Corneal Neurotization: Essentials for The Facial Paralysis Surgeon

Abstract

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

Keywords

neurotrophic keratopathy - corneal neurotization - corneal sensation - anesthetic cornea - corneal nerve

Publication History

Accepted Manuscript online:
20 February 2024

Article published online:
18 March 2024

• References

• 1 Peterson DC, Hamel RN. Corneal Reflex. Treasure Island, FL: StatPearls Publishing; 2023
• 2 Daeschler SC, Woo JH, Hussein I, Ali A, Borschel GH. Corneal neurotization: preoperative patient workup and surgical decision-making. Plast Reconstr Surg Glob Open 2023; 11 (10) e5334
• 3 Dua HS, Said DG, Messmer EM. et al. Neurotrophic keratopathy. Prog Retin Eye Res 2018; 66: 107-131
• 4 Dana R, Farid M, Gupta PK. et al. Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy. BMC Ophthalmol 2021; 21 (01) 327
• 5 Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol 2014; 8: 571-579
• 6 Feinberg K, Tajdaran K, Mirmoeini K. et al. The role of sensory innervation in homeostatic and injury-induced corneal epithelial renewal. Int J Mol Sci 2023; 24 (16) 12615
• 7 Ziai K, Thomas S, Weller C, Lighthall JG. Corneal neurotization in the setting of facial paralysis: a comprehensive review of surgical techniques. J Craniofac Surg 2021; 32 (06) 2210-2214
• 8 Allevi F, Fogagnolo P, Rossetti L, Biglioli F. Eyelid reanimation, neurotisation, and transplantation of the cornea in a patient with facial palsy. BMJ Case Rep 2014; 2014: bcr2014205372
• 9 Woo JH, Daeschler SC, Mireskandari K, Borschel GH, Ali A. Minimally invasive corneal neurotization provides sensory function, protects against recurrent ulceration, and improves visual acuity. Am J Ophthalmol 2022; 241: 179-189
• 10 Zhang J, Barmettler A. Corneal neurotization: a narrative review of techniques, outcomes, and surgical considerations. Ann Eye Sci 2023; 8: 7-7
• 11 Park JK, Charlson ES, Leyngold I, Kossler AL. Corneal neurotization: a review of pathophysiology and outcomes. Ophthal Plast Reconstr Surg 2020; 36 (05) 431-437
• 12 Swanson MA, Swanson RD, Kotha VS. et al. Corneal neurotization: a meta-analysis of outcomes and patient selection factors. Ann Plast Surg 2022; 88 (06) 687-694
• 13 Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye (Lond) 2006; 20 (07) 837-839
• 14 Iraha S, Kondo S, Yamaguchi T, Inoue T. Bilateral corneal perforation caused by neurotrophic keratopathy associated with leprosy: a case report. BMC Ophthalmol 2022; 22 (01) 42
• 15 Rathi A, Bothra N, Priyadarshini SR. et al. Neurotization of the human cornea: a comprehensive review and an interim report. Indian J Ophthalmol 2022; 70 (06) 1905-1917
• 16 Nassiri N, Assarzadegan F, Shahriari M. et al. Vitamin B12 deficiency as a cause of neurotrophic keratopathy. Open Ophthalmol J 2018; 12: 7-11
• 17 Liu CY, Arteaga AC, Fung SE, Cortina MS, Leyngold IM, Aakalu VK. Corneal neurotization for neurotrophic keratopathy: review of surgical techniques and outcomes. Ocul Surf 2021; 20: 163-172
• 18 Rosenberg ML. Congenital trigeminal anaesthesia. A review and classification. Brain 1984; 107 (Pt 4): 1073-1082
• 19 Ramaesh K, Stokes J, Henry E, Dutton GN, Dhillon B. Congenital corneal anesthesia. Surv Ophthalmol 2007; 52 (01) 50-60
• 20 Fausto R, Ceccuzzi R, Micheletti E. et al. A case report of pediatric neurotrophic keratopathy in pontine tegmental cap dysplasia treated with cenegermin eye drops. Medicine (Baltimore) 2020; 99 (30) e20816
• 21 Masri A, Shboul M, Khasawneh A. et al. Congenital insensitivity to pain with anhidrosis syndrome: a series from Jordan. Clin Neurol Neurosurg 2020; 189: 105636
• 22 Warnier H, Barrea C, Bethlen S, Schrouff I, Harvengt J. Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review. Orphanet J Rare Dis 2022; 17 (01) 174
• 23 Lambley RG, Pereyra-Muñoz N, Parulekar M, Mireskandari K, Ali A. Structural and functional outcomes of anaesthetic cornea in children. Br J Ophthalmol 2015; 99 (03) 418-424
