Research Original Investigation | CLINICAL SCIENCES Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis Alessandro Lambiase, MD, PhD; Marta Sacchetti, MD, PhD; Alessandra Mastropasqua, MD; Stefano Bonini, MD IMPORTANCE Neurotrophic keratitis (NK) represents a sight-threatening complication after trigeminal impairment. To our knowledge, the duration for which trigeminal injury may affect corneal structures and function has not been investigated previously. OBJECTIVE To describe the long-term clinical, morphological, and functional outcomes of NK after neurosurgical trigeminal damage. DESIGN, SETTING, AND PARTICIPANTS Observational case series performed at a corneal and ocular surface diseases referral center in 2010. Eight consecutive patients with monolateral NK from 1 to 19 years after neurosurgery and 20 age- and sex-matched healthy participants were included. MAIN OUTCOMES AND MEASURES Complete eye examination, tear film function tests, corneal staining, and Cochet-Bonnet esthesiometry were performed. The number and density of corneal nerves, number of hyperreflective keratocytes, and corneal epithelial, endothelial, and keratocyte cell densities were evaluated by in vivo slit scanning confocal microscopy. Clinical and morphological data were compared with the contralateral unaffected eyes and with the eyes of healthy control participants. RESULTS All patients showed superficial punctate keratitis and dry eye in the NK eye and a healthy contralateral eye. Decreased corneal sensitivity was observed in all affected eyes (mean [SD], 2.0 [1.9] mm in the affected eyes vs 5.8 [0.3] mm in the contralateral unaffected eyes; P = .01) and was related to decreased subbasal nerve length (P = .04; R = 0.895). Corneal epithelial and endothelial cell densities were significantly decreased and the number of hyperreflective keratocytes was significantly increased in NK eyes compared with contralateral unaffected eyes and with the eyes of healthy participants. A longer duration of NK was associated with lower endothelial cell density (P = .046; R = −0.715). CONCLUSIONS AND RELEVANCE Corneal morphology and function were impaired even years after neurosurgical trigeminal damage, suggesting that assessment of tear film and corneal sensitivity as well as in vivo confocal microscopy examination should be performed in all patients with trigeminal impairment. Author Affiliations: Department of Ophthalmology, University of Rome, Campus Bio-Medico, Rome, Italy (Lambiase, Mastropasqua, Bonini); Ospedale San Raffaele di Milano, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy (Sacchetti). Corresponding Author: Stefano Bonini, MD, Department of Ophthalmology, University of Rome, Campus Bio-Medico, Via Alvaro del JAMA Ophthalmol. 2013;131(12):1547-1553. doi:10.1001/jamaophthalmol.2013.5064 Portillo, 200, 00128 Rome, Italy Published online October 24, 2013. ([email protected]). 1547 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Research Original Investigation Corneal Changes in Neurotrophic Keratitis he cornea is the most densely innervated human tis- rosurgical damage to the trigeminal nerve as well as their con- sue. Corneal sensory nerves provide protective and tro- tralateral unaffected eyes were included in the study. Twenty T phic support to the cornea by regulating corneal epi- eyes of 20 healthy subjects (mean [SD] age, 53 [15] years; 15 fe- thelium integrity, proliferation, and wound healing.1,2 male, 5 male) were also included as a control group. Experimental and clinical data have clearly demonstrated that The diagnosis of NK was based on the history of trigemi- the impairment of corneal sensitive nerve function induces nal damage after neurosurgical interventions for brain neo- functional and morphological changes of the corneal epithe- plasia associated with ipsilateral corneal hypoesthesia or an- lium, leading to epithelial defects with poor tendency to spon- esthesia. taneous healing.1-3 In humans, injury of the trigeminal nerve All patients underwent evaluation for best spectacle- leads to a decrease or absence of corneal sensation and to de- corrected visual acuity as well as complete eye examination. velopment of neurotrophic keratitis (NK).1,2 This condition is Mechanical corneal sensation was measured at the cen- characterized by impairment of corneal sensitivity, corneal epi- tral cornea with the Cochet-Bonnet esthesiometer (Luneau thelial changes ranging from superficial punctate keratopa- Ophtalmologie). This uses nylon monofilaments that have a thy to corneal ulcer and perforation, stromal scarring, neovas- diameter of 0.027 mm (Toray Industries, Inc), range from 0 to cularization, tear function impairment, and decreased blink 6 cm in length, and apply