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In Vivo Confocal Laser Scanning Microscopy of Corneal Nerves in Leprosy

In Vivo Confocal Laser Scanning Microscopy of Corneal Nerves in Leprosy Leprosy has a high incidence of ocular complications, including corneal lesions, lagophthalmos, iridocyclitis, and cataract. Involvement of the trigeminal nerve is common and can result in corneal hypoesthesia. Changes in corneal nerves might be the initial ocular manifestation.1 We describe a patient in whom leprosy developed without any apparent ocular complications. In vivo confocal microscopy, however, revealed abnormal corneal nerves. Being a noninvasive imaging technique, confocal microscopy plays a valuable role in visualization of corneal nerves in that condition. Report of a Case A 43-year-old woman with multiple anesthetic skin lesions for 1 year was diagnosed with borderline leprosy by skin biopsy. Physical examination showed severe sensory and motor polyneuropathy, axonal and myelinic in nature. Muscle strength was preserved but severe hypoesthesia was found at the superior and inferior limbs. Using electroneuromyography, sensory assessment showed no responses to stimulations of left median and ulnar nerves. Motor evaluation revealed prolonged F waves in those nerves. Skin lesions and hypoesthesia partially regressed after a 1-year multidrug therapy including rifampicin, clofazimine, dapsone, and intravenous immunoglobulin. The patient was referred for ophthalmic evaluation, including visual acuity, anterior segment, fundus, and corneal sensitivity using cotton wool stimulus all over the corneal surface. Findings were unremarkable except for several visible nerves in inferior corneas found by slitlamp biomicroscopy. Full-thickness cornea examination was carried out using a confocal laser scanning microscope (Heidelberg Retina Tomograph II; Heidelberg Engineering, Heidelberg, Germany) fitted with a Rostock Cornea Module (Heidelberg Engineering).2 More than 500 digital images that were 400 μm × 400 μm were obtained, showing similar findings on both sides. Moreover, 10 normal corneas were similarly examined for comparison (Figure 1). The surface epithelium appeared normal, whereas several basal epithelial nerve bundles displayed prominent thickening with local enlargements (Figure 2A and B). There was no notable abnormality in the density of the subbasal nerve plexus. At the corneal apex, the orientations of the basal epithelial nerve bundles were unusually irregular (Figure 2C). The basal epithelium showed numerous dendritic particles (Figure 2D). In the stroma, the central nerves were very thin and tortuous, some showing beaded fiberlike structures and communicating branches (Figure 3A). The presence of numerous nerve bundles within a single image suggested an increased density of stromal nerves. In contrast, peripheral stromal nerves were thickened, tortuous, and less numerous than in the central stroma (Figure 3B). The endothelium appeared unremarkable in analyzed areas. Figure 1. View LargeDownload For comparison, these in vivo confocal microscopy images show the normal appearance of basal epithelial and stromal nerves. A, Basal epithelial nerve plexus showing a preferred direction from 6 to 12 o’clock. B, Stromal nerve bundle appearing straight without beading and communicating branches. Figure 2. View LargeDownload Corneal epithelium in vivo confocal microscopy image of the right (A) and left (B) eyes showing thickened basal epithelial nerve bundles with local enlargements (arrows). C, The epithelial nerve plexus at the corneal apex demonstrating irregular orientations. D, Dendritic particles (arrows), sometimes interspersed between nerve bundles. Figure 3. View LargeDownload In vivo confocal microscopy images. A, Stromal nerves in the central cornea. In vivo confocal microscopy shows numerous stromal nerve bundles appearing tortuous, thin, and beaded, with some abnormal communicating branches. B, Peripheral stromal nerves were thickened, tortuous, and less numerous than central stromal nerves. Comment In previous studies using slitlamp biomicroscopy, Allen and Byers3 described altered nerves as opaque, enlarged, and beaded. Beading was attributed to multiplication of bacilli and cell aggregation adjacent to the nerve. In another slitlamp study, Daniel et al4 noted that visibility of corneal nerves was due to 1 or several prominent thickened bundles. In our study using in vivo confocal microscopy, we defined more detailed changes in corneal nerves, particularly concerning thickening, beading, and orientation of basal epithelial nerve bundles. Moreover, in contrast to previous observations using slitlamp biomicroscopy,3,4 we were able to separately analyze nerve bundles at basal epithelial and stromal levels. Nerves showed more pronounced alterations in the stroma than in the basal epithelium. This might be related to the fact that, in contrast to epithelial axons, stromal nerves are surrounded by Schwann cells,1 which have a unique susceptibility to infection by Mycobacterium leprae.5 We distinguished the following 2 forms of changes in stromal nerves: (1) some were thickened, presumably as a result of direct infiltration by bacilli, whereas others were thinned, tortuous, and beaded; and (2) they occasionally showed communicating branches, which might express abnormal axonal regeneration following the immune response, a process playing a central role in leprosy.6 Dendritic structures, presumably representing Langerhans cells, may be another consequence of immune response.6 In vivo confocal microscopy is a powerful diagnostic tool that allows for noninvasive recognition of corneal nerve alterations in leprosy. Correspondence: Dr Safran, Ophthalmology Service, Department of Clinical Neurosciences, Geneva University Hospitals, 22 rue Alcide Jentzer, 1211 Geneva 14, Switzerland (a.b.safran@hcuge.ch). Author Contributions: Drs Zhao and Lu contributed equally to this study. Financial Disclosure: None reported. References 1. Kim SKDohlman CH Causes of enlarged corneal nerves. Int Ophthalmol Clin 2001;41 (1) 13- 23PubMedGoogle ScholarCrossref 2. Stachs OZhivov AKraak RStave JGuthoff R In vivo three-dimensional confocal laser scanning microscopy of the epithelial nerve structure in the human cornea. Graefes Arch Clin Exp Ophthalmol 2007;245 (4) 569- 575PubMedGoogle ScholarCrossref 3. Allen JHByers JL The pathology of ocular leprosy, I: cornea. Arch Ophthalmol 1960;64216- 220PubMedGoogle ScholarCrossref 4. Daniel EDavid ARao PS Quantitative assessment of the visibility of unmyelinated corneal nerves in leprosy. Int J Lepr Other Mycobact Dis 1994;62 (3) 374- 379PubMedGoogle Scholar 5. Spierings EDe Boer TZulianello LOttenhoff TH The role of Schwann cells, T cells and Mycobacterium leprae in the immunopathogenesis of nerve damage in leprosy. Lepr Rev 2000;71 ((suppl)) S121- S129PubMedGoogle Scholar 6. Scollard DM Endothelial cells and the pathogenesis of lepromatous neuritis: insights from the armadillo model. Microbes Infect 2000;2 (15) 1835- 1843PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

