Minimally Invasive Corneal Neurotization with Acellular Nerve Allograft: Surgical Technique and Clinical Outcomes

ORIGINAL INVESTIGATION

Minimally Invasive Corneal Neurotization With Acellular Nerve Allograft: Surgical Technique and Clinical Outcomes

Ilya M. Leyngold, M.D.*, Michael T. Yen, M.D.†, James Tian, B.S.‡, Mark M. Leyngold, M.D.§, Gargi K. Vora, M.D.║, and Christopher Weller, M.D.¶ *Division of Oculoplastic and Reconstructive Surgery, Department of Ophthalmology, Duke University Hospital, Durham, North Carolina; †Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; ‡Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina; §Division of Plastic and Reconstructive Surgery, Department of Surgery, University Florida College of Medicine, Gainesville, Florida; ║Cornea Division, Department of Ophthalmology, Duke University Hospital, Durham, North Carolina; and ¶Division of Oculofacial Plastic and Reconstructive Surgery, Department of Ophthalmology, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A.

topical autologous serum drops, and bandage contact lenses. Purpose: To describe a minimally invasive surgical technique More advanced disease may require surgical intervention, such and its clinical outcomes with the use of acellular nerve allograft as tarsorrhaphy, amniotic membrane grafts, and/or conjunctival to re-establish corneal sensibility in patients with neurotrophic flaps.3 In the presence of a corneal perforation, cyanoacrylate keratopathy. gluing or tectonic corneal transplantation may be needed.2,3 Methods: Acellular nerve allograft was coapted to an intact Neurotization is the process of transferring a healthy supraorbital, supratrochlear, or infraorbital nerve and transferred donor nerve segment to denervated tissue, thereby re-establish- to the affected eye. Donor nerve pedicles were isolated through ing either motor or sensory innervation.6,7 Corneal neurotization a transpalpebral or transconjunctival approach. Retrospective techniques have been described to treat patients with unilateral evaluation of preoperative and postoperative corneal sensibility, facial paralysis and corneal anesthesia from cerebellopontine ocular surface, and best-corrected visual acuity was performed angle tumors, trauma, and congenital lesions, as well as iso- in all patients. Mean follow-up period was 6 months (range: lated instances of NK.3,8–10 The reported techniques incorporate 3–10 months). contralateral or ipsilateral supraorbital and/or supratrochlear Results: Corneal neurotization with acellular nerve allograft nerve to reinnervate the anesthetic cornea. Previously described was successfully performed in 7 patients with restoration techniques involve the use of either a coronal or hemicoronal of corneal sensibility and corneal epithelial integrity. In vivo incision, endoscopic technique with small scalp and eyelid inci- confocal microscopy demonstrated increased nerve density in sions with direct nerve transfer,8–12 and indirect transfer using corneal stroma at 4 months after surgery. nerve autografts.3,4,13 Inherent risks of these techniques include Conclusions: The use of acellular nerve allograft allows for a long visible scars, subgaleal hematoma, alopecia, facial nerve minimally invasive approach to successful corneal neurotization. injury, prolonged operative time, and donor site morbidity. The (Ophthalmic Plast Reconstr Surg 2019;35:133–140) authors describe a new minimally invasive corneal neurotization technique with the use of processed acellular nerve allograft (Avance Nerve Graft, AxoGen, Alachua, FL, U.S.A.), which avoids these risks. This series is the first report of successful ormal sensation of the cornea, provided by the ophthalmic corneal neurotization with the acellular nerve allograft. division of the trigeminal nerve, is required for initiating N METHODS the blink reflex, maintaining corneal epithelial integrity and limbal stem cell function.1,2 The insensate cornea results in a A retrospective review was performed of patients who under- clinical condition known as neurotrophic keratopathy (NK). went corneal neurotization with acellular nerve allograft. The approval Complications of NK can lead to profound ocular consequences, for this retrospective study was obtained from the Duke University including corneal scarring, ulceration, perforation, vision loss, Institutional Review Board. The study was conducted in compli- and potential loss of an eye.3–5 Neurotrophic keratopathy can ance with Health Insurance Portability and Accountability Act and also complicate penetrating keratoplasty with nonhealing epi- Declaration of Helsinki. Assessment of average corneal sensibility (ei- thelium and graft failure.3 ther by Cochet–Bonnet esthesiometer in 4 peripheral quadrants of the Treatment options for NK are limited, and few preserve cornea and centrally or testing with a wisp of cotton) was performed vision. Initial treatments focus on maintaining the integrity of on all patients to diagnose NK. One patient underwent in vivo confocal the ocular surface. These include aggressive ocular lubrication, microscopy (Heidelberg Retina Tomograph III with the Rostock Cornea Module; Heidelberg Engineering GmBH, Heidelberg, Germany) of the affected cornea 4 months before and 4 months after the surgery. All Accepted for publication June 5, 2018. patients also underwent serial measurements of best-corrected visual The authors have no financial or conflicts of interest to disclose. acuity, a comprehensive ocular examination with slit-lamp biomicros- Address correspondence and reprint requests to Ilya M. Leyngold, M.D., Duke Aesthetic Center, DUMC 3810, Durham, NC 27710. E-mail: copy, and corneal esthesiometry spanning the pre- and postoperative [email protected] periods. Preoperative assessment of supraorbital, supratrochlear, and DOI: 10.1097/IOP.0000000000001181 infraorbital nerve functions bilaterally by light touch with a wisp of