• 24 Bains RD, Elbaz U, Zuker RM, Ali A, Borschel GH. Corneal neurotization from the supratrochlear nerve with sural nerve grafts: a minimally invasive approach. Plast Reconstr Surg 2015; 135 (02) 397e-400e
• 25 Hanna C, Bicknell DS, O'Brien JE. Cell turnover in the adult human eye. Arch Ophthalmol 1961; 65: 695-698
• 26 Cenedella RJ, Fleschner CR. Kinetics of corneal epithelium turnover in vivo. Studies of lovastatin. Invest Ophthalmol Vis Sci 1990; 31 (10) 1957-1962
• 27 Bentley AJ, Nakamura T, Hammiche A. et al. Characterization of human corneal stem cells by synchrotron infrared micro-spectroscopy. Mol Vis 2007; 13: 237-242
• 28 Chen Z, de Paiva CS, Luo L, Kretzer FL, Pflugfelder SC, Li DQ. Characterization of putative stem cell phenotype in human limbal epithelia. Stem Cells 2004; 22 (03) 355-366
• 29 Schlötzer-Schrehardt U, Kruse FE. Identification and characterization of limbal stem cells. Exp Eye Res 2005; 81 (03) 247-264
• 30 Romano AC, Espana EM, Yoo SH, Budak MT, Wolosin JM, Tseng SC. Different cell sizes in human limbal and central corneal basal epithelia measured by confocal microscopy and flow cytometry. Invest Ophthalmol Vis Sci 2003; 44 (12) 5125-5129
• 31 Di Girolamo N, Bobba S, Raviraj V. et al. Tracing the fate of limbal epithelial progenitor cells in the murine cornea. Stem Cells 2015; 33 (01) 157-169
• 32 Buck RC. Cell migration in repair of mouse corneal epithelium. Invest Ophthalmol Vis Sci 1979; 18 (08) 767-784
• 33 Yazdanpanah G, Haq Z, Kang K, Jabbehdari S, Rosenblatt ML, Djalilian AR. Strategies for reconstructing the limbal stem cell niche. Ocul Surf 2019; 17 (02) 230-240
• 34 Altshuler A, Amitai-Lange A, Tarazi N. et al. Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing. Cell Stem Cell 2021; 28 (07) 1248-1261.e8
• 35 Mirmoeini K, Tajdaran K, Zhang J. et al. Schwann cells are key regulators of corneal epithelial renewal. Invest Ophthalmol Vis Sci 2023; 64 (04) 7
• 36 Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res 2003; 76 (05) 521-542
• 37 Cavanagh HD, Colley AM. The molecular basis of neurotrophic keratitis. Acta Ophthalmol Suppl (1985) 1989; 192 (S192): 115-134
• 38 Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye (Lond) 2003; 17 (08) 989-995
• 39 Sigelman S, Friedenwald JS. Mitotic and wound-healing activities of the corneal epithelium; effect of sensory denervation. AMA Arch Opthalmol 1954; 52 (01) 46-57
• 40 Ueno H, Ferrari G, Hattori T. et al. Dependence of corneal stem/progenitor cells on ocular surface innervation. Invest Ophthalmol Vis Sci 2012; 53 (02) 867-872
• 41 Catapano J, Antonyshyn K, Zhang JJ, Gordon T, Borschel GH. Corneal neurotization improves ocular surface health in a novel rat model of neurotrophic keratopathy and corneal neurotization. Invest Ophthalmol Vis Sci 2018; 59 (11) 4345-4354
• 42 Ferrari G, Chauhan SK, Ueno H. et al. A novel mouse model for neurotrophic keratopathy: trigeminal nerve stereotactic electrolysis through the brain. Invest Ophthalmol Vis Sci 2011; 52 (05) 2532-2539
• 43 Catapano J, Fung SSM, Halliday W. et al. Treatment of neurotrophic keratopathy with minimally invasive corneal neurotisation: long-term clinical outcomes and evidence of corneal reinnervation. Br J Ophthalmol 2019; 103 (12) 1724-1731
• 44 Shimizu T, Izumi K, Fujita S. et al. Capsaicin-induced corneal lesions in mice and the effects of chemical sympathectomy. J Pharmacol Exp Ther 1987; 243 (02) 690-695
• 45 Yamada M, Ogata M, Kawai M, Mashima Y. Decreased substance P concentrations in tears from patients with corneal hypesthesia. Am J Ophthalmol 2000; 129 (05) 671-672
• 46 Nagano T, Nakamura M, Nakata K. et al. Effects of substance P and IGF-1 in corneal epithelial barrier function and wound healing in a rat model of neurotrophic keratopathy. Invest Ophthalmol Vis Sci 2003; 44 (09) 3810-3815
• 47 Nishida T. Neurotrophic mediators and corneal wound healing. Ocul Surf 2005; 3 (04) 194-202
• 48 Nishida T. Translational research in corneal epithelial wound healing. Eye Contact Lens 2010; 36 (05) 300-304
