Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis

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 Portillo, 200, 00128 Rome, Italy ([email protected]). JAMA Ophthalmol. 2013;131(12):1547-1553. doi:10.1001/jamaophthalmol.2013.5064 Published online October 24, 2013. 1547 Copyright 2013 American Medical Association. All rights reserved. <a href="/goto?url=https://jamanetwork.com/" target="_blank">Downloaded From: https://jamanetwork.com/ on 09/26/2021 </a>Research Original Investigation Corneal Changes in Neurotrophic Keratitis <ul style="display: flex;"><li style="flex:1">he cornea is the most densely innervated human tis- </li><li style="flex:1">rosurgical damage to the trigeminal nerve as well as their con- </li></ul>sue. Corneal sensory nerves provide protective and tro- tralateral unaffected eyes were included in the study. Twenty T<ul style="display: flex;"><li style="flex:1">phic support to the cornea by regulating corneal epi- </li><li style="flex:1">eyes of 20 healthy subjects (mean [SD] age, 53 [15] years; 15 fe- </li></ul>male, 5 male) were also included as a control group. The diagnosis of NK was based on the history of trigemithelium integrity, proliferation, and wound healing.1,2 Experimental and clinical data have clearly demonstrated that the impairment of corneal sensitive nerve function induces nal damage after neurosurgical interventions for brain neofunctional and morphological changes of the corneal epithe- plasia associated with ipsilateral corneal hypoesthesia or anlium, leading to epithelial defects with poor tendency to spon- esthesia. taneous healing.1-3 In humans, injury of the trigeminal nerve leads to a decrease or absence of corneal sensation and to development of neurotrophic keratitis (NK).1,2 This condition is All patients underwent evaluation for best spectaclecorrected visual acuity as well as complete eye examination. Mechanical corneal sensation was measured at the cencharacterized 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. Currently, corneal changes observed in NK are considshortening in steps of 1.0 cm if a positive response is not obtained. If a positive response is obtained, the thread is adered 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 threshchanges of keratocytes and corneal endothelium. In fact, the recent introduction of in vivo corneal confocal microscopy old, which was verified twice.2 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, keratocytes, and endothelium in healthy and pathological human corneas.4,5 Specifically, decreased corneal sensation in diato 5 according to the Oxford scale.13 In vivo slit scanning confocal microscopy examination (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 tarplex 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 hydrochloand 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 mechanisms 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 coroapplied to the tip of the lens as an immersion substance. Full- In this study, we evaluated corneal structures by IVCM in nal section of approximately 425 × 320 μm with magnificapatients 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- <ul style="display: flex;"><li style="flex:1">morphology. </li><li style="flex:1">ages were evaluated for superficial and basal epithelium, sub- </li></ul>basal nerve plexus, superficial and deep stromal layer, and endothelium.4,5 Two masked observers evaluated the confocal images (M.S. and A.M.). The epithelial, stromal, and endothelial cells were Methods 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 numwritten informed consent was obtained from the patients and ber of cells per square millimeter. Nerve density was assessed <ul style="display: flex;"><li style="flex:1">healthy volunteers before examinations were performed. </li><li style="flex:1">by measuring the total length of the nerve fibers in microm- </li></ul>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 imor lower according