In Vivo Confocal Laser Scanning Microscopy of Corneal Nerves in Leprosy

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Publisher
American Medical Association
Copyright
Copyright © 2008 American Medical Association. All Rights Reserved.
ISSN
0003-9950
eISSN
1538-3687
DOI
10.1001/archophthalmol.2007.67
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Abstract

Leprosy has a high incidence of ocular complications, including corneal lesions, lagophthalmos, iridocyclitis, and cataract. Involvement of the trigeminal nerve is common and can result in corneal hypoesthesia. Changes in corneal nerves might be the initial ocular manifestation.1 We describe a patient in whom leprosy developed without any apparent ocular complications. In vivo confocal microscopy, however, revealed abnormal corneal nerves. Being a noninvasive imaging technique, confocal microscopy plays a valuable role in visualization of corneal nerves in that condition. Report of a Case A 43-year-old woman with multiple anesthetic skin lesions for 1 year was diagnosed with borderline leprosy by skin biopsy. Physical examination showed severe sensory and motor polyneuropathy, axonal and myelinic in nature. Muscle strength was preserved but severe hypoesthesia was found at the superior and inferior limbs. Using electroneuromyography, sensory assessment showed no responses to stimulations of left median and ulnar nerves. Motor evaluation revealed prolonged F waves in those nerves. Skin lesions and hypoesthesia partially regressed after a 1-year multidrug therapy including rifampicin, clofazimine, dapsone, and intravenous immunoglobulin. The patient was referred for ophthalmic evaluation, including visual acuity, anterior segment, fundus, and corneal sensitivity using cotton wool stimulus all over the corneal surface. Findings were unremarkable except for several visible nerves in inferior corneas found by slitlamp biomicroscopy. Full-thickness cornea examination was carried out using a confocal laser scanning microscope (Heidelberg Retina Tomograph II; Heidelberg Engineering, Heidelberg, Germany) fitted with a Rostock Cornea Module (Heidelberg Engineering).2 More than 500 digital images that were 400 μm × 400 μm were obtained, showing similar findings on both sides. Moreover, 10 normal corneas were similarly examined for comparison (Figure 1). The surface epithelium appeared normal, whereas several basal epithelial nerve bundles displayed prominent thickening with local enlargements (Figure 2A and B). There was no notable abnormality in the density of the subbasal nerve plexus. At the corneal apex, the orientations of the basal epithelial nerve bundles were unusually irregular (Figure 2C). The basal epithelium showed numerous dendritic particles (Figure 2D). In the stroma, the central nerves were very thin and tortuous, some showing beaded fiberlike structures and communicating branches (Figure 3A). The presence of numerous nerve bundles within a single image suggested an increased density of stromal nerves. In contrast, peripheral stromal nerves were thickened, tortuous, and less numerous than in the central stroma (Figure 3B). The endothelium appeared unremarkable in analyzed areas. Figure 1. View LargeDownload For comparison, these in vivo confocal microscopy images show the normal appearance of basal epithelial and stromal nerves. A, Basal epithelial nerve plexus showing a preferred direction from 6 to 12 o’clock. B, Stromal nerve bundle appearing straight without beading and communicating branches. Figure 2. View LargeDownload Corneal epithelium in vivo confocal microscopy image of the right (A) and left (B) eyes showing thickened basal epithelial nerve bundles with local