Cryopreserved Amniotic Membrane as Adjunctive Therapy for Keratoconus After Corneal Collagen Cross-linking

Ranjan Malhotra, MD, FACS

Ophthalmologist at Ophthalmology Associates

About Author

In the healthy cornea, interlinking collagen fibers act as strong, steel-like scaffolding that help hold the cornea's shape. In patients with keratoconus (KC), those collagen bonds weaken and act more like aluminum, bending and moving with the slightest rub of the eye. KC is characterized by a progressive thinning and conical steepening of the corneal surface that results in distorted vision.

Prevalence & Cause of KC

The prevalence rate of KC is estimated to be between 0.2 and 4,790 per 100,000 persons, and the highest rates typically occur in 20- to 30-year-olds and people of Middle Eastern and Asian ethnicity. While the exact cause of KC remains unclear, there appears to be a genetic component, as patients with a familial history of KC are 6.4 times more likely to develop KC.¹ Certain genetic disorders, chronic allergies, dry eye disease, atopic eye disease, asthma, eczema, and excessive eye rubbing are risk factors for developing KC.^1,2 Early detection of KC remains a challenge, as I have seen the condition in both young and old patients, but an early diagnosis can lead to better disease management.

KC typically begins in early puberty and progresses into the mid-30s of patients. KC disease progression involves the rupture of the anterior limiting membrane, stromal thinning, and ectasia of the central and paracentral cornea, leading to degradation of the cornea.¹ In the early stages of KC, glasses are used to treat astigmatism and nearsightedness, but as the disease progresses, glasses may no longer provide clear vision, and patients may need to transition to a hard contact lens. Though prevalence of KC is relatively low, it can lead to significant visual impairment. It is critical that eyecare practitioners (ECPs) recognize patients with KC and treat them appropriately, conserving as much corneal tissue as possible.

Diagnosing KC

Patient symptoms usually include ocular allergies, ocular surface disease, dry eyes, and constant eye rubbing. The patients with these symptoms who are referred to me are typically in their teenage years, have a history of astigmatism, and their vision is no longer 100% correctable with glasses or contacts. Their prescription advances rapidly, before their next annual eye exam, which is highly indicative that the cornea may be progressively declining.

To screen for KC, I use corneal topography to map the surface of the patient's eye. When I see irregular or asymmetric astigmatism on the corneal topographer, that is when I suspect early KC and recommend corneal collagen cross-linking (CXL).

In some cases, and as required with most insurance, ophthalmologists will wait to see if the patient has KC progression before treating with corneal CXL. In general, though, most doctors do not delay corneal CXL in patients with KC to prevent further cornea degradation. The primary goal of corneal CXL is to stabilize corneal tissue and reduce the need for a corneal transplant.

CXL for KC

Corneal CXL uses ultraviolet-A (UV-A) light and the photosensitizer riboflavin (vitamin B₂), an ophthalmic eye drop solution, to stabilize corneal ectasia.⁵ In 2016, the FDA approved CXL for the treatment of progressive KC,³ and it has since been my choice of therapy for early KC.

In the first step of corneal CXL, we scrape away the tear film and roughen the corneal epithelium to aid riboflavin penetration into the cornea. After de-epithelization of the cornea, I drop the ophthalmic riboflavin solution into the eye. I then illuminate the patient's eye with a UV-A light, which reacts with the riboflavin-saturated cornea. This reaction creates free radicals that act on the corneal tissue to form covalent bonds and stromal cross-linking in the collagen fibers, which alters the biomechanics of the cornea, causing an increase in corneal stiffness.^4,5 Collagen CXL is used as a defensive procedure to inhibit KC progression, but it does not reverse the damage caused by KC. Thus, it is important to treat patients with corneal CXL as soon as a KC diagnosis is made.

I am part of a clinical trial that is currently investigating the epithelium-on technique, in which the epithelium is left intact during the corneal CXL procedure. However, the current epithelium-off protocol is the only FDA-approved technique for corneal CXL.

Post-CXL Management with Cryopreserved Amniotic Membranes (CAM)

Due to the corneal epithelium debridement step in CXL, post-procedure complications can occur. Because patients with KC have corneas that are steeper than they should be, the corneal epithelium takes much longer to heal, which further complicates the post-corneal CXL healing process, and puts patients at a higher risk of developing a scar, corneal haze, or infection.

The typical post-corneal CXL regimen involves a corneal bandage for 2 to 3 days, then a steroid and antibiotic ointment. But for patients with KC who have highly irregular corneas, I use amniotic membranes.

Amniotic membranes promote ocular epithelialization and reduce scarring. Dehydrated or cryopreserved amniotic membranes can be used, but because the dehydration process compromises the structure of amniotic tissue, I prefer CAM (Prokera; BioTissue). The cryopreservation process retains the native structure of the amniotic matrix, and this retained structure has the quantity and activity of key biological signals, including heavy-chain, high molecular weight hyaluronic acid/pentraxin 3 [HC-HA/PTX 3].⁶ CAM is placed in the eye like a contact lens; this allows easy application and removal, unlike with dehydrated amniotic membranes, which require careful application on the cornea.

Following corneal CXL, I use numbing drops and place CAM on the patient's eye for about 24 to 48 hours, depending on tissue damage severity. Because of the thickness of CAM, I use tape splint tarsorrhaphy to stabilize the eyelid. I counsel patients that they may experience some burning and irritation from the healing properties of CAM, but the experience is short-lived, and the recovery benefits outweigh the short inconvenience. These patients will then continue with corticosteroid and antibiotic ointment after CAM removal, as part of standard post-CXL after care.

Implementing Best Treatment Practices

Early disease identification of KC combined with prompt CXL intervention may improve patient vision and prolong cornea replacement. Optimizing patient healing and recovery from CXL with a short course of CAM can lead to improved patient outcomes. Counsel patients that the healing properties from CAM may sting for a few hours after placement, but if they can tolerate the short discomfort, then they may have an expedited recovery and better visual outcomes.

Ranjan Malhotra, MD, FACS, specializes in cornea, external ocular disease, and refractive surgery at Ophthalmology Associates in St. Louis, MO. He is the primary investigator for many FDA trials for ocular medications and has satellite offices in Sullivan and St. Peter's, MO.

References

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2. Hashemi H, Heydarian S, Hooshmand E, et al. The prevalence and risk factors for keratoconus: a systematic review and meta-analysis. Cornea. 2020;39(2):263-270.
3. Belin MW, Lim L, Rajpal RK, Hafezi F, Gomes JAP, Cochener B. Corneal cross-linking: current USA status: report from the cornea society [published correction appears in Cornea. 2019 Oct;38(10):e49]. Cornea. 2018;37(10):1218-1225.
4. Sorkin N, Varssano D. Corneal collagen crosslinking: a systematic review. Ophthalmologica. 2014;232(1):10-27.
5. Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012;53(4):2360-2367. Published 2012 Apr 30.
6. Cooke M, Tan EK, Mandrycky C, He H, O'Connell J, Tseng SC. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-476.