to the Fantes scale.12 Exclusion criteria were ages anterior and posterior to the analyzed image to confirm <ul style="display: flex;"><li style="flex:1">the presence of diabetes mellitus, previous intraocular sur- </li><li style="flex:1">that these did not branch from other nerves. Nerve branch- </li></ul>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. Eight eyes of 8 consecutive patients (mean [SD] age, 49 [18] to criteria described by Oliveira-Soto and Efron.15 Statistical analysis was performed using Wilcoxon rank test years; 6 female, 2 male) with monolateral NK caused by neu- and Mann-Whitney Utest to assess differences between groups. JAMA Ophthalmology December 2013 Volume 131, Number 12 jamaophthalmology.com Copyright 2013 American Medical Association. All rights reserved. 1548 <a href="/goto?url=https://jamanetwork.com/" target="_blank">Downloaded From: https://jamanetwork.com/ on 09/26/2021 </a>Corneal Changes in Neurotrophic Keratitis Original Investigation Research Table 1. Clinical and Demographic Characteristics of the Patients With Neurotrophic Keratitis Included in the Study Patient No. <ul style="display: flex;"><li style="flex:1">Characteristic </li><li style="flex:1">1</li><li style="flex:1">2</li><li style="flex:1">3</li><li style="flex:1">4</li><li style="flex:1">5</li><li style="flex:1">6</li><li style="flex:1">7</li><li style="flex:1">8</li></ul><ul style="display: flex;"><li style="flex:1">Age, y </li><li style="flex:1">38 </li><li style="flex:1">52 </li><li style="flex:1">42 </li><li style="flex:1">61 </li><li style="flex:1">32 </li><li style="flex:1">69 </li><li style="flex:1">77 </li><li style="flex:1">25 </li></ul><ul style="display: flex;"><li style="flex:1">Sex </li><li style="flex:1">M</li><li style="flex:1">F</li><li style="flex:1">F</li><li style="flex:1">F</li><li style="flex:1">M</li><li style="flex:1">F</li><li style="flex:1">F</li><li style="flex:1">F</li></ul>Disease for neurosurgery Acoustic neuroma <ul style="display: flex;"><li style="flex:1">Meningioma </li><li style="flex:1">Acoustic </li></ul>neuroma <ul style="display: flex;"><li style="flex:1">Chondroma </li><li style="flex:1">Meningioma </li><li style="flex:1">Meningioma </li><li style="flex:1">Meningioma </li><li style="flex:1">Meningioma </li></ul>Time from trigeminal damage, y <ul style="display: flex;"><li style="flex:1">6</li><li style="flex:1">5</li><li style="flex:1">7</li><li style="flex:1">7</li><li style="flex:1">1</li><li style="flex:1">8</li><li style="flex:1">7</li><li style="flex:1">19 </li></ul><ul style="display: flex;"><li style="flex:1">Duration of NK, y </li><li style="flex:1">5</li><li style="flex:1">5</li><li style="flex:1">5</li><li style="flex:1">5</li><li style="flex:1">1</li><li style="flex:1">7</li><li style="flex:1">7</li><li style="flex:1">18 </li></ul>Previous NK treatments <ul style="display: flex;"><li style="flex:1">Tarsorrhaphy </li><li style="flex:1">CL </li><li style="flex:1">CL </li><li style="flex:1">AMT </li><li style="flex:1">Autologous </li></ul>serum, CL <ul style="display: flex;"><li style="flex:1">Tarsorrhaphy </li><li style="flex:1">Tarsorrhaphy, </li></ul>CL Tarsorrhaphy <ul style="display: flex;"><li style="flex:1">Symptoms </li><li style="flex:1">Mild redness </li><li style="flex:1">Mild dryness </li><li style="flex:1">None </li><li style="flex:1">Visual </li></ul>impairment <ul style="display: flex;"><li style="flex:1">None </li><li style="flex:1">Visual </li></ul>impairment Mucous secretion None <ul style="display: flex;"><li style="flex:1">Lagophthalmos </li><li style="flex:1">Mild </li></ul>0.7 1 Absent 0.8 <ul style="display: flex;"><li style="flex:1">Moderate </li><li style="flex:1">Absent </li></ul>0.3 Absent 0.6 Absent 0.4 <ul style="display: flex;"><li style="flex:1">Moderate </li><li style="flex:1">Mild </li></ul>0.8 4<ul style="display: flex;"><li style="flex:1">BCVA, decimal units </li><li style="flex:1">0.8 </li></ul>4 0.7 <ul style="display: flex;"><li style="flex:1">4</li><li style="flex:1">Central corneal sen- </li></ul>sitivity threshold, cm <ul style="display: flex;"><li style="flex:1">0</li><li style="flex:1">0</li><li style="flex:1">0</li><li style="flex:1">3</li></ul><ul style="display: flex;"><li style="flex:1">Break-up time, s </li><li style="flex:1">8</li><li style="flex:1">5</li></ul>9 43 27<ul style="display: flex;"><li style="flex:1">6</li><li style="flex:1">7</li></ul>7<ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">6</li></ul>Schirmer test, mm/5 min <ul style="display: flex;"><li style="flex:1">>10 </li><li style="flex:1">>10 </li><li style="flex:1">>10 </li><li style="flex:1">>10 </li></ul><ul style="display: flex;"><li style="flex:1">Oxford score </li><li style="flex:1">1</li><li style="flex:1">1</li><li style="flex:1">1</li><li style="flex:1">2</li><li style="flex:1">1</li><li style="flex:1">2</li><li style="flex:1">1</li><li style="flex:1">3</li></ul>Abbreviations: AMT, amniotic membrane transplantation; BCVA, best-corrected visual acuity; CL, contact lens; NK, neurotrophic keratitis. <ul style="display: flex;"><li style="flex:1">Spearman ρ test was used to correlate clinical, demographic, </li><li style="flex:1">No significant correlations were observed between cor- </li></ul>and morphological parameters. We used SPSS version 18 sta- neal sensitivity and the tear function test and corneal staintistical software (SPSS Inc). P < .05 was considered statisti- ing results (P = .52 and P = .20, respectively), while the higher <ul style="display: flex;"><li style="flex:1">cally significant. </li><li style="flex:1">corneal sensitivity was significantly correlated with a longer </li></ul>history of NK (P = .048; R = 0.712). Results of IVCM evaluations are showed in Table 2. Eyes with NK showed a significant decrease of superficial and basal epithelial cell densities when compared with both contralateral unaffected eyes (mean [SD] superficial epithelial cell den- Results Clinical characteristics of the patients are summarized in Table 1. At the inclusion, all patients showed a stage 1 mono- sity, 1068 [567] vs 1877 [490] cells/mm2, respectively; P = .047; lateral NK according to criteria described by Mackie1 with mild mean [SD] basal epithelial cell density, 3241 [600] vs 4366 [794] to severe superficial punctate keratitis and were being treated cells/mm2, respectively; P = .04) (Figure 1) and with healthy only with preservative-free artificial tears. All contralateral eyes eyes of control participants (mean [SD] superficial epithelial showed absence of pathological changes and normal corneal cell density, 2145 [401] cells/mm2; P = .04; mean [SD] basal episensitivity, Schirmer test results, and break-up times. Patients underwent neurosurgery in the past 1 to 19 years thelial cell density, 5732 [1358] cells/mm2; P = .004). Subbasal nerves were also significantly reduced as com- (mean [SD], 7.5 [5] years) and were diagnosed as having NK from pared with both contralateral unaffected eyes (mean [SD] num1 to 24 months after neurosurgery. All patients also had a his- ber of nerve trunks, 1.0 [1.2] vs 4.4 [1.1], respectively; P = .04; tory of corneal ulcer 1 to 18 years (mean [SD], 6.6 [5] years) af- and mean [SD] total nerve length, 1814 [2614] vs 11 606 [5175] ter the onset of NK. Four patients had damage of the seventh cranial nerve with mild facial hemipalsy (Table 1). μm/mm2, respectively; P = .04) (Figure 2) and healthy eyes (mean [SD] number of nerve trunks, 4.5 [0.9]; P = .003; mean <ul style="display: flex;"><li style="flex:1">[SD] total nerve length, 15 250 [2440] μm/mm2; P = .001). In </li><li style="flex:1">All affected eyes showed a significant decrease in me- </li></ul>chanical corneal sensitivity evaluated by Cochet-Bonnet es- NK eyes, the lower subbasal nerve length directly correlated thesiometry when compared with the contralateral unaf- with lower corneal sensitivity values (P = .04; R = 0.895). <ul style="display: flex;"><li