Minimally Invasive Corneal Neurotization Provides Sensory Function, Protects Against Recurrent Ulceration, and Improves Visual Acuity


To measure sensory recovery after minimally invasive corneal neurotization, and to identify and quantify the extent to which patient and technical factors influence sensory recovery, ulceration rate, and visual outcomes.


Retrospective case series.


This study included 23 patients with neurotrophic keratopathy who underwent indirect corneal neurotization. The primary outcome measure was corneal sensitivity with Cochet−Bonnet aesthesiometry (CBA), and the secondary outcome measure was epithelial breakdown.


Over a 7-year period, 28 eyes of 23 patients (mean age, 15.6 ± 13.6 years) were included in the study. The CBA measurements improved from 3.5 ± 9.1 mm at baseline to 44.1 ± 18.2 mm at 24 months after surgery ( P < .001). Maximum CBA was reached after 11.1 ± 6.2 months (median, 9 months). Compared to eyes neurotized with a contralateral donor nerve, eyes with an ipsilateral donor nerve achieved a higher mean CBA (36.0 ± 10.9 vs 10.4 ± 14.0 mm, P = .001) at 3 months. Both the number of fascicles (Spearman correlation coefficient, r s −0.474, P = .11) and insertions ( r s −0.458, P = .014) negatively correlated with the final CBA. Nine eyes (32.1%) experienced at least 1 episode of epithelial breakdown after surgery. Visual acuity improved in the neurotized corneas from logMAR 0.57 ± 0.79 at baseline to 0.39 ± 0.66 at 12 months ( P = .043).


Corneal sensation improves over time after corneal neurotization. There is resultant improvement in visual acuity and protection against epithelial breakdown. It is important to maximize sensory recovery to protect against recurrent ulceration.

N eurotrophic keratopathy (NK) is a complex disease of the ocular surface, which results from the disruption of both sensory and trophic functions of normal corneal innervation. A multitude of underlying etiologies, including congenital, systemic, postsurgical, ocular, and postinfective causes, can lead to NK in adults and children. The impairment in corneal innervation triggers a cascade of events involving diminished protective blink reflexes and tear production, reduced expression of trophic factors, abnormal epithelial cell metabolism, and chronic inflammation. These interlinked factors contribute to the loss of epithelial cell vitality and ocular surface breakdown. Although the clinical manifestations of early NK may be mild, if not appropriately treated, late-stage disease may have devastating, sight-threatening sequelae of persistent epithelial defect, stromal melt, and perforation.

The management of NK is challenging. Conventional treatment strategies are centered on promoting epithelial healing and stability as well as preventing disease progression. These have been achieved with various medical (ocular lubricants, autologous serum, platelet-rich plasma, recombinant human nerve growth factor), nonsurgical (punctal occlusion, therapeutic contact lens), and surgical (tarsorrhaphy, amniotic membrane transplantation) interventions, either in a step-ladder approach or, more often, in combination. , However, none of these modalities directly address the underlying neurological deficit in NK.

In recent years, corneal neurotization has emerged as a novel surgical technique for NK, which aims to restore innervation to a severely hypoesthetic or anesthetic cornea. Conceptually, the procedure involves the transfer of a healthy sensory donor nerve to the anesthetic cornea. This may be achieved with a direct nerve transfer or an interpositional nerve graft for axons to cross from the donor sensory nerve into the cornea. Since the first description of modern corneal neurotization in 2009, in the form of a contralateral nerve transfer via a bicoronal incision, many different surgical approaches, donor nerves, and interpositional nerve graft options have been described for a variety of clinical indications and patient profiles. ,

A variety of surgical methods of corneal neurotization have been reported to provide corneal sensory function and epithelial healing. However, the metrics for surgical and functional outcomes are not well defined at present. Current knowledge on the rate of postoperative sensory recovery is largely derived from pooled data in published literature. It is also unclear how patient attributes and surgical factors affect these outcomes.

The purpose of this study was to measure the sensory recovery after minimally invasive corneal neurotization, and to identify and quantify the extent to which patient and technical factors influence sensory recovery, ulceration rate, and visual outcomes long term.



This was a retrospective case series conducted at The Hospital for Sick Children (Toronto, Ontario, Canada). Consecutive patients who underwent corneal neurotization between November 2012 and June 2019 were included. Written informed consent was obtained from each patient (or parents of pediatric patients). The study was approved by the Institutional Review Board (IRB) and Ethics Committee, and the described research adhered to the tenets of the Declaration of Helsinki.

