204 Introduction

Chapter INTRODUCTION
Tear film

7
Anatomy and physiology Surface cells
General
Wing cells

Cornea
The cornea is a complex structure which, as well as having a pro-
tective role, is responsible for about three-quarters of the optical
power of the eye. The normal cornea is free of blood vessels.
Basal cells
Nutrients are supplied and metabolic products removed via the
aqueous humour posteriorly and the tears anteriorly. The cornea Basement
is the most densely innervated tissue in the body and conditions membrane
such as abrasion and bullous keratopathy are associated with
marked pain, photophobia and reflex lacrimation. A subepithelial
INTRODUCTION 204 PROTOZOAN KERATITIS 232 CORNEAL DYSTROPHY 252 and a deeper stromal nerve plexus are supplied by the first division Epithelium
Anatomy and physiology 204 Acanthamoeba 232 Epithelial dystrophies 252 of the trigeminal nerve.
Basement
Signs of corneal disease 205 Bowman layer/anterior stromal membrane
Documentation of clinical signs 208
HELMINTHIC KERATITIS 234 dystrophies 254 Dimensions
Onchocerciasis 234 Stromal dystrophies 255 The average corneal diameter is 11.5 mm vertically and 12 mm Bowman
Specular microscopy 208 layer
Corneal topography 209 Descemet membrane and endothelial horizontally. It is 540 µm thick centrally on average and thicker
BACTERIAL
Principles of treatment 209 dystrophies 259 towards the periphery. Central corneal thickness does not differ
HYPERSENSITIVITY-MEDIATED
between males and females, but varies between individuals and
BACTERIAL KERATITIS 209 CORNEAL DISEASE 234 CORNEAL DEGENERATION 261 races. It is a key determinant of the intraocular pressure (IOP) Stroma
Marginal keratitis 234 Age-related degeneration 261
Pathogenesis 209 measured with conventional techniques.
Phlyctenulosis 235
Clinical features 211
METABOLIC KERATOPATHY 266
Investigations 212 ROSACEA 236 Structure
Cystinosis 266
Treatment 214 The cornea consists of the following layers (Fig. 7.1): Descemet
PERIPHERAL CORNEAL Mucopolysaccharidoses 266
FUNGAL KERATITIS 216 Wilson disease 267 • The epithelium is stratified squamous and non-keratinized, membrane
ULCERATION/THINNING 238 and is composed of:
Introduction 216 Mooren ulcer 238 Lecithin-cholesterol-acyltransferase Endothelium
deficiency 267 ○ A single layer of columnar basal cells attached by hemides-
Candida and filamentous keratitis 216 Peripheral ulcerative keratitis
Immunoprotein deposition 268 mosomes to an underlying basement membrane.
Microsporidial keratitis 218 associated with systemic autoimmune Fig. 7.1 Anatomy of the cornea
○ Two to three strata of ‘wing’ cells.
disease 239 Tyrosinaemia type 2 268
HERPES SIMPLEX KERATITIS 218 ○ Two layers of squamous surface cells.
Terrien marginal degeneration 241 Fabry disease 268
Introduction 218 ○ The surface area of the outermost cells is increased by • Descemet membrane is a discrete sheet composed of a fine
Epithelial keratitis 219 NEUROTROPHIC KERATOPATHY 241 CONTACT LENSES 268 microplicae and microvilli that facilitate the attachment latticework of collagen fibrils that are distinct from the col-
Disciform keratitis 221 Therapeutic uses 268 of the tear film and mucin. After a lifespan of a few days lagen of the stroma. The membrane consists of an anterior
Necrotizing stromal keratitis 222
EXPOSURE KERATOPATHY 242 Complications 269 superficial cells are shed into the tear film. banded zone that is deposited in utero and a posterior non-
Neurotrophic keratopathy 223 MISCELLANEOUS ○ Corneal stem cells are located at the corneoscleral limbus, banded zone laid down throughout life by the endothelium,
CONGENITAL ANOMALIES OF THE
Iridocyclitis 223 KERATOPATHIES 243 possibly in the palisades of Vogt. Deficiency may result for which it serves as a modified basement membrane. It has
CORNEA AND GLOBE 270
Other considerations 223 Infectious crystalline keratopathy 243 in chronic epithelial defects and ‘conjunctivalization’ regenerative potential.
Microcornea 270
Thygeson superficial punctate (epithelial instability, vascularization and the appear- • The endothelium consists of a monolayer of polygonal cells.
HERPES ZOSTER Microphthalmos 270 ance of goblet cells). They are thought to be critical in Endothelial cells maintain corneal deturgescence throughout
OPHTHALMICUS 224 keratitis 244 Nanophthalmos 271
Filamentary keratopathy 244 the maintenance of a physiological barrier, preventing life by pumping excess fluid out of the stroma. The young
Introduction 224 Anophthalmos 272 conjunctival tissue from growing onto the cornea (e.g. adult cell density is about 3000 cells/mm2. The number of
Acute shingles 226 Recurrent corneal epithelial erosion 246 Megalocornea 272
Xerophthalmia 247 pterygium). Deficiency may be addressed by stem cell cells decreases at about 0.6% per year and neighbouring cells
Eye disease 226 Sclerocornea 272 auto- or allotransplantation. enlarge to fill the space. The cells cannot regenerate. At a
Post-herpetic neuralgia 229 CORNEAL ECTASIA 248 Cornea plana 273
• Bowman layer is the acellular superficial layer of the stroma density of about 500 cells/mm2 corneal oedema develops and
Keratoconus 248 Keratectasia 273 and is formed from collagen fibres. transparency is impaired.
INTERSTITIAL KERATITIS 229 Posterior keratoconus 273
Introduction 229 Pellucid marginal degeneration 250 • The stroma makes up 90% of corneal thickness. It is arranged • The existence of a sixth corneal layer between the stroma and
Syphilitic IK 229 Keratoglobus 252 in regularly orientated layers of collagen fibrils whose spacing Descemet membrane (Dua layer) has been proposed, though
Cogan syndrome 231 is maintained by proteoglycan ground substance (chon- some authorities believe this to be a previously described
droitin sulphate and keratan sulphate) with interspersed continuation of the posterior stroma.
modified fibroblasts (keratocytes). Maintenance of the regular
arrangement and spacing of the collagen is critical to optical TIP The cornea is densely innervated and a corneal abrasion
clarity. The stroma can scar, but cannot regenerate following is usually associated with intense pain, photophobia and reflex
damage. lacrimation.
 7
CHAPTER
Cornea 205 206 Introduction

Signs of corneal disease Deep

• Infiltrates are yellow– or grey–white opacities located initially
Superficial within the anterior stroma (Fig. 7.3A), usually associated with
• Punctate epithelial erosions (PEE), tiny epithelial defects that limbal or conjunctival hyperaemia. They are stromal foci of
stain with fluorescein (Fig. 7.2A) and rose Bengal (Fig. 7.2B), acute inflammation composed of inflammatory cells, cellular
are generally an early sign of epithelial compromise. Causes and extracellular debris including necrosis. The key distinction
include a variety of stimuli. The location of the lesions may is between sterile and infective lesions (Table 7.1); ‘PEDAL’
give an indication of aetiology: mnemonic: Pain, Epithelial defects, Discharge, Anterior
○ Superior – vernal disease, chlamydial conjunctivitis, supe- chamber reaction, Location. Suppurative keratitis is caused by
rior limbic keratoconjunctivitis, floppy eyelid syndrome active infection with bacteria, fungi, protozoa and occasionally
and mechanically induced keratoconjunctivitis. viruses. Non-infectious ‘sterile keratitis’ is due to an immune
○ Interpalpebral – dry eye (can also be inferior), reduced hypersensitivity response to antigen as in marginal keratitis
corneal sensation and ultraviolet keratopathy. and with contact lens wear.
○ Inferior – chronic blepharitis, lagophthalmos, eye drop • Ulceration refers to tissue excavation associated with an
A B
toxicity, self-induced, aberrant eyelashes and entropion. epithelial defect (Fig. 7.3B), usually with infiltration and
○ Diffuse – some cases of viral conjunctivitis and toxicity to necrosis.
drops. • ‘Melting’ describes tissue disintegration in response to enzy-
○ Central – prolonged contact lens wear. matic activity, often with mild or no infiltrate, e.g. peripheral
• Punctate epithelial keratitis (PEK) appears as granular, ulcerative keratitis.
opalescent, swollen epithelial cells, with focal intraepithelial • Vascularization occurs in response to a wide variety of stimuli.
infiltrates (Fig. 7.2C). They are visible unstained but stain Venous channels are easily seen, whereas arterial feeding
well with rose Bengal and variably with fluorescein. Causes vessels are smaller and require higher magnification. Non-
include: perfused deep vessels appear as ‘ghost vessels’, best detected by
○ Infections: adenoviral, chlamydial, molluscum contagio- retroillumination.
sum, early herpes simplex and herpes zoster, microsporid- • Lipid deposition (Fig. 7.3C) may follow chronic inflammation
ial and systemic viral infections (e.g. measles, varicella, with leakage from corneal new vessels.
rubella). • Folds in Descemet membrane, also known as striate kera-
○ Miscellaneous: Thygeson superficial punctate keratitis and topathy (Fig. 7.3D), may result from corneal oedema. Causes
eye drop toxicity. include inflammation, trauma (including surgery) and ocular
• Subepithelial infiltrates. Tiny subsurface foci of non-staining hypotony.
inflammatory infiltrates. Causes include severe or prolonged C D
adenoviral keratoconjunctivitis, herpes zoster keratitis, adult
inclusion conjunctivitis, marginal keratitis, rosacea and Thy- Table 7.1 Characteristics of Infective Versus Sterile Corneal
geson superficial punctate keratitis. Infiltrates
• Superficial punctate keratitis is a non-specific term describ-
Infective Sterile
ing any corneal epithelial disturbance of dot-like morphology.
Size Tend to be larger Tend to be
• Filaments. Strands of mucus admixed with epithelium, smaller
attached at one end to the corneal surface, that stain well with
Progression Rapid Slow
rose Bengal (see Fig. 7.2B). The unattached end moves with
Epithelial defect Very common Much less
each blink. Grey subepithelial opacities may be seen at the and larger when common and if
site of attachment. Dry eye is by far the most common cause. present present tends
Other causes include superior limbic keratoconjunctivitis, to be small
neurotrophic keratopathy, long-term ocular patching and Pain Moderate–severe Mild
essential blepharospasm. Discharge Purulent Mucopurulent
• Epithelial oedema. Subtle oedema may manifest with loss of Single or Typically, single Commonly
normal corneal lustre, but more commonly, abundant tiny multiple multiple
epithelial vesicles are seen. Bullae form in moderate–severe Unilateral or Unilateral Often bilateral E F
cases (Fig. 7.2D). The cause is usually endothelial decompen- bilateral
sation, but it can follow acute elevation of IOP. Anterior chamber Severe Mild Fig. 7.2 Superficial corneal lesions. (A) Punctate epithelial erosions stained with fluorescein
• Superficial neovascularization (Fig. 7.2E) is a feature of reaction in dry eye; (B) filaments stained with rose Bengal; (C) punctate epithelial keratitis; (D) corneal
chronic ocular surface irritation or hypoxia, as in contact lens Location Often central Typically more oedema with bullae; (E) superficial vascularization; (F) pannus
wear. peripheral (Courtesy of C Barry – fig. F)
• Pannus describes superficial neovascularization accompanied Adjacent corneal Extensive Limited
by degenerative subepithelial change (Fig. 7.2F). reaction
 7
CHAPTER
Cornea 207 208 Introduction

• Descemetocoele (US spelling – descemetocele) is a bubble- • Physics. When a light beam of the specular photomicroscope
like herniation of Descemet membrane into the cornea (Fig. passes through the cornea it encounters a series of interfaces
7.3E), plugging a defect that would otherwise be full-thickness. between optically distinct regions. Some light is reflected spec-
• Breaks in Descemet membrane (Fig. 7.3F) may be due to ularly (i.e. like a mirror) back towards the photomicroscope
corneal enlargement (Haab striae in infantile glaucoma) or and forms an image that can be photographed and analyzed.
deformation such as keratoconus and birth trauma. Acute • Indications
influx of aqueous into the corneal stroma (acute hydrops) can ○ Evaluation of the functional reserve of the corneal
follow. endothelium prior to intraocular surgery is the most
• The Seidel test demonstrates aqueous leakage. A drop of 1% common indication. A clear cornea with normal thickness
or 2% fluorescein is applied to the surface of the eye. Using on pachymetry is not necessarily associated with normal
a slit lamp the cobalt blue filter is used to detect a change in endothelial morphology or cell density. Corneal oedema is
colour from dark orange to bright yellow–green secondary to considerably more likely to occur with a cell density below
localized dilution at a site of leakage. 700 cells/mm2 but unlikely above 1000 cells/mm2.

A B
Documentation of clinical signs
Clinical signs should be illustrated with a colour-coded labelled
diagram. Measuring lesion dimensions is particularly useful
to facilitate monitoring (Fig. 7.4). Slit lamp photography is an
increasingly used supplement or alternative, but must be of high
quality.
• Opacities such as scars and degenerations are drawn in black.
• Epithelial oedema is represented by fine blue circles, stromal
oedema as blue shading and folds in Descemet membrane as
wavy blue lines.
• Hypopyon is shown in yellow.
• Blood vessels are added in red. Superficial vessels are wavy
lines that begin outside the limbus and deep vessels are straight
lines that begin at the limbus.
• Pigmented lesions such as iron lines and Krukenberg spindles
C D are shown in brown.

A
Specular microscopy
Specular microscopy is the study of corneal layers under very high
magnification (100 times greater than slit lamp biomicroscopy). It
is mainly used to assess the endothelium, which can be analyzed
for cellular size, shape, density and distribution. The healthy
endothelial cell is a regular hexagon (Fig. 7.5A) and the normal cell
density in a young adult is about 3000 cells/mm2.

Pigment

E F Keratic
precipitate
Fig. 7.3 Deeper corneal lesions. (A) Infiltration; (B) ulceration (arrow); (C) lipid deposition with
vascularization; (D) folds in Descemet membrane; (E) descemetocoele (arrow heads); (F) Old scar
traumatic breaks in Descemet membrane
(Courtesy of C Barry – figs C and D; R Curtis – fig. F) B

Fig. 7.5 Specular micrograph. (A) Normal corneal endothe-

Hypopyon lium; (B) cornea guttata with marked loss of endothelial
mosaic
(Courtesy of T Casey and K Sharif, from A Colour Atlas of
Fig. 7.4 Documentation of corneal lesions Corneal Dystrophies and Degenerations, Wolfe 1991 – fig. B)
 7
CHAPTER
Cornea 209 210 Bacterial Keratitis

○ Donor cornea evaluation. • Surgical eyelid closure is particularly useful in exposure and
○ To demonstrate pathology, particularly cornea guttata neurotrophic keratopathy, as well as in persistent epithelial
(Fig. 7.5B), Descemet membrane irregularities and poste- defects. Lid closure may be used as a conservative method to
rior polymorphous dystrophy. heal an infective ulcer in selected cases, such as an eye with no
visual potential in a patient with severe dementia.
○ Botulinum toxin injection into the levator muscle to
Corneal topography induce a temporary (2–3 months) ptosis.
Corneal topography is used to image the cornea by projecting a ○ Temporary or permanent lateral tarsorrhaphy or medial
series of concentric rings of light on the anterior surface, constitut- canthoplasty and occasionally central tarsorrhaphy (Fig.
ing a Placido image. The reflected light is analyzed using computer 7.6B).
software to produce a detailed surface map. A major application • Conjunctival (Gundersen) flap will protect and allow healing
is the detection and management of corneal ectasia, principally of a corneal epithelial defect. It is particularly suitable for
keratoconus. Screening for corneal ectasia is especially important chronic unilateral disease in which the prognosis for restora-
prior to refractive surgery. It is used occasionally for contact lens tion of useful vision is poor. Buccal mucous membrane is an
fitting and to measure corneal thickness. Scheimpflug imaging is a alternative.
new technology that may offer advantages in topographic imaging. • Amniotic membrane patch grafting (Fig. 7.6C) for persistent A B
Anterior segment optical coherence tomography (OCT) and unresponsive epithelial defects.
ultrasound biomicroscopy can also be used to image the cornea. • Tissue adhesive (cyanoacrylate glue) to seal small perfora-
tions. The glue can be applied to one side of a bespoke trimmed
patch of sterile plastic drape, which is pressed over the defect
Principles of treatment after the edges are dried with a cellulose sponge. The patch
remains in place to seal the defect and a bandage contact lens
Control of infection and inflammation is inserted for comfort and to aid retention of the patch (Fig.
• Antimicrobial agents should be started as soon as preliminary 7.6D).
investigations have been performed. The choice of agent is • Limbal stem cell transplantation may be used if there is stem
determined by the likely aetiology according to clinical find- cell deficiency as in chemical burns and cicatrizing conjunc-
ings. Broad-spectrum treatment is generally used initially, tivitis. The source of the donor tissue may be the fellow eye
with more selective agents introduced if necessary when the (autograft) in unilateral disease or a living or cadaver donor
results of investigation are available. (allograft) when both eyes are affected. A newer technique
• Topical steroids should be used with caution as they may involves the in vitro replication of the patient’s own stem
promote replication of some microorganisms, notably herpes cells with subsequent re-implantation of the enhanced cell
simplex virus and fungi and retard reparative processes such population. C D
as re-epithelialization. Nevertheless, they are vital in a range • Smoking retards epithelialization and should be discontinued.
of conditions for the suppression of destructive vision- Fig. 7.6 Methods of promoting epithelial healing. (A) Bandage contact lens (arrow) in an
compromising inflammation. eye with a small perforation; (B) central tarsorrhaphy; (C) amniotic membrane graft over a
• Systemic immunosuppressive agents are useful in some persistent epithelial defect; (D) tissue glue under a bandage contact lens (arrow) in an eye
conditions, particularly autoimmune disease.
BACTERIAL KERATITIS with severe thinning
(Courtesy of S Tuft – figs A and C; S Chen – fig. B)
Promotion of epithelial healing Pathogenesis
Re-epithelialization is of great importance in any corneal disease, Pathogens
as thinning seldom progresses if the epithelium is intact. Bacterial keratitis usually develops only when ocular defences have
• Reduction of exposure to toxic medications and preservatives been compromised (see below). However, some bacteria, includ-
wherever possible. ing Neisseria gonorrhoeae, Neisseria meningitidis, Corynebacterium • Streptococci. S. pyogenes is a common Gram-positive com- • Trauma, including refractive surgery (particularly LASIK
• Lubrication with artificial tears (unpreserved if possible) and diphtheriae and Haemophilus influenzae are able to penetrate a mensal of the throat and vagina. S. pneumoniae (pneumococ- – laser-assisted in situ keratomileusis), has been linked to
ointment. Taping the lids closed as a temporary measure is healthy corneal epithelium, usually in association with severe cus) is a Gram-positive commensal of the upper respiratory bacterial infection, including with atypical mycobacteria.
often used as a nocturnal adjunct. conjunctivitis. It is important to remember that infections may tract. Infections with streptococci are often aggressive. In developing countries agricultural injury is the major risk
• Antibiotic ointment prophylaxis should be considered. be polymicrobial, including bacterial and fungal co-infection. factor, when fungal infection should be considered.
• Bandage soft contact lenses should be carefully supervised Common pathogens include: Risk factors • Ocular surface disease such as herpetic keratitis, bullous kera-
to exclude superinfection and duration kept to a minimum. • Pseudomonas aeruginosa is a ubiquitous Gram-negative • Contact lens wear, particularly if extended, is the most impor- topathy, dry eye, chronic blepharitis, trichiasis and entropion,
Indications include: bacillus (rod) commensal of the gastrointestinal tract. The tant risk factor. Corneal epithelial compromise secondary to exposure, severe allergic eye disease and corneal anaesthesia.
○ Promotion of healing by mechanically protecting regener- infection is typically aggressive and is responsible for over 60% hypoxia and minor trauma is thought to be important, as is • Other factors include local or systemic immunosuppression,
ating corneal epithelium from the constant rubbing of the of contact lens-related keratitis. bacterial adherence to the lens surface. Wearers of soft lenses diabetes and vitamin A deficiency.
eyelids. • Staphylococcus aureus is a common Gram-positive and are at higher risk than those wearing rigid gas permeable
○ To improve comfort, particularly in the presence of a large coagulase-positive commensal of the nares, skin and con- and other types. Infection is more likely if there is poor lens TIP Bacterial corneal ulceration should be excluded in a
corneal abrasion. junctiva. Keratitis tends to present with a focal and fairly hygiene, but it can also occur even with apparently meticulous patient who wears contact lenses and presents with a painful
○ To seal a small perforation (Fig. 7.6A). well-defined white or yellow–white infiltrate. lens care and with daily disposable lenses. red eye and blurred vision.
 7
CHAPTER
Cornea 211 212 Bacterial Keratitis

○ Scleritis can develop, particularly with severe perilimbal • Differential diagnosis includes keratitis due to other micro- ○ Scrapings are taken either with a disposable scalpel blade
Clinical features infection. organisms (fungi, acanthamoeba, stromal herpes simplex (e.g. No. 11 or Bard Parker), the bent tip of a larger diam-
• Presentation is with pain, photophobia, blurred vision and ○ Endophthalmitis is rare in the absence of perforation. keratitis and mycobacteria), marginal keratitis, sterile inflam- eter (e.g. 20- or 21-gauge) hypodermic needle, or a sterile
mucopurulent or purulent discharge. ○ Improvement is usually heralded by a reduction in eyelid matory corneal infiltrates associated with contact lens wear, spatula (e.g. Kimura).
• Signs oedema and chemosis, shrinking of the epithelial defect, peripheral ulcerative keratitis and toxic keratitis. ○ The easiest way to ‘plate’ scrapings without breaking
○ An epithelial defect with infiltrate involving a larger area decreasing infiltrate density and a reduction in anterior the gel surface is with a spatula. If a fresh spatula is not
and significant circumcorneal injection (Fig. 7.7A and B).
○ Stromal oedema, folds in Descemet membrane and ante-
chamber signs.
○ Subsequent scarring may be severe, including vasculariza-
Investigations available for each sample a single instrument should be
flame-sterilized between scrapes (heat for 5 seconds, cool
rior uveitis, commonly with a hypopyon (Fig. 7.7C) and tion. In addition to opacification irregular astigmatism • Corneal scraping. This may not be required for a small infil- for 20–30 seconds). Alternatively, a fresh scalpel blade or
posterior synechiae in moderate–severe keratitis. Plaque- may limit vision. trate, particularly one without an epithelial defect and away needle can be used for each pass. Calcium alginate swabs
like keratic precipitates can form on the endothelium • Reduced corneal sensation may suggest associated neuro- from the visual axis. may also be satisfactory.
contiguous with the affected stroma. trophic keratopathy, particularly where there is no other ○ A non-preserved topical anaesthetic is instilled (preserva- ○ Loose mucus and necrotic tissue should be removed from
○ Chemosis and eyelid swelling in moderate–severe cases. major risk factor. Sensation may also be reduced in chronic tives may lower bacterial viability for culture). One drop the surface of the ulcer prior to scraping.
○ Severe ulceration may lead to descemetocoele formation surface disease, herpetic keratitis and long-term contact lens of proxymetacaine 0.5% is usually sufficient but tetracaine ○ The margins and base (except if very thin) of the lesion are
and perforation, particularly in Pseudomonas infection wear. may have a greater bacteriostatic effect. scraped (Fig. 7.8A).
(Fig. 7.7D). • IOP should be monitored.

