Calcified Corneal Nerves

CASE REPORT

Calciﬁed Corneal Nerves

Marco Messina, MD, Mohamed Elalfy, FRCS, Noha Ghoz, MSc, Lana Faraj, MSc, Mouhamed Al-Aqaba, PhD, and Harminder S. Dua, MD, PhD

evaluate corneal nerves.6 We present the slit-lamp and IVCM Purpose: fi To report a case of calci ed corneal nerves in an eye with features of a rare case and, to our knowledge, the first reported long-standing diabetic eye disease. one of calcified sub-Bowman corneal nerves. Methods: This is a case report where the clinical diagnosis was made using a slit-lamp biomicroscope and confirmed using in vivo CASE REPORT confocal microscopy. Photoslit-lamp images were taken for both eyes, A 70-year-old woman with diabetes presented with no vision in and nerve thickness measurements made using ImageJ software. her right eye. She had advanced diabetic eye disease and consequently Results: A 70-year-old British white woman showed band developed mature cataract and band keratopathy (Fig. 1A). Her left eye had long-standing tractional retinal detachment with 6/60 best-corrected keratopathy in the right eye and dense white lines and dots in her visual acuity (BCVA). Corneal sensation was completely lost in the left cornea on slit-lamp examination. The left corneal images had an right eye and markedly reduced in the left eye. Slit-lamp examination of appearance exactly similar to stromal nerves and terminal bulbs the left eye showed multiple linear and discoid white lesions in the reported before. In vivo confocal microscopy (IVCM) of the left cornea at the subepithelial level (Figs. 1B, C). These had the cornea showed hyperreflective and thickened stromal and sub- characteristic configuration of the sub-Bowman nerves terminating in Bowman nerves and their characteristic termination in bulbous bulb-like structures previously described by acetylcholinesterase stain- thickenings. ing of whole-mount corneas.3 Images of the whole-mount histology of corneal nerves in donor eyes are given for comparison (Fig. 1D). No Conclusions: Clinically detected corneal nerve calcification has white lines corresponding to nerve fibers of the subbasal plexus were not been described before. This report presents the direct visualiza- seen. tion of calcified corneal nerves and their terminal bulbs and IVCM In vivo confocal microscopy (Heidelberg Retina Tomograph II— characteristics. Rostock Corneal Module, Heidelberg Engineering GmbH, Dossenheim, Germany) of the left cornea showed bands of hyperreflective areas in Key Words: corneal nerves, calcification, band keratopathy, in vivo which discrete white bulbous structures could be seen (Figs. 2A, B). confocal microscopy Nerves of the subbasal plexus could be seen arising from the bulb-like structures and traveling in the subbasal plane (Figs. 2A, B). Thicker – (Cornea 2015;34:707 709) hyperreflective linear structures consistent with stromal nerves were seen in the anterior stroma (Figs. 2C, D). Thinner stromal nerves could also be detected showing focal areas of hyperreflective thickening (Fig. 2D). We uman cornea is one of the most sensitive tissues in the used ImageJ software (Version 1.31; Wayne Rasband, Research Services Hbody, receiving sensory, sympathetic, and parasympa- Branch, National Institute of Mental Health, Bethesda, MD) to measure thetic innervation.1 Sensory neurons derived from the long the stromal and basal nerve diameters in different IVCM frames of the ’ ciliary nerves of the ophthalmic branch of the trigeminal nerve patient s left cornea and compared these with previously published predominate.2 The long posterior ciliary nerves arborize to normal values. form the pericorneal plexus from which stromal nerves enter the limbus and travel centripetally and anteriorly to reach the DISCUSSION sub-Bowman zone. From here, nerve fibers penetrate the The density of the nerve endings in the cornea is 300 Bowman membrane (BM) to terminate in bulb-like structures 1 from which the subbasal nerves originate.3 to 500 times greater than that of the skin. In a previous Corneal nerves have an important role in maintaining study, we demonstrated the anatomical relationship between corneal health and respond actively to injury and insult.4,5 In the subbasal and anterior stromal nerves in terms of the vivo confocal microscopy (IVCM) is a useful clinical tool to location and distribution of perforation sites at the Bowman layer.3 We showed that the stromal nerves divide and subdivide until they reach the sub-Bowman zone and Received for publication November 25, 2014; revision received February 11, penetrate the BM to terminate in discoid or bulbous 2015; accepted February 15, 2015. Published online ahead of print April 3 7, 2015. thickenings, which give rise to subbasal nerves (Fig. 1D). From the Department of Ophthalmology, Nottingham University Hospitals, This pattern strongly corresponded to the slit-lamp images University of Nottingham, Nottingham, United Kingdom. seen in the patient. The authors have no funding or conflicts of interest to disclose. Calcification of the Bowman membrane is classically Reprints: Harminder S. Dua, MD, PhD, Department of Ophthalmology, Queens Medical Centre, University of Nottingham, Derby Rd, Nottingham, NG7 seen in band keratopathy. It is usually seen as a horizontal 2UH, United Kingdom (e-mail: [email protected]). band extending between the 3 and 9 o’clock position. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Calcareous degeneration is another type of corneal calcific