Ophthalmic Plast Reconstr Surg, Vol. 35, No. 2, 2019 133

FIG. 1. Marking for contralateral transfer of the either a supraorbital or supratrochlear nerve. A higher crease is marked on the donor side (left upper eyelid) and the approximate location FIG. 2. Isolated supraorbital nerve segment severed ~2 cm of the sensory donor nerves is marked with small vertical lines. from the supraorbital notch. Natural eyelid crease is marked on the recipient side (right upper eyelid). then tunneled in the subgaleal plane to the eyelid crease incision at the recipient side (Fig. 4). cotton or Cochet–Bonnet esthesiometer was performed to determine vi- Any preexisting tarsorrhaphy was severed to allow for wide able donor nerve sites. During all visits, patients were asked to report exposure of the ocular surface. In cases where supraorbital or su- their dry eye symptoms (e.g., ocular irritation, foreign body sensation, pratrochlear nerves were transferred, a blepharotomy medial to the etc.), ability to feel eye drops in the operative eye, symptoms of synes- medial horn of the levator aponeurosis was then performed through thesia, and sensibility in the donor dermatome. Careful ocular surface the medial portion of the eyelid incision using Westcott scissors. The evaluation using fluorescein staining was performed to note changes nerve graft was then tunneled through the blepharotomy incision into in corneal appearance and integrity, and health of the donor nerve fas- the superior medial conjunctival fornix with a hemostat (Fig. 5A). In cicles. Postoperatively, patients were given topical antibiotic ointment patients who underwent ipsilateral transfer, the excess nerve graft to apply to the incision and topical antibiotic drops four times daily tissue was then sharply trimmed to the desired length. For the patient to the operative eye for 2 weeks following surgery. Patients with visu- in whom the infraorbital nerve was used, the nerve graft was directly ally significant corneal injury due to NK (e.g., dense punctate epithe- brought from the inferior orbit into the inferior bulbar subconjunc- lial erosions, persistent corneal epithelial defect or ulceration, corneal tival space. The epineurium was then incised, and nerve fascicles scarring or neovascularization, etc.), and viable donor sensory nerves were released along the graft segment just distal to the conjunctival were deemed to be candidates for the procedure. Patients with active fornix (Fig. 5B). ocular inflammatory or infectious conditions (e.g., microbial keratitis, The nerve fascicles were then tunneled in the subconjunctival ocular cicatricial pemphigoid, uveitis, etc.), poor systemic health, bleed- space to the corneoscleral limbus (Fig. 5C). Additional conjunctival ing diathesis, and those with limbal stem cell deficiency were excluded incisions were made at the terminal ends of the fascicles adjacent to from the study. Informed consent and preoperative medical clearance the limbus, and an 8-0 vicryl suture on a spatulated needle was used for general anesthesia were obtained in all patients. to secure the perineurium of the fascicle to the sclera (Fig. 5D). The conjunctival incisions were then closed with 8-0 vicryl sutures. Either Operative Approach. All procedures were performed under general a temporary or permanent tarsorrhaphy depending on particular pa- anesthesia. After infiltrating the surgical sites with 1% lidocaine with tient’s risk for corneal decompensation was performed or reformed (if 1:100,000 epinephrine, the procedure was initiated by making an in- one was already in place prior to surgery) to protect the cornea dur- cision in the recipient and donor site(s) (Fig. 1). For supraorbital or ing early postoperative period. Postoperatively, an eye patch was placed supratrochlear nerve transfers, bilateral eyelid crease incisions were performed for contralateral transfer (in cases of ipsilateral trigeminal neuropathy) and unilateral crease incision was performed if the ipsilateral sensory nerves were intact. The supraorbital and supratrochlear nerves were then exposed through the eyelid incision. Given the innate anatomic variability in caliber of the potential donor pedicles and allograft, the final determination to use either the supratrochlear or supraorbital donor pedicle was based on intraoperative best fit assessment. Once identified, the donor nerve was severed 1 to 2 cm distal to the supraorbital rim (Fig. 2). For the infraorbital nerve, a transconjunctival fornix incision was used to access the orbit where the orbital floor was removed to unroof the infraorbital groove. Next, processed acellular nerve allograft (Avance Nerve Graft) measuring 70 mm × 1–3 mm was coapted to the donor nerve (Fig. 3). A nerve connector, wrap, or an amniotic membrane graft derived from umbilical cord was used, based on surgeon’s preference, to protect the neurorrhaphy for all the end to end coaptations. For the end to side coaptation, no material was used to protect the neurorrhaphy based on technical preference. In cases of FIG. 3. Coaptation between nerve allograft (long arrow) and contralateral supraorbital or supratrochlear nerve transfer, the graft was supraorbital nerve (short arrow).