A B

A B

C D

C D Fig. 7.8 Bacteriology. (A) Corneal scraping; (B) culture media; (C) S. aureus grown on blood
agar forming golden colonies with a shiny surface; (D) N. gonorrhoeae grown on chocolate
Fig. 7.7 Bacterial keratitis. (A) Early ulcer; (B) large ulcer; (C) ulcer with hypopyon (arrow); (D) agar
perforation associated with Pseudomonas infection (Courtesy of J Harry – A; R Emond, P Welsby and H Rowland, from Colour Atlas of Infectious
(Courtesy of T Carmichael - fig. A; C Barry – fig. B; S Tuft – fig. D) Diseases, Mosby 2003 – figs B–D)
 7
CHAPTER
Cornea 213 214 Bacterial Keratitis

○ A thin smear is placed on one or two glass slides for ○ Bacteria that take up crystal violet are Gram-positive ○ Ciprofloxacin or ofloxacin are used in countries where
microscopy, including Gram stain (see below). A surface is and those that allow the dye to wash off are Gram-
Treatment widespread resistance to earlier-generation fluoroqui-
provided on one side of one end of the slide (convention- negative. nolones has not been identified. Activity against some
ally ‘up’) for pencil labelling. The sample is allowed to dry ○ Other stains, generally not requested at initial investiga- General considerations Gram-positive organisms, particularly some streptococci,
in air at room temperature for several minutes then placed tion, are listed in Table 7.3. • Hospital admission should be considered for patients who are may be limited.
in a slide carrier. • Culture and sensitivity reports should be obtained as soon as not likely to comply or are unable to self-administer treatment. ○ Resistance to fluoroquinolones has been reported in some
○ Re-scraping is performed for each medium and samples possible. The type of bacteria will provide an indication of the It should also be considered for aggressive disease, particularly areas (e.g. Staphylococcus spp. in the USA and Pseudomonas
are plated onto culture media (Table 7.2), taking care not antibiotic category to be used. An indication of resistance on if involving an only eye. in India). Moxifloxacin, gatifloxacin and besifloxacin are
to break the surface of the gel. standard sensitivity testing does not necessarily extrapolate to • Discontinuation of contact lens wear is mandatory. new generation fluoroquinolones that largely address this
○ Routinely, blood, chocolate and Sabouraud media (Fig. topical antibiotic instillation, where very high tissue levels can • A clear plastic eye shield should be worn between eye drop and also have better activity against Gram-positive patho-
7.8B–D) are used initially and the samples are placed in an be achieved. instillation if significant thinning (or perforation) is present. gens. Moxifloxacin has superior ocular penetration. Novel
incubator until transported to the laboratory. Refrigerated • Decision to treat drug preparations, with higher concentrations or modified
media should be gently warmed to room temperature ○ Intensive treatment may not be required for small infil- vehicles, have been introduced to enhance antibacterial
prior to sample application. TIP Corneal scraping should be undertaken in most cases trates that are clinically sterile and may be treated by activity.
○ A blade or needle can be placed directly into bottled media of corneal ulceration, so that the causative organism can be lower-frequency topical antibiotic and/or steroid and by ○ Ciprofloxacin instillation is associated with white corneal
cultured and its sensitivity determined.
such as brain–heart infusion (BHI). There is evidence that temporary cessation of contact lens wear. precipitates (Fig. 7.9) that may delay epithelial healing.
a single scrape, sent in BHI to the laboratory where it is ○ It is important to note that the causative organism cannot • Antibiotic duotherapy may be preferred as first-line empiri-
homogenized and plated, provides similar results to the be defined reliably from the morphological appearance of cal treatment in aggressive disease or if microscopy suggests
traditional multi-scrape method. the ulcer. streptococci or a specific microorganism that may be more
○ Scraping may be delayed without treatment for 12 hours if Table 7.3 Stains for Corneal and Conjunctival Scrapings ○ Empirical broad-spectrum treatment is usually initiated effectively treated by a tailored regimen (see Table 7.4).
antibiotics have previously been commenced. before microscopy results are available. ○ Empirical duotherapy usually involves a combination of
Stain Organism
• Conjunctival swabs may be worthwhile in addition to corneal two fortified antibiotics, typically a cephalosporin and an
scraping, particularly in severe cases, as occasionally an organ- Gram Bacteria, fungi, microsporidia Local therapy aminoglycoside, in order to cover common Gram-positive
ism may be cultured when a corneal scrape is negative. Cotton Giemsa Bacteria, fungi, Acanthamoeba, Topical therapy (Table 7.4) can achieve high tissue concentration and Gram-negative pathogens.
microsporidia
wool, calcium alginate and synthetic swabs have all been found and initially should consist of broad-spectrum antibiotics that ○ The antibiotics are not commercially available and must
to have some bacteriostatic effect; calcium alginate may be the Calcofluor white Acanthamoeba, fungi, cover most common pathogens. Initially instillation is at hourly be specially prepared (Table 7.5). A standard parenteral
(fluorescent microsporidia
best option. microscope) intervals day and night for 24–48 hours and then is tapered accord- or lyophilized antibiotic preparation is combined with a
• Contact lens cases, as well as bottles of solution and lenses Acid-fast stain (AFB) Mycobacterium, Nocardia spp.
ing to clinical progress. compatible vehicle such that the antibiotic does not pre-
themselves, should be obtained when possible and sent to the e.g. Ziehl–Neelsen, • Antibiotic monotherapy has the major advantage over duo- cipitate. Optimally, constitution should take place in the
laboratory for culture. The case should not be cleaned by the auramine O therapy of lower surface toxicity, as well as greater convenience. sterile preparation area of a pharmaceutical dispensary.
patient first! (fluorescent) ○ A commercially available fluoroquinolone is the usual ○ Disadvantages of fortified antibiotics include high cost,
• Gram staining Grocott–Gömöri Fungi, Acanthamoeba, choice for empirical monotherapy and appears to be about limited availability, contamination risk, short shelf-life
○ Differentiates bacterial species into ‘Gram-positive’ and methenamine silver microsporidia as effective as duotherapy. and the need for refrigeration.
‘Gram-negative’ based on the ability of the dye (crystal Periodic acid–Schiff Fungi, Acanthamoeba • Subconjunctival antibiotics are usually only indicated if there
violet) to penetrate the cell wall. (PAS) is poor compliance with topical treatment.
Table 7.4 Antibiotics for the Treatment of Keratitis
Isolate Antibiotic Concentration
Empirical Fluoroquinolone Varies with
Table 7.2 Culture Media for Corneal Scrapings treatment monotherapy or preparation
Medium Notes Specificity cefuroxime + 5%
‘fortified’ gentamicin 1.5%
Blood agar 5–10% sheep or horse blood Most bacteria and fungi except duotherapy
Neisseria, Haemophilus and Moraxella
Gram-positive Cefuroxime 0.3%
Chocolate agar Blood agar in which the cells have been Fastidious bacteria, particularly H. cocci vancomycin or 5%
lysed by heating. Does not contain influenzae, Neisseria and Moraxella teicoplanin 1%
chocolate!
Gram- ‘Fortified’ 1.5%
Sabouraud dextrose agar Low pH and antibiotic (e.g. chloramphenicol) Fungi negative rods gentamicin or
to deter bacterial growth fluoroquinolone or Varies with
Non-nutrient agar seeded with E. coli is a food source for Acanthamoeba Acanthamoeba preparation
Escherichia coli ceftazidime 5%
Brain–heart infusion Rich lightly buffered medium providing a Difficult-to-culture organisms; Gram- Fluoroquinolone or Varies with
wide range of substrates particularly suitable for streptococci negative preparation
and meningococci. Supports yeast cocci ceftriaxone 5%
and fungal growth Mycobacteria Amikacin or 2%
Cooked meat broth Developed during the First World War for the Anaerobic (e.g. Propionibacterium clarithromycin 1%
growth of battlefield anaerobes acnes) as well as fastidious bacteria Nocardia Amikacin or 2%
Löwenstein–Jensen Contains various nutrients together with Mycobacteria, Nocardia trimethoprim 1.6%
bacterial growth inhibitors + sulfamethoxazole 8% Fig. 7.9 Ciprofloxacin corneal precipitates
 7
CHAPTER
Cornea 215 216 Fungal Keratitis

Table 7.5 Preparation of Fortified Antibiotics • Excisional keratoplasty, penetrating or deep lamellar, may be known as hyphae. They are the most common pathogens in
considered in cases resistant to medical therapy, or for incipi- tropical climates, but are not uncommon in cooler regions.
Antibiotic Method Concentration Shelf-life ent or actual perforation (see below). The keratitis frequently follows an aggressive course.
Cephalosporins: cefazolin, 500 mg parenteral antibiotic is diluted with 50 mg/ml (5%) 24 hours at room
cefuroxime, or ceftazidime 2.5 ml sterile water and added to 7.5 ml temperature; at least Predisposing factors
of preservative-free artificial tears 4 days if refrigerated TIP Topical drug and preservative toxicity may cause a failure Common predisposing factors include chronic ocular surface
Gentamicin 2 ml parenteral antibiotic (40 mg/ml) 15 mg/ml Up to 14 days if of corneal re-epithelialization, which can be confused with
is added to 5 ml commercially available (1.5%) refrigerated disease, the long-term use of topical steroids (often in conjunction
persistent infection.
gentamicin ophthalmic solution (0.3%) with prior corneal transplantation), contact lens wear, systemic
immunosuppression and diabetes. Filamentary keratitis may be
Perforation associated with trauma, often relatively minor, involving plant
A small perforation in which infection is controlled may be man- matter or gardening/agricultural tools.
ageable with a bandage contact lens. Tissue glue is often adequate
• Mydriatics (cyclopentolate 1%, homatropine 2% or atropine for a slightly larger dehiscence. A penetrating keratoplasty or
1%) are used to prevent the formation of posterior synechiae Systemic antibiotics corneal patch graft may be necessary for larger perforations, or
Candida and filamentous keratitis
and to reduce pain. Systemic antibiotics are not usually given, but may be appropriate in those where infection is extensive or inadequately controlled.
• Steroids in the following circumstances: Occlusive surface repair techniques may be appropriate in some Clinical features
○ Steroids reduce host inflammation, improve comfort • Potential for systemic involvement, when microbiological/ circumstances, such as an eye with no useful visual potential. The diagnosis is frequently delayed unless there is a high index
and minimize corneal scarring. However, they promote infectious disease specialist advice should optimally be sought of suspicion and often bacterial infection will initially have been
replication of some microorganisms, particularly fungi, but should not delay treatment: Endophthalmitis presumed. Clinical signs are not a definitive means of distinguish-
herpes simplex and mycobacteria and are contraindicated ○ N. meningitidis, in which early systemic prophylaxis may No clear protocol exists for the management of this rare compli- ing bacterial and fungal corneal infection. Signs such as satellite
if a fungal or mycobacterial agent is suspected (beware be life-saving. Treatment is usually with intramuscular cation, but a similar approach to postoperative endophthalmitis infiltrates (see below) can be caused by other microorganisms.
prior refractive surgery and trauma involving vegetation). benzylpenicillin, ceftriaxone or cefotaxime, or oral should be considered, whilst continuing specific management of • Symptoms. Gradual onset of pain, grittiness, photophobia,
By suppressing inflammation, they also retard the eye’s ciprofloxacin. the corneal infection (see Ch. 10). Secondary sterile intraocular blurred vision and watery or mucopurulent discharge.
response to bacteria and this can be clinically significant, ○ H. influenzae infection should be treated with oral amoxi- inflammation should not be mistaken for intraocular infection. • Candida keratitis
particularly if an antibiotic is of limited effect or bacterio- cillin with clavulanic acid. ○ Yellow–white densely suppurative infiltrate is typical.
static rather than bactericidal. ○ N. gonorrhoeae requires a third-generation cephalosporin Visual rehabilitation • Filamentous keratitis
○ Evidence that topical steroids improve the final visual such as ceftriaxone. • Keratoplasty (lamellar may be adequate) may be required for ○ Grey or yellow–white stromal infiltrate with indistinct
outcome is mainly empirical. The Steroids for Corneal • Severe corneal thinning with threatened or actual perforation residual dense corneal scarring. fluffy margins (Fig. 7.10A).
Ulcers Trial (SCUT) found no eventual benefit in most requires: • Rigid contact lenses may be required for irregular astigmatism ○ Progressive infiltration, often with satellite lesions (Fig.
cases, but severe cases (counting fingers vision or large ○ Ciprofloxacin for its antibacterial activity. but are generally only introduced at least 3 months after 7.10B).
ulcers involving the central 4 mm of the cornea) tended ○ A tetracycline (e.g. doxycycline 100 mg twice daily) for its re-epithelialization. ○ Feathery branch-like extensions or a ring-shaped infiltrate
to do better. A positive culture result was an inclusion anticollagenase effect. • Cataract surgery may be required because secondary lens (Fig. 7.10C) may develop.
criterion and steroids were introduced after 48 hours of • Scleral involvement may respond to oral or intravenous opacities are common following severe inflammation. Even ○ Rapid progression with necrosis and thinning can occur.
moxifloxacin. treatment. in the absence of severe corneal opacification, surgery may be ○ Penetration of an intact Descemet membrane may occur
○ Epithelialization may be retarded by steroids and they hampered by corneal haze, posterior synechiae and zonular and lead to endophthalmitis without evident perforation.
should be avoided if there is significant thinning or delayed Management of apparent treatment failure fragility. • An epithelial defect is not invariable and is sometimes small
epithelial healing. Corneal melting can occasionally be It is important not to confuse ongoing failure of re-epithelialization when present.
precipitated or worsened. with continued infection. Drug toxicity, particularly following fre- • Other features include anterior uveitis, hypopyon, endothe-
○ Many authorities do not commence topical steroids until
evidence of clinical improvement is seen with antibiotics
quent instillation of fortified aminoglycosides, may give increas-
ing discomfort, redness and discharge despite the eradication of
FUNGAL KERATITIS lial plaque, raised IOP, scleritis and sterile or infective
endophthalmitis.
alone, typically 24–48 hours after starting treatment. infection. Introduction • Differential diagnosis includes bacterial, herpetic and acan-
Others delay their use at least until the sensitivity of the • If no improvement is evident following 24–48 hours of inten- thamoebal keratitis. Bacterial infection may sometimes present
isolate to antibiotics has been demonstrated, or do not use sive treatment, the antibiotic regimen should be reviewed, Pathogenesis in a subacute fashion, particularly when atypical organisms are
them at all. including contact with the microbiology laboratory to obtain Fungi are a group of microorganisms that have rigid walls and responsible. It is important to beware of co-infection, includ-
○ Regimens vary from minimal strength preparations at the latest report. a distinct nucleus with multiple chromosomes containing both ing with an additional fungal species.
low frequency to dexamethasone 0.1% every 2 hours or • There is no need to change the initial therapy if this has DNA and RNA. Fungal keratitis is rare in temperate countries but
prednisolone 0.5–1% four times daily. induced a favourable response, even if cultures show a resist- is a major cause of visual loss in tropical and developing countries. Investigations
○ Early discontinuation may lead to a rebound recurrence of ant organism. Though often evolving insidiously, fungal keratitis can elicit a Samples for laboratory investigation should be acquired before
sterile inflammation. • If there is still no improvement after a further 48 hours, sus- severe inflammatory response – corneal perforation is common commencing antifungal therapy.
○ The threshold for topical steroid use may be lower in cases pension of treatment should be considered for 24 hours then and the outlook for vision is frequently poor. Two main types of • Staining
of corneal graft infection, as they may reduce the risk of re-scraping performed with inoculation on a broader range fungi cause keratitis: ○ Potassium hydroxide (KOH) preparation with direct
rejection. of media (see Table 7.2) and additional staining techniques • Yeasts (e.g. genus Candida), ovoid unicellular organisms that microscopic evaluation is a rapid diagnostic tool that can
requested (see Table 7.3). Consideration should be given to the reproduce by budding, are responsible for most cases of fungal be highly sensitive.
possibility of a non-bacterial causative microorganism. keratitis in temperate climates. ○ Gram and Giemsa staining are both about 50% sensitive.
TIP Fluoroquinolone eyedrops have limited effectivity against
• If cultures remain negative, it may be necessary to perform a • Filamentous fungi (e.g. genera Fusarium and Aspergillus), ○ Other stains include periodic acid–Schiff, calcofluor white
Gram-positive organisms (particularly Streptococcus).
corneal biopsy for histology and culture. multicellular organisms that produce tubular projections (Fig. 7.10D) and methenamine silver.
 7
CHAPTER
Cornea 217 218 Herpes Simplex Keratitis

○ Filamentous infection is treated with natamycin 5% or

econazole 1% (alternatives are amphotericin B 0.15%,
miconazole 1% and voriconazole 1 or 2%).
○ Several others are available.
• A broad-spectrum antibiotic might also be considered to
address or prevent bacterial co-infection.
• Cycloplegia as for bacterial keratitis.
• Subconjunctival fluconazole may be used in severe cases.
• Systemic antifungals may be given in severe cases, when
lesions are near the limbus and for suspected endophthalmitis.
Options include voriconazole 400 mg twice daily for one
day then 200 mg twice daily, itraconazole 200 mg once daily,
reduced to 100 mg once daily, or fluconazole 200 mg twice
A B daily.
• Tetracycline (e.g. doxycycline 100 mg twice daily) may be
given for its anticollagenase effect when there is significant
thinning. A
• Perforation – actual or impending – is managed as for bacte-
rial keratitis.
• Superficial keratectomy can be effective to de-bulk a lesion.
• Therapeutic keratoplasty (penetrating or deep anterior
lamellar) is considered when medical therapy is ineffective or
following perforation.
• Anterior chamber washout with intracameral antifungal
injection may be considered for unresponsive cases in which
there is a stable corneal infiltrate but enlarging endothelial
exudation.

C D

Fig. 7.10 Fungal keratitis. (A) Filamentous keratitis with fluffy edges (arrow). There is a large Microsporidial keratitis
epithelial defect, and folds in Descemet membrane; (B) satellite lesions; (C) ring infiltrate,
with hypopyon; (D) candida mycology stained with calcofluor white Introduction
(Courtesy of S Tuft – fig. A; R Fogla – fig. B)
Microsporidia (phylum Microspora) are obligate intracellular
single-celled parasites previously thought to be protozoa but now
B
reclassified as fungi. They rarely cause disease in the immuno-
• Culture. Corneal scrapes should be plated on Sabouraud dex- • Anterior chamber tap has been advocated in resistant cases competent and until the advent of acquired immunodeficiency
Fig. 7.11 Microsporidial keratitis. (A) Diffuse punctate epithe-
trose agar, although most fungi will also grow on blood agar with endothelial exudate, because organisms may penetrate syndrome (AIDS) were rarely pathogenic for humans. The most lial keratitis; (B) deep stromal infiltrates
or in enrichment media. It is important to obtain an effective the endothelium. common general infection is enteritis and the most common (Courtesy of S Tuft)
scrape from the ulcer base. Sensitivity testing for antifungal • Confocal microscopy frequently permits identification of ocular manifestation is keratoconjunctivitis.
agents can be performed in reference laboratories but the rel- organisms in vivo, but is not widely available outside tertiary
evance of these results to clinical effectiveness is uncertain. If centres. Diagnosis
applicable, contact lenses and cases should be sent for culture. • Signs hepatic toxicity. Long-term fumagillin treatment may be
• Polymerase chain reaction (PCR) analysis of specimens is Treatment ○ Bilateral chronic diffuse PEK (Fig. 7.11A). required and it is difficult to eradicate the parasites in immu-
rapid and highly sensitive (up to 90%) and may be the current Improvement may be slow in comparison to bacterial infection. ○ Unilateral slowly progressive deep stromal keratitis (Fig. nocompromised patients.
investigation of choice. Calcium-containing swabs can inhibit • General measures are as for bacterial keratitis although hospi- 7.11B) may rarely affect immunocompetent patients. • Keratoplasty may be indicated although recurrence of disease
polymerase activity and local collection protocols should be tal admission is usually required. ○ Sclerokeratitis and endophthalmitis are rare. can occur in the graft periphery. Cryotherapy to the residual
ascertained prior to specimen collection. • Removal of the epithelium over the lesion may enhance pen- • Biopsy shows characteristic spores and intracellular parasites. tissue may reduce this risk.
• Corneal biopsy is indicated in suspected fungal keratitis in etration of antifungal agents. It may also be helpful to regularly • PCR of scrapings may have relatively low sensitivity.
the absence of clinical improvement after 3–4 days and if no remove mucus and necrotic tissue with a spatula.
growth develops from scrapings after a week. A 2–3 mm block • Topical antifungals should initially be given hourly for 48 Treatment
should be taken, similar to scleral block excision during trab- hours and then reduced as signs permit. • Medical therapy of epithelial disease is with topical fumagillin.
HERPES SIMPLEX KERATITIS
○ Candida infection is treated with amphotericin B 0.15%
eculectomy. Filamentous fungi tend to proliferate just anterior
to Descemet membrane and a deep stromal specimen may be or econazole 1% (alternatives include natamycin 5%,
Highly active antiretroviral therapy (HAART) for associated
AIDS may also help resolution. Stromal disease is treated
Introduction
required. The excised block is sent for culture and histopatho- fluconazole 2%, clotrimazole 1% and voriconazole 1 with a combination of topical fumagillin and oral albendazole Herpetic eye disease is the most common infectious cause of
logical analysis. or 2%). 400 mg once daily for 2 weeks, repeated 2 weeks later with corneal blindness in developed countries. As many as 60% of
a second course. Patients should be closely monitored for corneal ulcers in developing countries may be the result of herpes
 7
CHAPTER
Cornea 219 220 Herpes Simplex Keratitis

simplex virus and 10 million people worldwide may have herpetic

TIP Herpes simplex is the commonest infectious cause of
eye disease. corneal disease in developed countries.

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
Epithelial keratitis
and these reside in almost all neuronal ganglia. HSV-1 causes
infection above the waist (principally the face, lips and eyes), Clinical features
whereas HSV-2 causes venereally acquired infection (genital Epithelial (dendritic or geographic) keratitis is associated with
herpes). Rarely HSV-2 may be transmitted to the eye through active virus replication.
infected secretions, either venereally or at birth (neonatal conjunc- • Symptoms. Mild–moderate discomfort, redness, photopho-
tivitis). HSV transmission is facilitated in conditions of crowding bia, watering and blurred vision.
and poor hygiene. • Signs in approximately chronological order:
○ Reduced visual acuity.
Primary infection ○ Swollen opaque epithelial cells arranged in a coarse punc-
Primary infection, without previous viral exposure, usually tate or stellate (Fig. 7.12A) pattern.
A B
occurs in childhood and is spread by droplet transmission, or less ○ Central desquamation results in a linear-branching (den-
frequently by direct inoculation. Due to protection by maternal dritic) ulcer (Fig. 7.12B), most frequent located centrally.
antibodies, it is uncommon during the first 6 months of life. The branches of the ulcer have characteristic terminal
Occasionally severe neonatal systemic disease may occur in which buds and its bed stains well with fluorescein.
early diagnosis and intravenous antiviral treatment are critical to ○ The virus-laden cells at the margin of the ulcer stain with
reduce mortality and disability. The presence of maternal anti- rose Bengal (Fig. 7.12C). This may help distinction of her-
bodies means that dendritic corneal ulcers may be seen. Most petic ulceration from alternative conditions, particularly
primary infections with HSV are subclinical or cause only mild an atypical recurrent corneal abrasion.
fever, malaise and upper respiratory tract symptoms. Blepharitis ○ Corneal sensation is reduced.
and follicular conjunctivitis may develop but are usually mild ○ Inadvertent topical steroid treatment may promote
and self-limited. Treatment, if necessary, involves topical aci- progressive enlargement of the ulcer to a geographical or
clovir ointment for the eye and/or cream for skin lesions and ‘amoeboid’ configuration (Fig. 7.12D).
occasionally oral antivirals. There is unfortunately no evidence ○ Mild associated subepithelial haze is typical.
that antiviral treatment at this stage reduces the likelihood of ○ Anterior chamber activity may be present, but is usually
recurrent disease. mild.
○ Follicular conjunctivitis may be associated; topical antivi-
Recurrent infection rals can also cause this.
Recurrent disease (reactivation in the presence of cellular and ○ Vesicular eyelid lesions may coincide with epithelial C D
humoral immunity) occurs as follows: ulceration.
• After primary infection the virus is carried to the sensory ○ Elevated IOP is not uncommon (tonometry should be
ganglion for that dermatome (e.g. trigeminal ganglion) where performed on the unaffected eye first and a disposable
latent infection is established. Latent virus is incorporated in prism used).
host DNA and cannot be eradicated with presently available ○ Following healing, there may be persistent PEE and
treatment. irregular epithelium that settle spontaneously and should
• Subclinical reactivation can periodically occur, during which not be mistaken for persistent active infection. A whorled
HSV is shed and patients are contagious. epithelial appearance commonly results from assiduous,
• Clinical reactivation. A variety of stress factors such as fever, especially prolonged, topical antiviral instillation.
hormonal change, ultraviolet radiation, trauma, or trigeminal ○ Mild subepithelial haze (Fig. 7.12E) may persist for weeks
injury may cause clinical reactivation, when the virus replicates after the epithelium heals. In some cases mild scarring may
and is transported in the sensory axons to the periphery. develop, which tends to become more evident after each
• The pattern of disease depends on the site of reactivation, recurrence and may eventually threaten vision.
which may be remote from the site of primary disease. Hun- ○ Recurrence may occur after a corneal graft, undertaken for
dreds of reactivations can occur during a lifetime. stromal scarring (Fig. 7.12F).
• The rate of ocular recurrence after one episode is about 10% • Investigation is usually unnecessary as the diagnosis can
at 1 year and 50% at 10 years. The higher the number of previ- be made clinically. Pre-treatment scrapings can be sent in
E F
ous attacks the greater the risk of recurrence. viral transport medium for culture. PCR and immuno-
• Risk factors for severe disease, which may be frequently recur- cytochemistry are also available. Giemsa staining shows
Fig. 7.12 Epithelial herpes simplex keratitis. (A) Stellate lesions; (B) bed of a dendritic ulcer
rent, include atopic eye disease, childhood, immunodeficiency multinucleated giant cells. HSV serological titres rise only on stained with fluorescein; (C) margins of a dendritic ulcer stained with rose Bengal; (D) geo-
or suppression, malnutrition, measles and malaria. Inappro- primary infection, but can be used to confirm previous viral graphic ulcer; (E) residual subepithelial haze; (F) recurrent ulceration after a corneal graft
priate use of topical steroids may enhance the development of exposure, usually in cases of stromal disease when the diagno- (Courtesy of S Tuft – fig. C; T Carmichael – fig. F)
geographic ulceration (see below). sis is in doubt.
 7
CHAPTER
Cornea 221 222 Herpes Simplex Keratitis

