Clinicians often face challenges and difficulties in managing ocular surface and corneal conditions. Included amongst the sight-threatening conditions that patients may face are non-healing epithelial defects, neurotrophic corneal ulcers, infectious and non-infectious keratitis, or chemical and thermal burns. Failure to initiate effective treatment can result in corneal scarring, infection, perforation, and permanent visual impairment that can affect quality of life, independence, and other important activities of daily living.

There are a variety of treatment options for patients presenting with significant ocular surface disease. The therapeutic options depend strongly on both the underlying cause, as well as clinical findings. One effective therapy to accelerate healing of the damaged ocular surface in these conditions is amniotic membrane grafts.

History

Surprisingly, amniotic grafts have been used since the 1940s to treat ocular conditions.¹ Yet it was not until a major breakthrough occurred in the early 2000s, with the development of improved harvesting and cryopreservation technologies, that surgeons could access amniotic membrane grafts with their beneficial properties intact.²

An additional hurdle was overcome in 2003 by Scheffer Tseng, MD, who worked with the FDA to reclassify amniotic membranes, which were inaccurately labeled a “device,” to the more appropriate moniker of a “tissue.”³ This ultimately led to a CPT code and opened the door for insurance coverage of this treatment for patients in need.

Membrane Types/Benefits

There are a variety of amniotic membrane graft types, including cryopreserved and dehydrated. Given the readily available nature of these grafts, clinicians are now able to readily employ this technology in the office for conditions in which corneal inflammation and epithelial breakdown have the potential to adversely impact corneal clarity and vision. Amniotic membrane grafts provide growth factors, anti-inflammatory mediators, and also serve as a matrix to promote ocular surface healing.⁴

Membrane Uses

There are a variety of indications for the use of amniotic membranes, including: non-healing epithelial defect, herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis, neurotrophic keratitis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and dry eye disease.

Non-healing epithelial defects can occur following a direct injury or surgery, or in cases of a neurotrophic cornea, and represent one of the most common indications for use of amniotic membranes. While most epithelial defects heal over days, in some cases there can be significant delays in epithelial healing that can lead to corneal haze and loss of best-corrected vision, as well as pose an infection risk. Diabetic corneal neuropathy and limbal stem cell deficiency are conditions that may delay corneal epithelial wound healing. Besides using an amniotic graft, it is important to stop any epithelial-toxic eye drops, treat underlying dry eye — often with punctal occlusion and anti-inflammatory drops — and evaluate for any conditions that may pre-dispose patients to poor epithelial healing, including eyelid abnormalities. Typically, the epithelial defect will significantly improve within a matter of days following placement of an amniotic membrane graft.

Persistent epithelial defects can also develop in patients who have neurotrophic corneas. In these cases, there may be associated HSV or varicella zoster virus, chronic medication use, for example glaucoma drops, diabetes, overuse of topical anesthetics, a history of a corneal transplant, a history of trigeminal neuralgia surgery, or an acoustic neuroma. Limbal stem cell deficiency may also co-occur.

Epithelial irregularities and frank defects in neurotrophic corneas can be more difficult to treat than a typical persistent epithelial defect. In many cases, cryopreserved self-retaining amniotic grafts can be quite helpful. Clinicians may also consider adjunctive therapy with serum tears, as well as cenegermin (Oxervate, Dompé). While self-retaining amniotic membrane grafts are often helpful, some patients my require a more definitive surgical procedure, such as ocular surface reconstruction with an amniotic membrane graft. This surgery is performed with the placement of one to two layers of amniotic membrane graft across the cornea, which is secured with sutures and/or glue. When limbal stem cell deficiency is also present, placement of the amniotic membrane graft alone may not be curative. Instead, placement of the amniotic membrane graft, along with an allograft of stem cells beneath the graft (simple limbal epithelial transplantation procedure), may be required.

Infectious keratitis represents another sight-threatening condition for which amniotic membrane grafting can play a role in certain circumstances, especially in those involving the central visual axis. With infections of the cornea, the goal is to use antibiotics to eradicate the infectious organism. The main consequences of corneal infections are haze or scarring, which can dramatically impair vision. Topical steroids can exert their anti-inflammatory effects to help limit the degree of corneal haze or scarring. However, topical steroids can also suppress local immunity and impair the body’s ability to fight the infection. Amniotic membrane grafts are an effective option here, as patients can continue to use anti-infective agents, while the membrane’s additional anti-inflammatory properties allow for corneal repair by suppressing collagenases and activating keratocytes.

