Diseases of the Cornea

Overview and Classification

1. Infections (Keratitis) - bacterial, fungal, viral, protozoal, helminthic
2. Corneal Ectasias - keratoconus, pellucid marginal degeneration
3. Corneal Dystrophies - epithelial, Bowman layer, stromal, endothelial
4. Corneal Degenerations - age-related and other
5. Metabolic Keratopathies - drug-induced, systemic disease
6. Immune-mediated / Hypersensitivity disorders
7. Interstitial Keratitis

1. BACTERIAL KERATITIS

Pathogens

• Pseudomonas aeruginosa - Gram-negative; responsible for >60% of contact lens-related keratitis; typically aggressive
• Staphylococcus aureus - Gram-positive, coagulase-positive; presents with a focal, well-defined white or yellow-white infiltrate
• Streptococci (S. pyogenes, S. pneumoniae) - often aggressive
• Neisseria gonorrhoeae, C. diphtheriae, H. influenzae - can penetrate an intact epithelium

Risk Factors

• Contact lens wear (especially extended-wear soft lenses) - the most important risk factor
• Corneal trauma, including refractive surgery (LASIK)
• Ocular surface disease, dry eye
• Topical steroid use
• Systemic immunosuppression

Clinical Features

• Pain, photophobia, redness, discharge, reduced vision
• Stromal infiltrate with overlying epithelial defect
• Anterior chamber reaction, hypopyon in severe cases
• Pseudomonas: rapid progression, stromal lysis, ring infiltrate
• S. aureus: fairly well-demarcated yellow-white infiltrate

Management

• Corneal scraping for microscopy and culture before treatment
• Intensive topical fluoroquinolones (ciprofloxacin or moxifloxacin) first-line
• Fortified antibiotics (vancomycin + ceftazidime/tobramycin) for severe cases
• Cycloplegia for pain and to prevent posterior synechiae

2. FUNGAL KERATITIS

Pathogens

• Yeasts (Candida) - predominant in temperate climates, immunocompromised hosts
• Filamentous fungi (Fusarium, Aspergillus) - predominant in tropical climates; often post-trauma with plant material

Predisposing Factors

Clinical Features

• Gradual onset of pain, grittiness, photophobia, blurred vision
• Candida: dense, yellow-white suppurative infiltrate
• Filamentous: grey/yellow-white stromal infiltrate with indistinct fluffy margins, feathery branch-like extensions, satellite lesions
• Progressive necrosis and thinning
• Penetration of Descemet membrane can occur without frank perforation → endophthalmitis

Management

• Natamycin (5%) - first-line for filamentous fungi
• Voriconazole - broad-spectrum, good penetration
• Amphotericin B - for Candida and some filamentous
• Treatment often prolonged (weeks to months); penetrating keratoplasty may be required

3. HERPES SIMPLEX KERATITIS (HSK)

Epithelial (Dendritic) Keratitis

• Linear-branching (dendritic) ulcer with characteristic terminal buds staining with fluorescein
• Virus-laden marginal cells stain with rose Bengal
• Reduced corneal sensation
• Inadvertent topical steroid use causes enlargement to a geographic/amoeboid ulcer

Disciform (Stromal Immune) Keratitis

• Central disc-shaped stromal edema with overlying epithelial bullae
• Descemet folds
• Reduced corneal sensation
• Mild anterior uveitis

Treatment

• Epithelial: topical aciclovir 3% ointment 5x/day for 10-14 days (or ganciclovir gel)
• Disciform: topical steroids + antiviral cover
• Long-term oral aciclovir/valaciclovir reduces recurrence frequency (HEDS trial)

4. ACANTHAMOEBA KERATITIS

Epidemiology

Clinical Features

• Pain often disproportionately severe relative to clinical signs (pathognomonic clue)
• Early: irregular, greyish epithelial surface; pseudodendrites (mimics HSV)
• Radial keratoneuritis (perineural infiltrates) - virtually pathognomonic
• Ring abscess formation (late stage)
• Scleritis (reactive)
• Often misdiagnosed initially as herpes simplex keratitis

Investigations

• Calcofluor white or PAS staining of scrapings (detects cysts)
• Non-nutrient agar seeded with dead E. coli for culture
• In vivo confocal microscopy
• PCR

Treatment

• Polyhexamethylene biguanide (PHMB) + propamidine isethionate (Brolene) - first-line
• Chlorhexidine as alternative
• Avoid steroids before commencing specific treatment
• Treatment is prolonged (6+ months)