• Differential diagnosis of dendritic ulceration includes herpes • IOP control. If glaucoma treatment is necessary, prostaglandin
zoster keratitis, healing corneal abrasion (pseudodendrite), derivatives should probably be avoided as they may promote
acanthamoeba keratitis, epithelial rejection in a corneal graft, herpes virus activity and inflammation generally.
tyrosinaemia type 2, the epithelial effects of soft contact lenses • Topical steroids are not used unless significant disciform
and toxic keratopathy secondary to topical medication. It has keratitis is also present (see below).
recently been reported that dendritiform keratopathy can • Slow healing or frequent recurrence may indicate the pres-
be caused by polyquadernium-1, a common preservative in ence of a resistant viral strain and an alternative topical agent
contact lens solutions and tear replacement products. or debridement may be tried. In especially refractory cases,
a combination of two topical agents with oral valaciclovir or
Treatment famciclovir may be effective. A significant minority of resistant
Treatment of HSV disease is predominantly with nucleoside cases are due to varicella-zoster virus.
(purine or pyrimidine) analogues that disrupt viral DNA. The
majority of dendritic ulcers will eventually heal spontaneously
without treatment, though scarring and vascularization may be TIP Topical steroids should not be used in epithelial herpes
A B
more significant. keratitis as this can result in corneal perforation.
• Topical. The most frequently used drugs are aciclovir 3% oint-
ment or ganciclovir 0.15% gel, each administered five times
daily. Trifluridine is an alternative, but requires instillation up
Disciform keratitis
to nine times daily until the epithelium closes and then five The aetiology of disciform keratitis (endotheliitis) is unclear.
times daily. The drugs are relatively non-toxic, even when It may be the result of active HSV infection of keratocytes or
given for up to 60 days. They have approximately equivalent endothelium, or a hypersensitivity reaction to viral antigen in the
effect, acting preferentially on virus-laden epithelial cells and cornea.
penetrating effectively into the stroma; 99% of ulcers heal
within 2 weeks. Idoxuridine and vidarabine are older drugs Clinical features
that are probably less effective and more toxic. • Symptoms. Blurred vision of gradual onset, which may be
• Debridement may be used for resistant cases. The corneal associated with haloes around lights. Discomfort and redness
surface is wiped with a sterile cellulose sponge or cotton- are common, but tend to be milder than in purely epithelial
tipped applicator (cotton bud). Epithelium should be removed disease. A clear past history of epithelial ulceration is not
2 mm beyond the edge of the ulcer, since involvement extends always present and the possibility of a mimicking infection
C D
beyond the visible dendrite. The removal of the virus-containing such as acanthamoeba or fungal keratitis should be borne in
cells protects adjacent healthy epithelium from infection and mind.
Fig. 7.13 Disciform herpes simplex keratitis. (A) Epithelial and stromal oedema, with Descemet
eliminates the antigenic stimulus to stromal inflammation. A • Signs membrane folds; (B) stromal oedema; (C) Wessely ring; (D) scarring with vascularization from
topical antiviral agent should be used in conjunction. ○ A central zone of stromal oedema, often with overlying recurrent disease
• Signs of treatment toxicity include superficial punctate ero- epithelial oedema (Fig. 7.13A). Occasionally the lesion is
sions, waves of whorled epithelium, follicular conjunctivitis eccentric.
and, rarely, punctal occlusion. Absence of epithelial whorling ○ Large (granulomatous) keratic precipitates underlying the
with a persistent epithelial lesion raises the possibility of poor oedema (Fig. 7.13B). minimize progression of scarring. Patients should be cautioned to antiviral five times daily, with steroid two or three times daily,
or non-compliance. ○ Folds in Descemet membrane in severe cases. seek treatment at the first suggestion of recurrence, though some titrated according to the signs of activity of both. Oral antiviral
• Oral antiviral therapy (e.g. aciclovir 200–400 mg five times a ○ A surrounding (Wessely) immune ring of deep stromal authorities feel that minimal inflammation may not warrant treat- treatment may be helpful but its efficacy in this situation has
day for 5–10 days, famciclovir or valaciclovir) is indicated in haze (Fig. 7.13C) signifies deposition of viral antigen and ment or can be addressed with cycloplegia alone. not been established.
most immunodeficient patients, in children and patients with host antibody complexes. • Initial treatment is with topical steroids (prednisolone 1% or • Oral steroids are sometimes used in severe stromal inflamma-
marked ocular surface disease. It is an effective alternative to ○ The IOP may be elevated. dexamethasone 0.1%) with antiviral cover, both four times tion as an adjunct, or to reduce steroid-induced IOP elevation
topical treatment when the latter is poorly tolerated, or in ○ Reduced corneal sensation. This may aid in distinguishing daily. As improvement occurs, the frequency of administra- and/or to avoid viral promotion in infectious viral keratitis.
resistant cases. The newer oral agents may be better tolerated other forms of infection. tion of both is reduced in parallel over not less than 4 weeks. • Topical ciclosporin 0.05% may be useful, particularly in the
than aciclovir and require less frequent dosing, but optimal ○ Healed lesions often have a faint ring of stromal or subepi- It is prudent to keep steroid intensity and duration to the presence of epithelial ulceration and to facilitate tapering of
regimens are not yet defined. thelial opacification and thinning. minimum required for effective control of inflammation. IOP topical steroids such as in steroid-related IOP elevation.
• Interferon monotherapy does not seem to be more effective ○ Consecutive episodes may be associated with gradually should be monitored. Cycloplegia can be used to improve • Fine needle diathermy and laser techniques have been reported
than antivirals, but the combination of a nucleoside antiviral worsening subepithelial and/or stromal scarring and comfort if necessary. as successfully addressing established corneal neovasculariza-
with either interferon or debridement seems to speed healing. superficial or deep vascularization (Fig. 7.13D). • Subsequently prednisolone 0.5% once daily is usually a safe tion and improving vision.
• Skin lesions (see Ch. 2) may be treated with aciclovir cream ○ Mid-stromal scarring from disciform keratitis is a cause of dose at which to stop topical antiviral cover. Some patients
five times daily, as for cold sores, and if extensive an oral anti­
viral may be given.
interstitial keratitis. require a weaker steroid such as fluorometholone 0.1% or
loteprednol 0.2% on alternate days for many months. Periodic
Necrotizing stromal keratitis
• Cycloplegia, e.g. homatropine 1% once or twice daily can be Treatment attempts should be made to stop the steroid altogether. This rare condition is thought to result from active viral replica-
given to improve comfort if necessary. A broad approach to management is set out below, but regimens • With active epithelial ulceration it is reasonable to try to keep tion within the stroma, though immune-mediated inflammation
• Topical antibiotic prophylaxis is recommended by some should be tailored individually. Careful monitoring and adequate the steroid intensity as low as possible for adequate effect, is likely to play a significant role. It may be difficult to distinguish
practitioners. treatment, dependent on severity of inflammation, is critical to with a more frequent antiviral regimen, e.g. initially topical from severe disciform keratitis and there may be a spectrum of
 7
CHAPTER
Cornea 223 224 Herpes Zoster Ophthalmicus

disease, including overlap with neurotrophic keratopathy. As with atrophy (Fig. 7.16A) may provide a clue and transillumination treatment and the optimum dose has not been established.
disciform keratitis, a similar clinical picture may be caused by (Fig. 7.16B) may demonstrate subtle lesions. Aqueous sampling for Immunohistochemistry should be performed on the excised
other infections. PCR is diagnostic. Treatment is primarily with topical steroids, but tissue to confirm the presence of herpes antigen.
• Signs adjunctive oral aciclovir may be given.
○ Stromal necrosis and melting, often with profound inter-
stitial opacification (Fig. 7.14).
HERPES ZOSTER OPHTHALMICUS
○ Anterior uveitis with keratic precipitates underlying the
Other considerations
area of active stromal infiltration.
Introduction
○ An epithelial defect may be present. Prophylaxis Herpes zoster is common, and it has been estimated that one in
○ Progression to scarring, vascularization and lipid deposi- • Long-term oral aciclovir reduces the rate of recurrence of three people will develop the condition in their lifetime. Most
tion is common. epithelial and stromal keratitis by about 50% and is usually patients are not immunocompromised.
• Treatment is broadly similar to that of aggressive disciform tolerated well. Prophylaxis should be considered in patients
keratitis, but oral antiviral supplementation, initially at the with frequent debilitating recurrences, particularly if bilateral A Pathogenesis
upper end of the dose range, is commonly used. The restora- or involving an only eye. The standard daily dose of aciclovir Herpes zoster ophthalmicus (HZO) is the term used for shingles
tion of epithelial integrity is critical. is 400 mg twice daily, but if necessary a higher dose can be involving the dermatome supplied by the ophthalmic division of
tried, based on practice in the management of systemic herpes the fifth cranial (trigeminal) nerve. Ocular involvement can also

Neurotrophic keratopathy simplex infection. Continual use for many years has been
documented for systemic indications. The prophylactic effect
occur (though is rarely clinically significant) when the disease
affects the maxillary division alone. Varicella-zoster virus (VZV)
Neurotrophic keratopathy (see also separate topic) is caused by decreases or disappears when the drug is stopped. Excretion is causes both chickenpox (varicella) and shingles (herpes zoster).
failure of re-epithelialization resulting from corneal anaesthesia, via the kidney, so renal function should be checked periodi- VZV belongs to the same subfamily of the herpes virus group as
often exacerbated by other factors such as drug toxicity. cally during long-term treatment. HSV – the viruses are morphologically identical, but antigenically
• Signs • Oral valaciclovir (500 mg once daily) or famciclovir are alter- distinct. After an episode of chickenpox, the virus travels in a
○ A non-healing epithelial defect (Fig. 7.15), sometimes after natives that are probably as effective as aciclovir, require less retrograde manner to the dorsal root and cranial nerve sensory
prolonged topical treatment, is an early sign. frequent dosing and may be better tolerated. ganglia, where it may remain dormant for decades, with reactiva-
○ The stroma beneath the defect is grey and opaque and may • Topical. Oral prophylaxis tends to be preferred to long-term tion thought to occur after VZV-specific cell-mediated immunity
become thin. topical administration as epithelial toxicity may occur, leading has faded. Re-exposure to VZV via contact with chickenpox, or
○ Secondary bacterial or fungal infection may occur. to mild blurring and persistent discomfort. Allergy and B by vaccination, may reinforce immunity and protect against the
• Treatment is that of persistent epithelial defects. Topical ster- punctal stenosis are also potential problems. development of shingles.
oids to control any inflammatory component should be kept • Vaccination. Therapeutic vaccination strategies are under Fig. 7.16 Iris atrophy in herpetic iridocyclitis. (A) Characteris-
to a minimum. investigation. tic patchy appearance; (B) transillumination Mechanisms of ocular involvement
(Courtesy of S Tuft – fig. A)
• Direct viral invasion may lead to conjunctivitis and epithelial
Iridocyclitis TIP Long-term use of oral aciclovir reduces the recurrence
keratitis.
• Secondary inflammation and occlusive vasculitis may cause
Herpetic iridocyclitis can occur without signs of active corneal rate of epithelial and stromal herpes keratitis. Complications episcleritis, scleritis, keratitis, uveitis (including segmental iris
inflammation and may be associated with direct viral activity. IOP • Secondary infection. Herpetic eye disease is a major predis- infarction), optic neuritis and cranial nerve palsies. Inflam-
elevation is common and is often presumed to be due to trabeculi- posing factor for microbial keratitis. mation and destruction of the peripheral nerves or central
tis. However, steroid-induced IOP elevation may also be relatively • Glaucoma secondary to inflammation or chronic steroid use ganglia, or altered signal processing in the central nervous
common in herpetic iritis. The aetiology may be missed unless may progress undetected, particularly if there is a poor view of system (CNS) may be responsible for post-herpetic neuralgia.
there is a history of previous herpes simplex keratitis. Patchy iris the optic disc. Corneal thinning and distortion may give rise Cicatrizing complications may arise following severe eyelid,
to an inaccurate reading on applanation and alternative forms periocular skin and conjunctival involvement.
of tonometry may be superior in these cases. • Reactivation causes necrosis and inflammation in the affected
• Cataract secondary to inflammation or prolonged steroid use. sensory ganglia, causing corneal anaesthesia that may result in
• Iris atrophy secondary to kerato-uveitis (see Fig. 7.16). neurotrophic keratopathy.

Keratoplasty Risk of ocular involvement

A trial of a rigid contact lens is often worthwhile prior to commit- • Hutchinson sign describes vesicles in the skin supplied by the
ting to surgery. Recurrence of herpetic eye disease and rejection external nasal nerve, a branch of the nasociliary nerve supply-
are common and threaten the survival of corneal grafts. ing the tip, side and root of the nose and ophthalmic herpes
• Topical antivirals given during a rejection episode may zoster (Fig. 7.17A). The sign correlates strongly with ocular
reduce epithelial viral reactivation but toxicity may delay involvement, but there is no apparent correlation between the
re-epithelialization. severity of the nasal rash and that of ocular complications.
• Prophylactic oral aciclovir (400 mg twice daily) improves • Age. HZO occurs most frequently in the sixth and seventh
graft survival and should be given to patients undergoing decades. In the elderly, signs and symptoms tend to be more
Fig. 7.14 Necrotizing stromal herpes simplex keratitis with Fig. 7.15 Neurotrophic epithelial defect stained with rose penetrating keratoplasty for herpetic eye disease. It should severe than in the young and of longer duration.
peripheral vascularization Bengal also be considered in patients with severe atopic eye disease • AIDS patients tend to have severe disease, and shingles can be
(Courtesy of T Carmichael) (Courtesy of S Tuft) but no history of ocular HSV involvement. The duration of an early indicator of human immunodeficiency virus (HIV)
 7
CHAPTER
Cornea 225 226 Herpes Zoster Ophthalmicus

infection. A lower threshold for HIV testing should be adopted

in populations at particular risk. The development of shingles Treatment
in children or young adults classically has prompted a search • Oral antiviral treatment, optimally given within 72 hours
for immunodeficiency or malignancy, though the requirement of rash onset, reduces the severity and duration of the acute
for this has been questioned as an abnormality will be found in episode and the risk of post-herpetic neuralgia. The incidence
only a small minority. of late ophthalmic complications is also reduced by about
50%. Patients presenting later than 72 hours but still at the
vesicular stage also derive benefit from treatment. Aciclovir
TIP Vesicles involving the tip or side of the nose precede the (800 mg five times daily for 7–10 days) has been the mainstay
development of ophthalmic herpes zoster (Hutchinson sign). of treatment, but newer agents such as valaciclovir 1 g three
times daily or famciclovir 250–500 mg three times daily have
more convenient regimens, are better tolerated and are at
Acute shingles least as effective as aciclovir. Brivudine is available in some
countries. Fatal interactions with 5-fluoropyrimidines have
A B General features been reported and it should not be used in combination with
• A prodromal phase precedes the appearance of the rash. It even regional 5-fluorouracil.
lasts 3–5 days and is characterized by tiredness, fever, malaise • Intravenous aciclovir 5–10 mg/kg three times daily is gener-
and headache. Symptoms involving the affected dermatome ally indicated only for severe disease, particularly encephalitis
vary from a superficial itching, tingling or burning sensation and for moderate–severe immunocompromise.
to a severe boring or lancing pain that is either constant or • Systemic steroids (e.g. prednisolone 60 mg daily for 4 days,
intermittent. Older patients with early severe pain and a larger then 40 mg for 4 days, then 20 mg for 4 days) remain some-
area of involvement are at particular risk of post-herpetic what controversial but are commonly used in moderate–severe
neuralgia. disease, particularly for neurological complications. They
• Skin lesions should be given only in conjunction with a systemic antiviral
○ Painful erythematous areas with a maculopapular rash and should probably be avoided in immunodeficiency. A
develop (Fig. 7.17B) and may be confused with cellulitis or moderate reduction in acute pain and accelerated skin healing
contact dermatitis. is conferred, but steroids have no effect on the incidence or
○ The rash respects the midline, which may aid in distin- severity of post-herpetic neuralgia.
guishing shingles from HSV skin infection. Pain is also • Immunocompromised patients require the input of an infec-
markedly worse in shingles. Bilateral disease is very rare. tious disease specialist. Antiviral treatment should be extended
C D ○ Within 24 hours, groups of vesicles (Fig. 7.17C) appear and and intravenous treatment may be optimal. Systemic steroids
these become confluent over 2–4 days. should probably be avoided.
○ Although the rash itself does not affect the lower eyelid in • Symptomatic treatment of skin lesions is by drying, antisepsis
HZO, boggy oedema of the upper and lower lids is common and cold compresses. The benefit of topical antibiotic-steroid
(see Fig. 7.17B) and often spreads to the contralateral side combinations is uncertain.
of the face. • Patients with shingles can transmit chickenpox so that
○ The vesicles often pass through a pustular phase before contact with people not known to be immune (particularly
they crust (Fig. 7.17D) and dry after 2–3 weeks. pregnant women) and immunodeficient individuals should be
○ Large, deep haemorrhagic lesions are more common in avoided at least until crusting is complete.
immunodeficient patients (Fig. 7.17E). • VZV uveitis is considered in depth in Chapter 12.
○ The lesions heal to leave residual skin destruction and
depigmented scars (Fig. 7.17F). Prevention
○ Zoster sine herpete is shingles without a rash and may be Vaccination against herpes zoster reduces the incidence of HZO.
more common than previously realized. Two vaccines are available and both are approved for individuals
• Disseminated zoster involving multiple dermatomes and over the age of 50 years.
organ systems may develop in immunodeficiency or malig- • Zoster vaccine live is an attenuated live virus with an impor-
E F
nancy and with the advent of PCR testing, complications such tant limitation that efficacy is lost within 10 years.
as meningoencephalitis have increasingly been identified in • Recombinant zoster vaccine requires two injections and has a
Fig. 7.17 Herpes zoster ophthalmicus. (A) Hutchinson sign – vesicles involving the side of
immunocompetent individuals. 10% incidence of local or acute systemic reaction.
the nose; (B) erythema and oedema (the swelling on the right is not a sign of infection on
that side); (C) vesicular stage; (D) mixed vesicular and pustular rash beginning to show • Investigation. In the event that clinical diagnosis is uncertain,
crusting – note the boggy oedema affecting the medial part of both upper lids; (E) severe typically in immunodeficiency, vesicular fluid can be sent for
rash in a patient with AIDS; (F) typical healed appearance with mild–moderate scarring and PCR, or immunomicroscopy. A viraemia lasting a few days
Eye disease
depigmentation occurs in acute shingles. PCR of plasma for VZV DNA may be
(Courtesy of S Chen – fig. E)
positive (40%), especially in immunosuppressed patients and Acute eye disease
can be particularly useful if zoster sine herpete is suspected. • Acute epithelial keratitis develops in over 50% of patients
IgM antibodies to VZV are found in only a minority of early within 2 days of the onset of the rash and usually resolves spon-
stage and convalescent patients. taneously within a few days. It is characterized by dendritic
 7
CHAPTER
Cornea 227 228 Herpes Zoster Ophthalmicus

A B

A B

C D
C D

Fig. 7.18 Acute lesions in herpes zoster ophthalmicus. (A) Dendritic epithelial lesions with
tapered ends stained with fluorescein; (B) dendritic epithelial lesions stained with rose
Bengal; (C) nummular keratitis; (D) stromal keratitis
(Courtesy of C Barry – fig. D)

lesions that are smaller and finer than herpes simplex dendrites characterized by fine granular subepithelial deposits sur-
and have tapered ends without terminal bulbs (Fig. 7.18A). The rounded by a halo of stromal haze (Fig. 7.18C). The lesions
lesions stain better with rose Bengal than with fluorescein (Fig. fade in response to topical steroids but recur if treatment is
7.18B). Treatment, if required, is with a topical antiviral. discontinued prematurely.
• Conjunctivitis (follicular and/or papillary) is common and • Stromal (interstitial) keratitis (Fig. 7.18D) develops in about
often occurs in conjunction with lid margin vesicles. Treat- 5% 3 weeks after the onset of the rash and significant scarring
ment is not required in the absence of corneal disease, though can occur (Fig. 7.19A). It usually responds to topical steroids
some practitioners give topical antibiotic and/or antiviral but can become chronic and require slow tapering. E F
prophylaxis. • Disciform keratitis (immune-mediated endotheliitis) is
• Episcleritis occurs at the onset of the rash and usually resolves less common than with herpes simplex infection but may Fig. 7.19 Chronic lesions in herpes zoster ophthalmicus. (A) Scarring following stromal kera-
spontaneously. A mild non-steroidal anti-inflammatory may lead to corneal decompensation. Treatment is with topical titis, with crystalline lipid degeneration; (B) iris atrophy in a typical sectoral pattern; (C) more
be used if necessary. steroids. severe sectoral iris atrophy on transillumination; (D) scleral atrophy; (E) staphyloma with
severe corneal scarring; (F) mucous plaque keratitis
• Scleritis and sclerokeratitis are uncommon but may develop • Anterior uveitis affects at least a third of patients and can be
(Courtesy of R Marsh – fig. F)
at the end of the first week. Treatment of indolent lesions is associated with sectoral iris ischaemia and atrophy (Figs 7.19B
with oral flurbiprofen 100 mg three times daily. Oral steroids and C).
with antiviral cover may be required for severe involvement. • Posterior uveitis (see Ch. 12). Progressive retinal necrosis is
• Nummular keratitis usually develops at the site of epi- an aggressive retinitis usually occurring in immunodeficient
thelial lesions about 10 days after the onset of the rash. It is individuals. Acute retinal necrosis can also be caused by VZV.
 7
CHAPTER
Cornea 229 230 Interstitial Keratitis

Posterior segment examination should always be performed in • Systemic treatment may be used in a staged fashion
patients with HZO as retinal vasculitis may occasionally occur. ○ Simple analgesics such as paracetamol.
• IOP should be monitored as elevation is common, including ○ Stronger analgesics such as codeine.
steroid-induced. Prostaglandin derivatives should be avoided ○ Tricyclic antidepressants, e.g. nortriptyline, amitriptyline,
if treatment is necessary. initially 25 mg nightly adjusted up to 75 mg for several
• Neurological complications may require intravenous antivi- weeks if necessary.
rals and systemic steroids. ○ Carbamazepine 400 mg daily for lancinating pain.
○ Cranial nerve palsy affecting the third (most common), ○ Gabapentin (300–600 mg up to three times daily),
fourth and sixth nerves usually recover within 6 months. sustained-release oxycodone (10–30 mg twice daily), or
○ Optic neuritis is rare. both.
○ CNS manifestations are rare but include encephalitis,
cranial arteritis and Guillain–Barré syndrome.