Case Studies

1. Severe Exposure Keratopathy

Patient: A 32-year-old female.

History: Type 1 diabetes, dry eye disease (DED) and exposure keratopathy (OD>OS), due to incomplete blinking and lagophthalmos after ptosis repair. No response to topical lubricants and punctal plugs; VA 20/100.

Management: Amniotic membrane graft for seven days.

Outcome: Eye was quiet, with a clear cornea. (See Case 1).

2. Limbal Cell Deficiency Related to Dry Eye Disease and Keratitis

Patient: A 50-year-old woman with complaint of blurry vision and irritation OU.

History: Diabetes, dry eye disease, mild cataract. She had been treated with tears and lubricating ointments, and now conjunctival “growths” were noticed by a local ophthalmologist, and she was referred for a second opinion. She was diagnosed as having limbal stem cell deficiency related to DED and keratitis.

Management: Aggressive lubrication via preservative-free tears and lubricating tear ointment; suppression of inflammation via cyclosporine 0.05% (Restasis, Allergan) and prednisolone acetate 1% (Pred Forte, Allergan) and amniotic membrane graft for two weeks.

Outcome: The amniotic membrane aided in treating the underlying inflammation, improved epithelial cell regeneration and provided an anti-scarring effect. (See Case 2).

3. Salzmann Nodular Degeneration

Patient: A 40-year-old woman with complaint of chronic “dry” feeling OU, who notices some glare in vision, though no pain.

History: “Growing white spot” in both eyes, though no redness or discharge. BCVA is 20/25 OU.

Management: Patient had a superficial keratectomy and bandage contact lens placed. At follow-up, patient was given an amniotic membrane graft to minimize scar formation, given the large area of nodular removal.

Outcome: A clear and pristine eye. (See Case 3).

4. Neurotrophic Keratitis

Patient: A 56 year-old male, complaining of blurry vision, redness and irritation OS for three days. His VA was 20/400, with diffuse punctate epithelial keratitis, though no dendrite.

History: Herpes zoster keratitis two years ago in the left eye. He has been stable with no recurrences of zoster keratitis. He uses tears, a beta-adrenergic antagonist twice a day, a corticosteroid 4 times a day and Valacyclovir (Valtrex, GlaxoSmithKline) 500 mg daily.

Management: Amniotic membrane graft.

Outcome: Resolution of dense keratitis, modulation of wound healing, minimizing of scar formation and a reduction in inflammation. (See Case 4).

Relief

In summary, amniotic grafts can provide significant relief to patients who have corneal epithelial compromise, and in eyes with sight-threatening corneal conditions may limit scar and haze formation. They can be placed in either the office or operating room setting and should be considered an important tool in our armamentarium in the early intervention and management of patients who have corneal compromise. CP

References

1. Rahmen I, Said DG, Maharajan VS, Dua HS. Amniotic membrane in ophthalmology: indications and limitations. Eye (Lond). 2009;23(10):1954-1961.
2. Madhavan HN, Priya K, Malathi J, Joseph PR. Preparation of amniotic membrane for ocular surface reconstruction. Indian J Ophthalmol. 2000;50(3):227-231.
3. Grueterich M, Espana EM, Tseng SCG. Ex vivo expansion of limbal epithelial stem cells: Amniotic membrane serving as a stem cell niche. Surv Ophthalmol. 2003;48(6):631-646.
4. Tseng SCG, Espana EM, Kawakita T, et al. How does amniotic membrane work? Ocul Surf. 2004;2(3):177-187.

DR. TRATTLER is a refractive, corneal and cataract surgeon at the Center For Excellence In Eye Care, in Miami, FL. He lectures on various procedures. Disclosures: Alcon, Allergan, ArcScan, Avedro/Glaukos, Azura Ophthalmics, Bausch + Lomb, CXLO, Guardian Health, Johnson & Johnson, Kala, LENSAR, Novabay, Ocular Therapeutix, Oculus, Omeros, SightSciences, Sun Pharmaceuticals, TissueTech, Zeiss.

DR. SHULMAN practices at the Center for Excellence in Eye Care, in Miami, FL, where he specializes in cornea and external disease.

DR. MONTENEGRO practices at the Center for Excellence in Miami, FL. He specializes in the medical and surgical management of cataract, as well as corneal and external disease.

DR. GUPTA is an associate professor of Ophthalmology at Duke University Eye Center in Durham, NC. She is a consultant to Alcon, Allergan, Johnson & Johnson Vision, Kala, New World Medical, Novartis and Oyster Point, among others.