Neurotrophic keratopathy: current challenges and future prospects

Abstract

Neurotrophic keratopathy (NK), or neurotrophic keratitis, is a degenerative condition that results from decreased innervation to the cornea. The cornea is innervated by the ophthalmic branch of the trigeminal nerve. Neurotrophic keratopathy is most commonly caused by herpes keratitis however, any condition that disrupts the normal corneal innervation can cause NK. Neurotrophic keratopathy is a clinical diagnosis and is classified into three stages based on the disease severity. Stage 1 has mild epithelial defects, such as punctate keratopathy, stage 2 disease has persistent epithelial defects, and stage 3 is defined by the presence of ulcers. Current treatment modalities consist of medical and surgical options. Stage 1 is treated with lubrication through artificial tears, eyelid taping, and punctal plug/cautery. Stage 2 treatment can involve therapeutic contact lenses, topical autologous or allogenic serum, tarsorrhaphy, botulinum toxin injections, and possibly anti-inflammatory medications. Stage 3 disease may require human nerve growth factor, amniotic membrane transplantation, conjunctival flap, or corneal neurotization. New therapies, such as matrix regenerating therapy, plasma rich in growth factors, Thymosin β4, Substance P/Insulin like growth factor-1, and nicergoline represent exciting future options. KEY MESSAGES Neurotrophic keratopathy is a rare degenerative disease defined by decreased innervation to the cornea that is associated with significant morbidity. Treatment options range from lubrication alone to various medical and surgical treatments. Matrix regenerating therapy, plasma rich in growth factors, Thymosin β4, Substance P/Insulin like growth factor-1, and nicergoline are exciting novel therapies that will influence how neurotrophic keratopathy is treated in the future.

Advanced surgeries, medicines and materials for corneal regeneration

“…Treatment of NK is very challenging and the main goal is to preserve the structural integrity of the cornea while vision improvement is often not achieved especially in severe cases of NK. Recombinant human nerve growth factor (Cenegermin) is the first treatment approved for moderate and severe NK in adult patients and targets the cause of NK, which is the defective sensory innervation of the cornea 35,36,105 . Despite all the therapeutic modalities, NK can progress rapidly leading to corneal melting and perforations.…”

“…Cenegermin 0.002% ophthalmic solution is a recombinant human NGF that has been approved for treatment of moderate to severe NK by the European Commission and United States Food and Drug Administration. In a multi-center, randomized, double-masked trial 27,36 , the patients with NK who were treated with Cenegermin drops had faster corneal healing, slower disease progression and lower rate of disease recurrence even though visual acuity and corneal sensitivity was not different between treatment and control groups 35 .…”

“…If lubrication is not enough, the use of therapeutic contact lenses, serum drops, tarsorrhaphy, botulinum toxin injection and anti-inflammatory drops may be necessary. In cases of corneal ulcers that may progress to perforations or stromal melting, amniotic membrane transplantation, Gundersen flap and topical application of NGF may be required 35 . NGF is involved in the survival and healing of nerves and is pivotal in the corneal response to injury 17 .…”

“…Corneal reinnervation is achieved through direct nerve transfer or grafting of the ipsilateral or contralateral infraorbital, supraorbital or supratrochlear nerve. The use of RGTA, plasma rich in growth factors (PRGF), thymosin 4 and nicergoline are new novel therapies that have been tested in a few patients with positive results 35 .…”

Acute management of ocular chemical burns: A review

“…In cases of limbal ischemia with loss of limbal stem cells, the surviving conjunctival epithelium grows and invades the corneal surface transforming then into epithelial cells with corneal phenotype (conjunctival transdifferentiation) and leading to delayed re-epithelialization, the presence of superficial neovascularization, and recurrent and persistent epithelial defects (Dua et al 2020;Forrester 1987, 1990;Dua, Gomes, and Singh 1994). In addition, the corneal nerves can be damaged and develop corneal hypoesthesia or anesthesia, with the consequent risk of neurotrophic keratopathy and subsequent hyperesthesia due to aberrant regeneration (Dua et al 2020(Dua et al , 2018NaPier et al 2022). On the other hand, damage to the bulbar and fornix conjunctival epithelium can favor the appearance of symblepharon, which can result in inadequate blinking, tear reduction, cicatricial entropion with trichiasis and ocular motility restriction (Dua et al 2020;Swarup, Ta, and Wu 2022).…”