• 49 Saika S, Okada Y, Miyamoto T. et al. Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium. Invest Ophthalmol Vis Sci 2004; 45 (01) 100-109
• 50 Terai K, Call MK, Liu H. et al. Crosstalk between TGF-β and MAPK signaling during corneal wound healing. Invest Ophthalmol Vis Sci 2011; 52 (11) 8208-8215
• 51 Wilson SE. Corneal wound healing. Exp Eye Res 2020; 197: 108089
• 52 Zhou Q, Chen P, Di G. et al. Ciliary neurotrophic factor promotes the activation of corneal epithelial stem/progenitor cells and accelerates corneal epithelial wound healing. Stem Cells 2015; 33 (05) 1566-1576
• 53 Matsumoto Y, Dogru M, Goto E. et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology 2004; 111 (06) 1115-1120
• 54 Yoon KC, You IC, Im SK, Jeong TS, Park YG, Choi J. Application of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis. Ophthalmology 2007; 114 (09) 1637-1642
• 55 Aggarwal S, Kheirkhah A, Cavalcanti BM. et al. Autologous serum tears for treatment of photoallodynia in patients with corneal neuropathy: efficacy and evaluation with in vivo confocal microscopy. Ocul Surf 2015; 13 (03) 250-262
• 56 Rao K, Leveque C, Pflugfelder SC. Corneal nerve regeneration in neurotrophic keratopathy following autologous plasma therapy. Br J Ophthalmol 2010; 94 (05) 584-591
• 57 You J, Hodge C, Hoque M, Petsoglou C, Sutton G. Human platelets and derived products in treating ocular surface diseases: a systematic review. Clin Ophthalmol 2020; 14: 3195-3210
• 58 Mussano F, Genova T, Munaron L, Petrillo S, Erovigni F, Carossa S. Cytokine, chemokine, and growth factor profile of platelet-rich plasma. Platelets 2016; 27 (05) 467-471
• 59 Wang AL, Weinlander E, Metcalf BM. et al. Use of topical insulin to treat refractory neurotrophic corneal ulcers. Cornea 2017; 36 (11) 1426-1428
• 60 Takanashi N, Haruki T, Miyazaki D, Inoue Y. Effects of the pharmaceutical formulation of topical medications on corneal epithelial healing after phototherapeutic keratectomy. Jpn J Ophthalmol 2023; 67 (04) 424-430
• 61 Soifer M, Starr CE, Mousa HM, Savarain C, Perez VL. Neurotrophic keratopathy: current perspectives. Curr Ophthalmol Rep 2020; 8 (02) 29-35
• 62 Deeks ED, Lamb YN. Cenegermin: a review in neurotrophic keratitis. Drugs 2020; 80 (05) 489-494
• 63 Bonini S, Lambiase A, Rama P. et al; REPARO Study Group. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology 2018; 125 (09) 1332-1343
• 64 Pflugfelder SC, Massaro-Giordano M, Perez VL. et al. Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial. Ophthalmology 2020; 127 (01) 14-26
• 65 Dai X, Jensen A, Dun C, Karakus S, Rajaii F, Woreta F. Cost and prescriber and patient characteristics of cenegermin use in the Medicare population. Am J Ophthalmol 2023; 250: 12-19
• 66 Katzman LR, Jeng BH. Management strategies for persistent epithelial defects of the cornea. Saudi J Ophthalmol 2014; 28 (03) 168-172
• 67 Dunn SP, Heidemann DG, Chow CY. et al. Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4. Ann N Y Acad Sci 2010; 1194: 199-206
• 68 Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance p-derived peptide and insulin-like growth factor 1. Jpn J Ophthalmol 2007; 51 (06) 442-447
• 69 Yamada N, Matsuda R, Morishige N. et al. Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulin-like growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy. Br J Ophthalmol 2008; 92 (07) 896-900
• 70 Dragnea DC, Krolo I, Koppen C, Faris C, Van den Bogerd B, Ní Dhubhghaill S. Corneal neurotization-indications, surgical techniques and outcomes. J Clin Med 2023; 12 (06) 2214
• 71 Terzis JK, Dryer MM, Bodner BI. Corneal neurotization: a novel solution to neurotrophic keratopathy. Plast Reconstr Surg 2009; 123 (01) 112-120
• 72 Gennaro P, Gabriele G, Aboh IV. et al. The second division of trigeminal nerve for corneal neurotization: a novel one-stage technique in combination with facial reanimation. J Craniofac Surg 2019; 30 (04) 1252-1254
