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Amniotic Membrane in Ophthalmology: A Complete Guide

What Is the Amniotic Membrane?

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Structure: What Is It Made Of?

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How It Works (Mechanism of Action)

1. Promotes Epithelial Healing

2. Anti-Scarring (Anti-Fibrotic)

3. Anti-Inflammatory

4. Supports Stem Cells

5. Anti-Vascular (Anti-Angiogenic)

6. Antimicrobial Properties

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Forms Available

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Indications in Ophthalmology

1. CORNEAL DISEASES

a) Persistent Epithelial Defects (PED)

• When the surface of the cornea (epithelium) fails to heal despite standard treatment
• Causes: neurotrophic keratopathy (loss of corneal sensation), dry eye, diabetes, previous infection
• AM acts as a bandage, protecting the area and actively promoting healing

b) Corneal Ulcers and Stromal Melting

• Deep ulcers that threaten to perforate the cornea
• AM is placed as a graft (inlay) to fill in thinned areas and prevent perforation
• It reduces the inflammation that is "melting" the cornea
• Can be used in single or multi-layer stacking for deep defects

c) Chemical and Thermal Burns (Ocular Surface Burns)

• One of the most time-critical uses - ideally applied within 2 weeks of the burn
• Chemical burns (acid or alkali) cause massive inflammation and scarring
• AM dramatically reduces scarring, symblepharon formation (eyelids sticking to eyeball), and conjunctival destruction
• The 2024 American Academy of Ophthalmology assessment confirmed the efficacy of AMG in chemical/thermal burns

d) Bullous Keratopathy

• When the cornea swells and blisters form on its surface causing severe pain
• AM is used as a bandage to relieve pain and promote healing while awaiting corneal transplant

e) Infectious Keratitis

• Severe bacterial, fungal, or viral (herpes) corneal infections with large ulcers
• AM helps by reducing inflammation and creating favorable conditions for healing alongside antimicrobial treatment

f) Corneal Perforations (Small)

• Small corneal holes (e.g., from ulcers or trauma) can be patched with layered AM
• Important: AM cannot provide tectonic support for large perforations - that requires a corneal transplant

g) Recurrent Corneal Erosion

• Condition where the corneal surface repeatedly breaks down (often after an old corneal scratch)
• AM overlay can help restore the basement membrane and stop recurrences

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2. CONJUNCTIVAL DISEASES

a) Pterygium Surgery

• Pterygium = a fleshy, wedge-shaped growth of conjunctiva that grows onto the cornea
• After surgical removal, AM is used to cover the raw area where tissue was removed
• Reduces recurrence rates and provides a better cosmetic outcome
• Alternative to conjunctival autograft (taking tissue from another part of the same eye)

b) Symblepharon Lysis

• Symblepharon = scar tissue causing the eyelid to stick to the eyeball
• After releasing these adhesions surgically, AM is placed to prevent them from reforming
• Used in conditions like Stevens-Johnson Syndrome, chemical burns, ocular cicatricial pemphigoid

c) Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

• Severe drug reaction causing widespread skin and eye surface destruction
• One of the most important uses - AM should be applied urgently (ideally within 72 hours of onset)
• Applied over the palpebral and bulbar conjunctiva, eyelid margins, and into the fornix
• Early AM grafting greatly improves visual prognosis
• Wills Eye Manual specifically recommends suturing AM over the eyelid margin, palpebral conjunctiva, and fornix in severe hyperacute cases (<72 hours)

d) Conjunctival Reconstruction

• After removal of large conjunctival tumors
• Mucous membrane autografting or amniotic membrane transplantation for conjunctival resurfacing and fornicial restoration (Kanski's Clinical Ophthalmology)

e) Ocular Cicatricial Pemphigoid (OCP)

• Autoimmune condition causing progressive scarring of the conjunctiva
• AM helps in reconstruction of the fornix and bulbar conjunctiva

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3. LIMBAL STEM CELL DEFICIENCY (LSCD)

• AM serves as the substrate (scaffold/bed) on which limbal stem cells are grown and then transplanted back onto the eye
• Two main approaches:

• Oral mucosal cells can also be grown on AM as an alternative (COMET - Cultivated Oral Mucosal Epithelial Transplantation) - useful when both eyes are affected

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4. SOCKET RECONSTRUCTION

• After removal of an eye (enucleation) or in contracted eye socket cases
• AM helps reconstruct conjunctival lining of the socket for prosthetic eye fitting

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5. GLAUCOMA SURGERY (Adjunct Use)

• AM can be used as a covering over trabeculectomy blebs (drainage sites) that are leaking or failing
• Helps reduce scarring of the filtration bleb

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6. DRY EYE DISEASE

• AM suspensions and dehydrated AM (e.g., Prokera device) are used for severe dry eye
• The Prokera device sits in the eye like a contact lens for several days, delivering the anti-inflammatory and healing benefits
• Particularly useful in severe, treatment-resistant dry eye

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How Is It Applied? (Techniques)

• Epithelial side UP = acts as a replacement surface (graft/onlay)
• Stromal side DOWN on wound = anti-scar, anti-inflammatory effects are maximized (inlay)
• The stromal side is identified by its stickiness

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Contraindications and Limitations

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Summary: Quick Reference Table

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Key Points to Remember

1. AM is the innermost layer of the placenta, harvested from consented donors during C-sections
2. It works by promoting healing, reducing scarring, suppressing inflammation, and supporting stem cells
3. It can be used as a graft (to fill/replace tissue) or as a bandage (to protect and promote healing)
4. Prokera allows in-office use without surgery
5. Chemical burns and SJS are time-critical indications - early application (<2 weeks and <72 hours respectively) improves outcomes significantly
6. It is a substrate for limbal stem cell transplantation - a potential cure for corneal blindness from LSCD
7. It cannot replace the cornea structurally - large perforations need corneal transplants

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Corneal Graft Rejection: Clinical Features and Management

What Is Corneal Graft Rejection?

Key point: Graft rejection can only occur in a graft that has previously been clear for at least 2 weeks after surgery. Before that, other causes of cloudiness (primary graft failure, surgical trauma) are more likely.

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Immunological Background

• Neovascularization grows into the cornea (new blood vessels carry immune cells)
• Lymphatic vessels develop in the limbal area
• Inflammation is present (pre- or post-op)

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Risk Factors

Pre-Operative (Host Eye Factors)

Donor Factors

• Male donor to female recipient - Gender incompatibility has emerged as a significant risk factor. A female donor cornea can go to either sex; a male donor cornea should NOT be given to a female recipient (HLA-Y antigen mismatch)
• Large donor button
• HLA mismatch (minor beneficial effect of HLA matching)

Post-Operative Factors

• Loose or broken sutures (induce vascularization)
• Steroid non-compliance (most preventable cause!)
• Secondary infection (especially herpes)
• Uncontrolled IOP
• Missed follow-up appointments

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Timing

• Can occur days to years after keratoplasty (even reported 20 years later)
• Most common in the first year after surgery
• Incidence is highest at ~12 months post-op

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Types of Corneal Graft Rejection

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Clinical Features

Symptoms (What the Patient Feels)

Mnemonic: RSVP

• Redness
• Sensitivity to light (photophobia)
• Vision decrease (blurred vision)
• Pain (mild to moderate)

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Signs (What You See on Slit Lamp)

1. Endothelial Rejection - THE MOST IMPORTANT

• A linear row of keratic precipitates (KPs) marching across the donor endothelium
• Starts at the graft-host interface inferiorly and moves superiorly
• Represents the advancing front of immune destruction
• To one side of the line: endothelium is destroyed - cornea is edematous (cloudy)
• To the other side: endothelium still intact - cornea is clear
• Associated with ciliary injection (redness around the cornea) and anterior chamber cells

• KPs localized only to donor endothelium (not on recipient) - this distinction from uveitis is critical
• Diffuse stromal and epithelial edema (graft becomes hazy/white)
• If early: AC cells without graft changes

