On this episode of Interventional Mindset, Sumitra Khandelwal, MD, reviews new treatment options for managing non-healing epithelial defects secondary to neurotrophic keratitis (NK).
Dr. Khandelwal is a professor of ophthalmology at the Baylor College of Medicine, Cullen Eye Institute in Houston, Texas, and also serves as Medical Director for the Lions Eye Bank of Texas.
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Brief overview of neurotrophic keratitis
Neurotrophic keratitis is a degenerative corneal disease caused by the disruption of trigeminal sensory innervation that results in diminished or absent corneal sensation, disrupted epithelial cell turnover, impaired wound healing, and abnormal blinking and tear production.1-3
NK can develop due to a variety of reasons, such as herpes simplex and zoster infections, prior ocular surgeries, systemic disorders, and contact lens misuse, noted Dr. Khandelwal.3
According to the Mackie classification system, NK can be organized into three stages based on the severity of corneal damage:3
- Stage 1: Corneal epithelial changes observed, often seen with diffuse staining and the presence of superficial punctate keratopathy and corneal edema
- Stage 2: Persistent and non-healing epithelial defect with no corneal ulceration or thinning
- Stage 3: Presence of corneal ulceration and/or thinning with stromal involvement (i.e., thinning and lysis) that can progress to corneal perforation
Slit lamp images of stages 1, 2, and 3 neurotrophic keratitis.
Images courtesy of Cory J Lappin, OD, MS, FAAO.
While it is best to intervene early in the disease course, in Dr. Khandelwal’s experience, patients tend to present to the clinic already at stages 2 or 3, and by then, some of the treatments for stage 1 NK are not sufficient. As such, it is exciting that there are new medical and surgical treatment options to offer patients with moderate to severe NK.
New medical treatments for healing epithelial defects due to NK
Stage 2 or 3 NK is a vision-threatening condition. Since its arrival on the scene, Oxervate (cenegermin-bkbj ophthalmic solution 0.002% [20mcg/mL], Dompé), a topical eye drop that uses nerve growth factor to treat corneal nerve damage, has become a first-line therapy for NK. However, as a prescription medication, it can take a few weeks or up to a month to order.
Consequently, Dr. Khandelwal’s first-line in-office approach for patients with moderate to severe NK is to “put out the fire” by covering up the area of persistent epithelial defect (PED) and treating for infection with a topical antibiotic while waiting for the prescriptions to come in.
This is her top priority because while the patient has an epithelial defect, they are at high risk of progressing to corneal scarring, melting, or perforation.4
Scleral lenses
Scleral lenses have been used to preserve epithelial integrity and heal the ocular surface in patients with chronic for years,5 but in Dr. Khandelwal’s practice, scleral lenses are also used for patients with stage 2 NK and PEDs.
Several studies have shown that this can be done safely;5 however, the patient has to commit to returning to the clinic every 1 to 2 days to remove the scleral lens, check the epithelial defect, and ensure that there is no swelling or vascularization from the lens.
With scleral lens use, Dr. Khandelwal has found that some patients may start to heal as quickly as within a few days, though studies have shown that it generally takes 20 to 30 days for the PED to fully improve.6
Plasma rich in growth factor (PRGF) tears
Another treatment option is plasma rich in growth factors (PRGF) therapy, which can be prescribed as a standalone treatment or in conjunction with scleral lenses by placing them in the reservoir of the lens.
PRGF differs from autologous serum tears because it contains higher concentrations of platelet-derived factors, such as:5
- Epidermal growth factor (EGF)
- Transforming growth factor beta (TGF-β)
- Platelet-derived growth factor (PDGF)
Studies have shown that PRGF therapy is safe and effective for patients with stages 2 and 3 NK, demonstrating high rates of corneal defect and ulcer resolution quickly and preventing NK's progression by reducing signs and symptoms.7 Further, a multicenter longitudinal study of patients with different ocular surface disorders treated with autologous PRGF for the first time resulted in an improvement in initial corneal epitheliopathy in 74.3% of patients.5
Of note, there is now an FDA-approved disposable kit (PRGF – ENDORET, BTI Biotechnology Institute) with the necessary equipment to prepare plasma under sterile conditions.8
Watch the full interview to learn how to make a graft from plasma rich in growth factors!