Chronic eye disease INTERSTITIAL KERATITIS

• Neurotrophic keratopathy similar to that seen in HSV infect-
ion develops in up to 50%, but is usually relatively mild and
Introduction
settles over several months. Prolonged severe disease occurs in Interstitial keratitis (IK) is an inflammation of the corneal stroma
a minority (see also separate topic). without primary involvement of the epithelium or endothelium.
• Scleritis may become chronic and lead to patchy scleral In most cases, the inflammation is thought to be an immune- A
atrophy (Fig. 7.19D). Staphyloma formation is rare (Fig. 7.19E). mediated process triggered by an appropriate antigen. The term
• Mucous plaque keratitis develops in about 5%, most com- is most commonly used to refer to the late appearance of feathery Fig. 7.21 Salt and pepper retinopathy following congenital
syphilitic infection
monly between the third and sixth months. It is characterized mid-stromal scarring with ghost vessels rather than the acute pres-
by elevated mucous plaques staining with rose Bengal (Fig. entation. The former is typically an incidental finding. Syphilitic
7.19F). Treatment involves a combination of topical steroid IK is the archetype, but the relative frequency of causes varies
and acetylcysteine. Untreated, plaques resolve after a few markedly by geographic region. There is a wide range of causes
months, leaving a faint diffuse corneal haze. including herpes simplex, varicella zoster and other viral infec- pepper pigmentary retinopathy (Fig. 7.21) and Argyll Robert-
• Lipid degeneration may develop in eyes with persistent severe tions, tuberculosis, Lyme disease and other infections (parasitic son pupils.
nummular or disciform keratitis (see Fig. 7.19A). diseases are an important cause in areas where these are endemic),
• Lipid-filled granulomata similar to those resulting from sarcoidosis, Cogan syndrome and non-infectious inflammatory Presentation of syphilitic IK
chronic irritation may develop in the tarsal conjunctiva and conditions. • Symptoms. The presentation of IK following congenital syphi-
may progress to erosive calcified concretions. litic infection is usually between the ages of 5 and 25 years. The
• Subconjunctival scarring may occur. initial symptoms are those of acute anterior uveitis with severe
• Eyelid scarring may result in ptosis, cicatricial entropion and
occasionally ectropion, trichiasis, lid notching and madarosis.
Syphilitic IK blurring. Involvement is bilateral in 80%, although usually
not simultaneous. In acquired disease IK is less common and
IK of syphilitic origin is usually the result of congenital infection, usually unilateral, typically occurring years after the age at
Relapsing eye disease though acquired syphilis can also be responsible. All patients with which the disease was contracted, although it can occur as part
In the relapsing phase lesions may reappear years after an acute acute IK, or with the incidental discovery of its chronic appear- of the syndrome of primary infection.
episode, which may have been forgotten and eyelid scarring may ance, should be investigated to exclude congenital (and acquired) B • Signs
be the only diagnostic clue. Reactivation of keratitis, episcleritis, syphilis, irrespective of the presence of systemic clinical signs. ○ Profoundly decreased visual acuity is typical in the active
scleritis or iritis can occur. There are numerous reported cases of congenital syphilis being stage.
identified for the first time in later life on this basis. ○ Limbitis associated with deep stromal vascularization,

Post-herpetic neuralgia Congenital syphilis

with cellular infiltration and clouding that may obscure
the still-perfused vessels to give the characteristic pinkish
Post-herpetic neuralgia is defined as pain that persists for more Infection of the fetus can occur across the placenta, leading to ‘salmon patch’ appearance (Fig. 7.22A).
than one month after the rash has healed. It develops in up to 75% stillbirth, subclinical infection, or a range of clinical features. ○ Granulomatous anterior uveitis.
of patients over 70 years of age. Pain may be constant or intermit- • Early systemic features include failure to thrive, a maculo- ○ After several months the cornea begins to clear and the
tent, worse at night and aggravated by minor stimuli (allodynia), papular rash, mucosal ulcers, characteristic fissures around the vessels become non-perfused (‘ghost vessels’ – Fig. 7.22B).
touch and heat. It generally improves slowly over time, with only lips (rhagades) and a range of organ involvement. ○ If the cornea later becomes inflamed, the vessels may re-fill
2% of patients affected after 5 years. Neuralgia can impair the • Late systemic signs include sensorineural deafness, saddle- with blood and may rarely bleed into the stroma. (Fig.
quality of life and may lead to depression of sufficient severity to shaped nasal deformity (Fig. 7.20A), sabre tibiae (Fig. 7.20B), 7.22C).
present a danger of suicide. Patients severely affected should be bulldog jaw (mandibular prominence due to maxillary ○ The healed stage is characterized by ghost vessels, feathery
referred to a specialist pain clinic. Treatment may involve the underdevelopment), Hutchinson teeth (notched, small,
C deep stromal scarring (Fig. 7.22D) and sometimes thin-
following: widely spaced teeth – Fig. 7.20C) and Clutton joints (painless ning, astigmatism and band keratopathy.
Fig. 7.20 Systemic signs of congenital syphilis. (A) Saddle-
• Local effusions in large joints, especially the knees).
shaped nasal deformity; (B) sabre tibiae; (C) Hutchinson • Treatment of active syphilitic IK is with topical steroids and
○ Cold compresses. • Ocular features include anterior uveitis, IK (see below), teeth cycloplegics, as well as immediate systemic therapy under the
○ Topical capsaicin 0.075% or lidocaine 5% patches. dislocated/subluxated lens, cataract, optic atrophy, salt and (Courtesy of R Marsh and S Ford – fig. C) care of a genitourinary or infectious diseases specialist.
 7
CHAPTER
Cornea 231 232 Protozoan Keratitis

A B
A B
Fig. 7.23 Old interstitial keratitis in Cogan syndrome. (A) Peripheral; (B) more central scarring
(Courtesy of R Curtis)

○ Limbitis with diffuse or focal anterior stromal infiltrates

Treatment (Fig. 7.24C).
• Topical steroids for keratitis, with additional measures as ○ Characteristic perineural infiltrates (radial keratoneuri-
appropriate. tis) are seen during the first few weeks and are virtually
• Systemic steroids. Vestibuloauditory symptoms require pathognomonic (Fig. 7.24D).
immediate treatment with 1–2 g/kg prednisolone to prevent ○ Gradual enlargement and coalescence of infiltrates to form
hearing loss. Immunosuppressive therapy may also be a ring abscess (Figs 7.25A and B) is typical.
required. Systemic steroids may also be required for scleritis ○ Scleritis may develop and is generally reactive rather than
or retinal vasculitis. an extension of infection.
○ Slowly progressive stromal opacification and
vascularization.
○ Corneal melting may occur at any stage when there is
C D PROTOZOAN KERATITIS stromal disease. The melt often develops at the periphery
Fig. 7.22 Syphilitic interstitial keratitis. (A) Salmon patch showing deep stromal vasculariza- Acanthamoeba of the area of infiltrate (Fig. 7.25C).
tion with clouding (arrow); (B) ghost vessels; (C) intrastromal corneal haemorrhage from re- • Investigations
perfused vessels; (D) typical feathery scarring – the tracks of ghost vessels are clearly seen Introduction ○ Staining of corneal scrapings using periodic acid–Schiff
Acanthamoeba spp. are ubiquitous free-living protozoa commonly or calcofluor white (a fluorescent dye with an affinity for
found in soil, fresh or brackish water and the upper respiratory amoebic cysts and fungi). Gram and Giemsa stains may
tract. The cystic form (Fig. 7.24A) is highly resilient. Under appro- also demonstrate cysts.
Susac syndrome (retinocochleocerebral vasculopathy) should be priate environmental conditions, the cysts turn into trophozoites, ○ Culture. Non-nutrient agar seeded with dead E. coli, which
Cogan syndrome considered in the differential diagnosis. with tissue penetration and destruction. In developed countries trophozoites consume.
• Vestibuloauditory symptoms. Deafness, tinnitus and vertigo. acanthamoeba keratitis is most frequently associated with contact ○ Other investigations include immunohistochemistry, PCR
Introduction • Ocular symptoms. Redness, pain, photophobia and blurred lens wear, especially if tap water is used for rinsing. and in vivo confocal microscopy. Corneal biopsy may be
Cogan syndrome is a rare systemic autoimmune vasculitis char- vision. necessary for diagnosis.
acterized by intraocular inflammation and vestibuloauditory dys- • Ocular signs. Corneal involvement commences with faint Diagnosis
function (particularly neurosensory) developing within months bilateral peripheral anterior stromal opacities. Deeper opaci- The condition is often diagnosed initially as herpes simplex Treatment
of each other. The disease primarily occurs in young adults, ties and corneal neovascularization (mid-stromal vascular keratitis. With more advanced signs the condition should be It is important to maintain a high index of suspicion for Acan-
with both sexes affected equally; children can also be affected. loops) then ensue (Fig. 7.23A), often with central progression distinguished from fungal keratitis. thamoeba in any patient with a limited response to antibacterial
Systemic features occur in 30% and may include multisystem (Fig. 7.23B). Uveitis, scleritis and retinal vasculitis may develop. • Symptoms. Blurred vision and discomfort. Pain is often severe therapy. The outcome is very much better if treatment is started
vasculitis that can be life-threatening; multispecialty management • Investigations and characteristically disproportionate to the clinical signs. early.
is vital. ○ Erythrocyte sedimentation rate (ESR) and C-reactive • Signs • Debridement of involved epithelium is believed to be helpful,
protein (CRP) may be elevated and the white cell count ○ In early disease the epithelial surface is irregular and as it may facilitate eye drop penetration.
Diagnosis raised. greyish (Fig. 7.24B). • Topical amoebicides. Acanthamoeba cysts are resistant to
Ocular and inner ear symptoms are often separated by a sub- ○ Antibodies to inner ear antigens may be detectable. ○ Epithelial pseudodendrites resembling herpetic lesions most antimicrobial agents and although successful outcomes
stantial period; the acute phase may last from months to years. ○ MRI may show inner ear and other abnormalities. may form. have been reported using a variety of topical preparations, it is
 7
CHAPTER
Cornea 233 234 Bacterial Hypersensitivity-Mediated Corneal Disease

○ Therapeutic keratoplasty may be necessary for resistant

cases, including perforation. Late scarring may also require
penetrating keratoplasty.

TIP Acanthamoeba infection of the cornea results in pain that

is often severe and disproportionate to the clinical signs.

HELMINTHIC KERATITIS
Onchocerciasis
Onchocerciasis (‘river blindness’) is discussed in Chapter 12. Kera-
titis is a common feature.
A
A B
BACTERIAL HYPERSENSITIVITY-
MEDIATED CORNEAL DISEASE
Marginal keratitis
Introduction
Marginal keratitis is believed to be 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
• Symptoms. Mild discomfort, redness and lacrimation. The
inflammation may involve both eyes.
B
C D • Signs
○ Chronic blepharitis is typical.
Fig. 7.24 Initial signs of acanthamoeba keratitis. (A) Cysts in a corneal biopsy; (B) greyish ○ Inferior punctate epitheliopathy is an early manifestation.
early epithelial involvement; (C) focal anterior stromal infiltrates; (D) radial perineuritis ○ Subepithelial marginal infiltrates separated from the
(arrows) limbus by a clear zone, often associated with an adjacent
(Courtesy of J Harry – fig. A) area of conjunctival hyperaemia (Fig. 7.26A and B).
○ Characteristically, any epithelial defect will be consider-
ably smaller than the area of infiltrate.
○ Coalescence and circumferential spread (Fig. 7.26C).
○ Usually little or no anterior chamber reaction, even with
likely that some of these are active only against the trophozoite ○ Simultaneous antibacterial treatment for co-infection may large infiltrates.
stage. be considered if the clinical picture suggests this. ○ Without treatment, resolution generally occurs in 1–4
○ Polyhexamethylene biguanide (PHMB) 0.02% and chlo- ○ Relapses are common as treatment is tapered and it weeks, depending on severity. Occasionally there is
rhexidine (0.02%) kill trophozoites and are cysticidal. may be necessary to continue treatment for many residual superficial scarring and slight thinning with mild
○ Hexamidine or propamidine (Brolene); the former prob- months. pannus (Fig. 7.26D). Iris new vessels may develop in the
ably has greater activity. • Topical steroids should be avoided if possible although low- presence of persistent large lesions, but resolve when
○ Voriconazole and other azole antifungals may be effective. dose therapy delayed for at least 2 weeks after starting anti- inflammation settles.
○ An optimal regimen has not been established. Examples amoebic treatment may be useful for persistent inflammation.
include PHMB as duotherapy with chlorhexidine, or either Amoebicidal treatment should be continued in concert with C Treatment
of these in combination with hexamidine or propamidine. and for several weeks after steroids. A weak topical steroid such as fluorometholone or predniso-
Instillation is hourly at first and gradually reduced. A clear ○ Pain control is with an oral non-steroidal anti- Fig. 7.25 Advanced acanthamoeba keratitis. (A) Progression lone 0.5% is instilled four times daily for 1–2 weeks, sometimes
response may take 2 weeks. inflammatory agent. of infiltration, with incipient formation of a ring abscess and
early melting; (B) ring abscess; (C) melting
(Courtesy of S Tuft – figs B and C)
 7
CHAPTER
Cornea 235 236 Rosacea

A B

A B

C D

Fig. 7.26 Marginal keratitis. (A) and (B) Marginal infiltrates; (C) coalescing infiltrate; (D) mild
scarring and pannus

combined with a topical antibiotic. An oral tetracycline course • Signs

(erythromycin in children, breastfeeding mothers and in preg- ○ A small white limbal (Fig. 7.27A) or conjunctival nodule C D
nancy) may be required for recurrent disease. Blepharitis is treated (Fig. 7.27B) associated with intense local hyperaemia.
as necessary. ○ A limbal phlycten may extend onto the cornea (Fig. 7.27C Fig. 7.27 Phlyctenulosis. (A) Limbal phlycten in an inflamed eye; (B) phlycten in a relatively
and D). quiet eye; (C) corneal phlycten; (D) corneal phlycten with intense vascularization
(Courtesy of S Tuft – fig. D)
○ Spontaneous resolution usually occurs within 2–3 weeks.
Phlyctenulosis A healed lesion often leaves a triangular limbal-based
scar associated with superficial vascularization and thin-
Introduction ning but occasionally severe thinning and perforation can
Phlyctenulosis is usually a self-limiting disease but may rarely be ensue. ROSACEA skin bacteria and Demodex follicular mites. Exacerbation by H.
severe. Most cases in developed countries are the result of a pre- ○ Very large necrotizing or multiple (miliary) lesions may pylori infection has been suspected.
sumed delayed hypersensitivity reaction to staphylococcal antigen, occur.
sometimes associated with rosacea. In developing countries, the • Investigation for tuberculosis is generally indicated only in
Introduction
majority are associated with tuberculosis or helminthic infesta- endemic areas or in the presence of specific risk factors. Rosacea (acne rosacea) is a common chronic idiopathic dermatosis Ocular rosacea
tion, but causation may be uncertain and a range of other agents involving the sun-exposed skin of the face and upper neck. Ocular • Symptoms include non-specific irritation and lacrimation.
has been implicated. Treatment complications develop in 6–18% of patients. Facial telangiectasia, • Lid signs include margin telangiectasia (Fig. 7.29A) and pos-
A short course of topical steroid accelerates healing and is often papule and pustule formation, rhinophyma and facial flushing terior blepharitis, often associated with recurrent meibomian
Diagnosis given with a topical antibiotic. Recurrent troublesome disease may may occur (Fig. 7.28). In contrast to acne vulgaris, comedones cyst formation.
• Symptoms. Photophobia, lacrimation and blepharospasm, require an oral tetracycline and it is important to treat associated (blackheads or whiteheads) are absent. • Conjunctival hyperaemia, especially bulbar. Rarely, cicatricial
often in a child or young adult. blepharitis. The aetiology is probably multifactorial and may involve vas- conjunctivitis, conjunctival granulomas and phlyctenulosis
cular factors, together with an abnormal response to commensal may occur.
 7
CHAPTER
Cornea 237 238 Peripheral Corneal Ulceration/Thinning

• Cornea action and so may retard thinning. In relatively low dose

○ Inferior punctate epithelial erosions. but extended duration (e.g. doxycycline, which has a
○ Peripheral vascularization (Fig. 7.29B). longer half-life than tetracycline, 100 mg once daily for
○ Marginal keratitis (see Fig. 7.26). 4 weeks then 50 mg daily if required) they may confer
○ Focal or diffuse corneal thinning (Fig. 7.29C), usually an improvement lasting several months but if necessary
inferiorly, in severe cases. can be continued long term. Tetracyclines should not be
○ Perforation may occur as a result of severe peripheral or used in children and pregnant or breastfeeding women,
central melting and may be precipitated by secondary in whom erythromycin is an alternative. Efficacy has also
bacterial infection. been reported with other antibiotics.
○ Corneal scarring and vascularization (Fig. 7.29D). ○ Severe disease may require immunosuppression, e.g. A
• Topical treatment azathioprine.
○ Lubricants (preferably unpreserved) for mild symptoms. ○ Retinoids can be helpful, but can worsen some features.
○ Hot compresses and lid hygiene. They are absolutely contraindicated in pregnancy.
○ Topical antibiotics (e.g. fusidic acid, erythromycin,
azithromycin) to the lid margins at bedtime for 4 weeks.
○ Steroids are helpful for exacerbations. The lowest potency PERIPHERAL CORNEAL
preparation compatible with improvement should be used
in order to minimize the promotion of thinning.
ULCERATION/THINNING
• Systemic therapy
○ Tetracyclines may work by altering meibomian gland Introduction
function to lower free fatty acid production in conjunction Peripheral corneal ulceration/thinning, known as ‘peripheral
Fig. 7.28 Acne rosacea papulopustular signs with a reduction in lid flora and probably by a direct anti- ulcerative keratitis’ (PUK) when inflammatory, refers to a presen-
inflammatory effect. They also have an anticollagenase tation characterized by thinning and/or ulceration preferentially
affecting the peripheral rather than central cornea and spreading
around the margin. It should be noted that any cause of corneal
ulceration can affect the periphery. B
• Marginal keratitis. This is discussed above.
• Mooren ulcer. Fig. 7.30 Non-inflammatory peripheral corneal thinning. (A)
• Terrien marginal degeneration. Dellen secondary to pterygium surgery; (B) extensive furrow
degeneration
• Dellen. Localized corneal disturbance associated with drying (Courtesy of S Tuft – fig. A)
of a focal area, usually associated with an adjacent elevated
lesion (e.g. pinguecula or a large subconjunctival haemor-
rhage – Fig. 7.30A) that impairs physiological lubrication.
Generally mild though can occasionally be severe, including
descemetocoele formation/corneal perforation. Diagnosis
• Associated with systemic autoimmune disease. • Symptoms. Pain is prominent and may be severe. There is
• Others. Ocular rosacea, furrow degeneration (mild peripheral photophobia and blurred vision.
thinning in the elderly, usually benign – Fig. 7.30B), pellucid • Signs
marginal degeneration. ○ Peripheral ulceration involving the superficial one-third
of the stroma (Fig. 7.31A), with variable epithelial loss.
Several distinct foci may be present and subsequently
A B Mooren ulcer coalesce.
○ An undermined and infiltrated leading edge is characteris-
Introduction tic (Fig. 7.31B).
Mooren ulcer is a rare autoimmune disease characterized by ○ Limbitis may be present, but not scleritis, which aids in
progressive circumferential peripheral stromal ulceration with distinguishing from systemic disease-associated PUK.
later central spread. There are two forms: the first affects mainly ○ Progressive circumferential and central stromal thinning
older patients, often in only one eye and usually responds well to (Fig. 7.31C).
medical therapy. The second is more aggressive and likely to need ○ Vascularization involving the bed of the ulcer up to its
systemic immunosuppression, carries a poorer prognosis, may leading edge but not beyond.
be bilateral and associated with severe pain and tends to occur ○ The healing stage is characterized by thinning, vasculariza-
in younger patients, including widespread reports in men from tion and scarring (Fig. 7.31D).
C D the Indian subcontinent. In at least some (usually milder) cases, ○ Iritis is not uncommon.
there is a precipitating corneal insult such as surgery or infection. • Complications include severe astigmatism, perforation
Fig. 7.29 Anterior segment in rosacea. (A) Eyelid margin telangiectasia; (B) peripheral corneal Associated systemic autoimmune disease and corneal infection following minor trauma (spontaneous perforation is rare),
vascularization; (C) focal corneal thinning; (D) severe scarring and vascularization should always be ruled out. secondary bacterial infection, cataract and glaucoma.
 7
CHAPTER
Cornea 239 240 Peripheral Corneal Ulceration/Thinning

A B

A B

C D

Fig. 7.31 Mooren ulcer. (A) Local peripheral ulceration; (B) undermined and infiltrated central
edge; (C) advanced disease; (D) healed stage

TIP Peripheral ulcerative keratitis is caused by an infection bilateral disease, or if involvement is advanced at first exami-
until proven otherwise. In the absence of an infection nation. Biological blockers show some promise.
investigate for systemic autoimmune disease. • Systemic collagenase inhibitors such as doxycycline may be C D
beneficial.
Fig. 7.32 Keratitis in systemic autoimmune disease. (A) Corneal infiltrate in Crohn disease;
• Lamellar keratectomy involving dissection of the residual
(B) early peripheral ulcerative keratitis; (C) peripheral guttering in rheumatoid arthritis;
Treatment central island in advanced disease may remove the stimulus ‘contact lens’ cornea; (D) rheumatoid paracentral ulcerative keratitis
• Topical steroids as frequently as hourly are combined with a for further inflammation.
low-frequency prophylactic topical antibiotic. If an effective • Perforations. Management is as discussed earlier in this
response is seen, treatment is tapered over several months. chapter.
• Topical ciclosporin (up to 2%) may be effective, but can take • Visual rehabilitation. Keratoplasty (with immunosuppressive upregulation of collagenases and reduced activity of their inhibi-
weeks to exert a significant effect. cover) may be considered once inflammation has settled. tors. Systemic associations include: Clinical features
• Tacrolimus 0.1% ointment is effective in controlling refrac- • Rheumatoid arthritis (RA – the most common). PUK is • Crescentic ulceration with an epithelial defect, thinning and
tory cases. bilateral in 30% and tends to occur in advanced RA. stromal infiltration at the limbus (Fig. 7.32A and B). Spread
• Adjunctive topical therapy includes artificial tears and col- Peripheral ulcerative keratitis associated • Granulomatosis with polyangiitis (Wegener granulomatosis) is circumferential and occasionally central. In contrast to
lagenase inhibitors such as acetylcysteine 10–20%. is the second most common systemic association of PUK. In Mooren ulcer, extension into the sclera may occur.
• Conjunctival resection, which may be combined with exci-
with systemic autoimmune disease contrast to RA ocular complications are the initial presenta- • Limbitis, episcleritis or scleritis are usually present. As with
sion of necrotic tissue, is performed if there is no response tion in 50%. a Mooren ulcer, there is no separation between the ulcerative
to topical steroids. The excised area should extend 4 mm Introduction • Other conditions include polyarteritis nodosa, relapsing poly- process and the limbus.
back from the limbus and 2 mm beyond the circumferential PUK may precede or follow the onset of systemic features. Severe chondritis, systemic lupus erythematosus and Crohn disease • Advanced disease may result in a ‘contact lens’ cornea (Fig.
margins. Keratoepithelioplasty (suturing of a donor corneal peripheral corneal infiltration, ulceration or thinning unexplained (Fig. 7.32A). 7.32C) or perforation.
lenticule onto the scleral bed) may be combined to produce by evident ocular disease should prompt investigation for a • Rheumatoid paracentral ulcerative keratitis (PCUK) is
a physical barrier against conjunctival regrowth and further (potentially life-threatening) systemic collagen vascular disorder. thought to be a distinct entity, with a punched-out more
melting. Steroids are continued postoperatively. The mechanism includes immune complex deposition in periph- TIP Peripheral ulcerative keratitis in the absence of other centrally located lesion with little infiltrate in a quiet eye (Fig.
ocular disease should prompt investigation for a systemic
• Systemic immunosuppression may be needed, including eral cornea, episcleral and conjunctival capillary occlusion with 7.32D). Perforation can occur rapidly and there is usually a
autoimmune disease.
steroids for rapid effect and should be instituted earlier for secondary cytokine release and inflammatory cell recruitment, the good response to topical ciclosporin, with bandage contact
 7
CHAPTER
Cornea 241 242 Exposure Keratopathy