5. INTERSTITIAL KERATITIS (IK)

Syphilitic IK

• Usually due to congenital syphilis; presents between ages 5-25 years
• Bilateral in 80% (but usually not simultaneous)
• Deep stromal vascularization giving a "salmon patch" appearance
• Granulomatous anterior uveitis
• After months, cornea clears with ghost vessels (non-perfused vessels) remaining
• Associated systemic signs: Hutchinson teeth, saddle-nose deformity, sensorineural deafness, sabre tibiae

Cogan Syndrome

• Non-syphilitic IK + audiovestibular dysfunction
• Associated with systemic vasculitis (up to 10% develop aortitis)
• Treatment: systemic steroids

6. CORNEAL ECTASIA

Keratoconus (KC)

• Prevalence: 0.1-0.2%; slightly more common in men
• Onset: typically teens to twenties
• Risk factors: eye rubbing, allergy, eczema, asthma
• Systemic associations: Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta

Signs

• "Oil droplet" red reflex on ophthalmoscopy (classic sign)
• "Scissoring" retinoscopy reflex
• Vogt striae: fine vertical stress lines in deep stroma
• Munson sign: V-shaped deformation of lower eyelid on downgaze
• Fleischer ring: iron deposition at base of cone (Perl's stain)
• Corneal thinning and protrusion
• Acute hydrops: sudden Descemet rupture → corneal edema → spontaneously resolves over 3 months

Grading

• Mild: <48 D, Moderate: 48-54 D, Severe: >54 D (corneal power on keratometry)

Management

7. CORNEAL DYSTROPHIES

General rule: most dystrophies are bilateral, affect primarily one layer, and are slowly progressive.

A. Epithelial Dystrophies

• Usually sporadic (degenerative); rare AD familial cases
• Thickening of basement membrane; deficient hemidesmosomes
• Classic "map-dot-fingerprint" pattern
• ~10% develop recurrent corneal erosions
• Treatment: lubricants, hypertonic saline, PTK (phototherapeutic keratectomy)

• Rare, AD; mutations in corneal epithelial keratin genes
• Myriad tiny intraepithelial cysts of uniform size, maximal centrally
• Usually mild symptoms; recurrent erosions possible

B. Bowman Layer / Anterior Stromal Dystrophies

• AD; gene TGFB1
• Histology: replacement of Bowman layer by connective tissue
• Grey-white geographic subepithelial opacities, denser centrally
• Severe recurrent erosions in childhood; visual impairment with age

• AD; gene TGFB1 and others
• "Curly fibres" on electron microscopy
• Honeycomb-like subepithelial opacities
• Less severe than Reis-Bücklers

C. Stromal Dystrophies

• AD; gene TGFB1
• Histology: amyloid deposits staining with Congo red; green birefringence with polarizing filter
• Recurrent erosions + progressive visual deterioration
• Signs: fine linear branching opacities in anterior stroma, with intervening haze; clear peripheral zone
• Treatment: PTK; penetrating keratoplasty in advanced cases; recurrence in grafts common

• AD; gene TGFB1
• Histology: hyaline deposits (Masson trichrome stain: red)
• Well-defined, discrete white granular opacities in anterior stroma, separated by clear intervals
• Superficial erosions may occur

• Autosomal recessive (unusual among dystrophies); gene CHST6
• Histology: glycosaminoglycan accumulation; stains with Alcian blue and colloidal iron
• Dense greyish-white spots in anterior stroma centrally; no clear zone between opacities
• Progression to full-thickness stroma; corneal thinning; worst visual prognosis among stromal dystrophies
• Treatment: penetrating keratoplasty (frequent recurrence)

• AD; gene UBIAD1
• Disorder of corneal lipid metabolism; phospholipid and cholesterol deposits
• Central haze, glare; corneal crystals (variable)
• Associated systemic dyslipidaemia in some patients

D. Endothelial Dystrophies

• Most common endothelial dystrophy; usually sporadic; more common in women
• AD in familial cases
• Histology: guttae (excrescences of Descemet membrane), endothelial cell loss
• Early: bilateral guttae (cornea guttata), halos/glare, worse in morning
• Late: stromal and epithelial edema, painful bullous keratopathy, visual failure
• Treatment: DSEK/DMEK (Descemet membrane endothelial keratoplasty) preferred over penetrating keratoplasty