Copyright © 2019 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited. Ophthalmic Plast Reconstr Surg, Vol. 35, No. 2, 2019 Corneal Neurotization With Acellular Nerve Allograft

FIG. 5. A, A hemostat is tunneled through the blepharotomy incision to retrieve the graft. B, The epineurium in the incised and the fascicle are released on the ocular surface. C, A conjunctival incision is then created 7–8 mm above 12 o’clock limbus, and the fascicles are tunneled in the subconjunctival plane around the superior limbus.

dense central corneal opacity due to corneal ulceration and perforation 2 years ago for which she had undergone corneal gluing, tarsorrhaphies, and gold weight placement. Preoperative Cochet–Bonnet esthesiometry FIG. 4. A, In case of contralateral transfer, a large hemostat tunneled in subgaleal plane from the recipient side is used to revealed decreased corneal sensation in the left eye (Table). retrieve the nerve allograft via a 4-0 silk suture attached to epi- Following corneal neurotization with the nerve allograft coapted neurium of the graft. B, Nerve allograft tunneled to the upper to the contralateral supratrochlear nerve, she reported more ocular sur- eyelid crease incision on the recipient side. face comfort, improvement in dry eye symptoms, and subjective improvement in vision at 4 months postoperatively. Objectively, she had improvement in corneal sensibility in the inferior and superior quad- over the affected eye for 24 hours, and the patients were instructed to rants by Cochet–Bonnet testing at 4 months follow up (average 0.5 cm) place topical antibiotic drops 4 times daily into the affected eye for 1 with full restoration of sensation within the donor nerve dermatome. week. Strenuous activity and heavy lifting were restricted for 2 weeks In vivo confocal microscopy at 4 months postoperatively demonstrated postoperatively. Timing of tarsorrhaphy removal was based on corneal increased density of the corneal anterior stromal nerves (Fig. 6). Her examination. Patients resumed all preoperative ocular medications after visual acuity improved from 20/150 to 20/40 at 10-month follow up the eye patch was removed. at the outside institution. She did not have her corneal sensibility mea- RESULTS sured at 10-month follow up but continued to subjectively experience improvement in her ocular surface symptoms. No complications were A total of 7 patients underwent corneal neurotization with nerve noted during the follow-up period. allograft at the Duke University Medical Center (5 patients), Baylor College of Medicine (1 patient), and Penn State University Medical Patient 2. A 62-year-old Caucasian male with medical history signifi- Center (1 patient). Average age of the patients was 46 years (range: 6– cant for hyperthyroidism, ulcerative colitis on immunosuppression, was 75 years). Average postoperative follow up was 6 months (range: 3–10 referred for management of NK with persistent corneal epithelial defect months). Successful end-to-end coaptation of the acellular nerve al- in his right eye despite maximal medical therapy and multiple tarsor- lograft to the deep division of the supraorbital nerve was performed in 5 rhaphies. His ocular history was notable for stable thyroid eye disease patients, side-to-end coaptation of the allograft to the infraorbital nerve with moderate proptosis, advanced open-angle glaucoma on maximal in 1 patient, and end-to-end coaptation to the supratrochlear nerve in 1 medical therapy, and recent pars plana vitrectomy with endolaser for patient. All patients showed improvement in corneal sensibility. Central rhegmatogenous retinal detachment in the affected eye. On dilated fun- improvement was seen in 5 patients and peripheral improvement in all doscopic examination, he had evidence of dense chorioretinal scarring patients at their last follow-up examination. Patient characteristics and from retinal laser treatment in the 3 and 9 o’clock meridians (in the postoperative results are summarized in Table. Description of each pa- locations of long posterior ciliary nerves). Preoperative Cochet–Bonnet tient is detailed below. esthesiometry measured 0 cm in the right eye (Table). The patient underwent corneal neurotization using nerve al- Patient 1. A 45-year-old Caucasian female with history of left vestibu- lograft coapted to the ipsilateral supraorbital nerve and aggressive lar schwannoma resected 15 years ago was referred for management of tarsorrhaphy in attempts to avoid further corneal deterioration and NK in her left eye. She also had partial facial paralysis on her left side potential Gundersen flap. At 1-month follow up, his corneal epithelial with secondary lagophthalmos. Her ocular examination demonstrated defect was completely healed, but no return of corneal sensibility was