lens and tissue glue application if necessary, rather than sys-

temic treatment.
NEUROTROPHIC KERATOPATHY
Treatment Introduction
Treatment is principally with systemic immunosuppression in Neurotrophic keratopathy occurs when there is loss of trigeminal
collaboration with a rheumatologist. innervation to the cornea resulting in partial or complete anaesthe-
• Systemic steroids, sometimes via pulsed intravenous admin- sia. In addition to loss of the protective sensory stimulus, reduced
istration, are used to control acute disease, with immunosup- innervation results in intracellular oedema, exfoliation, loss of
pressive therapy and biological blockers for longer-term goblet cells and epithelial breakdown with persistent ulceration.
management. Causes include trigeminal ganglion surgical ablation for neuralgia,
• Topical lubricants (preservative-free). stroke, tumour, peripheral neuropathy (e.g. diabetes) and ocular
• Topical antibiotics as prophylaxis if an epithelial defect is disease such as herpes simplex and herpes zoster keratitis (when
present. sensation loss may be sectoral).
• Oral tetracycline (e.g. doxycycline 100 mg once or twice daily) A B
for its anticollagenase effect. Diagnosis
• Topical steroids may worsen thinning so are generally A full cranial nerve examination is mandatory.
avoided; relapsing polychondritis may be an exception. • Signs
• Surgical management is generally as for Mooren ulcer, includ- ○ Corneal sensation is reduced.
ing conjunctival excision if medical treatment is ineffective. ○ Stage 1: interpalpebral epithelial irregularity and staining,
with mild opacification, oedema and tiny focal defects
Terrien marginal degeneration (Fig. 7.34A).
○ Stage 2: larger persistent epithelial defect with rolled and
Terrien disease is an uncommon idiopathic thinning of the thickened edges (Fig. 7.34B), subsequently assuming a
peripheral cornea occurring in young adult to elderly patients. punched-out configuration with underlying stromal
Although usually categorized as a degeneration, some cases are oedema.
associated with episodic episcleritis or scleritis. About 75% of ○ Stage 3: stromal melting, often with minimal discomfort.
affected patients are male and the condition is usually bilateral but Secondary infection may occur (Fig. 7.34C).
may be asymmetrical. ○ Perforation is uncommon but may occur rapidly, espe-
cially with secondary infection (Fig. 7.34D).
C D
Diagnosis
• Symptoms. The condition is commonly asymptomatic, but Treatment
Fig. 7.33 Terrien marginal degeneration. (A) Circumferential thinning with peripheral guttering;
gradual visual deterioration can occur due to astigmatism. A • Discontinuation, if possible, of potentially toxic medications. (B) thinning, vascularization and lipid band at the central edge; (C) pseudopterygia; (D) gutter
few patients experience episodic pain and inflammation. • Topical lubricants (non-preserved) for associated dry eye or excision with lamellar graft repair
• Signs corneal exposure. Topical insulin-like growth factor-1, sub- (Courtesy of C Barry – figs C and D)
○ Fine yellow–white refractile stromal opacities, frequently stance P and neurogenic growth factor have been evaluated
associated with mild superficial vascularization, usually but are not commercially available.
start superiorly, spread circumferentially and are separated • Anticollagenase agents: topical (e.g. acetylcysteine, tetracy-
from the limbus by a clear zone. There is no epithelial cline ointment) or systemic (e.g. tetracyclines).
defect and on cursory examination the condition may • Cenegermin, a topical recombinant human nerve growth
resemble arcus senilis. factor, appears to be beneficial in moderate (persistent epi- cutaneous branches of the sural nerve is connected to the include neuroparalytic, especially facial nerve palsy, reduced
○ Slowly progressive circumferential thinning results in a thelial defect) or severe (corneal ulcer) neurotrophic ulcer in contralateral supratrochlear nerve (Fig. 7.35A and B). The muscle tone as in parkinsonism, mechanical such as lid scar-
peripheral gutter, the outer slope of which shelves gradu- adults. Long-term effectiveness is not known. grafted nerve is brought under the skin and into the opposite ring, eczematous skin tightening and post-blepharoplasty and
ally, while the central part rises sharply (Fig. 7.33A). A • Protection of the ocular surface orbit (Fig. 7.35C and D). The nerve is divided and positioned proptosis.
band of lipid is commonly present at the central edge (Fig. ○ Simple taping of the lids, particularly at night, may provide under the conjunctiva and attached to the peripheral corneo-
7.33B). modest protection. scleral junction (Fig. 7.35E). The conjunctiva is closed over the Diagnosis
○ Perforation is rare but may be spontaneous or follow blunt ○ Botulinum toxin-induced ptosis. branches (Fig. 7.35F). Sensation returns 6-8 months after the • Symptoms are those of dry eye.
trauma. ○ Tarsorrhaphy: temporary or permanent, lateral or central, surgery. • Signs
○ Pseudopterygia sometimes develop (Fig. 7.33C). according to the underlying pathology and visual potential. ○ Mild punctate epithelial changes involving the infe-
○ Therapeutic silicone contact lenses may be fitted, provided rior third of the cornea, particularly with nocturnal
Treatment the eye is carefully monitored for infection.
EXPOSURE KERATOPATHY lagophthalmos.
• Safety spectacles (e.g. polycarbonate) if thinning is significant. ○ Amniotic membrane patching with temporary central ○ Epithelial breakdown (Fig. 7.36A).
• Contact lenses for astigmatism. Scleral or soft lenses with rigid tarsorrhaphy. Introduction ○ Stromal melting (Fig. 7.36B), occasionally leading to
gas permeable ‘piggybacking’. • Perforation is dealt with as discussed earlier in the chapter. Exposure keratopathy is the result of incomplete lid closure perforation.
• Surgery – crescentic or annular excision of the gutter with • Corneal neurotization from the supratrochlear nerve using (lagophthalmos), with drying of the cornea despite normal ○ Inferior fibrovascular change with Salzmann degeneration
lamellar (Fig. 7.33D) or full-thickness transplantation – gives a sural nerve graft. Corneal sensation can be restored using a tear production. Lagophthalmos may only be present on blink- may develop over time.
reasonable results and may arrest progression. multidisciplinary surgical approach. A segment of the medial ing or gentle lid closure, with full forced lid closure. Causes ○ Secondary infection (Fig. 7.36C).
 7
CHAPTER
Cornea 243 244 Miscellaneous Keratopathies

A B C

A B
D E F

Fig. 7.35 Technique of corneal neurotization. (A) Left neurotrophic keratopathy showing skin
incision sites; (B) isolation of contralateral supraorbital nerve; (C) and (D) the sural nerve
graft is brought under the skin and into the opposite orbit; (E) the nerve is divided and the
branches are sutured at the limbus; (F) the conjunctiva is closed over the branches
(Courtesy of JH Norris)

overlying epithelium (Fig. 7.37). A biofilm is present that allows

survival of the microorganism, reduces antibiotic bioavailability Treatment
and makes diagnostic detection difficult. Culture or biopsy is per- • Topical
formed to determine the organism and topical antibiotics instilled ○ Lubricants may suffice in mild cases.
for several weeks. Adjunctive therapies to enhance the efficacy of ○ Steroids. A low-potency preparation is used twice daily
C D treatment include disruption of the microorganism biofilm by initially, with gradual tapering to as little as once-weekly
laser, intrastromal antibiotic and keratectomy. In cases that do not instillation. High intensity treatment may sometimes be
Fig. 7.34 Neurotrophic keratopathy. (A) Early central epithelial changes; (B) large epithelial respond to treatment or where corneal scarring is present, corneal needed initially.
defect; (C) secondary infection with marked thinning; (D) perforation with iris prolapse
(Courtesy of S Tuft – fig. B; S Bonini – fig. C) transplantation is required. ○ Ciclosporin 0.05% is generally used if the response to
steroids is inadequate, or as an alternative in longer-

Thygeson superficial punctate keratitis term therapy. However, some authorities recommend
ciclosporin for initial treatment. Tacrolimus may also be
Thygeson superficial punctate keratitis is an uncommon idi- effective.
Treatment ○ Permanent central tarsorrhaphy, amniotic membrane opathic, usually bilateral, condition characterized by exacerbations ○ Antivirals have not been found to be consistently helpful.
Treatment depends on the severity of exposure and whether grafting or conjunctival flap when vision is poor. and remissions. It is commonly of onset in young adulthood but • Contact lenses (extended wear or daily disposable soft) may
recovery is anticipated. can affect patients of any age and may recur over decades. be considered if steroids are ineffective or contraindicated, as
• Reversible exposure an alternative to ciclosporin.
○ Artificial tears (unpreserved) during the day and ointment Diagnosis • Phototherapeutic keratectomy brings short-term relief but
at night.
MISCELLANEOUS KERATOPATHIES • Symptoms consist of recurrent attacks of irritation, photo- recurrence is likely.
○ Taping the lid closed at night may be an alternative to
ointment.
Infectious crystalline keratopathy phobia, blurred vision and watering.
• Signs
○ Bandage silicone hydrogel or scleral contact lenses. Infectious crystalline keratopathy is a rare indolent infection ○ Granular, coarse, slightly elevated greyish epithelial lesions
Filamentary keratopathy
○ Management of proptosis by orbital decompression if usually occurring in a patient on long-term topical steroid therapy that stain with fluorescein and mainly involve the central
necessary. with an associated epithelial defect, most frequently following cornea (Fig. 7.38A). Introduction
○ Temporary tarsorrhaphy, Frost suture or overlay amniotic penetrating keratoplasty. Streptococcus viridans is most commonly ○ A mild subepithelial haze may be present (Fig. 7.38B), Filamentary keratopathy is a common condition that can cause
membrane grafting. isolated, although numerous other bacteria and fungi have been especially if topical antivirals have been used. considerable discomfort. It is thought that a loose area of epithe-
• Permanent exposure implicated. ○ There is little or no conjunctival hyperaemia. lium acts as a focus for deposition of mucus and cellular debris.
○ Permanent tarsorrhaphy. Slowly progressive, grey–white, branching stromal opacities • Differential diagnosis includes post-adenoviral keratitis. The causes are shown in Table 7.6.
○ Gold weight upper lid insertion for facial nerve palsy. are seen, associated with minimal inflammation and usually intact
 7
CHAPTER
Cornea 245 246 Miscellaneous Keratopathies

A A

A A

B B

Fig. 7.38 (A) Thygeson superficial punctate keratitis; (B) Fig. 7.39 Corneal filaments. (A) Comma-shaped lesions
associated subepithelial haze attached to the cornea at one end; (B) stained with rose
B B (Courtesy of R Curtis – fig. B) Bengal
(Courtesy of S Tuft – fig. A; R Bates – fig. B)
Fig. 7.37 (A) Infectious crystalline keratitis; (B) crystalline
keratitis in a graft
(Courtesy of M Kerr-Muir – fig. A)
Diagnosis
• Symptoms consist of discomfort with foreign body sensation, • Mucolytics such as 5% or 10% acetylcysteine drops.
redness and sometimes photophobia. • Non-steroidal anti-inflammatory drops, e.g. diclofenac.
• Signs • Hypertonic saline (5% drops four times daily, ointment at
○ Strands of degenerated epithelial cells and mucus that bedtime) may encourage adhesion of loose epithelium.
Table 7.6 Causes of Filamentary Keratopathy move with blinking and are typically attached to the • Bandage contact lenses may protect the cornea from the
cornea at one end (Fig. 7.39A). shearing action of the lids.
Aqueous deficiency (keratoconjunctivitis sicca)
Excessive contact lens wear ○ Filaments stain well with rose Bengal (Fig. 7.39B) and to a
Corneal epithelial instability (recurrent erosion syndrome, lesser extent with fluorescein.
corneal graft, cataract surgery, refractive surgery and ○ A small epithelial defect may be present at the base of a
Recurrent corneal epithelial erosion
drug toxicity) filament.
Superior limbic keratoconjunctivitis Introduction
○ Chronic filaments may form plaques.
Bullous keratopathy
Neurotrophic keratopathy Recurrent corneal epithelial erosion is caused by an abnor-
C Prolonged or frequent eye closure Treatment mally weak attachment between the basal cells of the corneal
• Any underlying cause should be treated. epithelium and their basement membrane. Minor trauma,
Fig. 7.36 Exposure keratopathy. (A) Inferior epithelial defect; • Topical medication should be changed if a toxic effect is such as eyelid–cornea interaction during sleep, can be suf-
(B) stromal melting with pannus formation; (C) secondary suspected and unpreserved preparations used where possible. ficient to precipitate detachment. Erosions may be associated
bacterial infection
(Courtesy of T Carmichael – fig. C) • Mechanical removal of filaments gives short-term sympto- with previous trauma or rarely corneal surgery and with some
matic relief. corneal dystrophies. Intervals between episodes can be very
 7
CHAPTER
Cornea 247 248 Corneal Ectasia

variable, even in the same patient, but may occur in spates over a (cotton bud) may improve comfort and allow healing • Conjunctiva • Retinopathy, characterized by yellowish peripheral dots,
short period. from the edges of the defect. ○ Xerosis is characterized by dryness of the conjunctiva in may occur in advanced cases and is associated with decreased
○ Topical diclofenac 0.1% reduces pain. the interpalpebral zone with loss of goblet cells, squamous electroretinogram amplitude.
Diagnosis ○ Topical anaesthetic dramatically relieves pain but should metaplasia and keratinization.
• Symptoms. Severe pain, photophobia, redness, blepharospasm not be dispensed for patient use. ○ Bitot spots are triangular patches of foamy keratinized Treatment
and watering typically waken the patient during the night or ○ Hypertonic sodium chloride 5% drops four times daily epithelium (Fig. 7.41A) in the interpalpebral zone thought Keratomalacia is an indicator of very severe vitamin A deficiency
are present on awaking in the morning. There is usually (but and ointment at bedtime may improve epithelial adhesion. to be caused by Corynebacterium xerosis. and should be treated as a medical emergency due to the risk of
not invariably) a prior history of corneal abrasion, sometimes ○ Following resolution, some authorities advise using a • Cornea death, particularly in infants.
years previously, which may have been minor compared with prophylactic topical lubricant such as carbomer gel three ○ Lustreless appearance due to secondary xerosis. • Systemic treatment involves oral (oil-based 200 000 IU) or
the recurrent symptoms. or four times daily for several months. ○ Bilateral punctate corneal epithelial erosions in the inter- intramuscular (aqueous-based 100 000 IU) vitamin A for
• Signs • Recurrent symptoms palpebral zone can progress to epithelial defects but are keratomalacia. Multivitamin supplements and dietary sources
○ An epithelial defect (Fig. 7.40) may not be present by the ○ Topical lubricant gel or ointment, or hypertonic saline reversible with treatment. of vitamin A are also administered.
time the patient is examined, as healing can often be very ointment, instilled at bedtime used long term may be ○ Keratinization. • Local treatment consists of intense lubrication, topical retinoic
rapid (hours), but the extent of loose epithelium may be sufficient. ○ Sterile corneal melting by liquefactive necrosis (keratoma- acid and management of perforation.
highlighted by areas of pooling of fluorescein and rapid ○ A combination of oral doxycycline and topical steroid lacia), which may lead to perforation (Fig. 7.41B).
tear film breakup. may be helpful. Both have been shown to inhibit metallo-
○ Infiltrate should not be present, though greyish sloughed
and rolled epithelium may sometimes be reminiscent of
proteinase inhibitors important to disease pathogenesis.
○ Long-term extended-wear bandage contact lens.
CORNEAL ECTASIA
this. ○ Simple debridement of the epithelium in involved areas, Keratoconus
○ There may be no sign of abnormality once a defect has which may be followed by smoothing of Bowman layer
healed, but signs of epithelial basement membrane distur- with a diamond burr or excimer laser. Most patients Introduction
bance, such as microcysts, punctate or linear/fingerprint treated with excimer keratectomy do not get recurrences Keratoconus (KC) is a progressive disorder in which central or
opacities are often present. These will typically be bilateral and the side effects are minimal. paracentral corneal stromal thinning occurs, accompanied by
in a stromal dystrophy and unilateral if injury is the cause. ○ Anterior stromal puncture for localized areas off the visual apical protrusion and irregular astigmatism. Approximately 50%
axis. It may not be necessary to remove the epithelium to of normal fellow eyes will progress to KC within 16 years. Both
Treatment facilitate this. eyes are affected eventually, at least on topographical imaging, in
• Acute symptoms almost all cases. It can be graded by the highest axis of corneal
○ Antibiotic ointment four times daily and cyclopentolate power on keratometry as mild (<48 D), moderate (48–54 D)
1% twice daily.
Xerophthalmia or severe (>54 D). Most patients do not have a family history,
○ Pressure patching should not be used as it may impair with only about 10% of offspring developing KC; autosomal
healing and does not improve comfort. Introduction dominant transmission with incomplete penetrance has been
○ In severe cases a bandage contact lens alleviates pain but Vitamin A is essential for the maintenance of the body’s epithelial proposed. Presentation is commonly during the teens or twen-
may not improve healing. Antibiotic drops rather than surfaces, for immune function and for the synthesis of retinal ties, with features initially in only one eye. Systemic associations
ointment should be used. photoreceptor proteins. Xerophthalmia refers to the spectrum of include Down, Ehlers–Danlos and Marfan syndromes and
○ Debridement of heaped/scrolled areas of epithelium with ocular disease caused by inadequate vitamin A intake and is a late A osteogenesis imperfecta. Ocular associations include vernal
a sterile cellulose sponge or cotton-tipped applicator manifestation of severe deficiency. Lack of vitamin A in the diet keratoconjunctivitis, blue sclera, aniridia, Leber congenital amau-
may be caused by malnutrition, malabsorption, chronic alcohol- rosis, retinitis pigmentosa, as well as persistent eye rubbing from
ism or by highly selective dieting. The risk in infants is increased any cause.
if their mothers are malnourished and by coexisting diarrhoea or
measles. Diagnosis
• Symptoms. Unilateral impairment of vision due to progressive
Diagnosis myopia and astigmatism. Occasionally, initial presentation is
A World Health Organization (WHO) grading system is set out with acute hydrops (see below).
in Table 7.7. • Signs
• Symptoms are night blindness (nyctalopia), discomfort and ○ Direct ophthalmoscopy from a distance of half a metre
loss of vision. shows a fairly well delineated ‘oil droplet’ reflex (Fig.
7.42A).
○ Retinoscopy shows an irregular ‘scissoring’ reflex.
○ Slit lamp biomicroscopy shows very fine, vertical, deep
Table 7.7 WHO Grading of Xerophthalmia
stromal stress lines (Vogt striae – Fig. 7.42B), which disap-
XN = night blindness pear with pressure on the globe.
X1 = conjunctival xerosis (X1A) with Bitot spots (X1B)
○ Epithelial iron deposits, best seen with a cobalt blue filter,
X2 = corneal xerosis B
X3 = corneal ulceration, less than one-third (X3A); more may surround the base of the cone (Fleischer ring – Fig.
than one-third (X3B) Fig. 7.41 Xerophthalmia. (A) Bitot spot; (B) keratomalacia 7.42C).
Fig. 7.40 Recurrent corneal erosion syndrome showing epi- XS = corneal scar with central corneal melting and vascularization ○ Progressive corneal protrusion in a cone configuration
thelial defect stained with fluorescein XF = xerophthalmic fundus (Courtesy of N Rogers – fig. A) (Fig. 7.42D), with thinning maximal at the apex.
 7
CHAPTER
Cornea 249 250 Corneal Ectasia

A B

A B

C D

Fig. 7.42 Keratoconus. (A) ‘Oil droplet’ red reflex; (B) Vogt striae in the deep stroma (arrow);
(C) Fleischer ring demonstrated by cobalt blue light as a blue circle (arrow); (D) typical cone
(Courtesy of R Fogla – fig. C)

C D
○ Bulging of the lower lid in downgaze (Munson sign) (Fig. steep-sided cone (Fig. 7.44). Sometimes a central (‘nipple’)
Fig. 7.43 Acute hydrops. (A) Munson sign with localized hydrops; (B) localized corneal
7.43A). cone may develop. Contact lens warpage can sometimes oedema; ‘nipple’ cone (arrow); (C) severe diffuse oedema; (D) late scarring
○ Acute hydrops is caused by a rupture in the stretched appear similar to a cone on topography, but is generally more (Courtesy of C Barry – figs C and D)
Descemet membrane that allows a sudden influx arcuate-shaped.
of aqueous into the cornea (Figs 7.43B and C), with
accompanying pain, photophobia and decreased vision.
Although the break usually heals within 6–10 weeks and Treatment
• Eye rubbing should be avoided. • Intracorneal ring segment implantation (Fig. 7.45) using laser
the oedema clears, a variable amount of stromal scarring
(Fig. 7.43D) may develop. This sometimes gives improved • Spectacles or soft contact lenses are generally sufficient in or mechanical channel creation is relatively safe and typically
Pellucid marginal degeneration
vision by flattening the cornea. Acute episodes are initially early cases. If thinning is marked, it may be prudent to con- provides at least a moderate visual improvement, facilitating Pellucid marginal degeneration is a rare progressive peripheral
treated with cycloplegia, hypertonic (5%) saline ointment sider wearing safety spectacles over contact lenses. contact lens tolerance in advanced cases. corneal thinning disorder, typically involving the inferior cornea
and patching or a soft bandage contact lens. Accelerated • Rigid contact lenses, sometimes scleral, are required for • Keratoplasty, either penetrating or deep anterior lamellar in both eyes. Presentation is usually in adulthood.
resolution has been reported with intracameral gas injec- higher degrees of astigmatism to provide a regular refracting (DALK), may be necessary in patients with severe disease. A
tion in the acute stage. surface. history of hydrops is a contraindication to DALK due to the
• Keratometry readings are steep. • Corneal collagen cross-linking (CXL), using riboflavin drops presence of a Descemet membrane discontinuity. Outcomes Diagnosis
• Corneal topography (video keratography) and various novel to photosensitize the eye followed by exposure to ultraviolet-A may be compromised by residual astigmatism and by aniso- • Symptoms. Slowly progressive blurring due to astigmatism.
corneal profiling techniques are highly sensitive for detection light, may stabilize or even reverse ectasia, but is not without metropia, necessitating contact lens correction for optimal • Signs
and essential in monitoring. Characteristically, astigmatism adverse effects. It can be combined with ring segment inser- acuity. ○ Bilateral, slowly progressive, crescentic 1–2 mm band of
progresses from a symmetrical bow-tie pattern, through an tion. CXL is commonly used after progression has been • LASIK is contraindicated. Patients should be screened for KC inferior corneal thinning extending from 4 to 8 o’clock,
asymmetrical appearance to an inferotemporally displaced documented. prior to corneal refractive surgery. 1 mm from the limbus (Fig. 7.46A).
 7
CHAPTER
Cornea 251 252 Corneal Dystrophy

01/09/97 11:49 01/13/97 09:31

90 90 73.00
120 60 Nasal Nasal 120 60
69.38

65.77
150 30 150 30
62.15

58.54
180 00180 00
54.92

51.31
210 330 210 330 47.69

44.08
Tang 240 300 OD Tang 240 300 OS
270 270 40.46
Axis Dist Pwr Rad Z Axis Dist Pwr Rad Z
000 0.00 69.81 4.83 0.00 000 0.00 47.26 7.14 0.00 36.85 A
KS: 60.68D @ 110 KS: 45.90D @ 020 33.23
KF: 52.26D @ 030 KF: 45.26D @ 150
KD: 8.42D KD: 0.64D 29.62
Real K / Avg (1.60) Real K / Avg (1.60)
26.00

EH Rel A

Fig. 7.44 Corneal topography showing severe keratoconus in the right eye and an early para-
central cone in the left
(Courtesy of E Morris)

Fig. 7.47 (A) Keratoglobus; (B) Munson sign in keratoglobus

CORNEAL DYSTROPHY
A The corneal dystrophies are a group of progressive, usually
B
bilateral, variable corneal opacifying disorders, many of which are
associated with decreased vision and discomfort. Based on biomi-
Fig. 7.46 (A) Pellucid marginal degeneration; (B) topography
croscopical and histopathological features they are classified into
showing severe astigmatism and diffuse steepening of the
inferior cornea epithelial, Bowman layer, stromal and Descemet membrane and
(Courtesy of R Visser – fig. A; R Fogla – fig. B) endothelial. One or more underlying genetic abnormalities have
been identified for most.