• AR (CHED2, gene SLC4A11); presents at birth or shortly after
• Diffuse ground-glass corneal clouding; nystagmus may develop
• Treatment: early keratoplasty

• AD; usually asymptomatic
• Vesicular, band-like or diffuse endothelial lesions
• Rarely progresses to corneal edema

8. CORNEAL DEGENERATIONS

Age-Related Degenerations

• Most common peripheral corneal opacity
• Stromal lipid deposition in perilimbal cornea forming a white band ~1 mm wide; sharp peripheral edge, diffuse central border, clear zone between band and limbus
• In elderly, no systemic significance; in younger patients (arcus juvenilis) investigate for dyslipidaemia

• Present in up to 60% of individuals >40 years
• Whitish crescentic bands at 3 and 9 o'clock; harmless

• Bilateral minute flour-like deposits in deep stroma; visually insignificant

Other Degenerations

• Calcium deposition in Bowman layer, progressing as a band across the interpalpebral zone
• Causes: chronic ocular inflammation (especially JIA-associated uveitis), hypercalcaemia, renal failure, sarcoidosis, chronic corneal disease
• Treatment: EDTA chelation under topical anaesthesia; PTK

• Triangular fibrovascular growth of conjunctival tissue encroaching onto cornea, usually nasally
• Risk factors: UV exposure, dry/dusty environments
• Treatment: surgical excision with conjunctival autograft (bare sclera technique has high recurrence)

• Yellow-white deposits in bulbar conjunctiva at 3 and 9 o'clock; does not usually extend onto cornea

• Inferior peripheral thinning without vascularization or inflammation
• Differentiated from keratoconus by inferior peripheral (not central/paracentral) location
• Treatment similar to keratoconus

• Bilateral, slowly progressive peripheral thinning; predominantly superior
• Non-inflammatory; vascularized

9. METABOLIC KERATOPATHY / DRUG-INDUCED

• Whorl-like golden-brown opacities in corneal epithelium below the pupil
• Causes: amiodarone (virtually all patients), antimalarials (chloroquine/hydroxychloroquine), Fabry disease, numerous other drugs

• Yellowish-brown granular deposits in endothelium, Descemet membrane and deep stroma

• Kayser-Fleischer ring: golden-brown copper deposits in peripheral Descemet membrane; seen in hepatolenticular degeneration

10. IMMUNE / HYPERSENSITIVITY-MEDIATED DISEASE

• Bacterial (staphylococcal) hypersensitivity reaction
• Peripheral crescent-shaped infiltrates with a clear zone between infiltrate and limbus
• Distinct from bacterial keratitis (no organisms in infiltrate)
• Treatment: topical steroids ± antibiotics (for associated blepharitis)

• Nodular hypersensitivity reaction at limbus; associated with TB, staphylococcal antigen
• Leads to corneal vascularization if repeated

• Progressive painful peripheral ulceration; cause unknown (possibly autoimmune)
• Bilateral form is more common in Africa
• Treatment: aggressive immunosuppression; keratoplasty in severe cases

Summary Table: Key Differentiating Features

Keratoconus - Notes

Definition

• Central or paracentral corneal stromal thinning
• Apical protrusion (cone formation)
• Irregular astigmatism and progressive myopia

Epidemiology

• Prevalence: 0.1-0.2% of the population
• Slightly more common in males
• Typically presents in the teens or twenties
• Initially unilateral, but both eyes are eventually affected in almost all cases (at least on topography)
• ~50% of clinically normal fellow eyes progress to KC within 16 years

Genetics

• Most cases are sporadic (no family history)
• Only ~10% of offspring develop KC
• Autosomal dominant with incomplete penetrance has been proposed

Associations

Risk Factors

• Eye rubbing (persistent, from any cause) - modifiable and important
• Allergy, asthma, eczema
• Atopic disease (vernal keratoconjunctivitis - strong ocular association)

Systemic Associations

Ocular Associations

• Vernal keratoconjunctivitis
• Blue sclera
• Aniridia
• Leber congenital amaurosis
• Retinitis pigmentosa

Clinical Features

Symptoms

• Progressive, often initially unilateral blurring of vision
• Increasing myopia and astigmatism
• Monocular diplopia / ghost images
• Glare and haloes
• Difficulty with spectacle correction (frequently changing prescription)
• Occasionally first presents with acute hydrops