2. Epithelial Rejection

• An elevated, irregular, winding line of abnormal epithelium
• Crosses the graft from periphery to center
• Eye is relatively quiet (mildly inflamed or even white)
• Occurs at average of 3 months post-op
• Best prognosis of all types - responds readily to treatment

3. Subepithelial Rejection (Krachmer Spots)

• Multiple round, white subepithelial infiltrates scattered across the donor cornea
• Look similar to adenoviral keratoconjunctivitis (important differential)
• Located only on the donor tissue
• Associated with mild stromal involvement in severe cases

4. Stromal Rejection

• Deep stromal haze or infiltrate in the graft
• Can be chronic (slowly progressive) or hyperacute (rapid onset, often with endothelial involvement)
• Stromal neovascularization may be seen at the graft margin

5. Ciliary Injection

• Earliest, non-specific sign - redness concentrated around the corneal limbus
• Usually the first thing the patient notices

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Progression of Endothelial Rejection (Timeline on Slit Lamp)

Key concept: Every visible KP on the endothelium represents a focal, irreversible area of endothelial cell death. This is why speed of treatment matters enormously.

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Differential Diagnosis

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Workup

1. Detailed history - Date of transplant, indication for transplant, current steroid regimen, compliance, recent steroid taper, history of HSV
2. Slit lamp examination - Systematic inspection of epithelium, stroma, endothelium; look for KPs, rejection lines, subepithelial infiltrates, neovascularization
3. IOP measurement - Mandatory (steroids can raise IOP; raised IOP itself causes edema)
4. Specular microscopy - To assess endothelial cell count and early cellular changes

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Management

The Golden Rule:

"Early intensive treatment greatly improves the likelihood of reversing the rejection" - Kanski's Clinical Ophthalmology

Do not delay. Treat the same day.

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Step 1: Endothelial Rejection (Most Urgent)

Topical Steroids (First Line - Always):

• Prednisolone acetate 1% every 1 hour while awake
• OR Difluprednate 0.05% every 2 hours while awake
• Add dexamethasone 0.1% ointment at bedtime
• Taper very slowly over weeks to months once improvement is noted

Systemic Steroids (For Severe/Recurrent/Resistant Cases):

• Oral prednisone 40-80 mg/day for 1-2 weeks, then tapered
• OR IV methylprednisolone 500 mg/day for 1-3 consecutive days (pulse therapy)
  • Most effective when given within 8 days of symptom onset
  • Can suppress the rejection AND reduce the risk of future episodes
• Subconjunctival injection: Betamethasone 3 mg in 0.5 mL or dexamethasone 4 mg/mL

Adjunct Treatment:

• Cycloplegic (e.g., cyclopentolate 1% three times daily, or homatropine 2% twice daily) - relieves ciliary spasm, prevents synechiae formation
• IOP control - timolol 0.5% or other glaucoma drops if pressure is elevated
• Topical cyclosporine 0.05-2% twice to four times daily - adjunct; slower onset but useful for prevention and recurrence

Hospitalization:

• Severe rejection cases: admit for IV steroids + close monitoring

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Step 2: Epithelial and Stromal Rejection (Less Urgent, but Act Promptly)

• Double the current topical steroid dose, or use prednisolone acetate 1% four times daily (whichever is more frequent)
• Add cycloplegic agent and IOP control
• Topical cyclosporine as adjunct
• These types have a higher reversibility rate than endothelial rejection

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Step 3: Follow-Up After Starting Treatment

• Review every 3-7 days initially
• Once improvement confirmed: slowly taper steroids (over weeks to months)
• Some patients need low-dose maintenance steroids for months to years
• Regularly check IOP in anyone on long-term topical steroids (risk of steroid-induced glaucoma)

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If Treatment Fails (Irreversible Rejection)

• A graft is labeled immunologically failed if rejection does not clear after 2 months of intensive treatment
• At this point, a repeat corneal transplant is the only option
• Note: repeat grafts have a significantly higher rejection risk

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Prevention of Rejection

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Rejection Rates by Graft Type

This is one reason the field is shifting toward lamellar (partial-thickness) grafts - significantly lower rejection risk than full-thickness PKP.

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Summary: Quick Reference

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