Cornea Volume 34, Number 6, June 2015 www.corneajrnl.com | 707

FIGURE 1. Slit-lamp photomicro- graph showing: A, Band keratopathy righteye.B,Lefteyecalcifiedsub- Bowman corneal nerves. C, Higher magnification of (B) showing the classic pattern of corneal sub-Bowman nerves and their termination in multiple (arrow) or single (arrowhead) bulbous thickenings. D, High-resolution image of corneal nerves in a donor eye showing the characteristic configuration of the sub-Bowman nerves (arrow) terminating in bulb- like structures corresponding to those on the slit-lamp images. The image is taken using a Leica micro- scope (Leica DM4000B; Leica Mi- crosystems, Nussloch, Germany), and the corneal whole mount is stained using the acetylcholinesterase staining method3 (scale bar = 500 mm).

degeneration, which, like band keratopathy, occurs in dis- Specific calcification of corneal nerves has not been eased eyes but involves the posterior stroma and sometimes reported. There have been several reports in the literature full corneal thickness. describing optic nerve calcification. Nicholson et al7 described

FIGURE 2. In vivo confocal images of the central area of the left cornea: A, Image acquisition at 38 mmdepth. Discrete white bulbous structures are seen (arrows). B, Image acquisition at 41 mm depth. Bands of hyperreflective areas that represent the Bowman layer with fine linear structures representing the subbasal nerves. C, D, Thicker hyperreflective linear structures consistent with stromal nerves (arrows) were seen in the anterior stroma (acquired at 59 and 97 mmdepth,respectively).Notethe thinner stromal nerve showing local- ized hyperreflective thickenings along its length in (D) (arrowheads).

optic nerve sheath calcification, and Crompton et al8 reported IVCM images was also observed with the hyperreflective full-thickness traumatic optic nerve calcification. Calcified segments being thicker. Subbasal nerves showed normal cavernous malformation of the lower cranial nerves has been diameter compared with healthy corneas (mean, 2.2 6 1.5 also described.9 Calcification of the optic nerve is largely mm; SD, 0.97). related to the nerve sheaths.7 The corneal sensory nerves can be either finely myelinated or unmyelinated axons, deter- REFERENCES mined by the size and presence of myelin sheaths around the 1. Muller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents axon. The central stromal axons are unmyelinated, and this is and function. Exp Eye Res. 2003;76:521–542. particularly important for corneal transparency. Corneal nerve 2. Morgan CW, Nadelhaft I, de Groat WC. Anatomical localization of corneal afferent cells in the trigeminal ganglion. Neurosurgery. 1978;2: axons are grouped in small bundles and fascicles surrounded – 10 252 258. by the perineurium or perineural sheath. The fact that 3. Al-Aqaba MA, Fares U, Suleman H, et al. Architecture and distribution calcification was noted up to the terminal bulbs would suggest of human corneal nerves. Br J Ophthalmol. 2010;94:784–789. that calcification occurred in this sheath. There is some 4. Al-Aqaba M, Alomar T, Lowe J, et al. Corneal nerve aberrations in – suggestion that the terminal bulbs are formed by the folding bullous keratopathy. Am J Ophthalmol. 2011;151:840 849. 5. Al-Aqaba M, Faraj L, Fares U, et al. The morphologic characteristics of of the perineural sheath (unpublished observations), hence corneal nerves in advanced keratoconus as evaluated by acetylcholines- they too would be susceptible to calcification. Thereafter, the terase technique. Am J Ophthalmol. 2011;152:364–376. axons emerge to form the fine subbasal nerve plexus. This 6. Patel DV, McGhee CNJ. In vivo confocal microscopy of human corneal was not visible on slit-lamp examination but clearly demon- nerves in health, in ocular and systemic disease, and following corneal fi surgery: a review. Br J Ophthalmol. 2009;93:853–860. strated on IVCM, suggesting that these bers were not 7. Nicholson B, Lystad L, Emch T, et al. Idiopathic dural optic nerve sheath calcified. The stromal nerves were hyperreflective and calcification. Br J Ophthalmol. 2011;95:2. thickened on IVCM on account of the calcification. 8. Crompton JL, O’Day J, Hassan A. Optic nerve calcification after trauma. Several studies reported the stromal nerve diameter in J Neuroophthalmol. 2004;24:293–294. m 11 9. Nair BR, Prabhu K, Chacko G, et al. Calcified cavernous malformation healthy corneas in a range from 5.5 to 11.4 m and subbasal – m 12 of the lower cranial nerves. Neurol India. 2014;62:104 105. nerve diameter from 0.5 to 4.7 m. This variation can be 10. Bron AJ, Tripathi RC, Tripathi BJ. Wolff’s Anatomy of the Eye and Orbit. explained by the fact that the path of nerves in the corneal London: Chapman and Hall Medical; 1997:233–278. stroma can be oblique as a result of which the cross section is 11. Benítez del Castillo JM, Wasfy MA, Fernandez C, et al. An in vivo not always through the center of the nerve. Our data showed confocal masked study on corneal epithelium and subbasal nerves in fi patients with dry eye. Invest Ophthalmol Vis Sci. 2004;45:3030–3035. that the calci ed nerves were toward the higher end or beyond 12. Hos¸al BM, Ornek N, Zilelioglu G, et al. Morphology of corneal nerves the measurements of normal nerve thickness (mean, 9.6 6 6.3 and corneal sensation in dry eye: a preliminary study. Eye (Lond). 2005; mm; SD, 3.5). Irregular thickening in the same frame of 19:1276–1279.