Copyright © 2019 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited. I. M. Leyngold et al. Ophthalmic Plast Reconstr Surg, Vol. 35, No. 2, 2019 BCVA BCVA 20/30 20/200 20/20 CF at 3 feet CF at 5 feet HM 20/40 (postoperatively) BCVA BCVA 20/40 HM 20/70 HM LP HM 20/150 (preoperatively) corneal corneal sensibility confirmed corneal nerve regeneration† Postoperative Postoperative 0.4 cm 5.0 cm 6.0 cm Improved Improved 3.4 cm 3.0 cm IVCM corneal corneal sensibility* 0 cm 1 cm 1.3 cm None None 0 cm 2.3 cm Preoperative Preoperative

nerve Donor Cont SO Ipsi IO Cont SO Ipsi SO Cont SO Ipsi SO Cont ST No/no No/no Yes/no Yes/no Yes/no Yes/no Yes/no Epithelial defect pre/ postoperatively Follow up Follow 3 months 4 months 6 months 4 months 6 months 10 months 10 months Comorbidities syndrome HTN Smoking IDDM PVD, smoking, CAD, CM smoking, CAD, PVD, PDR, TRD, IDDM I, CP TRD, PDR, Amblyopia, Goldenhar Amblyopia, TED, UC, glaucoma, RRD, UC, glaucoma, RRD, TED, None Etiology nerve injury ocular surgery multiple ocular surgeries schwannoma Central trigeminal HZO, IDDM HZO, HZO DM, retinal laser, DM, retinal laser, Agenesis of CNV Retinal laser and Vestibular Vestibular

time Denervation Denervation 3 years >1 year 9 months 3 months 6 years 1 year 20 years F F F M M M M Sex 6 32 75 68 33 62 45 Age Age (years) *Cochet–Bonnet measurements are reported in centimeters. Measurements were taken in 4 quadrants and centrally with the average value reported. For those patients uncooperative with measurement, presence of those patients uncooperative reported. For value with the average in 4 quadrants and centrally taken *Cochet–Bonnet measurements are reported in centimeters. Measurements were obtained at 4 months postoperatively. †Cochet–Bonnet and IVCM measurements were herpes zoster HZO, hypertension; cerebral palsy; HTN, cranial nerve 5; Cont, contralateral; CP, V, cranial nerve; CN CN, coronary artery best-corrected disease; CM, cardiomyopathy; visual acuity; CAD, BCVA, 7 6 5 4 3 2 Patient characteristics and outcomes Patient corneal sensibility is reported as either “none” or “improved” by testing the cornea with a wisp of cotton. by corneal sensibility is reported as either “none” or “improved” retinal detachment; SO, rhegmatogenous RRD, diabetic retinopathy; PDR, proliferative confocal microscopy; infraorbital; Ipsi, ipsilateral; IVCM, in vivo ophthalmicus; IDDM, insulin-dependent diabetes mellitus; IO, colitis. tractional retinal detachment; UC, ulcerative TRD, disease; eye thyroid TED, supratrochlear; supraorbital; ST, 1

FIG. 6. Representative in vivo confocal micrographs showing paucity of the corneal anterior stromal nerves before corneal neurotization and their increased density 4 months after corneal neurotization. White arrows point to the stromal nerves.