The current cohort included some patients whose short-term outcomes have been previously described. We have since expanded on our registry of corneal neurotization patients. This paper presents new analyses of updated longitudinal data over an extended follow-up period to demonstrate the temporal trends and influencing factors of sensory recovery after surgery.

All patients included in the study had an established diagnosis of neurotrophic keratopathy of at least stage II or III in severity (according to the Mackie classification ), for whom spontaneous recovery was unlikely. This was defined as the most severe stage throughout the clinical course of the patient, rather than at the time of surgery, as corneal neurotization was not performed in patients with active epithelial breakdown, corneal melt, or perforation. For patients whose condition was caused by a specific denervation event (such as nerve resection), surgery was performed only after a denervation time of at least 12 months. Patients who did not have at least 6 months of follow-up data were excluded.

All patients underwent a standardized preoperative evaluation by the teams led by the senior authors. This included medical and ophthalmic history, best-corrected visual acuity (BCVA), slitlamp and dilated fundus examination, Cochet−Bonnet Aesthesiometry (CBA; Luneau Ophthalmologie) testing, as well as sensory mapping of the face and neck.

Corneal sensory function was measured using the CBA in 5 sectors sequentially (central, superior, inferior, nasal and temporal). The range of threshold values ranged from 0 mm (absent sensation) to 60 mm (full sensation). Each patient was assessed independently by 2 members of the Ophthalmology team, and the final corneal sensitivity threshold was verified twice before being recorded. Readings that were deemed unreliable on repeated testing (the absence of consistent subjective response to the stimulus as verified by the 2 testers) were excluded from the study.

Systematic sensory mapping of the face and neck regions was performed using the Semmes−Weinstein monofilaments (Weinstein Enhanced Sensory Test, WEST facial set) for measurement of tactile thresholds, to identify potential donor nerves. Patients were also assessed for subjective touch perception (“Ten Test” ) and pain (pinch test) to uncover areas with potential impaired donor site sensation.

Our surgical technique for corneal neurotization has been previously described. Briefly, a normal segment of the sural nerve was first harvested from the patient’s lower leg, to be used as an interpositional graft, of approximately 10 to 15 cm in length. A predetermined (based on preoperative sensory mapping) functional branch of the trigeminal nerve (or the great auricular nerve) was usually selected as the donor sensory nerve. For cases in which the supratrochlear or supraorbital nerve served as the donor sensory nerve, a 2-cm upper lid incision was made to locate and isolate the nerve. In contralateral cases, the nerve graft was tunneled subcutaneously between the brows. Using a Wright needle, the sural nerve graft was then introduced into the superior fornix and then tunneled subconjunctivally to the perilimbal area of the cornea After an epineurectomy, the distal end of the nerve graft was divided into its component fascicles before being positioned circumferentially around the cornea. In our earlier cases, these fascicles were laid in the perilimbal subconjunctival space. For the later cases, we directly inserted the ends of the fascicles into the peripheral cornea via short corneoscleral tunnels. The perineurium of the nerve fascicles was then fixated to the sclera using a single 10/0 absorbable monofilament suture. The proximal end of the nerve graft was then coapted to the donor nerve in either end-to-end or side-to-end configuration. This was performed using either fibrin glue (Tisseel, Baxter) alone, with epineural sutures (10-0 nylon), or both. The conjunctival and skin incisions were then closed, and a temporary tarsorrhaphy was performed in all cases for ocular surface protection.

All patients received a combination antibiotic−corticosteroid ointment (Tobradex, Novartis AG), administered 3 times a day after the surgery. The temporary tarsorrhaphy was removed after 1 week. Patients were assessed at 1 week and 1 month after corneal neurotization, and at 3-monthly intervals or as needed thereafter.

The primary outcome measure of corneal sensitivity was measured at every postoperative visit from the third month after surgery. The secondary outcome measure of epithelial breakdown was also assessed postoperatively. A significant episode of corneal epithelial breakdown was defined as the presence of at least 1.0 mm of fluorescein staining (measured using the slitlamp under cobalt blue light) in the greatest dimension of the corneal epithelial defect. Any other side effects or complications from the surgery were also recorded. Of note, we also documented the subjective qualitative feedback from patients regarding their perception of corneal sensation.


All data were entered onto an Excel (Microsoft Corp.) spreadsheet and statistical analysis was performed using SPSS version 25.0 (IBM Corp.). Statistical analysis included descriptive statistics, where the mean and SD were calculated for the continuous variables, whereas frequency distribution and percentages were used for categorical variables. Categorical factors such as sex and surgical indications were compared using the Pearson χ 2 and Fisher exact test where appropriate. Analysis of the change in CBA over time and across sectors was performed using 1-way analysis of variance with repeated measures. Correlation between variables was analyzed using the Pearson correlation or Spearman rank-order correlation coefficient where appropriate.