B C TIP As a general rule, most types of corneal dystrophy are

Keratoglobus bilateral, primarily affect one layer of the cornea and are slowly
Fig. 7.45 Intracorneal ring segments in situ progressive.
Keratoglobus is an extremely rare condition that can be present
(Courtesy of C Barry) at birth when differential diagnosis is from congenital glaucoma
and megalocornea and associations may be present, or acquired,
with onset in adulthood. In contrast to keratoconus, the cornea
Epithelial dystrophies
○ The epithelium is intact and the cornea above the thinned Treatment develops globular rather than conical ectasia and is associated with
area shows ectasia and appears flattened. Early cases are managed with spectacles and contact lenses. Surgi- generalized corneal thinning (Fig. 7.47). Acute hydrops is rare, but Cogan (epithelial basement membrane)
○ In contrast to keratoconus, Fleischer rings and Vogt striae cal options, none of which is ideal, in patients intolerant to contact the cornea is more prone to rupture on relatively mild trauma. dystrophy
do not occur and acute hydrops is rare. lenses include large eccentric penetrating keratoplasty, thermo- Corneal topography shows generalized steepening. Surgery is dif- Isolated familial cases of epithelial basement membrane (map-
• Corneal topography shows a ‘butterfly’ pattern, with severe cauterization, crescentic lamellar keratoplasty, wedge resection ficult and contact lens wear is often unsatisfactory. Intrastromal dot-fingerprint) corneal dystrophy have been reported. Since
astigmatism and diffuse steepening of the inferior cornea (Fig. of diseased tissue, epikeratoplasty and intracorneal ring segment ring segments and cross-linking may have utility. Special care most patients seen in clinical practice have no documented family
7.46B). implantation. Results of collagen cross-linking are encouraging. should be taken to protect the eyes from trauma. history of the condition, these corneal changes are now considered
 7
CHAPTER
Cornea 253 254 Corneal Dystrophy

degenerative or secondary to trauma. The disease is often misdiag- • Signs. Lesions are often best visualized by retroillumination or
nosed, principally because of the variable appearance. scleral scatter. Over time pattern and distribution varies; they
• Inheritance. The condition is usually sporadic and these cases may be absent or subtle in a fellow eye. Similar features can be
may be degenerations rather than true dystrophies, in contrast seen with recurrent erosions from any cause.
to the rare familial (autosomal dominant – AD) cases. ○ Dot-like and microcystic epithelial lesions (Fig. 7.48B).
• Histology shows thickening of the basement membrane with ○ Subepithelial map-like patterns surrounded by a faint haze
deposition of fibrillary protein between the basement mem- (Fig. 7.48C).
brane and the Bowman layer. Basal epithelial cell hemides- ○ Whorled fingerprint-like lines.
mosomes are deficient (Fig. 7.48A). ○ Bleb-like subepithelial pebbled glass pattern.
• Onset is in the second decade. About 10% of patients develop • Treatment is similar to that of recurrent corneal erosions.
recurrent corneal erosions in the third decade and the remain-
der are asymptomatic throughout life. The occurrence of Meesmann epithelial dystrophy
bilateral recurrent erosions with no history of trauma suggests Meesmann dystrophy is a rare non-progressive abnormality
basement membrane dystrophy. of corneal epithelial metabolism, underlying which mutations

E F

A B
G H

Fig. 7.48, cont’d (E) histology showing thickening of the epithelial basement membrane and
intraepithelial cysts – PAS stain; (F) Meesmann – myriad intraepithelial cysts; (G) Lisch – grey
bands with a whorled configuration; (H) Lisch – retroillumination showing densely crowded
microcysts
(Courtesy of D Palay, from J Krachmer, M Mannis and E Holland, Cornea, Mosby 2005 – fig. D;
R Fogla – fig. F; W Lisch – figs G and H)

in the genes encoding corneal epithelial keratins have been Others

reported. Other epithelial and subepithelial dystrophies are Lisch epithelial
• Inheritance. AD. corneal dystrophy (Figs 7.48G and H), subepithelial mucinous
• Histology shows irregular thickening of the epithelial base- corneal dystrophy and gelatinous drop-like corneal dystrophy
ment membrane and intraepithelial cysts (Fig. 7.48E). (Fig. 7.48D).
• Symptoms. Patients may be asymptomatic, or there may be
recurrent erosions and blurring (usually mild). Bowman layer/anterior
• Signs
C D
○ Myriad tiny intraepithelial cysts of uniform size but vari-
stromal dystrophies
able density is maximal centrally and extend towards but
Fig. 7.48 Corneal epithelial and subepithelial dystrophies. (A) Histology showing intraepi-
do not reach the limbus (Fig. 7.48F). Reis–Bücklers corneal dystrophy
thelial extension of the basement membrane above the intraepithelial cyst – toluidine blue
stain; (B) Cogan – dots and microcysts; (C) Cogan – map-like pattern; (D) gelatinous drop-like ○ The cornea may be slightly thinned and sensation This may be categorized as an anterior variant of granular stromal
dystrophy; Continued reduced. dystrophy (GCD type 3 – see below) and is also known as corneal
• Treatment other than lubrication is not normally required. basement dystrophy type I (CBD1).
 7
CHAPTER
Cornea 255 256 Corneal Dystrophy

• Inheritance is AD; the affected gene is TGFB1.

• Histology. Replacement of the Bowman layer by connective
tissue bands (Fig. 7.49A).
• Symptoms. Severe recurrent corneal erosions in childhood.
Visual impairment may occur.
• Signs
○ Grey–white geographic subepithelial opacities, most
dense centrally (Fig. 7.49B), increasing in density with
age to form a reticular pattern. Histopathology, includ-
ing electron microscopy, may be required for definitive
distinction from Thiel–Behnke dystrophy in some cases.
○ Corneal sensation is reduced.
• Treatment is directed at the recurrent erosions. Excimer
A B
keratectomy achieves satisfactory control in some patients.
Fig. 7.50 Thiel–Behnke dystrophy
Thiel–Behnke corneal dystrophy
Also termed honeycomb-shaped corneal dystrophy and corneal
basement dystrophy type II (CBD2); features are generally less
severe than Reis–Bücklers. • Symptoms. Recurrent erosions in childhood.
• Inheritance. AD; gene TGFB1 and at least one other. • Signs. Subepithelial opacities are less individually defined than
• Histology. Bowman layer ‘curly fibres’ on electron microscopy. the granular dystrophy-type lesions (see below) seen in Reis–
Bücklers dystrophy. They develop in a network of tiny rings
or honeycomb-like morphology, predominantly involving the
central cornea (Fig. 7.50).
• Treatment is not always necessary.

Stromal dystrophies C D

Lattice corneal dystrophy, TGFB1 type

This is usually regarded as the classic form of lattice dystrophy.
Clinical variants (e.g. IIIA – Fig. 7.51C) associated with more than
25 heterozygous mutations in TGFB1 have been described.
• Inheritance. AD; gene TGFB1.
• Histology. Amyloid, staining with Congo red (Fig. 7.51A) and
A exhibiting green birefringence with a polarizing filter (Fig.
7.51B).
• Symptoms. Recurrent erosions occur at the end of the first
decade in the classic form, when typical stromal signs may not
yet be present. Blurring may occur later.
• Signs
○ Refractile anterior stromal dots (Fig. 7.51D), coalescing E F
into a relatively fine filamentous lattice that spreads gradu-
ally but spares the periphery (Fig. 7.51E). Fig. 7.51 Lattice dystrophy. (A) Histology showing amyloid staining with Congo red; (B) green
○ A generalized stromal haze (Fig. 7.51F) may progressively birefringence of amyloid when viewed through polarized light; (C) lattice dystrophy type IIIA;
impair vision. (D) glassy dots in the anterior stroma in type I; (E) fine lattice lines in type I; (F) early central
○ Corneal sensation is reduced. stromal haze in type I (arrow)
(Courtesy of J Harry – fig. A; C Barry – figs E and F)
• Treatment by penetrating or deep lamellar keratoplasty is
frequently required. Recurrence is not uncommon.
B • Ocular signs • Treatment. Keratoplasty may rarely be required in later
Lattice corneal dystrophy, gelsolin type ○ Sparse stromal lattice lines spread centrally from the life.
Fig. 7.49 Reis–Bücklers dystrophy. (A) Histology showing Also known as LCD2 and Meretoja syndrome, this is a systemic periphery.
replacement of Bowman layer and epithelial basement mem- condition rather than a true corneal dystrophy. ○ Corneal sensation is impaired.
brane by fibrinous tissue; (B) typical moderately discrete
• Inheritance. AD; gene GSN. • Systemic features. Progressive cranial and peripheral neuro- Granular corneal dystrophy, type 1 (classic)
geographical opacities
(Courtesy of J Harry and G Misson, from Clinical Ophthalmic • Histology shows amyloid deposits in the corneal stroma. pathy, mask-like facies and autonomic features. Homozygous • Inheritance. AD; gene TGFB1. Homozygous disease gives
Pathology, Butterworth-Heinemann, 2001 – fig. A; W Lisch – • Ocular symptoms. Ocular irritation and late impairment of disease is rare but severe. more severe features.
fig. B) vision; erosions are rare.
 7
CHAPTER
Cornea 257 258 Corneal Dystrophy

• Treatment is usually not required. Corneal trauma accelerates

progression; refractive surgery is contraindicated.

Macular corneal dystrophy

• Inheritance. Autosomal recessive (AR); gene CHST6; the
condition is relatively common in Iceland.
• Histology. Aggregations of glycosaminoglycans intra- and
extracellularly; stain with Alcian blue and colloidal iron (Fig.
7.54A).
• Symptoms. Early (end of first decade) visual deterioration;
recurrent erosions are very common.
• Signs
○ Dense but poorly delineated greyish-white spots centrally
in the anterior stroma and peripherally in the posterior
stroma (Figs 7.54B and C). There is no clear delineation
Fig. 7.53 Granular dystrophy type II (Avellino) between opacities, which may be elevated.
A B (Courtesy of W Lisch)

A B

C D

Fig. 7.52 Granular dystrophy type I. (A) Histology showing red-staining material with Masson
trichrome; (B) sharply demarcated crumb-like opacities; (C) increase in number and outward
spread; (D) confluence
(Courtesy of J Harry – fig. A)

• Histology. Amorphous hyaline deposits staining bright red • Treatment by penetrating or deep lamellar keratoplasty is
with Masson trichrome (Fig. 7.52A). usually required by the fifth decade. Superficial recurrences
• Symptoms. Glare and photophobia, with blurring as progres- may require repeated excimer laser keratectomy.
sion occurs. Recurrent erosions are uncommon.
• Signs Granular corneal dystrophy, type 2
○ Discrete white central anterior stromal deposits resembling Also known as Avellino and combined granular-lattice dystrophy.
sugar granules, breadcrumbs or glass splinters separated • Inheritance. AD; gene TGFB1.
by clear stroma (Fig. 7.52B). • Histology shows both hyaline and amyloid.
○ Gradual increase in number and size of the deposits with • Symptoms. Recurrent erosions tend to be mild. Visual impair- C D
deeper and outward spread, sparing the limbus (Fig. ment is a later feature.
7.52C). • Signs are usually present by the end of the first decade in Fig. 7.54 Macular dystrophy. (A) Histology showing deposits of abnormal glycosaminoglycans
that appear blue with colloidal iron stain; (B) and (C) poorly delineated deposits increasing in
○ Gradual confluence and diffuse haze lead to visual impair- heterozygotes. Fine superficial opacities progress to form stel- number; (D) increase in size and confluence of lesions, with stromal haze
ment (Fig. 7.52D). late or annular lesions (Fig. 7.53), sometimes associated with (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann,
○ Corneal sensation is impaired. deeper linear opacities. 2001 – fig. A; A Ridgway – figs C and D)
 7
CHAPTER
Cornea 259 260 Corneal Dystrophy

○ Progression of the lesions occurs in conjunction with • Inheritance. Most are sporadic, with occasional AD inherit- ○ Specular reflection shows tiny dark spots caused by
anterior stromal haze, initially involving the central cornea ance. Mutation in COL8A2 has been identified in an early- disruption of the regular endothelial mosaic (Fig. 7.57B).
(Fig. 7.54D). onset variant and in the TCF4 gene in most other cases. Progression occurs to a ‘beaten metal’ appearance (Fig.
○ There is eventual involvement of full-thickness stroma, • Symptoms. Gradually worsening blurring, particularly in the 7.57C).
extending to the limbus with no clear zone. morning, due to corneal oedema. Onset is usually in middle ○ Endothelial decompensation gradually leads to central
○ Thinning is a fairly early feature, with late thickening from age or later. stromal oedema and blurred vision, worse in the
oedema due to endothelial dysfunction. • Signs morning.
○ Sensation is reduced. ○ Cornea guttata: the presence of irregular warts or ‘excres- ○ Epithelial oedema develops in more advanced cases, with
• Treatment. Penetrating keratoplasty. Recurrence is common. cences’ on Descemet membrane secreted by abnormal the formation of microcysts and bullae (bullous keratopa-
endothelial cells (Fig. 7.57A). thy – Fig. 7.57D) accompanied by discomfort. Rupture of
Schnyder (crystalline) corneal dystrophy
This is a disorder of corneal lipid metabolism, associated in some
patients with systemic dyslipidaemia. The use of crystalline in
the name is no longer recommended as corneal crystals are not a
ubiquitous feature.
• Inheritance. AD; gene UBIAD1.
• Histology. Phospholipid and cholesterol deposits.
• Symptoms. Visual impairment and glare.
• Signs
Fig. 7.56 Marked signs in François central cloudy dystrophy
(Courtesy of W Lisch)

○ Central haze is an early feature (Fig. 7.55A), progressing

to more widespread full-thickness involvement over time
(Fig. 7.55B).
○ Subepithelial crystalline opacities are present in only
around 50%.
○ Prominent corneal arcus is typical and gradually pro-
gresses centrally leading to diffuse haze.
• Treatment is by excimer keratectomy or corneal transplantation.
A B
François central cloudy dystrophy
It is not certain that this entity is a dystrophy; it may be clinically
indistinguishable from the degeneration posterior crocodile
shagreen.
A • Inheritance. AD has been reported, but not clearly established.
• Symptoms. Almost always none.
• Signs
○ Cloudy greyish polygonal or rounded posterior stromal
opacities, most prominent centrally (Fig. 7.56).
• Treatment is not required.

Others
Congenital stromal corneal dystrophy, fleck corneal dystrophy,
posterior amorphous corneal dystrophy and pre-Descemet
corneal dystrophy.

Descemet membrane and

D
endothelial dystrophies C

B Fig. 7.57 Fuchs endothelial dystrophy. (A) Histology of cornea guttata showing irregular
Fuchs endothelial corneal dystrophy excrescences of Descemet membrane – PAS stain; (B) cornea guttata seen on specular
Fig. 7.55 Schnyder dystrophy. (A) Early lesion; (B) late appear- This disorder is characterized by bilateral accelerated endothelial reflection; (C) ‘beaten-bronze’ endothelium (arrow); (D) bullous keratopathy
ance showing diffuse haze cell loss. It is more common in women and is associated with a (Courtesy of J Harry – fig. A)
(Courtesy of K Nischal – fig. A; T Carmichael – fig. B) slightly increased prevalence of open-angle glaucoma.
 7
CHAPTER
Cornea 261 262 Corneal Degeneration

bullae is associated with marked acute pain secondary to

the exposure of nerve fibres. Subepithelial scarring and Congenital hereditary endothelial dystrophy
peripheral vascularization may be seen in longstanding Congenital hereditary endothelial dystrophy (CHED) is a rare
cases. dystrophy in which there is focal or diffuse thickening of Descemet
• Treatment membrane and endothelial degeneration. CHED2 is a more
○ Conservative options include topical sodium chloride 5% common and more severe form than CHED1 and is occasionally
drops or ointment, reduction of IOP and use of a hair associated with deafness (Harboyan syndrome).
dryer for corneal dehydration. • Inheritance
○ Ruptured bullae can be made more comfortable by the ○ CHED1 is AD with the gene locus on chromosome 20.
use of bandage contact lenses, cycloplegia, antibiotic oint- CHED1 may not be distinct from PPCD.
ment and lubricants. Anterior stromal puncture may be ○ CHED2 is AR; gene SLC4A11.
helpful. • Symptoms. Photophobia and watering are common in
○ Posterior lamellar (e.g. Descemet membrane-stripping CHED1, but not in CHED2.
endothelial keratoplasty – DSAEK – or Descemet mem- • Signs
brane endothelial keratoplasty – DMEK) and penetrating ○ Corneal clouding and thickening (Fig. 7.59) are neonatal
keratoplasty (see Ch. 7) have a high success rate. in CHED2 and develop during the first year or two in
○ Options in eyes with poor visual potential include CHED1.
conjunctival flaps and amniotic membrane transplanta- ○ Visual impairment is variable and visual acuity may A B
tion. surpass that expected from the corneal appearance.
○ A promising new treatment, topical Rho-kinase inhibitor ○ Nystagmus is more common in CHED2.
with prior transcorneal endothelial cryotherapy, seems • Treatment. Lamellar or penetrating keratoplasty.
to stimulate endothelial cell proliferation and improve
function.
• Cataract surgery may worsen the corneal status because CORNEAL DEGENERATION
of endothelial cell loss and protective steps should be
taken to reduce this. Modern machines using torsional Age-related degeneration
phacoemulsification use less ultrasound time than the older
machines, which used longitudinal phacoemulsification and Arcus senilis
are therefore less likely to cause endothelial loss. A ‘triple Arcus senilis (gerontoxon, arcus lipoides) is the most common
procedure’ (combined cataract surgery, lens implantation peripheral corneal opacity. It frequently occurs without any
and keratoplasty) may be considered in eyes with corneal predisposing systemic condition in elderly individuals, but may
oedema. Corneal oedema is less likely to occur after be associated with dyslipidaemia in younger patients (arcus
cataract surgery if the central corneal thickness is less than juvenilis).
630–640 µm. • Signs
○ Stromal lipid deposition, initially in the superior and
inferior perilimbal cornea, progressing circumferentially Fig. 7.58 Posterior polymorphous dystrophy. (A) Vesicles; (B)
C confluent vesicles (arrow); (C) band-like lesions (arrow)
TIP Persistent corneal oedema may follow cataract surgery to form a band about 1 mm wide (Fig. 7.60A).
(Courtesy of W Lisch – fig. B)
in a patient with Fuchs endothelial dystrophy, particularly ○ The band is usually wider in the vertical than horizontal
if the preoperative central corneal thickness is more than meridian.
630–640 µm. ○ The central border is diffuse, and the peripheral edge is
sharp and separated from the limbus by a clear zone that
may undergo mild thinning.

Posterior polymorphous corneal dystrophy Vogt limbal girdle

There are three forms of posterior polymorphous dystrophy, Vogt limbal girdle is an innocuous condition that is present in up
PPCD1–3. Associations include iris abnormalities, glaucoma and to 60% of individuals over 40 years of age, more commonly in
Alport syndrome. The pathological basis involves metaplasia of women. It consists of whitish crescentic limbal bands composed of
endothelial cells. chalk-like flecks centred at 9 and/or 3 o’clock, more often nasally.
• Inheritance is usually AD. The gene VSX1 has been implicated There may be irregular central extension. Type I may be a variant
in PPCD1, PPCD2 is caused by mutations in COL8A2 and of band keratopathy, featuring a ‘Swiss cheese’ hole pattern and a
PPCD3 by ZEB1 mutations. clear area separating the lesion from the scleral margin (Fig. 7.60B).
A B
• Symptoms. Usually absent, with incidental diagnosis. Type II is more prevalent and is distinguished by the absence of
• Signs. Subtle vesicular, band-like or diffuse endothelial lesions holes and typically also of a juxtalimbal clear zone (Fig. 7.60C).
Fig. 7.59 Congenital hereditary endothelial dystrophy. (A) Bilateral perinatal corneal opacifica-
(Fig. 7.58). Histologically the changes in both are similar to pinguecula and tion; (B) moderate severity in an older child. Visual acuity may surpass that expected from
• Treatment is not required. pterygium. the corneal appearance
(Courtesy of K Nischal – fig. A)
 7
CHAPTER
Cornea 263 264 Corneal Degeneration

Cornea farinata
Cornea farinata is a visually insignificant condition characterized
by bilateral, minute, flour-like deposits in the deep stroma, most
prominent centrally (Fig. 7.60D).

Crocodile shagreen
Crocodile shagreen is characterized by asymptomatic, greyish-white,
polygonal stromal opacities separated by relatively clear spaces
(Fig. 7.60E). 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 may be indistinguishable from François
central cloudy dystrophy; conventionally the distinction is on
the basis of François dystrophy being inherited, but this has been
A B questioned.

West Indian punctate keratopathy

A
This is an unusual condition of unknown cause that is seen
in elderly asymptomatic individuals, generally of West Indian
origin. Males are more affected than females. It normally affects
only one eye, but is occasionally bilateral, with one to four lesions
found in the interpalpebral fissure outside the visual axis. The
lesions are round, measuring 0.5 mm or less and are located at
the level of Bowman membrane, extending just into the super-
ficial stroma. They usually have a central dot which is intensely
white in colour, surrounded by a paler halo which merges with
the adjacent cornea. The corneal epithelium appears normal
and does not stain with fluorescein. Treatment is not required
(Fig. 7.60F).

C D Lipid keratopathy
• Primary lipid keratopathy is rare and occurs apparently
spontaneously. It is characterized by white or yellowish, often
with a crystalline element, stromal deposits consisting of
cholesterol, fats and phospholipids and is not associated with
vascularization (Fig. 7.61A).
• Secondary lipid keratopathy is much more common and is B
associated with previous ocular injury or dis1ease that has
resulted in corneal vascularization. The most common causes Fig. 7.61 Lipid keratopathy. (A) Primary; (B) secondary to
are herpes simplex and herpes zoster keratitis (Fig. 7.61B). vascularization (arrows)
(Courtesy T Carmichael – fig. B)
• Treatment is primarily aimed at medical control of the
underlying inflammatory disease. Other options include:
○ Photocoagulation or needle cautery (suture needle grasped bulbi, silicone oil in the anterior chamber, chronic corneal
with cautery forceps) of feeder vessels. oedema and severe chronic keratitis.
○ Penetrating keratoplasty may be required in advanced but ○ Age-related affecting otherwise healthy individuals.
quiescent disease, though vascularization, thinning and ○ Metabolic (metastatic calcification) secondary to hyper-
reduced sensation may affect the outcome. calcaemia is uncommon and includes causes like hyper-
E F parathyroidism, vitamin D toxicity, milk-alkali syndrome,
Band keratopathy sarcoidosis, end-stage renal disease, Paget disease and
Fig. 7.60 Age-related degenerations. (A) Arcus senilis; (B) Vogt limbal girdle type I; (C) Vogt Band keratopathy consists of the age-related deposition of calcium multiple myeloma. Hyperuricaemia is a rare cause.
limbal girdle type II; (D) cornea farinata (arrow); (E) crocodile shagreen; (F) West Indian
punctate keratopathy (arrow) salts in the Bowman layer, epithelial basement membrane and ○ Hereditary causes include familial cases and ichthyosis.
anterior stroma. • Signs
• Causes ○ Peripheral interpalpebral calcification with clear cornea
○ Ocular. Chronic anterior uveitis (particularly in children separating the sharp peripheral margins of the band from
with juvenile idiopathic arthritis), glaucoma, phthisis the limbus (Fig. 7.62A).
 7
CHAPTER
Cornea 265 266 Metabolic Keratopathy

○ Gradual central spread to form a band-like chalky plaque acid (EDTA) 1.5–3.0% until all calcium has been removed.
containing transparent small holes (Fig. 7.62B) and occa- Adequate time (15–20 minutes) must be allowed for chela-
sionally clefts. tion to occur and more than one session may be necessary.
○ Advanced lesions may become nodular and elevated with Re-epithelialization can take many days.
considerable discomfort due to epithelial breakdown. ○ Other modalities: diamond burr, excimer laser keratec-
• Treatment is indicated if vision is threatened or if the eye tomy and lamellar keratoplasty.
is uncomfortable. It is important to recognize and treat any
underlying condition. Spheroidal degeneration
○ Chelation is simple and effective for relatively mild cases Spheroidal degeneration (Labrador keratopathy, climatic droplet
and is performed using a microscope. The corneal epithe- keratopathy) typically occurs in men whose working lives are spent
lium overlying the opacity and a solid layer of calcification outdoors. Ultraviolet exposure is likely to be an aetiological factor.
are first scraped off with forceps and a scalpel blade (e.g. No. The condition is relatively innocuous but visual impairment may
15). The cornea is then rubbed with a cotton-tipped appli- occur. A secondary form can follow inflammation or injury.
cator dipped in a solution of ethylenediaminetetraacetic • Histology. Irregular proteinaceous deposits in the anterior
stroma that replace the Bowman layer.
• Signs A
○ Amber-coloured granules in the superficial stroma of the
peripheral interpalpebral cornea. Fig. 7.65 Advancing wave-like epitheliopathy (arrow heads).
○ Increasing opacification, coalescence and central spread. Inferior extent illuminated in the slit beam (arrow)
○ Advanced lesions commonly protrude above the corneal
surface (Fig. 7.63) and the surrounding stroma is often
hazy. The conjunctiva can be involved. wear, certain contact lens solutions, topical glaucoma medication,
• Treatment. Protection against ultraviolet damage with sun- prior ocular surgery and some skin conditions such as rosacea.
glasses and superficial keratectomy or lamellar keratoplasty in Treatment of the cause may be curative, but otherwise is with 1%
a minority. silver nitrate solution to the adjacent limbus or cryotherapy (1–2
seconds twice) to the limbus and abnormal tissue. Distinction
Salzmann nodular degeneration from neoplasia may occasionally warrant impression cytology or
Salzmann nodular degeneration consists of nodules of hyaline tissue, excision biopsy.
usually located anterior to the Bowman layer. It can occur in any
form of chronic corneal irritation or inflammation such as trachoma,
dry eye, chronic blepharitis and chronic allergic keratoconjunctivitis.
METABOLIC KERATOPATHY
• Signs
○ Superficial stromal opacities progressing to elevated
Cystinosis
B
A whitish or blue–grey nodular lesions that may be round or Cystinosis is a rare AR (gene: CTNS) lysosomal storage disorder
elongated (Fig. 7.64). characterized by widespread tissue deposition of cystine crystals,
Fig. 7.64 Salzmann nodular degeneration. (A) Typical appear-
○ The base of a nodule may be associated with pannus and ance (arrow); (B) multiple lesions leading to paediatric renal failure and a range of other severe
epithelial iron deposition. (Courtesy of R Bates – fig. B) systemic problems. Non-nephropathic (ocular), nephropathic
and intermediate forms can occur. Keratopathy may develop
in the first year, with progressive deposition of crystals in the
• Treatment consists mainly of lubrication together with control cornea (Fig. 7.66A) and conjunctiva associated with photophobia,
of the cause. Removal is via manual superficial keratectomy – epithelial erosions and visual impairment. Systemic treatment is
the lesions can often be ‘peeled’ away and the surface flattened with cysteamine, which can be given in eye drop form to reverse
with a diamond burr. Adjunctive mitomycin C applied for 10 corneal crystal formation.
seconds with a sponge may reduce the recurrence rate, though
some authorities restrict its use to reoperations. Excimer laser
phototherapeutic keratectomy or lamellar keratoplasty are
Mucopolysaccharidoses
occasionally required. The mucopolysaccharidoses (MPS) are a group of lysosomal
storage disorders involving enzyme dysfunction along the
Advancing wave-like epitheliopathy pathways for breakdown of glycosaminoglycans, long chain
Advancing wave-like epitheliopathy (AWE) is characterized by carbohydrates formerly known as mucopolysaccharides. Al-
an irregular advancing epithelial plaque encroaching gradually on tered metabolites accumulate intracellularly in various tissues.
the cornea, typically originating at the superior limbus (Fig. 7.65) Inheritance is mainly AR. Systemic features vary with the type
B
and sometimes extending circumferentially from a pterygium. of MPS, but can include facial coarseness, skeletal anomalies,
Fig. 7.62 Band keratopathy. (A) Typical appearance outside Fig. 7.63 Spheroidal degeneration Topical fluorescein generally demonstrates the lesion well. Irrita- heart disease and learning difficulties. Keratopathy comprises
the visual axis; (B) advanced disease with small epithelial tion and redness are common. The vision may be affected with punctate corneal opacification and diffuse stromal haze (Fig.
holes central involvement. Reported risk factors include contact lens 7.66B) and occurs in all MPS except Hunter and Sanfilippo. Other
 7
CHAPTER
Cornea 267 268 Contact Lenses

Immunoprotein deposition
Diffuse or focal immunoprotein deposition is a relatively uncom-
mon manifestation of several systemic diseases, including multiple
myeloma, Waldenström macroglobulinaemia, monoclonal
gammopathy of unknown cause, some lymphoproliferative
disorders and leukaemia. Corneal involvement may be the earli-
est manifestation. Bands of punctate flake-like opacities are seen,
mostly at the level of the posterior stroma. Treatment is that of
the underlying disease. Severe corneal involvement may require
corneal transplantation.