noted at that time. By 3 months, he started feeling eye drops in his right for proliferative diabetic retinopathy with tractional retinal detachments eye and noted dry eye symptoms. He did note symptoms of synesthesia and multiple vitreoretinal procedures. Preoperative corneal sensibility at 3 months (i.e., he felt the eye drops placed in the affected eye in his testing with a wisp of cotton revealed absent corneal sensation in the left ipsilateral scalp). He also had initial symptoms of bulbar conjunctival eye. Accurate measurement of corneal sensibility with Cochet–Bonnet hyperesthesia on testing with Cochet–Bonnet. Both of these symptoms esthesiometer was not possible due to patient’s poor cooperation. resolved over the subsequent 7 months. At 10-month follow up, he con- She underwent corneal neurotization with nerve allograft coapt- tinued to demonstrate corneal epithelial integrity and improvement in ed to ipsilateral supraorbital nerve. Her ocular surface exam and corneal corneal sensibility in all 4 quadrants and centrally (average of 3.4 cm). sensibility started improving at 1 month demonstrating withdrawal and His visual acuity remained stable limited by posterior segment patho- blink when testing corneal sensation with a wisp of cotton in 4 quad- logic factors. His scalp sensation was completely restored. His postop- rants and centrally. Her corneal epithelial defect was healed, but she still erative period was complicated by recurrence of the corneal epithelial demonstrated punctate keratopathy. She also demonstrated superior bul- defect at 3 months postoperatively during a flare up of his ulcerative bar conjunctival hyperesthesia on testing with a wisp of cotton. Her ip- colitis. After initiating a short taper of oral prednisone, his corneal silateral scalp sensation returned at 1 month postoperative. At 4 months epithelial defect healed within 1 week. No recurrence of the epithelial postoperatively, she continued to demonstrate improvement in corneal defect or any other postoperative complications were noted during the sensibility as tested by a wisp of cotton in all 4 quadrants and centrally, follow-up period. and resolution of corneal opacification and punctate keratopathy. Her conjunctival hyperesthesia resolved, and visual acuity remained stable Patient 3. A 6-year-old Caucasian male with Goldenhar’s syndrome and limited by her retinal pathology. She had no postoperative complications right-sided agenesis of trigeminal nerve was referred for management during the follow-up period. of NK complicated by persistent corneal epithelial defect in his right eye despite intensive medical management (i.e., preservative-free artificial Patient 5. A 68-year-old male with medical history significant for smok- tears every 1 hour, nighttime lubricant eye ointment, and moxifloxacin ing and coronary artery disease was referred for management of NK eye drops 4 times daily) and lateral tarsorrhaphy. His ocular history was 9 months after suffering from herpes zoster ophthalmicus in his right significant for dense amblyopia in his right eye due to corneal opacifi- eye. Despite intensive ocular lubrication, he continued to have severe cation and tarsorrhaphy. Preoperative corneal sensibility testing with a punctate keratopathy and decreased visual acuity. He had paresthesia wisp of cotton revealed absent corneal sensation in the left eye. Accu- and decreased sensibility to light touch in the ipsilateral V1 dermatome. rate measurement of corneal sensibility with Cochet–Bonnet esthesiom- Preoperative average Cochet–Bonnet esthesiometry revealed decreased eter was not possible due to patient’s poor cooperation. corneal sensation in the right eye at 1.3 cm. He underwent corneal neurotization on the right side with nerve He underwent corneal neurotization with nerve allograft coapted allograft coapted to the contralateral supraorbital nerve. His corneal epi- to the contralateral supraorbital nerve. After he completed his standard thelial defect was healed at 1-month follow up with no apparent return postoperative topical ocular regimen, he continued to use artificial tear of corneal sensibility. At 6-month follow up, he continued to demonstrate corneal epithelial integrity and blink reflex upon testing his corneal sensibility with a wisp of cotton in all 4 quadrants and centrally. He was noted to have improvement in his best-corrected visual acuity from light perception to counting fingers at 5 feet. No postoperative complications were noted during the postoperative period. His scalp sensation on the donor side returned at 6 months postoperatively.

Patient 4. A 33-year-old Caucasian female with cerebral palsy, cogni- tive impairment, and diabetes mellitus type I was referred for management of NK complicated by persistent corneal epithelial defect and FIG. 7. Appearance of the nerve allograft and ocular surface at stromal scarring in her left eye following pars plana vitrectomy and en- postoperative month 6 after corneal neurotization using contra- dolaser for tractional retinal detachment. Her ocular history was notable lateral supraorbital nerve in primary gaze (A) in infraduction (B).

her central corneal scarring, was noted. Her best-corrected visual acuity had improved from 20/40 to 20/30 at 3-month follow up (Table). No postoperative complications were noted during the follow-up period.

