Corneal Neurotization

Corneal neurotization involves a set of new surgical techniques that directly address the loss of corneal nerves by transferring sensory nerves from nearby areas to the perilimbal region. Samii et al first described using the sural nerve as an interposition graft between the transected ophthalmic nerve and the greater occipital nerve. However, this procedure was lengthy and required a large frontal craniotomy, leading to its rare utilization. Terzis et al demonstrated a direct transfer technique in 2009, which proved more practical.  Neurotrophic keratopathy results from permanent damage to the corneal nerves (see  Neurotrophic Cornea), leading to corneal hypoesthesia, with a prevalence of 1.6 to 11 per 10,000. The most common causes of neurotrophic keratopathy are herpetic disease, diabetes, dry eye syndrome, tumors, chemical or surgical trauma, and iatrogenic medication. Corneal nerves play a vital role in maintaining the homeostasis of the ocular surface, including tear production and epithelial regeneration. They secrete substance P and calcitonin gene-related factors involved in epithelial cell proliferation and wound healing. Corneal epithelial cells also produce neurotrophin-like nerve growth factor and neurotrophin 3, promoting nerve survival. The corneal sensation is crucial for reflex blinking and tearing. Corneal hypoesthesia increases the risk of corneal microtrauma, epithelial breakdown, and delayed wound healing. Traditional management strategies have been predominantly supportive but do not reverse the loss of corneal nerves (see The Mackie Classification of Neurotrophic Keratopathy and Traditional Supportive Treatment Options). Serum tears are blood derivatives containing multiple growth factors that aid in epithelial healing and allow some improvement in corneal sensation. External replacement of nerve growth factors, including topical insulin-derived growth factor and human recombinant nerve growth factor, aims to promote nerve regeneration. While topical nerve growth factors have improved corneal sensitivity in animal models, recent randomized clinical trials have not demonstrated the same effect in humans.                                                                                                                                                    The treatment objectives include promoting reepithelialization and preventing the further progression of ocular surface disease and neurotrophic keratopathy. Preservative-free artificial tears and autologous serum can be considered in the initial phases. Topical recombinant human nerve growth factor can be effective in patients with Mackie stage 2 to 3 neurotrophic corneas, with low recurrence rates after epithelial defect healing up to 48 weeks after treatment. The aim is to replace nerve growth factors with external applications. Medical treatment can be attempted before considering corneal neurotization. Topical insulin eye drops have improved nerve regeneration and corneal sensitivity in animal models. Still, in randomized studies, no significant improvement in corneal sensation was found in human patients. Amniotic membrane transplant can reduce ocular surface inflammation and vascularization. Contact lenses and autologous serum tears are part of the traditional supportive approach that does not address the root cause of neurotrophic keratopathy. Severe damage may require more complex surgical planning and can affect the success of the neurotization procedure. Surgery should be considered an option when vision is compromised, in the presence of stromal thinning, or when medical therapy alone is not sufficient. The availability of suitable donor nerves is necessary for the procedure, but donor nerve selection and surgical technique can be adapted based on the case's specifics. Other considerations for donor nerve selection are the distance from the donor to the affected cornea, the nerve caliber, and axon count. Both the sural and the great auricular nerves are purely sensory. High rates of corneal healing have been observed with direct and indirect corneal neurotization. Results from a recent meta-analysis have shown a significant improvement in healing, with the Mackie grade decreasing from an average of 2.46 ± 0.77 to 0.86 ± 0.79. Corneal sensation, however, does not fully return after corneal neurotization, especially when compared to the opposite cornea. Patients may begin feeling subjective sensations such as pain and discomfort several weeks after surgery, with objective improvements occurring several months later and continuing for up to a year. Corneal nerves are organized into bundles that divide before entering the corneal tissue, passing through various layers before finally ending in free nerve endings. The corneal tissue's density and number of nerves are related to its sensitivity. The speed of corneal sensation recovery is linked to the distance between the injured and the distal nerve. The density and visualization of corneal nerves can be measured using in vivo confocal microscopy, starting from 3 months post-surgery, with improvement observed up to 6 months. Unfortunately, the blink reflex is not restored after corneal neurotization. The density of nerves varies throughout the cornea, with thinner axons, higher numbers of myelinated fibers, and the characteristic subbasal plexus whorl pattern not being fully restored. Visual improvement depends on corneal scarring, amblyopia, and other eye-related conditions. There is a suggestion to consider corneal neurotization at earlier clinical stages before permanent scarring or amblyopia develops. Patients younger than 18 tend to recover more rapidly and completely than older patients. Keratoplasty can be performed after or simultaneously with corneal neurotization to improve vision. Special considerations are necessary when considering corneal neurotization for patients with herpetic disease due to the risks of reinfection and reactivation. Preoperative and postoperative oral antiviral prophylaxis is recommended. Both direct and indirect methods with ipsilateral or contralateral donor nerves have been used with similar outcomes. Lin et al used the ipsilateral supratrochlear nerve in a direct transfer technique, with 78% of cases (n= 13 eyes) showing resolution of presenting corneal pathology and a shift from 70% Mackie stage III to 53% Mackie stage I after surgery. In patients with shorter denervation time (less than 2 years), improvements in corneal sensation can be rapid and detectable at 3 months postoperatively. Persistent epithelial defects usually occur in the first 6 months following corneal neurotization but resolve with conventional management. There is no consensus regarding the timing of surgical intervention; the eye needs to be stable and free from reactivation. Other ocular comorbidities, corneal fibrosis, and scarring limit the final visual potential. Some treatments on the horizon, such as topical losartan, show promise in reversing stromal scarring fibrosis.