Insulin drops
Insulin, which can be found on the ocular surface and in tears, has been shown to contribute to epithelial healing.9 In fact, researchers have utilized topical insulin drops to manage refractory NK with success.10 Dr. Khandelwal noted that insulin is relatively affordable, especially compared to scleral lenses and PRGF, which tend not to be covered by insurance.
As such, in her practice, she prefers to use insulin drops for patients with stage 2 or 3 NK who were unresponsive to conventional treatments or for patients with stage 1 NK who can’t afford/do not have access to Oxervate or have recurring NK despite treatment. She recommends that patients use topical insulin drops 4 times per day for ~3 months or until the PED or ulcer is resolved—which is in line with what recent studies have proposed.10
Procedural treatment options for non-healing epithelial defects
Umbilical cord serum
Similar to peripheral blood serum, umbilical cord serum (UCS) contains a high concentration of essential tear components and basic nutrients for epithelial renewal that can facilitate the proliferation, migration, and differentiation of the epithelium.11 One study found that epithelial defects in patients with refractory NK who instilled UCS drops healed within 4 weeks, and visual acuity and corneal sensitivity improved after treatment.12
Dr. Khandelwal noted that UCS can be used to develop an eye drop by companies like BioTissue or it can be used to create a precipitate that is then put into a balanced salt solution (BSS) and placed under a bandage contact lens as an umbilical cord tissue graft, which has also been shown to facilitate corneal healing.13
Amniotic membrane transplantation
Several amniotic membranes (AMs) are now available to use in the operating room, and Dr. Khandelwal’s practice often uses a specific technique with AM transplantation for patients with stage 2 NK.
Instead of simply placing the AM on top and gluing it, she assesses the area with corneal thinning (ex., a 4mm ulcer with 2mm area of central thinning), takes the AM and cuts out 2mm to place in the area of thinning—similar to an inlay technique. Then, she uses a slightly larger piece of the AM (ex., a 3mm area), places it on top of the first AM graft, and attaches it with fibrin glue like Tisseel.
Subsequently, she uses another slightly larger AM graft (ex., 4mm, or the size of the epithelial defect) and places one final piece on top. This technique of using the AM in an inlay fashion helps to thicken the cornea. Research has shown that this not only stabilizes the corneal surface, but also acts as a substrate or scaffold for epithelial cells to promote regeneration.14
Corneal allografts
BrightMEM is a corneal allograft made from Descemet’s membrane that is designed to promote durable regeneration of the corneal epithelium while protecting the underlying stromal treatment.15 Dr. Khandelwal explained that her clinic uses the BrightMEM for non-healing epithelial defects and corneal thinning by using the abovementioned AM inlay technique and placing the BrightMEM on top. She has also used it in tandem with a bandage contact lens or a tarsorrhaphy if warranted.
In Dr. Khandelwal’s opinion, the BrightMem functions similarly to a Gundersen conjunctival flap but without many of the issues associated with the Gundersen flap, such as needing healthy conjunctiva, buttonholes, and patient dissatisfaction with the cosmetic outcome.16 In addition, the BrightMem is an exciting development for patients with PEDs and NK who have concomitant retinal disease as there is still a relatively good view of the retina.
To note, there will be data presented at ASCRS by Brightstar Therapeutics and other investigators on the efficacy of BrightMEM.
To hear pearls for successfully placing a corneal allograft, watch the full interview!
Conclusion
The growing field of regenerative medicine continues to produce effective interventions for moderate to severe NK that not only stabilize the corneal surface but encourage healing and restoration of nerve function as well.9,17
Treatment options ophthalmologists can consider adding to their armamentarium for patients with stage 2 or 3 NK include:
- Scleral lenses (which can be used in conjunction with the biologics treatments listed below)
- PRGF therapy
- Topical insulin drops
- Umbilical cord serum
- Amniotic membrane transplantation
- Corneal allografts