DISCUSSION The ophthalmic division of the trigeminal nerve controls the sensation of the cornea, providing protection and lubrication of the ocular surface through its role as the afferent pathway for the FIG. 8. A, The infraorbital groove is unroofed and the infra- blink reflex.1,2 In addition, sensory corneal innervation supplies orbital nerve is isolated. B, Side-to-end coaptation of the nerve allograft to the infraorbital nerve. local neurotrophic factors believed to play a role in the regenerative capacity of the corneal epithelium, which is crucial for normal wound healing.1 drops on as needed basis. At 2 months postoperatively, he showed im- When the trigeminal nerve is impaired, these protec- provement of corneal sensibility in all 4 quadrants and centrally (aver- tive mechanisms are deficient, leading to ocular morbidity. age 3.5 cm). His best-corrected visual acuity also improved from 20/70 to Following desensitization, the cornea undergoes structural 20/40. He noted improving sensation of the scalp on the donor side. His change, including decreased levels of both epithelial and endo- ocular examination was notable for decreased keratopathy and improved thelial cells, as well as increased number of hyper-reflective corneal clarity (Fig. 7). By 6 months postoperatively, his average corneal keratocytes.14 These innervation-dependent anatomic changes sensibility improved to 6.0 cm and visual acuity to 20/20 in the affected provide a potential pathophysiologic framework for the clinical eye. On slit-lamp examination, he had mild punctate corneal staining with manifestations of NK. There are 3 stages of NK with increas- fluorescein but denied any dry eye symptoms. The patient had full restora- ing severity of disease. Stage I involves punctate keratopathy, tion of scalp sensation on the donor side. He stopped using ocular lubri- stromal scarring, and corneal neovascularization.10 Stage II cants. He had no complications during the postoperative period. is characterized by a persistent epithelial defect with stromal opacification. Stage III involves severe corneal ulceration with Patient 6. A 75-year-old Hispanic male with insulin-dependent diabetes stromal thinning and perforation potentially leading to loss of mellitus and a history of herpes zoster ophthalmicus presented with an the eye. 8-month history of nonhealing corneal epithelial defect and microbial Treatment for NK depends on the stage of the disease.10 keratitis of the right eye. He had previously undergone treatments with Stage I disease is usually treated with ocular lubrication. As topical fortified antibiotics, topical and oral antivirals, topical antifun- the disease progresses to stages II and III, antibiotic drops and gals drops, topical corticosteroids drops, bandage contact lens, amniotic ointments are used for prevention of secondary infectious com- membrane grafts (twice), and lateral tarsorrhaphy (twice). On presenta- plications. Contact lenses can be placed to protect the corneal tion, he was noted to have a persistent corneal epithelial defect with cor- epithelium. New topical treatments, such as autologous serum neal thinning, and a neurotrophic cornea was diagnosed with Cochet– drops, have been used to replace the proteins and molecules Bonnet sensation measured at 1 cm on the right eye. A global decrease usually found in tears.15 Prokera lenses or dried amniotic mem-

in right V1 sensation and symmetric V2 sensation was noted. brane with a bandage contact lens can be used to temporarily The patient underwent corneal neurotization with nerve allograft co- treat the ocular surface and help heal the epithelial defect. apted to the ipsilateral infraorbital nerve (Fig. 8A,B) in a side-to-end fashion. Surgical treatment is employed for severe cases. At 4 months postoperatively, corneal sensation improved to 5 cm with the Tarsorrhaphy and amniotic membrane grafts are commonly per- Cochet–Bonnet esthesiometer in all 4 quadrants and centrally. Visual acuity formed for this disease with variable success in achieving clo- improved from hand motions preoperatively to 20/200 postoperatively with sure of the persistent epithelial defects.10 Botulinum toxin has residual corneal scarring, but complete healing of the corneal epithelium. also been used to induce temporary ptosis to protect the corneal Sensation in the donor infraorbital nerve distribution was decreased initially epithelium.16 These measures are preventative to ensure no fur- after surgery but was significantly improved at 4 months postoperatively. ther damage to the eye, but they do not address the underlying Future visual rehabilitation will include penetrating keratoplasty. problem of insensate cornea. New surgical approaches have been studied that would Patient 7. A 32-year-old Caucasian female with a history of gamma restore sensation to the cornea, thus preventing further dam- knife surgery and microvascular decompression of the right trigeminal age and improving wound healing. Terzis et al.8 first described

