The cornea is one of the most richly innervated organs. Normal innervation is vital for maintaining epithelial integrity in the cornea and wound healing. NK is a degenerative disease of the cornea characterized by the absence of corneal sensitivity and impaired epithelial healing. The early signs of NK are increased viscosity of tear mucus and punctate fluorescein staining of the corneal epithelium, which constitute the extent of Mackie’s stage I of NK. Mackie’s stage II is characterized by the acute loss of epithelium, with the defect surrounded by loose epithelium that forms a smooth edge. Folds develop in Descemet’s membrane as the stroma begins to swell. Stage III involves stromal lysis and eventually corneal perforation.

The causes of NK include various ocular and systemic conditions. The most common causes are herpes simplex and herpes zoster virus infections [15]. Intracranial space-occupying tumors and neurosurgical procedures that damage the ophthalmic branch of the trigeminal nerve can also result in this refractory disease. Chemical injuries, especially those caused by alkalis, lead to the most severe damage to the trophic cord. If the process reaches the deeper stroma, the corneal nerves are damaged, and the sensitivity may be markedly affected. Various treatments for NK (including preservative-free lubricants, autologous serum eye drops, and therapeutic contact lenses) can promote corneal epithelial regrowth over a neurotrophic corneal defect. However, conventional treatments for NK may increase the risk of disease recurrence because these treatments do not address the underlying injury of corneal innervation. Recently, the surgical procedure of corneal neurotization has been introduced as a surgical replacement for dysfunctional nerves in cases of unilateral NK. This can be either by direct nerve transfer or by indirect corneal neurotization, which involves the interposition of a nerve graft between a healthy donor nerve and the affected cornea.

In this study, nine patients with active NK underwent surgery. Preoperatively, the baseline volume of the corneal epithelial defect was 14.3 ± 6.1 mm [2]. The ulcers of all 9 patients healed within 3 months after surgery, which was maintained throughout the follow-up period. Compared with that in patients with multiple cranial nerve palsy after surgery, the epithelial defect in 6 patients with single fifth cranial nerve palsy was reduced substantially from baseline. Eyelid dysfunction in conjunction with neurotrophic corneal epithelium defects renders treatment more difficult. Abnormal eyelid blinking inhibits corneal epithelial growth in concert with suboptimal sensory innervation. Changes in eyelid structure and function need to be carefully assessed and treated to prevent exposure keratopathy and vision deterioration.

In this study, an intact epithelium was restored, and corneal transparency was maintained, with an improvement in visual acuity in some of our patients. Most of our patients with visual improvement were in the active stage. Yen reported that there was no significant difference in visual acuity after neurotization in their series. The reason was that most of their patients had corneal scars [16]. Other factors affecting postoperative visual acuity include amblyopia, large-angle esotropia, cataracts, and retinal detachment [17, 18]. In contrast, 3 of the 4 patients demonstrated significant improvement in visual acuity postoperatively in another study [19]. All of our patients were adults, and none of them had amblyopia or posterior ocular disease. Timely surgical intervention to stabilize the ocular surface to control the development of corneal scars is helpful for achieving better postoperative visual acuity. In patients whose deep stromal scars remain, keratoplasty secondary to corneal neurotization surgery is needed to restore corneal clarity and improve visual acuity.

IVCM is a useful clinical diagnostic tool for evaluating regenerated nerves during corneal neurotization. Preoperatively, the subbasal neural plexus was not visible by IVCM in any of the patients. After surgical neurotization, a small number of attenuated subbasal nerve fibres were present as early as 3 months after surgery. One year after surgery, corneal nerves in the subbasal layer were detectable in all patients; however, the quantity and quality of these nerves were poorer than those in the contralateral unaffected eye. This finding suggests that the recovery process of the regenerated nerves was not yet complete. The result of slower subbasal nerve recovery after multiple nerve injury than after single trigeminal injury is not clear. The higher prevalence of abnormal blinking, dry eyes, and altered tear film after multiple nerve injury than after single trigeminal nerve injury may be attributed to the slow recovery of corneal nerves. However, complete recovery of subbasal nerves does not seem to be necessary for corneal epithelial healing, and the limbal vessel subsides. All our patients had the corneal epithelium defects healed 3 months postoperatively, which suggests that only partial recovery of subbasal nerves is sufficient for maintaining homeostasis of the ocular surface and preventing the deterioration of corneal ulcers.

Vessels may invade the cornea from the limbal vascular plexus under pathological conditions. Corneal neovascularization may affect visual acuity via corneal scarring, oedema and lipid deprivation. It also alters the immune privilege of the cornea, thereby increasing the risk of graft rejection resulting from penetrating kertoplasty [20]. Corneal neovascularization occurs secondarily to postinfection, inflammation, keratoplasty, loss of the limbal stem cell barrier, and corneal denervation. Ferrari suggested that corneal nerves and vessels inhibit one another by reducing the number of angiostatic molecules expressed by the cornea, including pigment epithelial-derived factor (PEDF) and epithelial VEGFR3 [21]. In this study, corneal neurotization surgery was not only useful in facilitating corneal epithelial healing and halting stromal melts but also effective in occluding actively growing corneal blood vessels. Improving vascularized corneal recipient beds can reduce graft rejection by blocking the trafficking of graft-derived antigens to regional lymph nodes in subsequent keratoplasty [22, 23]. Thus, corneal neurotization may be helpful for long-term corneal graft survival in NK patients with penetrating keratoplasty.

Various techniques are employed in corneal neurotization. The advantage of direct corneal neurotization is the shorter regeneration distance could result in higher corneal sensation compared with indirect at early postoperative time points. With the use of a more proximal section of the donor nerve, indirect corneal neurotization potentially leading to increased innervation and enhanced corneal sensation. However, the long-term outcomes of direct and indirect neurotization are the same [10]. The drawback of direct corneal neurotization lies in the requirement for a wide facial dissection and extensive nerve manipulation. The sural nerve is a cutaneous sensory nerve of the posterolateral leg to the lateral ankle. The plastic surgeons are familiar with the technique to harvest the sural nerve graft. The use of a sural nerve graft as a conduit allows for the surgical flexibility to use a variety of donor sensory nerve, including the supraorbital nerve, supratrochlear nerve, great auricular nerve, and occipital nerves [24]. In our study, this procedure allowed the healing of NK and recovery of corneal sensations in all patients. In consideration of experience of the surgeon, the surgical technique of MICN is now considered an efficient and safe procedure in resource-limited hospitals.

One of the primary limitations of this study was it was a small retrospective study of 11 patients and short-term follow-up. In addition, the sensation of conjunctiva of the affected eye was not tested. In eyes with partial trigeminal nerve function, a topical recombinant human nerve growth factor, cenegermin (Oxervate, Dompe, Milan) may be an option to promote corneal nerve health and restore the ocular surface homeostasis. A major limitation to the use of the cenegermin in clinical practice is the cost of therapy. Another limitation is cenegermin did not demonstrate a significant improvement in central corneal sensation or bestcorrected visual acuity in clinical trials [25, 26].

In conclusion, this series of NK patients presented with a very harmful corneal condition with a poor prognosis for permanent corneal epithelium healing and ocular surface homeostasis with conventional management techniques. We observed the absence of the corneal nerve plexus preoperatively in all our patients. After surgery, favorable trophic changes, particularly in the subbasal nerve plexus, were observed in our patients. However, the nerve fibers are less in number as compared to a normal eye. Combination of MICN with cenegermin may enhance corneal lesion healing. We suggest that MICN is a useful alternative treatment for this difficult corneal degenerative disease.