are aimed at improving visual acuity when this cannot be achieved by spectacles in the following conditions:

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1 Irregular astigmatism associated with keratoconus can be corrected with rigid contact lenses after spectacles have failed and long before corneal grafting becomes necessary. Patients with astigmatism following corneal grafting may also benefit.
2 Superficial corneal irregularities can be neutralized by rigid contact lenses providing a smoother and optically more regular surface. Visual acuity can thus be improved, if irregularities are not too severe.
3 Anisometropia in which binocular vision cannot be achieved by spectacles due to aniseikonia and prismatic effects, as may occur following cataract surgery.

Promotion of epithelial healing

1 Persistent epithelial defects often heal if the regenerating corneal epithelium is protected from constant rubbing action of the lids. This allows the development of hemidesmosomal attachments to the basement membrane.
2 Recurrent corneal erosions, if associated with basement membrane dystrophy, may require long-term contact lens wear. In post-traumatic cases, lens wear can usually be discontinued after a few weeks. Lens wear also improves comfort.

Pain relief

1 Bullous keratopathy can be managed with soft bandage lenses which relieve pain by protecting the exposed corneal nerve endings from the shearing forces of the lids during blinking. The lens may also flatten bullae into diffuse fine epithelial cysts.
2 Filamentary keratitis associated with profuse lacrimation, as seen in patients with brainstem strokes and essential blepharospasm, can be treated with soft contact lenses.
3 Other indications include Thygeson superficial punctate keratitis and protection of the corneal epithelium from aberrant lashes.

Preservation of corneal integrity

1 A descemetocele can be temporarily capped with a tight-fitting, large-diameter soft or scleral lens to prevent perforation and allow natural healing to occur.
2 Splinting and apposition of the edges of a small corneal wound can be achieved by means of a contact lens which supports the cornea during healing (see Fig. 4.6A). Slightly larger perforations may be sealed with glue followed by insertion of a bandage contact lens to both protect the glue and prevent irritation of the lids from the glue’s irregular surface.

Miscellaneous indications

1 Ptosis props to support the upper lids in patients with ocular myopathies.
2 Maintenance of the fornices to prevent symblepharon formation in cicatrizing conjunctivitis.
3 Drug delivery can be enhanced by a hydrogel lens imbued with topical medication.

Complications

Mechanical and hypoxic keratitis

1 Pathogenesis. Insufficient oxygen transmission through the lens. A tightly fitting contact lens which does not move with blinking will impair tear circulation under the lens. This is exacerbated by lid closure if the lens is worn during sleep. Hypoxia leads to anaerobic metabolism and lactic acidosis that inhibits the normal barrier and pump mechanisms of the cornea.
2 Superficial punctate keratitis is the most common complication. The pattern may give a clue as to the aetiology. For example, staining at 3 and 9 o’clock is associated with incomplete blinking and drying in rigid lens wearers.
3 The tight lens syndrome is characterized by indentation and staining of the conjunctival epithelium in a ring around the cornea.
4 Acute hypoxia is characterized by epithelial microcysts (Fig. 6.69A) and necrosis, and endothelial blebs. Very painful macroerosions may develop several hours after lenses are removed following a period of overwear.
5 Chronic hypoxia may result in vascularization and lipid deposition (Fig. 6.69B); superficial peripheral neovascularization of <1.5 mm is common in myopic contact lens wearers and can be monitored.
6 Treatment depends on the cause and may involve the following:
• Increasing oxygen permeability by refitting with a thinner lens, a gas permeable rigid lens or a silicone hydrogel soft lens.
• Modifying lens fit to increase movement.
• Reducing lens wearing time.
image

Fig. 6.69 Complications of contact lens wear. (A) Epithelial microcysts from acute hypoxia; (B) lipid deposition from chronic hypoxia; (C) marginal infiltrates in immune response keratitis; (D) vascularization and scarring in chronic toxic keratitis

(Courtesy of S Tuft – figs A and B; J Dart – fig. D)

Immune response keratitis

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1 Pathogenesis. A hypersensitivity response to bacterial antigen or the chemicals used in lens care can lead to the development of sterile marginal corneal infiltrates; the mechanism is thought to be similar to that of marginal keratitis.
2 Signs. Mildly red eye associated with marginal infiltrates with no or minimal epithelial defects (Fig. 6.69C).
3 Treatment involves cessation of lens wear until resolution occurs. Topical antibiotics and steroids may be used in some cases, but if the diagnosis is uncertain treatment should be that of bacterial keratitis.

Toxic keratitis

1 Pathogenesis. Acute chemical injury may be caused by inadvertently placing a contact lens on the eye without first neutralizing toxic cleaning agents such as hydrogen peroxide. Chronic toxicity can result from long-term exposure to disinfecting preservatives such as thiomersal or benzalkonium chloride.
2 Signs
• Acute pain, redness, and chemosis on lens insertion, which may take 48 hours to resolve completely.
• Vascularization and scarring of the cornea and limbal conjunctiva in chronic cases (Fig. 6.69D).
3 Treatment may involve switching to daily disposable lenses or using a non-preserved disinfectant such as hydrogen peroxide.

Suppurative keratitis

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Contact lens wear is the greatest risk factor for the development of bacterial keratitis; the risk is probably least for rigid contact lenses. Bacteria in the tear film are normally unable to bind to the corneal epithelium, but following an abrasion and in association with hypoxia, bacteria can attach and penetrate the epithelium with the potential to cause infection. Bacteria and protozoa may also be introduced onto the corneal surface by poor lens hygiene or the use of tap water to rinse lenses.