• 73 Benkhatar H, Levy O, Goemaere I, Borderie V, Laroche L, Bouheraoua N. Corneal neurotization with a great auricular nerve graft: effective reinnervation demonstrated by in vivo confocal microscopy. Cornea 2018; 37 (05) 647-650
• 74 Elbaz U, Bains R, Zuker RM, Borschel GH, Ali A. Restoration of corneal sensation with regional nerve transfers and nerve grafts: a new approach to a difficult problem. JAMA Ophthalmol 2014; 132 (11) 1289-1295
• 75 Leyngold I, Weller C, Leyngold M, Tabor M. Endoscopic corneal neurotization: technique and initial experience. Ophthal Plast Reconstr Surg 2018; 34 (01) 82-85
• 76 Leyngold IM, Yen MT, Tian J, Leyngold MM, Vora GK, Weller C. Minimally invasive corneal neurotization with acellular nerve allograft: surgical technique and clinical outcomes. Ophthal Plast Reconstr Surg 2019; 35 (02) 133-140
• 77 Sweeney AR, Wang M, Weller CL. et al. Outcomes of corneal neurotisation using processed nerve allografts: a multicentre case series. Br J Ophthalmol 2022; 106 (03) 326-330
• 78 Liu C, Wang C, Zhao Q. et al. Incorporation and release of dual growth factors for nerve tissue engineering using nanofibrous bicomponent scaffolds. Biomed Mater 2018; 13 (04) 044107
• 79 Koaik M, Baig K. Corneal neurotization. Curr Opin Ophthalmol 2019; 30 (04) 292-298
• 80 Weis E, Rubinov A, Al-Ghoul AR, Yau FM. Sural nerve graft for neurotrophic keratitis: early results. Can J Ophthalmol 2018; 53 (01) 24-29
• 81 Lau N, Osborne SF, Vasquez-Perez A, Wilde CL, Manisali M, Jayaram R. Corneal neurotization using the great auricular nerve for bilateral congenital trigeminal anesthesia. Cornea 2022; 41 (05) 654-657
• 82 Jowett N, Pineda Ii R. Corneal neurotisation by great auricular nerve transfer and scleral-corneal tunnel incisions for neurotrophic keratopathy. Br J Ophthalmol 2019; 103 (09) 1235-1238
• 83 Rowe LW, Berns J, Boente CS, Borschel GH. Bilateral corneal neurotization for ramos-arroyo syndrome and developmental neurotrophic keratopathy: case report and literature review. Cornea 2023; 42 (03) 369-371
• 84 Malhotra R, Elalfy MS, Kannan R, Nduka C, Hamada S. Update on corneal neurotisation. Br J Ophthalmol 2019; 103 (01) 26-35
• 85 Braam MJI, Nicolai J-PA. Axonal regeneration rate through cross-face nerve grafts. Microsurgery 1993; 14 (09) 589-591
• 86 Zuo KJ, Gordon T, Chan KM, Borschel GH. Electrical stimulation to enhance peripheral nerve regeneration: update in molecular investigations and clinical translation. Exp Neurol 2020; 332: 113397
• 87 Gordon T. Neurotrophic factor expression in denervated motor and sensory Schwann cells: relevance to specificity of peripheral nerve regeneration. Exp Neurol 2014; 254: 99-108
• 88 Giannaccare G, Bolognesi F, Pellegrini M. et al. Corneal neurotization: a novel surgical procedure for neurotrophic keratopathy. Cornea 2022; 41 (04) 403-407
• 89 Giannaccare G, Bolognesi F, Biglioli F. et al. In vivo and ex vivo comprehensive evaluation of corneal reinnervation in eyes neurotized with contralateral supratrochlear and supraorbital nerves. Cornea 2020; 39 (02) 210-214
• 90 Giannaccare G, Pellegrini M, Bolognesi F. et al. Spotlight on corneal neurotization. Expert Rev Ophthalmol 2021; 16 (03) 175-184
• 91 Whitlock EL, Tuffaha SH, Luciano JP. et al. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve 2009; 39 (06) 787-799
• 92 Pedrotti E, Bonacci E, Chierego C. et al. Eight months follow-up of corneal nerves and sensitivity after treatment with cenegermin for neurotrophic keratopathy. Orphanet J Rare Dis 2022; 17 (01) 63
• 93 Wisely CE, Rafailov L, Cypen S, Proia AD, Boehlke CS, Leyngold IM. Clinical and morphologic outcomes of minimally invasive direct corneal neurotization. Ophthal Plast Reconstr Surg 2020; 36 (05) 451-457
• 94 Standring S. The anatomy of the peripheral nervous system. In: Gray's Anatomy: The Anatomical Basis of Clinical Practice. 42nd ed.. Amsterdam: Elsevier; 2021
• 95 Konofaos P, Soto-Miranda MA, Ver Halen J, Fleming JC. Supratrochlear and supraorbital nerves: an anatomical study and applications in the head and neck area. Ophthal Plast Reconstr Surg 2013; 29 (05) 403-408