Tyrosinaemia type 2
Tyrosinaemia type 2 (oculocutaneous tyrosinaemia, Richner–
Hanhart syndrome) is a very rare AR disease (gene: TAT) in which
an enzyme deficiency leads to elevated plasma tyrosine levels.
A B A
Ocular involvement may occasionally be the presenting feature.
Painful palmar and plantar hyperkeratotic lesions and variable
CNS involvement are seen. A bilateral pseudodendritic keratitis
with crystalline edges often begins in childhood and causes photo-
phobia, watering and redness.

Fabry disease
Fabry disease is an X-linked lysosomal storage disorder caused
by a deficiency of the enzyme alpha-galactosidase A that leads
to abnormal tissue accumulation of a glycolipid. All males with
the gene develop the disease and some heterozygous females.
Systemic features include periodic burning pain in the extremi-
ties (acroparaesthesia) and GI tract, angiokeratomas (Fig. 7.67A),
cardiomyopathy and renal disease. Ocular manifestations include
white to golden-brown corneal opacities in a vortex pattern (75%)
that may be the first feature of the disease (Fig. 7.67B) facilitating
B
early intervention, wedge- or spoke-shaped posterior cataract
C D (Fabry cataract), conjunctival vascular tortuosity (corkscrew
vessels) and aneurysm formation (Fig. 7.67C) and retinal vascular
Fig. 7.66 Metabolic keratopathy. (A) Cystinosis; (B) typical appearance in a mucopolysac- tortuosity.
charidosis; (C) Wilson disease; (D) LCAT (see text) deficiency
(Courtesy of S Chen – fig. C; W Lisch – fig. D)
CONTACT LENSES
ocular features may include pigmentary retinopathy and optic
atrophy.
penicillamine therapy. Anterior capsular ‘sunflower’ cataract is
seen in some patients.
Therapeutic uses
The risks of fitting a contact lens to an already compromised eye

Wilson disease are greater than with lens wear for cosmetic reasons. The benefit–
Lecithin-cholesterol-acyltransferase risk balance should be considered in each case individually, with
Wilson disease (hepatolenticular degeneration) is a rare condi-
tion involving the widespread abnormal deposition of copper in
deficiency education and regular review to ensure early diagnosis and treat-
ment of complications. The choice of lens type is dictated by the
tissues. It is caused by a deficiency of caeruloplasmin, the major Lecithin-cholesterol-acyltransferase (LCAT) deficiency is a nature of the ocular pathology.
copper-carrying blood protein. Presentation is with liver disease, disorder of lipoprotein metabolism that has complete (Norum
basal ganglia dysfunction or psychiatric disturbances. A Kayser– disease, with systemic manifestations including renal failure) Optical
Fleischer ring is present in 95% of patients with neurological signs and partial (fish eye disease, causing only corneal opacification) Optical indications are aimed at improving visual acuity when this
and consists of a brownish-yellow zone of fine copper dusting in forms that are both AR (gene: LCAT). Keratopathy is character- cannot be achieved by spectacles in the following situations: C
peripheral Descemet membrane (Fig. 7.66C). This is best detected ized by numerous minute greyish dots throughout the stroma, • Irregular astigmatism associated with keratoconus can be
on gonioscopy when subtle. The deposits are preferentially often concentrated in the periphery in an arcus-like configuration corrected with rigid contact lenses after spectacles have failed Fig. 7.67 Fabry disease. (A) Angiokeratomas; (B) vortex
distributed in the vertical meridian and may disappear with (Fig. 7.66D). and before corneal grafting becomes necessary. Patients with keratopathy (arrow); (C) conjunctival vessel tortuosity and
astigmatism following corneal grafting may also benefit. aneurysms
 7
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Cornea 269 270 Congenital Anomalies of the Cornea and Globe

• Superficial corneal irregularities can be neutralized by blinking will impair tear circulation under the lens. This is
rigid contact lenses, which provide a smoother and optically exacerbated by lid closure if the lens is worn during sleep.
more regular surface. Visual acuity can only be substantially Hypoxia leads to anaerobic metabolism and lactic acidosis
improved if irregularities are not too severe. that inhibits the normal barrier and pump mechanisms of the
• Anisometropia in which binocular vision cannot be achieved cornea.
by spectacles due to aniseikonia, such as may occur follow- • Superficial punctate keratitis is the most common compli-
ing monocular cataract surgery with high refractive error cation. The pattern may give a clue as to the aetiology. For
correction. example, staining at 3 and 9 o’clock is associated with incom-
plete blinking and drying in rigid lens wearers.
Promotion of epithelial healing • The tight lens syndrome is characterized by indentation and
• Persistent epithelial defects often heal if the regenerating staining of the conjunctival epithelium in a ring around the
corneal epithelium is protected from the constant rubbing cornea.
of the lids, allowing the development of hemidesmosomal • Acute hypoxia is characterized by epithelial microcysts (Fig.
attachments to the basement membrane. 7.68A) and necrosis and endothelial blebs. Very painful mac-
• Recurrent corneal erosions associated with basement mem- roerosions may develop several hours after lenses are removed A B
brane dystrophy may require long-term contact lens wear to following a period of overwear.
reduce the recurrence rate. In post-traumatic cases, lens wear • Chronic hypoxia may result in vascularization (Fig. 7.68B)
can usually be discontinued after a few weeks. Lens wear also and lipid deposition. Superficial peripheral neovascularization
improves comfort. of <1.5 mm is common in myopic contact lens wearers and can
be monitored.
Pain relief • Treatment depends on the cause but may involve:
• Bullous keratopathy can be managed with soft bandage lenses ○ Increasing oxygen permeability by refitting with a thinner
that relieve pain by protecting the exposed corneal nerve lens, a gas permeable rigid lens or a silicone hydrogel soft
endings from the shearing forces of the lids during blinking. lens.
The lens may also flatten bullae into diffuse fine epithelial ○ Modifying lens fit to increase movement.
cysts. ○ Reducing lens wearing time.
• Filamentary keratopathy resistant to topical treatment will
usually achieve some relief from soft contact lens wear. Immune response (hypersensitivity) keratitis
• Other indications include Thygeson superficial punctate A hypersensitivity response to bacterial antigen or the chemicals
keratitis and protection of the corneal epithelium from aber- used in lens care can lead to the development of sterile marginal
rant lashes in trichiasis. They can also be used as a temporizing corneal infiltrates. The mechanism is thought to be similar to that C D
measure in entropion prior to definitive surgery. of marginal keratitis.
• Signs. Mildly red eye associated with infiltrates, often margin- Fig. 7.68 Complications of contact lens wear. (A) Epithelial microcysts in acute hypoxia;
Preservation of corneal integrity ally located, with no or minimal epithelial defects. (B) superior pannus from chronic hypoxia; (C) vascularization and scarring in chronic toxic
• A descemetocoele can be temporarily capped with a tight- • Treatment involves cessation of lens wear until resolution keratitis; (D) acute bacterial keratitis with vascularization
fitting, large-diameter soft or scleral lens to prevent perfora- occurs. Topical antibiotics and steroids may be used in some (Courtesy of S Tuft – fig. A; J Dart – fig. C)
tion and encourage healing. cases, but if the diagnosis is uncertain, treatment should be
• Splinting and apposition of the edges of a small corneal that of bacterial keratitis. lenses (Fig. 7.68D). Bacteria in the tear film are normally unable Microcornea is a rare autosomal dominant (sometimes sporadic)
wound can be achieved by means of a contact lens. Slightly to bind to the corneal epithelium, but following an abrasion unilateral or bilateral condition in which the horizontal corneal
larger perforations may be sealed with glue followed by inser- Toxic keratitis and in association with hypoxia, they can attach and invade the diameter is 10 mm or less over 2 years of age (Fig. 7.69A), or less
tion of a bandage contact lens to both protect the glue and • Pathogenesis. Acute chemical injury may be caused by epithelium. Microorganisms may also be introduced onto the than 9 mm in the newborn. The cornea is steep on keratometry.
prevent irritation of the lids from the glue’s irregular surface. inadvertently placing a contact lens on the eye without first corneal surface by poor lens hygiene or the use of tap water for There may be hypermetropia and a shallow anterior chamber
neutralizing toxic cleaning agents such as hydrogen peroxide. rinsing. but other dimensions are normal. Ocular associations include
Miscellaneous indications Chronic toxicity can result from long-term exposure to dis- glaucoma (angle-closure and open angle), congenital cataract,
• Ptosis props to support the upper lids in patients with ocular infecting preservatives such as thiomersal or benzalkonium Contact lens-associated giant papillary leukoma (Fig. 7.69B), persistent fetal vasculature, coloboma, optic
myopathies. chloride. conjunctivitis nerve hypoplasia, aniridia and nanophthalmos. Systemic associa-
• Maintenance of the fornices to prevent symblepharon forma- • Signs tions have been reported. Refractive error and amblyopia should
tion in cicatrizing conjunctivitis. ○ Acute pain, redness and chemosis on lens insertion, which See Chapter 6. be managed appropriately.
• Drug delivery enhancement by a hydrogel lens imbued with may take 48 hours to resolve completely.
topical medication is an occasional indication. ○ Vascularization and scarring of the cornea (Fig. 7.68C) CONGENITAL ANOMALIES OF THE Microphthalmos
and limbal conjunctiva in chronic cases.
• Treatment may involve switching to daily disposable lenses or
CORNEA AND GLOBE Microphthalmos (microphthalmia – Fig. 7.70A) is a condition
Complications using a non-preserved disinfectant such as hydrogen peroxide.
Microcornea in which the entire eye is small, with an axial length at least two
standard deviations below the mean for age. Simple or pure
Mechanical and hypoxic keratitis Suppurative keratitis The normal neonatal corneal diameter is 10 mm and the adult microphthalmos (nanophthalmos – see below) refers to an eye
• Pathogenesis. Insufficient oxygen transmission through the Contact lens wear is the greatest risk factor for the development diameter of 12 mm is usually reached by the age of 2 years. that is structurally normal apart from a short length and complex
lens. A tightly fitting contact lens that does not move with of bacterial keratitis. The risk is probably least for rigid contact
 7
CHAPTER
Cornea 271 272 Congenital Anomalies of the Cornea and Globe

Anophthalmos Sclerocornea
Anophthalmos (anophthalmia) refers to the complete absence of Sclerocornea is a very rare, usually bilateral, condition that may
any visible globe structure (Fig. 7.71A), though a microphthalmic be associated with cornea plana (see below). Sporadic cases are
remnant or cyst may be present (Fig. 7.71B). It is associated with common, but a milder form can be inherited as AD and a more
other abnormalities such as absence of extraocular muscles, a severe form as AR. Peripheral corneal opacification, with no visible
short conjunctival sac and microblepharon. Causative factors are border between the sclera and cornea, confers the appearance of
probably broadly similar to those of microphthalmos. apparently reduced corneal diameter in mild–moderate disease
(Fig. 7.73A). Occasionally the entire cornea is involved (Fig. 7.73B).

Megalocornea
A Megalocornea is a rare bilateral non-progressive condition that is
usually X-linked recessive. Approximately 90% of affected indi-
viduals are male. The adult horizontal corneal diameter is 13 mm
or more, with a very deep anterior chamber (Fig. 7.72). There is
A usually high myopia and astigmatism but normal corrected visual
acuity. Lens subluxation may occur due to zonular stretching and
pigment dispersion syndrome may occur (see Ch. 11). Numerous
systemic associations have been reported.

Fig. 7.69 (A) Microcornea; (B) microcornea and corneal Fig. 7.72 Clinical appearance of megalocornea
opacity with dense cataract

microphthalmos to eyes with other features of dysgenesis for

example: a coloboma (Fig. 7.70B) or orbital cyst (Fig. 7.70C) and B
a range of other ocular abnormalities. It may be unilateral or
bilateral; when unilateral, abnormalities may be present in the
fellow eye. Vision is variably affected, in conjunction with sever-
A
ity. It is typically sporadic but mutations in numerous genes have
been implicated. Around 50% of cases may be associated with
systemic abnormalities, including of the CNS. Potential environ-
mental causes include fetal alcohol syndrome and intrauterine
A
infections.

Nanophthalmos
In nanophthalmos the entire eye is small with an axial length of
less than 20 mm. Both eyes are usually affected. Ocular associa-
tions include glaucoma (especially angle-closure as the lens is large
relative to the size of the eye), hypermetropia, ametropia, amblyo-
pia and strabismus. In childhood, management of refractive error
and amblyopia are critical. Surgery for glaucoma is particularly C
hazardous and can result in aqueous misdirection and choroidal
B
effusion (‘small eye–big trouble’). Lens extraction is technically Fig. 7.70 (A) Left microphthalmos; (B) left microphthalmos
challenging, but has the advantage of deepening the anterior and bilateral iris colobomas; (C) axial CT showing right micro- B
Fig. 7.71 (A) Bilateral simple anophthalmos; (B) anophthal-
chamber and reducing the refractive error if a suitable high-power phthalmos with cyst
mos with cyst
(Courtesy of L MacKeen – fig. C)
lens implant is inserted. (Courtesy of U Raina – fig. B) Fig. 7.73 Sclerocornea. (A) Moderate; (B) severe
 7
CHAPTER
Cornea 273

Chapter
Corneal and
Refractive Surgery 8
KERATOPLASTY 276 Deep anterior lamellar keratoplasty 280 KERATOPROSTHESES 283
Introduction 276 Endothelial keratoplasty 280
Limbal stem cell grafting 281 REFRACTIVE PROCEDURES 283
Penetrating keratoplasty 277
Introduction 283
Superficial lamellar keratoplasty 279
Laser refractive procedures 286

Fig. 7.74 Cornea plana Fig. 7.75 Keratectasia

(Courtesy of R Visser)

Cornea plana
This is an extremely rare bilateral condition in which the cornea
is flatter than normal (Fig. 7.74) – the radius of curvature is larger.
There is a corresponding reduction in refractive power resulting
in high hypermetropia. Two forms are described, cornea plana
1 (CNA1) being milder than cornea plana 2. Associated ocular
abnormalities are common.

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 of a severely
opacified and sometimes vascularized cornea (Fig. 7.75). It is often
associated with raised IOP.

Posterior keratoconus
Fig. 7.76 Posterior keratoconus (arrow)
Posterior keratoconus is a sporadic condition in which there is (Courtesy of S Johns)
unilateral non-progressive increase in curvature of the posterior
corneal surface. The anterior surface is normal and visual acuity
relatively unimpaired because of the similar refractive indices of
the cornea and aqueous humour. Generalized (involvement of
the entire posterior corneal surface) and localized (paracentral or
central posterior indentation – Fig. 7.76) types are described.
 8
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276 Keratoplasty Corneal and Refractive Surgery 277

increasing tendency to peripheral anterior synechiae forma-

KERATOPLASTY tion and raised intraocular pressure (IOP).
•
Introduction The donor button is usually about 0.25 mm larger in diameter
than the host site.
Corneal transplantation (grafting) refers to the replacement of • Preparation of donor cornea should always precede excision of
diseased host corneal tissue by healthy donor cornea. A corneal host tissue, in case a problem with the former means that the
graft (keratoplasty) may be partial-thickness (anterior or posterior surgery cannot be completed.
lamellar) or full-thickness (penetrating). • Either mechanically guided manual or automated (including
laser) trephination is commonly used.
General indications • The graft may be secured with either continuous (Fig. 8.5A) or
• Optical keratoplasty is performed to improve vision. interrupted (Fig. 8.5B) suture techniques, or a combination of
Important indications include keratoconus, scarring, corneal both.
dystrophies (Fig. 8.1A), pseudophakic bullous keratopathy and
corneal degenerations. Postoperative management
• Tectonic grafting may be carried out to restore or preserve • Topical steroids (e.g. prednisolone acetate 1%, dexamethasone
corneal integrity in eyes with severe structural changes such as phosphate 0.1%) are used to decrease the risk of immuno-
thinning with descemetocoele (US spelling – descemetocele) A logical graft rejection. Initial administration is typically every
(Fig. 8.1B). 2 hours with gradual tapering depending on the likelihood of
• Therapeutic corneal transplantation facilitates removal of Fig. 8.2 Retroillumination of heavily vascularized cornea rejection and clinical progress. Long-term instillation at low
infected corneal tissue in eyes unresponsive to antimicrobial resulting from recurrent herpes simplex keratitis intensity, such as once daily for a year or more, is usual.
(Courtesy of C Barry)
therapy (Fig. 8.1C). • Other immunosuppressants such as oral azathioprine and
• Cosmetic grafting may be performed to improve the appear- topical and systemic ciclosporin are usually reserved for high-
ance of the eye, but is a rare indication. • Receipt of a transplanted organ. risk patients.
• Receipt of human pituitary-derived growth hormone. • Cycloplegia (e.g. homatropine 2% twice daily) is typically
Donor tissue • Brain or spinal surgery before 1992. used for 1–2 weeks.
Donor tissue should be removed within 12–24 hours of death. • Most haematological malignancies. • Oral aciclovir may be used in the context of pre-existing
There is an attempt to age-match donors and recipients. Corneas • Ocular disease such as inflammation and disease likely to herpes simplex keratitis to minimize the risk of recurrence.
from infants (3 years and under) are used only very occasionally, compromise graft outcome, some malignant ocular tumours • Monitoring of IOP. Applanation tonometry is relatively unre-
even for paediatric transplants, as they are associated with surgical, (e.g. retinoblastoma) and corneal refractive surgery. liable so measurement is commonly performed during the
refractive and rejection problems. Most corneas are stored in coor- early postoperative period with a non-applanation method.
dinating ‘eye banks’ prior to transplantation, where pre-release Recipient prognostic factors • Removal of sutures is performed when the graft–host junc-
evaluation includes medical history review and donor blood The following host factors may adversely affect the prognosis of a tion has healed. This is often after 12–18 months, although in
screening to exclude contraindications and microscopic examina- corneal graft and if possible should be optimized prior to surgery. elderly patients it may take much longer. Removal of broken
tion of the cornea including endothelial cell count determination. In general, the most favourable cases are keratoconus, localized or loose individual sutures should be performed as soon as
Corneas are preserved in hypothermic storage (up to 7–10 days) B scars and dystrophies. identified, as this reduces the risk of graft rejection.
or organ culture medium (4 weeks) until needed. Culture allows • Severe stromal vascularization (Fig. 8.2), absence of corneal
extended testing for infective contamination. Contraindications sensation, extreme thinning at the proposed host–graft junc-
to ocular tissue donation are set out below, though there is tion and active corneal inflammation. TIP In a patient with a corneal graft, broken or loose sutures
should be removed as this reduces the risk of localized
international variation and the list is not exhaustive: • Abnormalities of the eyelids, such as blepharitis, ectropion,
vascularization and graft rejection.
• Death from unknown cause. entropion and trichiasis. These conditions should be addressed
• Certain systemic infections such as human immunodeficiency before surgery.
virus (HIV), viral hepatitis, syphilis, congenital rubella, tuber- • Recurrent or progressive forms of conjunctival inflammation,
culosis, septicaemia and active malaria. such as atopic conjunctivitis and ocular cicatricial pemphigoid. Postoperative complications
• Prior high-risk behaviour for HIV and hepatitis such as sex • Tear film dysfunction. • Early complications include persistent epithelial defects, loose
with someone HIV-positive, men who have sex with men, • Anterior synechiae. or protruding sutures (Fig. 8.6A and B) (risk of infection –
intravenous drug abuse and prostitution. • Uncontrolled glaucoma. marked sterile reaction, papillary hypertrophy), wound leak
• Within the last 12 months: sex with someone who has engaged • Uveitis. (sometimes with flat anterior chamber or iris prolapse), uveitis,
in high-risk behaviour, who has received blood clotting factor elevation of intraocular pressure, traumatic graft rupture
concentrates or has undergone tattooing, acupuncture, ear/
body piercing. C
Penetrating keratoplasty (Fig. 8.7A), cystoid macular oedema, microbial keratitis (Fig.
8.7B), endophthalmitis (Fig. 8.7C) and rejection (see below).
• Infectious and possibly infectious diseases of the central Component layer grafting of the cornea is increasingly utilized, A rare complication is a fixed dilated pupil (Urrets-Zavalia
nervous system, such as Creutzfeldt–Jakob disease, systemic Fig. 8.1 (A) Optical penetrating keratoplasty for macular but full-thickness keratoplasty remains commonly performed and syndrome).
sclerosing panencephalitis, progressive multifocal leukoen- corneal dystrophy; (B) tectonic lamellar patch graft for is the appropriate procedure for disease involving all layers of the • Late complications include astigmatism, recurrence of
descemetocoele; (C) penetrating keratoplasty for pseu-
cephalopathy, encephalitis, Alzheimer disease and other cornea (Fig. 8.3 and Fig. 8.4). Key surgical points include: underlying disease, late wound dehiscence, retro-corneal
domonas keratitis – a dense cataract and posterior syn-
dementias, Parkinson disease, multiple sclerosis and motor echiae are visible • A common graft size is 7.5 mm. Smaller grafts may lead to membrane formation, glaucoma, rejection (see below) and
neurone disease. (Courtesy of S Tuft – fig. B) high astigmatism and larger diameters are associated with an failure without rejection.
 8
CHAPTER
278 Keratoplasty Corneal and Refractive Surgery 279

A B A B

C D C D

Fig. 8.3 Excision of host tissue. (A) Partial-thickness trephination; (B) incision into the ante- Fig. 8.4 Fixation of donor button. (A) and (B) Donor button is placed onto the viscoelastic bed;
rior chamber; (C) and (D) completion of excision (C) initial cardinal suture; (D) eight interrupted cardinal sutures in place
(Courtesy of R Fogla) (Courtesy of R Fogla)

Corneal graft rejection cornea of a male donor should not be allocated to female
Immunological rejection of any layer of the cornea can occur. recipients. aggressive regimen is generally required for endothelial • Differential diagnosis includes graft failure (no inflamma-
Rejection of separate layers (endothelial, stromal and epithelial) • Symptoms. Blurred vision, redness, photophobia and pain rejection, followed in order of severity by stromal, sub- tion), infective keratitis including fungal and herpetic, uveitis,
can occur in isolation, but typically a combination is present. are typical, but many cases are asymptomatic until rejection epithelial and epithelial. Intraocular pressure monitoring is sterile suture reaction, raised IOP and epithelial ingrowth.
Simple graft failure can occur in the absence of rejection, although is established. The timing of onset is very variable, occurring critical.
rejection is a common contributory factor. from days to years after keratoplasty. ○ Preservative-free topical steroids hourly for 24 hours are
• Signs vary depending on the type of graft. the mainstay of therapy. The frequency is reduced gradu- TIP In a patient with acute corneal graft rejection, early
○ Ciliary injection associated with anterior uveitis is an early ally over several weeks. Steroid ointment can be used at intensive treatment greatly improves the likelihood of reversing
TIP The risk of corneal graft rejection is increased manifestation (Fig. 8.8A). bedtime as the regimen is tapered. High-risk patients can
the episode of rejection.
significantly by the presence of host stromal vascularization. ○ Epithelial rejection may be accompanied by an elevated be maintained on the highest tolerated topical dose (e.g.