enlargements (arrows). C, The epithelial nerve plexus at the corneal apex demonstrating irregular orientations. D, Dendritic particles (arrows), sometimes interspersed between nerve bundles. Figure 3. View LargeDownload In vivo confocal microscopy images. A, Stromal nerves in the central cornea. In vivo confocal microscopy shows numerous stromal nerve bundles appearing tortuous, thin, and beaded, with some abnormal communicating branches. B, Peripheral stromal nerves were thickened, tortuous, and less numerous than central stromal nerves. Comment In previous studies using slitlamp biomicroscopy, Allen and Byers3 described altered nerves as opaque, enlarged, and beaded. Beading was attributed to multiplication of bacilli and cell aggregation adjacent to the nerve. In another slitlamp study, Daniel et al4 noted that visibility of corneal nerves was due to 1 or several prominent thickened bundles. In our study using in vivo confocal microscopy, we defined more detailed changes in corneal nerves, particularly concerning thickening, beading, and orientation of basal epithelial nerve bundles. Moreover, in contrast to previous observations using slitlamp biomicroscopy,3,4 we were able to separately analyze nerve bundles at basal epithelial and stromal levels. Nerves showed more pronounced alterations in the stroma than in the basal epithelium. This might be related to the fact that, in contrast to epithelial axons, stromal nerves are surrounded by Schwann cells,1 which have a unique susceptibility to infection by Mycobacterium leprae.5 We distinguished the following 2 forms of changes in stromal nerves: (1) some were thickened, presumably as a result of direct infiltration by bacilli, whereas others were thinned, tortuous, and beaded; and (2) they occasionally showed communicating branches, which might express abnormal axonal regeneration following the immune response, a process playing a central role in leprosy.6 Dendritic structures, presumably representing Langerhans cells, may be another consequence of immune response.6 In vivo confocal microscopy is a powerful diagnostic tool that allows for noninvasive recognition of corneal nerve alterations in leprosy. Correspondence: Dr Safran, Ophthalmology Service, Department of Clinical Neurosciences, Geneva University Hospitals, 22 rue Alcide Jentzer, 1211 Geneva 14, Switzerland (a.b.safran@hcuge.ch). Author Contributions: Drs Zhao and Lu contributed equally to this study. Financial Disclosure: None reported. References 1. Kim SKDohlman CH Causes of enlarged corneal nerves. Int Ophthalmol Clin 2001;41 (1) 13- 23PubMedGoogle ScholarCrossref 2. Stachs OZhivov AKraak RStave JGuthoff R In vivo three-dimensional confocal laser scanning microscopy of the epithelial nerve structure in the human cornea. Graefes Arch Clin Exp Ophthalmol 2007;245 (4) 569- 575PubMedGoogle ScholarCrossref 3. Allen JHByers JL The pathology of ocular leprosy, I: cornea. Arch Ophthalmol 1960;64216- 220PubMedGoogle ScholarCrossref 4. Daniel EDavid ARao PS Quantitative assessment of the visibility of unmyelinated corneal nerves in leprosy. Int J Lepr Other Mycobact Dis 1994;62 (3) 374- 379PubMedGoogle Scholar 5. Spierings EDe Boer TZulianello LOttenhoff TH The role of Schwann cells, T cells and Mycobacterium leprae in the immunopathogenesis of nerve damage in leprosy. Lepr Rev 2000;71 ((suppl)) S121- S129PubMedGoogle Scholar 6. Scollard DM Endothelial cells and the pathogenesis of lepromatous neuritis: insights from the armadillo model. Microbes Infect 2000;2 (15) 1835- 1843PubMedGoogle ScholarCrossref

Journal

Archives of Ophthalmology – American Medical Association

Published: Feb 1, 2008

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