nerve with subsequent V1-V2 anesthesia was referred for management corneal neurotization in 2009. Six patients in their study with of recalcitrant NK. The patient was noted to have recurrent epithelial ipsilateral trigeminal nerve palsy underwent reinnervation of defects of the right eye despite maximum medical therapy as well as the cornea, via a coronal approach, with the contralateral supra- dense central corneal scarring and lipid keratopathy. Preoperative Co- orbital and supratrochlear branches of the ophthalmic division chet–Bonnet esthesiometry revealed diffuse loss of corneal sensation of the trigeminal nerve. Subsequently, Elbaz et al3 described a with readings of 0 cm in all quadrants and centrally. technique of using a sural nerve autograft anastomosed to either The patient underwent corneal neurotization with nerve allograft co- an ipsilateral or contralateral supratrochlear nerve and tunneled apted to the contralateral supraorbital nerve. At 6 weeks postoperatively, the through the upper eyelid incision avoiding a coronal incision. patient reported improved corneal sensation in the supratemporal quadrant The most recent report by the authors of this study described an measuring 1 cm with Cochet–Bonnet esthesiometry. At 3 months postopera- endoscopic technique for corneal neurotization.10 All of these tively, corneal sensibility was improved to 1 cm in the super temporal and techniques allowed for successful transfer of the nerves and superonasal quadrants. Subjectively, the patient reported the development of return of corneal sensation. dry eye symptoms including intermittent irritation and foreign body sensa- All studies to date have focused on direct nerve transfers tion in the operative eye, which were not present prior to neurotization despite or use of a nerve autograft. We describe the largest case series significant keratopathy, as well as restoration of scalp sensation throughout to date of corneal neurotization and the first case series of suc- the donor dermatome. During the postoperative period, the patient was with- cessful corneal neurotization with the use of nerve allograft. out recurrence of her epithelial defect, and upon slit-lamp examination, a The technique for supraorbital and supratrochlear nerve trans- generalized improvement in keratopathy, as well as decrease in the density of fers is similar to that described by Elbaz et al.,3 but instead of