style="flex:1">fected eye (mean [SD], 2.0 [1.9] vs 5.8 [0.3] mm, respectively; </li><li style="flex:1">The number of hyperreflective keratocytes was signifi- </li></ul>P = .01). Fluorescein staining demonstrated mild to severe epi- cantly increased in NK eyes when compared with contralattheliopathy in NK eyes compared with unaffected eyes (mean eral unaffected eyes (mean [SD], 4.0 [2.2] vs 1.5 [2.2] hyperre[SD] Oxford score, 1.6 [0.7] vs 0, respectively; P < .001). Eyes flective keratocytes/frame, respectively; P = .04) and with with NK also showed a significant decrease in break-up time healthy eyes (mean [SD], 1.2 [1.2] hyperreflective keratocytes/ compared with contralateral unaffected eyes (mean [SD], 5.0 frame; P = .02) (Figure 3). [2.0] vs 7.5 [2.3] seconds, respectively; P = .004), while Schirmer test results were not significantly different between the contralateral and pathological eyes (P = .66). Interestingly, corneal endothelial cell density was significantly reduced in NK eyes when compared with both contralateral unaffected eyes (mean [SD], 2187 [582] vs 3059 [352] <ul style="display: flex;"><li style="flex:1">jamaophthalmology.com </li><li style="flex:1">JAMA Ophthalmology December 2013 Volume 131, Number 12 </li></ul>1549 Copyright 2013 American Medical Association. All rights reserved. <a href="/goto?url=https://jamanetwork.com/" target="_blank">Downloaded From: https://jamanetwork.com/ on 09/26/2021 </a>Research Original Investigation Corneal Changes in Neurotrophic Keratitis Table 2. Results of In Vivo Confocal Microscopy Evaluations in Patients With Monolateral Neurotrophic Keratitis Compared With Contralateral Unaffected Eyes and With Eyes of Healthy Participants Table 2. Results of In Vivo Confocal Microscopy Evaluations in Patients With Monolateral Neurotrophic Keratitis Compared With Contralateral Unaffected Eyes and With Eyes of Healthy Participants (continued) <ul style="display: flex;"><li style="flex:1">P</li><li style="flex:1">P</li></ul><ul style="display: flex;"><li style="flex:1">Variable </li><li style="flex:1">Mean (SD) </li><li style="flex:1">Value </li><li style="flex:1">Variable </li><li style="flex:1">Mean (SD) </li><li style="flex:1">Value </li></ul>Central corneal thickness, μm Beadlike formations, No./frame Contralateral eyes NK eyes 530 (56) 560 (93) 551 (71) Contralateral eyes NK eyes 7.4 (6.0) 2.5 (3.1) 5.9 (3.2) .28a .39b .14a .28b Healthy eyes Healthy eyes Superficial epithelial cell density, cells/mm2 Nerve branching, No./frame Contralateral eyes NK eyes 2.7 (3.0) 0.3 (0.6) 3.1 (2.5) Contralateral eyes NK eyes 1877 (490) 1068 (567) 2145 (401) .03a .03b .047a .04b Healthy eyes Healthy eyes Endothelial cell density, cells/mm2 Contralateral eyes NK eyes Basal epithelial cell density, cells/mm2 3059 (352) 2187 (582) 2960 (323) .01a .004b Contralateral eyes NK eyes 4366 (794) 3241 (600) 5732 (1358) .04a .004b Healthy eyes Healthy eyes Abbreviation: NK, neurotrophic keratitis. a Comparing NK eyes vs contralateral unaffected eyes (Wilcoxon rank test). b Comparing NK eyes vs healthy eyes (Mann-Whitney U test). Anterior stromal cell density, cells/mm2 Contralateral eyes NK eyes 949 (243) 990 (274) 894 (250) .60a .43b cells/mm2, respectively; P = .01) and with healthy eyes (mean [SD], 2960 [323] cells/mm2; P = .004) (Figure 4A-C). Eyes with NK showed a significant correlation between the longer duration of NK and the lower endothelial cell density (P = .046; R = −0.715) (Figure 4D). No significant difference in all morphological parameters were observed in the subgroup of patients with both NK and lagophthalmos. Healthy eyes Hyperreflective keratocytes, No./frame Contralateral eyes NK eyes 1.5 (2.2) 4.0 (2.2) 1.2 (1.2) .04a <ul style="display: flex;"><li style="flex:1">.02b </li><li style="flex:1">Healthy eyes </li></ul>Posterior stromal cell density, cells/mm2

Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis

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