Corneal Graft Rejection - Clinical Features & Management

What Is Corneal Graft Rejection?

Think of it like this: the body's security system (immune system) finds an intruder (donor cornea) and tries to destroy it.

Why Does Rejection Happen? (Pathogenesis)

• No blood vessels (antigens can't be "seen" by immune cells)
• No lymphatics
• Very few antigen-presenting cells

• Blood vessels grow into the cornea (neovascularization)
• Inflammation occurs
• The host gets sensitized to HLA antigens on the donor cornea

Risk Factors for Rejection

Key pearl: A male donor cornea should NOT be given to a female recipient - this is a newer recognized risk factor.

When Does It Occur?

Clinical Features (Symptoms + Signs)

Symptoms (What the Patient Feels)

• R - Redness
• S - Sensitivity to light (photophobia)
• V - Vision decrease (blurred vision)
• P - Pain (mild)

Many patients have NO symptoms early on and are only caught on routine exam!

Signs (What the Doctor Sees)

1. Epithelial Rejection (mildest)

• An elevated line of abnormal epithelium moves across the cornea
• Occurs around 3 months after surgery
• Eye may look relatively quiet (mild or no inflammation)
• Easiest to treat

2. Subepithelial Rejection

• Krachmer spots - small gray-white subepithelial infiltrates on the donor cornea
• Look like the spots seen in adenoviral eye infection
• Deeper edema and hazy opacification

3. Stromal Rejection

• Deeper stromal haze
• Can be chronic (slowly progressive) or hyperacute (rapid, usually with endothelial rejection)
• Stromal edema = sign of endothelial failure

4. Endothelial Rejection (most serious)

• The MOST DANGEROUS type - endothelial cells don't regenerate!
• Khodadoust line - a characteristic linear row of keratic precipitates (inflammatory deposits) on the endothelium, advancing from the graft margin toward the center
• Corneal edema (graft swells and goes cloudy)
• Anterior chamber reaction (cells and flare)

5. General Signs (Any Type)

• Ciliary injection (redness around the cornea = limbal flush) - often the first visible sign
• Anterior chamber inflammation (cells + flare on slit lamp)
• Neovascularization growing onto the graft
• Broken suture

Summary Table of Rejection Types

Differential Diagnosis

1. Infective keratitis (bacterial, fungal, herpetic) - look for corneal infiltrate, hypopyon, discharge
2. Uveitis - keratic precipitates NOT limited to graft endothelium; history of uveitis
3. Suture abscess - focal infiltrate near suture
4. Raised IOP - corneal edema without inflammation; clears when IOP controlled
5. Epithelial downgrowth - advancing smooth/scalloped line; does NOT respond to steroids
6. Non-immune graft failure - no inflammation, just slow clouding

Workup

1. Full history - when was the transplant? what eye drops is the patient using? any recent steroid taper? reason for original transplant (HSV history?)
2. Slit lamp examination - look for Khodadoust line, Krachmer spots, epithelial line, keratic precipitates
3. IOP measurement - always check, steroids can raise it
4. Specular microscopy - assess endothelial cell density if available

Management

Golden rule: START TREATMENT IMMEDIATELY. Earlier treatment = better chance of saving the graft.

Treatment is stepped up based on the TYPE and SEVERITY:

For Endothelial Rejection (most aggressive treatment needed)

• Prednisolone acetate 1% every hour while awake (for first 24 hours)
• Can also use difluprednate 0.05% every 2 hours
• Add dexamethasone 0.1% ointment at bedtime
• Gradually taper over several weeks as the eye improves

• Oral prednisolone 1 mg/kg/day for 1-2 weeks, then taper
• If started within 8 days of onset: IV methylprednisolone 500 mg/day for up to 3 days - this is especially effective and reduces risk of further episodes

• Homatropine 2% or atropine 1%, once or twice daily
• Dilates pupil, reduces pain from ciliary spasm, prevents synechiae

• Topical cyclosporine 0.05%-2% (onset is delayed; useful for prevention too)
• Subconjunctival dexamethasone injection (4 mg/mL, 0.5 mL)
• Systemic cyclosporine, tacrolimus, or azathioprine

For Epithelial and Stromal Rejection (less aggressive)

• Double the current topical steroid dose or use prednisolone acetate 1% four times daily (whichever is higher)
• Add cycloplegic and topical cyclosporine as above

IOP Monitoring (critical throughout)

• Steroids raise IOP - must monitor regularly
• If IOP elevated, add topical IOP-lowering drops
• Uncontrolled high IOP can itself cause corneal edema that mimics rejection

Follow-up Schedule

Once improvement is noted, steroids must be tapered very slowly - sometimes continued at low doses for months to years to prevent recurrence.

Prevention of Rejection

• Maintain long-term low-dose topical steroids in high-risk patients (e.g., prednisolone acetate 1% QID indefinitely)
• Topical cyclosporine as prophylaxis in high-risk cases
• Avoid triggers: treat infections early, manage IOP, prevent suture-related inflammation
• Patient education: know the symptoms of rejection (RSVP) and seek help immediately - hours matter!

Key Take-Home Points

1. Rejection can affect epithelium, stroma, or endothelium - endothelial rejection is most serious
2. The pathognomonic sign is the Khodadoust line (linear keratic precipitates on the endothelium)
3. Symptoms = RSVP (Redness, Sensitivity, Vision loss, Pain) - but many cases are asymptomatic
4. Treat immediately and aggressively - delay = irreversible endothelial damage = permanent graft failure
5. IV methylprednisolone within 8 days of onset can be particularly effective
6. Monitor IOP regularly in all patients on steroid therapy