harvesting a nerve autograft, the authors use a nerve allograft tumor resection, and other causes of peripheral nerve injury.17–25 avoiding donor site morbidity while maintaining the minimal Clinical studies have demonstrated that nerve allografts hold invasive nature of surgery. Similar to the technique described promise as successful alternatives to the current standard treat- by Elbaz et al., the reported technique avoids risks of alopecia, ment of autogenous nerve grafting.26 Regardless of the material injury to the frontal branch of the facial nerve, scalp incisions, used, the ideal nerve repair should be tension free, with no addi- and extensive dissection needed with a coronal approach. In the tional scarring or nerve entrapment and enhanced neural regen- authors’ experience, the recovery of sensory dermatome of the eration. Nerve repair methods include epineurial repair, group donor nerve is faster with the current technique compared with fascicular repair, and combination of the 2.26 Due to the small either endoscopic or coronal approaches. In addition, the opera- caliber of the coapted nerves in this study (1–3 mm), epineu- tive time required to execute the procedure is shorter (~≤90 rial technique was used. During anastomosis between the donor minutes) compared with all the previously described techniques. nerve and the graft, care must be taken to avoid tension on the Although all of the procedures were conducted under general repair and to engage only epineurium to avoid fascicular dam- anesthesia, it may be feasible to safely perform this procedure age and possible neuroma formation.27 The suture line can be with local and topical anesthesia under conscious sedation in protected by nerve conduits, wraps, and umbilical cord–derived selected patients. amniotic membrane grafts but can also be shielded by grafts of Determination of the optimal donor nerve pedicle for healthy muscle or fat. Protection of the anastomotic site, theoret- corneal neurotization relies on a combination of preoperative ically, decreases the rate of axonal escape, reduces scaring with and intraoperative assessment, as well as surgeon’s preference. ultimate neuroma formation, and improves the success of axonal During preoperative evaluation, both ipsilateral and contralat- regeneration. After coaptation, it takes on average 2 to 4 weeks eral sensation in the supraorbital, supratrochlear, and infraor- for initiation of axonal regeneration into the graft that serves as a bital nerve distribution is performed. This allows the surgeon to conduit for axons to reach their target.26 After this latency period, identify viable donor sites, while eliminating those with subop- the axons then grow on average 1 mm per day, which corre- timal function. Patients with NK stemming from a local ocular sponds to the rate of slow transport of the neurofilament protein, process may have unaffected nerve function within the remain- although this is almost certainly faster in children.27 The axons der of the V dermatome, while those with a central cause are 1 then invade the anterior corneal stroma as evidenced by our post- more likely to have diminished function in V and potentially 1 operative in vivo confocal microscopic evaluation in patient 1 V dermatomal distributions. When using a nerve graft, one 2 as well as other recently published reports.27,28 Given the rate of attempts to minimize the graft length, to decrease the required axonal regeneration, there is an expected delay of at least 2 to distance of axonal regeneration and match donor and graft 3 months or longer in re-establishment of sensibility following nerve caliber to aid in anastomosis formation. The ideal donor neurotization. This is consistent with our experience and that of is close to the site of interest, easily accessible, and carries mini- other authors.3,27,28 In patient 4, improvement in corneal sensi- mal donor site morbidity. Based on these principles, the authors bility was noted as early as 1 month postoperatively. Her slit- prefer to use intact ipsilateral supraorbital or supratrochlear lamp biomicroscopy at the same follow-up visit demonstrated nerves as primary donors. When used, the final determination resolved corneal epithelial defect and improved corneal clarity, between supratrochlear and supraorbital nerve donor sites is implying either accelerated axonal regeneration compared with made intraoperatively based on the best donor-graft size match the expected rate or neurotrophic factor support of her corneal for anastomosis creation. Generally, the authors have found that the deep division of the supraorbital nerve has a more reliable epithelium. The lag in re-establishment of corneal sensibility anatomy and provides a larger diameter with robust structure for seen in other patients may also be due to delay in dermatomal successful neurorrhaphy. If the ipsilateral supraorbital/supra- remapping by the brain as noted by synesthesia described by patient 2 in this cohort and by some of the patients in the study trochlear donor sites are unavailable, the next options are the 3 ipsilateral infraorbital and contralateral supraorbital/supratroch- by Elbaz et al. Two out of 6 patients (Patients 2 and 4) were lear nerves. Using the ipsilateral infraorbital nerve maintains a found to have initial conjunctival hyperesthesia likely related to limited graft length but requires more extensive and intricate axonal ingrowth into the conjunctiva from the underlying nerve dissection into the orbit including bone removal. Given that the fascicles. This has resolved at their last follow up. We have also infraorbital nerve is coapted in a side-to-end fashion to the nerve noted improvement of the ocular surface (e.g., closure of epi- allograft, the postoperative sensory recovery in the donor nerve thelial defects, decreased corneal epithelial fluorescein staining) dermatome is expected to be faster compared with end-to-end and subjective improvement in ocular surface symptoms as early coaptation. Using a contralateral supraorbital/supratrochlear as 1 month postoperatively (patients 2 and 4 who underwent ipsi- donor pedicle requires a longer graft length but can be achieved lateral transfers). This occurred in patients 2 and 3 before any through a more straight forward and universally employable objective re-establishment of corneal sensibility. This phenom- dissection technique. In the authors’ experience, transection of enon may be due to release of neurotrophic factors by the axonal the supratrochlear or supraorbital nerves carries less morbidity terminals that nourish corneal epithelium that occurs before any compared with transection of the infraorbital nerve. Therefore, clinical detection of improved corneal sensibility. a side-to-end coaptation was performed when infraorbital nerve Although all patients in the study demonstrated improve- was used. If both of these options are available, the final deter- ment in ocular surface and corneal sensibility, there are poten- mination is based on the surgeon’s familiarity with pertinent tial limitations to this technique. First, additional neurorrhaphy anatomy and required technique. In instances when both ipsilat- may increase the risk of neuroma formation and axonal sprout- eral nerves are compromised, a contralateral donor is necessary. ing failing to reach the cornea. Permanent numbness and par- Avance Nerve Graft is an off-the-shelf processed human esthesia in the area of the sensory donor nerve dermatome are nerve allograft intended for the surgical repair of peripheral also potential complications. Also, nerve coaptation can be a nerve discontinuities. Through a proprietary cleansing process technical challenge requiring specialized training in microneu- for recovered human peripheral nerve tissue, the graft preserves rovascular surgery and precision in technique. In addition, the the essential inherent structure of the extracellular matrix while maximum length of nerve allograft is 7 cm, which may limit its cleansing away cellular and noncellular debris.17–25 The graft use in patients with widely spaced orbits or in those with more is currently used for peripheral nerve repair following trauma, distal donor nerves. Finally, nerve regeneration and outcomes

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Processed nerve allografts on in situ Schwann cell migration into the graft. This migration for peripheral nerve reconstruction: a multicenter study of utiliza- process is restricted by a gradual quiescence of the Schwann tion and outcomes in sensory, mixed, and motor nerve reconstruc- cells, which theoretically may limit the ultimate effective length tions. Microsurgery 2012;32:1–14. of the allograft.30 However, the acellular nerve allograft has been 18. Johnson PJ, Newton P, Hunter DA, et al. Nerve endoneurial mi- shown to have similar functional success rate compared with crostructure facilitates uniform distribution of regenerative bers: a post hoc comparison of midgraft nerve ber densities. J Reconstr nerve autograft in both sensory and motor reinnervation at gap 17,31,32 Microsurg 2011;27:83–90. lengths as long as 7 cm and with a variety of nerve caliber. 19. Whitlock EL, Tuffaha SH, Luciano JP, et al. 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