Contact lens-associated giant papillary conjunctivitis

See Chapter 5.

Congenital anomalies of the cornea and globe

Microcornea

Microcornea is a rare AD unilateral or bilateral condition.

1 Signs
• The adult horizontal corneal diameter is 10 mm or less (Fig. 6.70A).
• Hypermetropia, shallow anterior chamber but other dimensions are normal.
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2 Ocular associations include glaucoma (closed and open angle), congenital cataract, leukoma (Fig. 6.70B), cornea plana, Rieger anomaly, microphakia and optic nerve hypoplasia.
3 Syndromic systemic associations include fetal alcohol, Ehlers–Danlos, Weill–Marchesani, Waardenburg, Nance Horan and Cornelia de Lange syndromes.
image

Fig. 6.70 (A) Severe microcornea; (B) microcornea and corneal opacity

(Courtesy of S Fogla – fig. A)

Megalocornea

Megalocornea is a rare, bilateral, non-progressive condition thought to be due to defective growth of the optic cup.

1 Inheritance is usually X-linked recessive so that 90% of affected individuals are males. The condition maps to Xq21.3-q22.
2 Signs
• Normal intraocular pressure.
• Large corneal diameter is 13 mm or over and a very deep anterior chamber (Fig. 6.71A).
• High myopia and astigmatism but normal visual acuity.
• Pigment dispersion with Krukenberg spindle, trabecular hyperpigmentation (Fig. 6.71B) and iris transillumination.
• Lens subluxation may occur due to zonular stretching.
3 Systemic associations include Alport syndrome, Marfan syndrome, Ehlers–Danlos syndrome, Down syndrome, osteogenesis imperfecta, progressive facial hemiatrophy, renal carcinoma and megalocornea-mental retardation syndrome.
image

Fig. 6.71 (A) Megalocornea; (B) trabecular hyperpigmentation due to pigment dispersion

Sclerocornea

Sclerocornea is a very rare, usually bilateral, condition that may be associated with cornea plana (see below).

1 Inheritance of the milder form is AD and the more severe is AR, although sporadic cases are probably more common.
2 Signs. Peripheral corneal opacification and vascularization that makes the cornea appear small (Fig. 6.72A). Occasionally the entire cornea is involved (Fig. 6.72B).
image

Fig. 6.72 Sclerocornea. (A) mild; (B) severe

Cornea plana

This is a rare bilateral condition.

1 Signs. Flat cornea, and a corresponding reduction in refractive power resulting in high hypermetropia; there are two types:
a Cornea plana 1 (CNA1) is AD with reduced corneal refractive power to 38–42 D.
b Cornea plana 2 (CNA2) is AR AD with reduced corneal refractive power to 23–35 D (Fig. 6.73).
2 Associations include shallow anterior chamber with predisposition to angle-closure glaucoma, scleroderma, microcornea and microphthalmos, Peters anomaly, and iris abnormalities including irido-corneal adhesions.
image

Fig. 6.73 Cornea plana

(Courtesy of R Visser)

Keratectasia

Keratectasia is a very rare, usually unilateral, condition thought to be the result of intrauterine keratitis and perforation. It is characterized by protuberance between the eyelids or a severely opacified and sometimes vascularized cornea (Fig. 6.74). It is often associated with raised intraocular pressure.

image

Fig. 6.74 Keratectasia

Posterior keratoconus

Posterior keratoconus is an uncommon, sporadic, unilateral, non-progressive increase in curvature of the posterior corneal surface. The anterior surface is normal and visual acuity unimpaired because of the similar refractive indices of the cornea and aqueous humour. Two types are recognized:

1 Generalis, in which there is an increase in curvature of the entire posterior corneal surface.
2 Conscriptus, which is characterized by a localized paracentral or central posterior corneal indentation (Fig. 6.75).
image

Fig. 6.75 Posterior keratoconus

(Courtesy of S Johns)

Microphthalmos

Microphthalmos is a developmental arrest of ocular growth, defined as total axial length (TAL) at least two standard deviations below age-similar controls. The TAL is reduced because of stunted growth of the anterior or posterior segment, or both. The condition is typically sporadic and may be unilateral or bilateral.

1 Simple microphthalmos is not associated with other major ocular malformations (Fig. 6.76A).
2 Complex (colobomatous) microphthalmos is associated with coloboma, usually of the iris (Fig. 6.76B).
3 Microphthalmos with cyst is caused by failure of the optic fissure to close, leading to the formation of an orbital cyst that communicates with the eye. The extent of the cystic component is best delineated on MR or CT (Fig. 6.76C).
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4 Posterior microphthalmos is a rare subset of microphthalmos in which TAL is reduced in the setting of normal corneal diameter, resulting in high hypermetropia and papillomacular retinal fold. This differs from nanophthalmos, which is described as eyes with microphthalmos, microcornea and a tendency toward uveal effusions.
image

Fig. 6.76 (A) Left simple microphthalmos; (B) left microphthalmos and bilateral iris colobomas; (C) axial CT shows right microphthalmos with cyst

(Courtesy of L MacKeen – fig. C)

Anophthalmos

1 Simple anophthalmos is caused either by complete failure of budding of the optic vesicle or early arrest in its development. It is associated with other abnormalities such as absence of extraocular muscles, a short conjunctival sac and microblepharon (Fig. 6.77A).
2 Anophthalmos with cyst (congenital cystic eyeball) is a condition in which the globe is replaced by a cyst (Fig. 6.77B).
image

Fig. 6.77 (A) Bilateral simple anophthalmos; (B) anophthalmos with cyst

(Courtesy of U Raina – fig. B)