Signs

On Ophthalmoscopy

On Retinoscopy

• Irregular "scissoring" reflex

On Slit-Lamp Biomicroscopy

Acute Hydrops

• Mechanism: Sudden rupture in the stretched Descemet membrane → aqueous floods the stroma → acute corneal edema
• Symptoms: Sudden onset pain, photophobia, dramatically decreased vision, lacrimation
• Signs: Localized opaque area of stromal edema; may be sectoral or diffuse
• Resolution: Descemet break heals within 6-10 weeks; edema gradually clears
• Outcome: Variable stromal scarring; paradoxically, scarring can sometimes flatten the cone and improve VA
• Management:
  • Cycloplegia
  • Hypertonic saline (5%) ointment
  • Soft bandage contact lens / patching
  • Intracameral gas injection may accelerate resolution

Grading (by Maximum Keratometry)

Investigations

Corneal Topography / Tomography

• Most sensitive for detection and monitoring
• Corneal power maps show characteristic asymmetric astigmatism evolving from:
  1. Symmetrical bow-tie → 2. Asymmetrical bow-tie → 3. Inferotemporal displaced steep-sided cone
• Sometimes a central ('nipple') cone develops

Keratometry

• Steep readings, often asymmetric between eyes

Pachymetry

• Corneal thinning, especially at the apex

Contact lens warpage can mimic KC on topography, but typically shows a more arcuate-shaped pattern

Management

Step 1 - Optical Correction (Early)

• Spectacles - adequate in very early cases
• Soft contact lenses - for mild irregular astigmatism

Step 2 - Rigid Contact Lenses (Moderate)

• Rigid gas-permeable (RGP) lenses - vault over the irregular surface and provide a regular refracting surface
• Scleral lenses - for higher degrees of astigmatism / lens intolerance; large-diameter lenses that vault the entire cornea

Step 3 - Corneal Collagen Cross-Linking (CXL) - For Progressive Disease

• Mechanism: Riboflavin (vitamin B2) drops photosensitize the corneal stroma, then exposure to UV-A light (370 nm) creates new covalent bonds between collagen fibrils → stiffens the cornea
• Indication: Documented progression (steepening on topography, worsening VA, increasing refraction)
• Efficacy: Successful in >90% of cases at halting progression; some cases show flattening
• Standard (epithelium-off / Dresden) protocol: Epithelium removed; riboflavin 0.1% drops instilled for 30 min; UV-A 3 mW/cm² for 30 min
• Accelerated (epithelium-on) protocol: Epithelium retained; higher UV-A intensity - a 2025 meta-analysis (PMID: 40856685) found epithelium-off remains more effective for halting progression
• Minimum requirement: Corneal thickness ≥400 µm to avoid endothelial damage

Step 4 - Intrastromal Corneal Ring Segments (ICRS / Ferrara/Intacs rings)

• Inserted into mid-peripheral stroma via femtosecond laser channels
• Flatten and regularize the cornea
• May allow patients to resume contact lens wear
• Does not halt progression - often combined with CXL

Step 5 - Keratoplasty (Advanced)

• Indicated when contact lenses are no longer tolerable or vision cannot be corrected adequately
• Deep Anterior Lamellar Keratoplasty (DALK) - preferred where possible; replaces stroma while preserving host Descemet membrane + endothelium → avoids endothelial rejection risk
• Penetrating Keratoplasty (PK) - full-thickness graft; used when DALK is not feasible (e.g. post-hydrops scarring involving deep stroma/Descemet)
• Excellent long-term outcomes; graft rejection is the main concern with PK

Summary Diagram

KERATOCONUS
│
├── Pathology: Stromal thinning + cone protrusion + irregular astigmatism
│
├── Key Signs
│     ├── Oil droplet reflex (ophthalmoscopy)
│     ├── Scissoring reflex (retinoscopy)
│     ├── Vogt striae (slit lamp - deep stroma)
│     ├── Fleischer ring (slit lamp - cobalt blue)
│     └── Munson sign (downgaze)
│
├── Complication: Acute Hydrops
│     └── Descemet rupture → acute edema → resolves 6-10 wks
│
└── Management (stepwise)
      ├── Spectacles / soft lenses
      ├── RGP / scleral lenses
      ├── CXL (if progressing) - >90% effective
      ├── ICRS (rings)
      └── DALK / PK (advanced)

Recent evidence note: A 2025 meta-analysis (PMID: 40856685) comparing epithelium-on vs epithelium-off CXL confirms that the standard epithelium-off (Dresden) protocol remains superior in halting keratoconus progression, though epithelium-on has less discomfort and faster recovery.