different pressures to the cornea, reflex. shortening in steps of 1.0 cm if a positive response is not ob- Currently, corneal changes observed in NK are consid- tained. If a positive response is obtained, the thread is ad- ered a consequence of epithelial breakdown, but some evi- vanced by 0.5 cm. The longest filament length resulting in a dence suggests that corneal nerve damage may also induce positive response was considered the corneal sensitivity thresh- changes of keratocytes and corneal endothelium. In fact, the old, which was verified twice.2 recent introduction of in vivo corneal confocal microscopy Tear function was evaluated by the Schirmer I and break-up (IVCM) has allowed for investigation of the entire corneal struc- time tests.13 Corneal fluorescein staining was graded from 0 ture including epithelium, subbasal nerve plexus, kerato- to 5 according to the Oxford scale.13 cytes, and endothelium in healthy and pathological human In vivo slit scanning confocal microscopy examination corneas.4,5 Specifically, decreased corneal sensation in dia- (Confoscan 4; Nidek Technologies) was performed bilaterally betic patients was associated with decreased subbasal nerve in the central cornea of all subjects with a 40×/0.75 objective and basal epithelium density as well as changes in corneal stro- lens. All Confoscan 4 examinations were performed by the mal keratocytes and endothelium.6-8 Patients with herpes sim- same operator (M.S.) using a Z-ring and an internal fixation tar- plex virus keratitis also showed a relationship between de- get to stabilize images. Eyes were anesthetized with 1 drop of creased corneal sensation and changes in subbasal nerve plexus oxybuprocaine hydrochloride,0.4% (benoxinate hydrochlo- and endothelium morphology.9-11 This evidence suggests that ride). The objective lens of the microscope was disinfected with alteration of corneal sensitivity may affect all corneal struc- isopropyl alcohol (70% vol/vol, with swabs). Then, a large drop tures; however, both diabetic keratitis and herpes simplex vi- of Viscotears liquid gel (Carbomer 940; Novartis Pharma) was rus keratitis result from a combination of different mecha- applied to the tip of the lens as an immersion substance. Full- nisms including decreased innervation and metabolic, thickness automated scanning mode with a 5-μm scan step was immune, and cytopathic effects. used during each examination. Each image represents a coro- In this study, we evaluated corneal structures by IVCM in nal section of approximately 425 × 320 μm with magnifica- patients with monolateral NK after neurosurgical trigeminal tion of ×500 and a lateral resolution of 1 μm/pixel. Corneal damage to assess long-term changes of corneal sensitivity and thickness was assessed and a minimum of 3 representative im- morphology. ages were evaluated for superficial and basal epithelium, sub- basal nerve plexus, superficial and deep stromal layer, and endothelium.4,5 Methods Two masked observers evaluated the confocal images (M.S. and A.M.). The epithelial, stromal, and endothelial cells were This study was performed in accordance with the Declaration manually counted using Adobe Photoshop 6.0 software (Adobe of Helsinki. The study was approved by the institutional re- Systems). All the cells were counted within a 0.05-mm2 frame view board of the University of Rome, Campus Bio-Medico, and to calculate the cell density, which was expressed as the num- written informed consent was obtained from the patients and ber of cells per square millimeter. Nerve density was assessed healthy volunteers before examinations were performed. by measuring the total length of the nerve fibers in microm- Inclusion criteria were the diagnosis of monolateral NK at eters per frame. Main nerve trunks were defined as the total stage 1 after neurosurgery1,2 and a corneal scarring grade of 0.5 number of main nerve trunks in 1 image after analyzing the im- or lower according to the Fantes scale.12 Exclusion criteria were ages anterior and posterior to the analyzed image to confirm the presence of diabetes mellitus, previous intraocular sur- that these did not branch from other nerves. Nerve branch- gery, history of ocular trauma, herpetic keratitis, and/or other ing was defined as the total number of nerve branches in 1 ocular-associated diseases, use of topical treatments with the image.14 Tortuosity and reflectivity were classified according exception of ocular lubricants, and use of contact lenses. to criteria described by Oliveira-Soto and Efron.15 Eight eyes of 8 consecutive patients (mean [SD] age, 49 [18] Statistical analysis was performed using Wilcoxon rank test years; 6 female, 2 male) with monolateral NK caused by neu- and Mann-Whitney U