In the analysis of the factors that influence sensory recovery after corneal neurotization, we compared the eyes that achieved a final maximum corneal CBA of less than 50 mm (group A) with those that achieved 50 mm and above (group B) with at least 12 months of follow-up. A Kaplan−Meier survival analysis using log-rank test was also conducted to compare groups A and B, using epithelial breakdown beyond the first postoperative year as the event of interest.

Nominal P values were used for all comparisons, and with values of <.05 considered significant



In all, 28 eyes of 23 patients were included in the study. The mean age was 15.6 ± 13.6 years (range, 2-62 years). Fourteen patients (60.9%) had corneal anesthesia due to a congenital or developmental cause, whereas 9 patients (39.1%) had an acquired cause. The mean follow-up duration for the entire cohort was 37.8 ± 22.5 months (range, 6-74 months). The baseline characteristics of the patients are summarized in Table 1 .

Table 1

Baseline Characteristics of Patients Who Underwent Corneal Neurotization

Patient No. Age, Sex Eye Diagnosis Mackie Stage Pre-neurotization Ocular Management Donor Sensory Nerve Follow-up, mo
1 4, F OS Oculocerebrocutaneous (Delleman) syndrome, cerebellar malformation III Excision of upper lid lesion, scar revision for lid retraction and lagophthalmos Contralateral ST 9
2 36, F OD Congenital brainstem malformation III Tarsorrhaphy Ipsilateral ST 6
3 6, M OD Congenital corneal anaesthesia III Tarsorrhaphy Ipsilateral ST 29
4 62, M OS Meningioma excision II Nil Contralateral ST 11
5 8, F OS Herpetic keratitis III PK, botulinum injection, intrastromal bevacizumab, tarsorrhaphy Contralateral ST and SO 54
6 22, F OD Congenital corneal anaesthesia III Intrastromal bevacizumab Contralateral ST 13
OS III Intrastromal bevacizumab Ipsilateral ST 13
7 9, M OD Cerebellar hypoplasia III 2 previous PK, tarsorrhaphy Ipsilateral ST 79
OS III Tarsorrhaphy Ipsilateral ST 79
8 15, M OD Brainstem cavernous malformation II Nil Contralateral ST 25
9 24, M OS Trigeminal schwannoma III Nil Contralateral ST 19
10 10, F OS Posterior cranial fossa astrocytoma II Nil Contralateral ST 25
11 16, M OS Congenital corneal anaesthesia III Multiple corneal gluing for perforation Ipsilateral IO 53
12 10, M OS Congenital corneal anaesthesia III Tarsorrhaphy Contralateral SO 12
13 18, F OD Cerebellar hypoplasia III Tarsorrhaphy Ipsilateral ST 40
OS III Tarsorrhaphy Ipsilateral ST 40
14 16, F OS Skull base meningioma III Tarsorrhaphy Contralateral ST 66
15 4, F OD Congenital corneal anaesthesia II Nil Contralateral ST 74
16 34, F OD Acoustic neuroma with trigeminal nerve palsy III PK, tarsorrhaphy Contralateral ST 40
17 8, M OD Congenital corneal anaesthesia, fetal alcohol syndrome III Tarsorrhaphy Ipsilateral ST 8
18 8, F OS Atypical teratoid rhabdoid tumour of cerebellopontine angle III Tarsorrhaphy Ipsilateral ST and SO 31
19 6, M OS Congenital corneal anaesthesia III Tarsorrhaphy Contralateral ST 64
20 16, M OD Traumatic brain injury III PK, tarsorrhaphy Contralateral ST 51
21 2, F OD Congenital corneal anaesthesia III Tarsorrhaphy Contralateral ST 47
OS II Nil Ipsilateral ST 47
22 4, M OS Congenital corneal anaesthesia III Tarsorrhaphy Contralateral ST 66
23 13, F OD Pontine hypoplasia III Tarsorrhaphy Ipsilateral ST 37
OS III Tarsorrhaphy Contralateral ST 37

IO = infraorbital nerve; OD = right; OS = left; PK = penetrating keratoplasty; SO = supraorbital nerve; ST = supratrochlear nerve.

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Sep 11, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Minimally Invasive Corneal Neurotization Provides Sensory Function, Protects Against Recurrent Ulceration, and Improves Visual Acuity
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