• Pathogenesis. The corneal graft is immunologically privi-

line of abnormal epithelium (Fig. 8.8B) in a quiet or mildly
inflamed eye, occurring at an average of 3 months.
prednisolone acetate 1% four times daily) for an extended
period.
Superficial lamellar keratoplasty
leged, with an absence of blood vessels and lymphatics and ○ Subepithelial rejection is characterized by subepithelial ○ Topical cycloplegia (e.g. homatropine 2% or atropine 1% This involves partial-thickness excision of the corneal epithelium
the presence of relatively few antigen-presenting cells. infiltrates, reminiscent of adenoviral infection (Krachmer once or twice daily). and stroma so that the endothelium and part of the deep stroma
Inflammation and neovascularization contribute to loss of spots – Fig. 8.8C) on the donor cornea, with deeper ○ Topical ciclosporin 0.05% to 2% may be of benefit, but the are left behind as a bed for appropriately partial-thickness donor
this privilege. Important predisposing factors for rejection oedema and infiltrative opacification. onset of action is delayed. cornea. The area grafted depends on the extent of the disease
include eccentric or larger grafts (over 8 mm in diameter), ○ Stromal rejection features deeper haze. It can be chronic ○ Systemic steroids. Oral prednisolone 1 mg/kg/day for 1–2 process to be addressed.
infection (particularly herpetic), glaucoma and previous or hyperacute, the latter in association with endothelial weeks with subsequent tapering. If given within 8 days • Indications
keratoplasty. If the host becomes sensitized to histocompat- rejection. of onset, intravenous methylprednisolone 500 mg daily ○ Opacification of the superficial one-third of the corneal
ibility antigens present in the donor cornea, rejection may ○ Endothelial rejection is characterized by a linear pattern of for up to 3 days may be particularly effective, suppressing stroma not caused by potentially recurrent disease.
result. Human leukocyte antigen (HLA) matching has a keratic precipitates (Khodadoust line – Fig. 8.8D) associ- rejection and reducing the risk of further episodes. ○ Marginal corneal thinning or infiltration as in recurrent
small beneficial effect on graft survival. Gender incompat- ated with an area of inflammation at the graft margin. ○ Subconjunctival steroid injection (e.g. 0.5 ml of 4 mg/ml pterygium, Terrien marginal degeneration and limbal
ibility has recently emerged as an important risk factor for ○ Stromal oedema is indicative of endothelial failure. dexamethasone) is sometimes used. dermoid or other tumours.
graft rejection and failure. Whereas the cornea of a female • Management. Early intensive treatment greatly improves ○ Other systemic immunosuppressants such as ciclosporin, ○ Localized thinning or descemetocoele formation (see Fig.
donor can be used in either male or female recipients, the the likelihood of reversing the rejection. The most tacrolimus or azathioprine can be considered. 8.1B).
 8
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280 Keratoplasty Corneal and Refractive Surgery 281

○ Increased availability of graft material since endothelial commonly performed technique. A small amount of posterior
quality is irrelevant. stromal thickness is transplanted along with DM and endothe-
• Disadvantages lium. In Descemet membrane endothelial keratoplasty (DMEK)
○ Difficult and time-consuming with a high risk of only the DM and endothelium are transplanted.
perforation. Because the graft is only 5–10 microns thick it is difficult to
○ Interface haze may limit the best final visual acuity. handle. However, the grafts are able to attach to the host tissue
○ Postoperative management is similar to penetrating with less unevenness, which leads to more rapid visual recovery.
keratoplasty except that lower intensity topical steroids Visual outcomes and lower rejection rates are achieved, but intra-
are needed and sutures can usually be removed after 6 operative complication rates are higher than DSAEK.
months. • Indications include endothelial disease such as Fuchs
endothelial corneal dystrophy.
• Advantages
Endothelial keratoplasty ○ Relatively little refractive change and a structurally more
A
Endothelial keratoplasty involves removal of diseased endothelium intact globe.
along with Descemet membrane (DM) through a corneoscleral or A ○ Faster visual rehabilitation than penetrating keratoplasty.
corneal incision. Folded donor tissue is introduced through the ○ Suturing is minimized.
same small (2.8–5.0 mm) incision. Descemet stripping (auto- • Disadvantages
mated) endothelial keratoplasty (DSAEK) uses an automated ○ Significant learning curve.
microkeratome to prepare donor tissue and is currently the most ○ Specialized equipment is required.
○ Endothelial rejection can still occur (Fig. 8.10).

TIP Endothelial keratoplasty (DSAEK) results in more rapid

visual improvement and less risk of rejection than penetrating
keratoplasty.

B Limbal stem cell grafting

Stem cells are undifferentiated cells that give rise to the differenti-
Fig. 8.5 Penetrating keratoplasty. (A) Secured by continuous ated cells that form tissues and organs. Tissue-specific stem cells
sutures; (B) interrupted sutures are important for maintaining homeostasis and for tissue repair
(Courtesy of C Barry)
B after injury. Corneal epithelium is constantly self-renewing and
does so throughout life. Progeny of corneal stem cells divide and
differentiate to form basal corneal epithelial cells (transient ampli-
Deep anterior lamellar keratoplasty fying cells) that differentiate into wing cells (post-mitotic cells)
and, finally, superficial squamous cells (terminally differentiated
Deep anterior lamellar keratoplasty (DALK) is a technique in A cells).
which corneal tissue is removed almost to the level of Descemet Various techniques have been described to replenish the limbal
membrane. A theoretical advantage is the decreased risk of rejec- stem cell population in patients with severe ocular surface disease
tion because the endothelium, a major target for rejection, is not and associated stem cell deficiency. These include transplantation
transplanted. The major technical difficulty lies in judging the of a limbal area of limited size from a healthy fellow eye (see Fig.
depth of the corneal dissection as close as possible to Descemet 8.9), complete limbal transplantation of a donor annulus and ex
membrane without perforation and if this is not achieved the vivo expansion by culture of either host or donor stem cells with
visual outcome may be compromised. subsequent transplantation. In patients with unilateral ocular
• Indications involvement in Stevens–Johnson syndrome and ocular cicatricial
○ Disease involving the anterior 95% of corneal thickness pemphigoid, donor tissue should not be taken from the unaffected
with normal endothelium and the absence of breaks or eye (autologous).
scars in Descemet membrane (e.g. keratoconus without a • Signs of limbal stem cell deficiency (LSCD) include:
history of acute hydrops, superficial trauma – Fig. 8.9). C ○ Conjunctivalization of cornea with goblet cells (confirmed
○ Chronic inflammatory disease such as atopic keratocon- with confocal microscopy, impression cytology with acid
junctivitis that carries an increased risk of graft rejection. Fig. 8.7 Postoperative complications. (A) Traumatic graft Schiff stain or monoclonal antibody against cytokeratin
• Advantages rupture and extrusion of intraocular lens implant; (B) micro- 19).
○ No risk of endothelial rejection, although epithelial/ bial keratitis; (C) endophthalmitis ○ Superficial and deep corneal vascularization.
(R Bates – fig. A; S Tuft – fig. C)
subepithelial/stromal rejection may occur. B ○ Fibrovascular pannus.
○ Less astigmatism and a structurally stronger globe com- ○ Persistent epithelial defects.
pared with penetrating keratoplasty. Fig. 8.6 (A) Protruding suture; (B) broken suture within stroma ○ Scarring.
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282 Keratoplasty Corneal and Refractive Surgery 283

A B

Fig. 8.9 Deep anterior lamellar keratoplasty for chemical Fig. 8.11 Keratoprosthesis
injury. A superior conjunctival limbal autograft has also been (Courtesy of R Bates)
performed

○ Visual acuity of counting finger or less in the better eye.

○ Intact optic nerve and retinal function, without marked
glaucomatous optic neuropathy.
○ High patient motivation.
• Complications include glaucoma (up to 75%), retroprosthesis
membrane formation, tilting or extrusion, retinal detachment
and endophthalmitis. Glaucoma management is inevitably
extremely challenging.
• Results. Approximately 80% of patients achieve visual acuity
C D between counting fingers and 6/12 and occasionally even
better. A poor outcome is often associated with pre-existing
Fig. 8.8 Allograft rejection. (A) Ciliary injection; (B) elevated epithelial line in epithelial rejec- optic nerve or retinal dysfunction.
tion (arrow); (C) Krachmer spots; (D) endothelial rejection with Khodadoust line (arrow). Note
intense peripheral vascularization
(Courtesy of S Tuft – figs A, B and C)
Fig. 8.10 Endothelial graft undergoing rejection REFRACTIVE PROCEDURES
(Courtesy of C Barry)
Introduction
• Algorithm for surgical interventions for LSCD ○ Ocular surface malignancy. Refractive surgery encompasses a range of procedures aimed at
○ All associated abnormalities (lids, conjunctiva, intraocular ○ Contact lens-related pathology.
pressure) should be treated first. • Advantages
KERATOPROSTHESES changing the refraction of the eye by altering the cornea or lens,
the principal refracting components. Myopia, hypermetropia
○ When the visual axis is involved, sequential sector ○ Regeneration of corneal surface epithelium. Keratoprostheses (Fig. 8.11) are artificial corneal implants used (hyperopia) and astigmatism can all be addressed, though correc-
conjunctival epitheliectomy should be considered with a ○ Visual improvement and improved comfort. in patients unsuitable for keratoplasty. The modern osteoodon- tion of presbyopia is yet to be achieved on a consistently satisfac-
sector limbal transplant. • Disadvantages tokeratoprosthesis consists of the patient’s own tooth root and tory basis.
○ In total unilateral stem cell deficiency, auto limbal trans- ○ Autologous graft: conjunctivalization, filamentary kerati- alveolar bone supporting a central optical cylinder and is usually
plantation is the procedure of choice. tis, scarring of donor eye. covered with a buccal mucous membrane graft. Surgery is difficult Correction of myopia
○ In total bilateral stem cell deficiency, use of allografts ○ Allogenic graft: infection (especially in immune- and time-consuming and is performed in two stages, 2–4 months • Surface ablation procedures (see below) can correct low–
from a living related donor or a cadaver donor is the only compromised patients), rejection. apart. moderate degrees of myopia.
option. • Indications • Laser in situ keratomileusis (LASIK – see below) can correct
• Indications ○ Bilateral blindness from severe but inactive anterior moderate to high myopia depending on initial corneal thick-
○ Congenital: for example, aniridia. segment disease with no realistic chance of success from ness, but for very high refractive errors one of the intraocular
○ Traumatic: chemical and thermal burns. TIP An important sign of limbal stem cell deficiency is conventional keratoplasty, e.g. Stevens–Johnson syn- procedures below is necessary.
○ Chronic inflammatory disease: Stevens–Johnson syn- colonization of the cornea with goblet cells, detected with drome, ocular cicatricial pemphigoid, chemical burns and • Refractive lenticule extraction (see below) is a newer tech-
impression cytology.
drome, ocular cicatricial pemphigoid. trachoma. nique for the correction of myopia and myopic astigmatism.
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284 Refractive Procedures Corneal and Refractive Surgery 285

• Clear lens exchange gives very good visual results but carries lens (Fig. 8.12B) and supported in the ciliary sulcus. The
a small risk of the complications of cataract surgery (see lens is composed of material derived from collagen (Col-
Ch. 10), particularly retinal detachment in individuals with lamer) with a power of −3 D to −20.50 D. Visual results are
high myopia. usually good, but complications include uveitis, pupillary
• Iris clip (‘lobster claw’) implant is attached to the iris (Fig. block, endothelial cell loss, cataract formation and retinal
8.12A). Complications include subluxation or dislocation due detachment.
to dislodgement of one or both attachments, an oval pupil, • Radial keratotomy (Fig. 8.13) is now predominantly of histori-
endothelial cell loss, cataract, pupillary-block glaucoma and cal interest.
retinal detachment.
• Phakic posterior chamber implant (implantable contact Correction of hypermetropia (hyperopia)
lens, ICL) is inserted behind the iris and in front of the • Surface ablation procedures can correct low degrees of
hypermetropia.
• LASIK can correct up to 4 D.
• Conductive keratoplasty (CK) involves the application of
radiofrequency energy to the corneal stroma and can correct
low–moderate hypermetropia and hypermetropic astig-
A
matism. Burns are placed in one or two rings in the corneal
periphery using a probe. The resultant thermally induced Fig. 8.14 Thermal keratoplasty
stromal shrinkage is accompanied by an increase in central (Courtesy of H Nano Jr)
corneal curvature. Significant regression may occur but the
procedure can be repeated. CK may also be helpful for pres-
byopia (see below). Complications are infrequent.
• Laser thermal keratoplasty with a holmium laser can correct
low hypermetropia. Laser burns are placed in one or two rings (the steep meridian). The resultant flattening of the steep
in the corneal mid-periphery (Fig. 8.14). As with CK, thermally meridian coupled with a smaller steepening of the flat merid-
induced stromal shrinkage is accompanied by increased ian at 90° to the incisions reduces astigmatism. The desired
corneal curvature. Correction decays over time but treatment result can be controlled by varying the length and depth of
can be repeated. the incisions and their distance from the optical centre of the
• Other modalities include clear lens extraction and phakic lens cornea. Arcuate keratotomy may be combined with compres-
implants as described above for myopia. Intraocular surgical sion sutures placed in the perpendicular meridian, when treat-
A procedures are the only options for high degrees of refractive ing large degrees of astigmatism such as can occur following
error. penetrating keratoplasty.
• PRK and LASEK can correct up to 3 D.
Correction of astigmatism • LASIK can correct up to 5 D. B
• Limbal relaxing incisions/arcuate keratotomy involves • Lens surgery involves using a ‘toric’ intraocular implant incor-
Fig. 8.15 Correction of astigmatism. (A) Arcuate keratotomies;
making paired arcuate incisions on opposite sides of the porating an astigmatic correction (Fig. 8.15B). Postoperative
(B) toric intraocular implant in situ – markings incorporated
cornea (Fig. 8.15A) in the axis of the correcting ‘plus’ cylinder rotation of the implant away from the desired axis occurs in a in the lens (arrows) facilitate correct orientation
minority of cases. (Courtesy of C Barry – fig. A)
• Conductive keratoplasty (see ‘Correction of hypermetropia’
above).

Correction of presbyopia
• Lens extraction, either to treat cataract or for purely refractive contraindication to the holding of a private or commercial
purposes. Acronyms used include clear lens exchange (CLE), pilot’s licence, or to military service.
refractive lens exchange (RLE) and presbyopic lens exchange ○ ‘Monovision’ consists of the targeting of IOL-induced
(PreLEx). Much research effort is being applied to the devel- refractive outcomes so that one eye (usually the dominant)
opment of effective accommodating prosthetic lenses. is optimized for clear uncorrected distance vision and the
○ Implantation of a multifocal, bifocal or ‘accommodating’/ other for near or intermediate vision, in order to facilitate
B pseudo-accommodative intraocular lens implant (IOL) both good distance and near vision when the eyes are used
can optically restore some reading vision, but reading together.
Fig. 8.12 Phakic intraocular implants for correction of myopia. glasses still have to be used for some tasks. Most recipients ○ Some studies show similar levels of functional near vision
(A) Anterior chamber iris claw implant with anterior iris attach- of multifocal IOLs are happy with the visual outcome. using bilateral distance-optimized monofocal IOLs in
ment at 3 and 9 o’clock; (B) emplacement of a posterior However, dissatisfaction may occur as a consequence comparison to multifocal IOLs.
chamber phakic implant between the iris and anterior lens
surface of nocturnal glare and reduced contrast sensitivity and • Conductive keratoplasty (see ‘Correction of hypermetropia’
(Courtesy of J Krachmer, M Mannis and E Holland, from Fig. 8.13 Radial keratotomy around 10% subsequently undergo IOL exchange surgery. above). There is some evidence that CK can impart a degree of
Cornea, Mosby 2005 – fig. B) (Courtesy of C Barry) In some jurisdictions, implantation of a multifocal IOL is a multifocal functionality to the cornea.
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• Laser-induced monovision refers to the use of laser refractive Laser refractive procedures be used to treat higher refractive errors than surface ablation low–moderate hypermetropia. The main disadvantages compared
surgery to optimize one eye for distance and the fellow for near techniques (see below): hypermetropia up to 4 D, astigmatism with LASIK are the lower degrees of refractive error correctable
or intermediate vision (see above under ‘Lens extraction’). To settle any contact lens-induced corneal distortion prior to up to 5 D and myopia up to 12 D depending on initial corneal and slower epithelial healing with unpredictable postoperative
• Corneal multifocality. Several different approaches are definitive keratometry, soft contact lenses should probably be thickness. To decrease the risk of subsequent ectasia, a residual discomfort. However, as a flap is not created there is a lower risk of
under development utilizing a laser procedure to alter the discontinued for 2 weeks and hard/rigid gas permeable lenses for corneal base at least 250 µm thickness must remain after abla- serious complications than with LASIK, including corneal ectasia
shape of the cornea such that a bifocal or transitional effect at least 3 weeks (some surgeons suggest 1 week for each year of tion. The amount of tissue removed, and therefore the amount and late flap dislocation and it may be the procedure of choice for
is induced. wear to date). of refractive error correctable, is limited by the original corneal patients at higher than average occupational or leisure-related risk
• Scleral expansion surgery. Results have been inconsistent and thickness. It follows that high refractive errors can be addressed of eye injury. It is also suitable for patients rendered ineligible for
unpredictable and this technique has not achieved sustained Laser in situ keratomileusis only by an intraocular procedure. In addition to treatment of a LASIK due to low corneal thickness. Other indications for surface
popularity. Laser (or laser-assisted) in situ keratomileusis (LASIK) is a very wider range of refractive errors, advantages over surface ablation ablation rather than LASIK include epithelial basement membrane
• Intracorneal inlays (Fig. 8.16A–D) commonly provide common refractive procedure. The excimer laser, which can ablate include greater postoperative comfort, faster visual rehabilitation, disease, prior corneal transplantation or radial keratotomy and
substantial benefit in presbyopia, though in the past the bio- tissue to a precise depth with negligible disruption of surrounding more rapid stabilization of refraction and milder stromal haze. large pupil size.
compatibility of some materials has been relatively poor and areas, is used to reshape corneal stroma exposed by the creation The major disadvantage is the potential for serious flap-related • Technique
complications such as extrusion can necessitate removal. of a superficial flap. The flap remains attached by a hinge to complications. ○ The corneal epithelium is removed prior to ablation.
• Laser modification of the natural lens. Research is ongoing facilitate accurate and secure repositioning. Myopia is corrected • Technique Methods used may include a sponge, an automated brush
into the use of a femtosecond laser to modulate crystalline lens by central ablative flattening and hypermetropia by ablation of the ○ A suction ring centred on the cornea is applied to the globe (Amoils epithelial scrubber) and alcohol.
elasticity. periphery so that the centre becomes steeper. LASIK can generally which raises the intraocular pressure substantially. ○ Ablation of the Bowman layer and anterior stroma (Fig.
○ The ring stabilizes the eye and provides the guide track for 8.18) is performed, generally taking 30–60 seconds. In
a mechanical microkeratome, which is advanced across modern systems, sophisticated tracking mechanisms
the cornea to create a thin flap. The flap can also be created adjust laser targeting with eye movement and will pause
using a femtosecond (and recently a picosecond) laser the procedure if the eye is significantly decentred.
microkeratome. ○ The epithelium usually heals within 48–72 hours. A
○ The flap is reflected (Fig. 8.17A) and the bed reshaped, bandage contact lens is generally used to minimize dis-
followed by flap repositioning. comfort. Subepithelial haze invariably develops within
• Intraoperative complications include ‘buttonholing’ (pene- 2 weeks and commonly persists for several weeks to
tration) or amputation of the flap, incomplete or irregular flap months. Diminished final visual acuity is rare but there
creation and, rarely, penetration into the anterior chamber. may be decreased contrast and nocturnal glare. Intraop-
• Postoperative complications erative application of mitomycin C (mitomycin-LASEK or
○ Tear instability is almost universal and may require M-LASEK) may reduce haze.
treatment. • Complications include slowly healing epithelial defects,
○ Wrinkling (Fig. 8.17B), distortion or dislocation of the corneal haze with blurring and haloes, poor night vision and
flap. regression of refractive correction. Uncommon problems
○ Subepithelial haze (Fig. 8.17C) with resultant glare, espe- include decentred ablation, scarring, abnormal epithelial
cially at night. healing, irregular astigmatism, reduced corneal sensation,
○ Persistent epithelial defects. sterile infiltrates, infection and acute corneal necrosis.
A B ○ Epithelial ingrowth under the flap (Fig. 8.17D). • Variations of PRK. A range of procedural variations with
○ Diffuse lamellar keratitis (‘sands of the Sahara’ – Fig. 8.17E) correspondingly varying terminology have been described.
may develop 1–7 days following LASIK. It is characterized LASEK (laser epithelial keratomileusis or laser-assisted
by granular deposits at the flap interface. Treatment is subepithelial keratectomy), Epi-LASIK (epipolis or epithelial
with intensive topical antibiotic and steroid. LASIK; epipolis is a Greek word meaning superficial), modi-
○ Bacterial keratitis (Fig. 8.17F) is rare. fied PRK, advanced surface (laser) ablation (ASA or ASLA)
○ Corneal ectasia (see Ch. 7). ‘Forme fruste’ (occult/mild) and Trans-PRK (trans-epithelial PRK) are variations of PRK
keratoconus and a low post-ablation corneal thickness are that utilize a variety of techniques to try to reduce discom-
the major risk factors and careful pre-procedure screening fort and post-laser haze and to speed visual recovery. ASA
should be performed to detect any predisposition. and modified PRK are sometimes used generally to refer to
all surface ablative procedures. In LASEK the epithelium is
detached and peeled back after pre-treatment with dilute
TIP LASIK may cause transient symptoms of dry eye and alcohol. Laser is then applied and the epithelium repositioned.
glare secondary to subepithelial haze. Epi-LASIK employs a mechanical device, an epikeratome, to
elevate a hinged sheet of epithelium with an oscillating blunt
C D plastic blade and alcohol application is not usually required.
Surface ablation procedures Some recent reports suggest that healing occurs more
Fig. 8.16 Intracorneal inlays for presbyopia correction. (A) and (B) Refractive inlay; (C) and (D) Like LASIK, photorefractive keratectomy (PRK) employs excimer rapidly if the epithelium is simply detached entirely without
small aperture inlay – utilizes the pinhole effect laser ablation to reshape the cornea. PRK is able to correct myopia replacement (flap-off Epi-LASIK). In Trans-PRK, epithelial
(Courtesy of C Barry) up to 6 D (sometimes higher), astigmatism up to around 3 D and ablation is performed with the laser prior to the refractive
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288 Refractive Procedures Corneal and Refractive Surgery 289

ablation, reducing operative time and possibly conferring

other benefits.

Refractive lenticule extraction

Refractive lenticule extraction (ReLEx) is a relatively new tech-
nique that uses a femtosecond laser to cut a lens-shaped piece of
corneal tissue (a lenticule) within the intact cornea. This is then
removed via either a LASIK-style flap or more recently using
a minimally invasive 4 mm incision (small incision lenticule
extraction – SMILE). Potential advantages include less marked
biomechanical and neurological corneal disturbance than LASIK
and a likely lower risk of infection and other flap complications.
Surface disturbance is minimal in comparison to surface ablation
procedures.
A B

Fig. 8.18 Corneal ablation during photorefractive keratectomy

(PRK or advanced surface (laser) ablation – ASA/ASLA)
(Courtesy of C Barry)

C D

E F

Fig. 8.17 Laser in situ keratomileusis (LASIK). (A) Elevating the flap; (B) retroillumination
showing the wrinkling of the flap; (C) subepithelial haze; (D) epithelial ingrowth; (E) diffuse
lamellar keratitis (‘sands of the Sahara’); (F) bacterial keratitis
(Courtesy of Eye Academy – fig. A; H Nano Jr – fig. C; M Leyland – fig. D; S Tuft – fig. E; R
Bates – fig. F)