{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T17:29:31Z","timestamp":1782581371653,"version":"3.54.5"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: In vivo confocal microscopy (IVCM) is a vital tool in studying dry eye disease (DED), providing insights into morphological changes at ocular surface unit levels. This review presents the main differences in corneal structure between aqueous-deficient dry eye disease (AD-DED) and normal eyes. Methods: A comprehensive search of PubMed, Web of Science, Embase, and MEDLINE databases from January 2000 to December 2023 was conducted. The study selection process, as well as data selection and examination, were independently performed by two members of the review team. Results: The review reveals a consistent decrease in corneal surface epithelial cell density in AD-DED cases compared to a control group, but conflicting data on basal epithelial cell density. Notably, the abnormal hyperreflectivity of keratocytes in patients with Sjogren\u2019s syndrome was recorded, and there was a significant keratocyte density in AD-DED subjects compared to evaporative DED and control groups. Studies also found a decrease in sub-basal nerve density, increased tortuosity, and the fragmentation of nerve fibers. Dendritic cell density and dendritic cell dendrites increase in AD-DED patients compared to healthy subjects. Conclusions: IVCM is a powerful tool for enhancing our understanding of the pathophysiological mechanisms underlying DED. However, the review underscores the urgent need to standardize the terminology, analysis, and units used for accurate interpretation, a crucial step in advancing our knowledge of DED.<\/jats:p>","DOI":"10.3390\/diagnostics14151613","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T06:17:44Z","timestamp":1721974664000},"page":"1613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Confocal Microscopy of the Cornea in Aqueous-Deficient Dry Eye Disease\u2014A Literature Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2429-7936","authenticated-orcid":false,"given":"Radu","family":"Bucsan","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Medicine and Pharmacy Carol Davila, 050747 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxandra","family":"Coroleuc\u0103","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Medicine and Pharmacy Carol Davila, 050747 Bucharest, Romania"},{"name":"Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Garh\u00f6fer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4189-6571","authenticated-orcid":false,"given":"Alina","family":"Popa-Cherecheanu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Medicine and Pharmacy Carol Davila, 050747 Bucharest, Romania"},{"name":"Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopold","family":"Schmetterer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore"},{"name":"SERI-NTU Advanced Ocular Engineering (STANCE), Singapore 639798, Singapore"},{"name":"School of Chemical and Biological Engineering, Nanyang Technological University, Singapore 637371, Singapore"},{"name":"Center for Medical Physics and Biomedical Engineering, Medical University Vienna, 1090 Vienna, Austria"},{"name":"IOB\u2014Institute of Molecular and Clinical Ophthalmology, 4031 Basel, Switzerland"},{"name":"Fondation Ophtalmologique Adolphe De Rothschild, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-8219","authenticated-orcid":false,"given":"Raluca","family":"Iancu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Medicine and Pharmacy Carol Davila, 050747 Bucharest, Romania"},{"name":"Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1542-0124(12)70081-2","article-title":"The definition and classification of dry eye disease","volume":"5","author":"Lemp","year":"2007","journal-title":"Ocul. Surf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1542-0124(12)70086-1","article-title":"Research in dry eye: Report of the Research Subcommittee of the International Dry Eye WorkShop (2007)","volume":"5","author":"Gipson","year":"2007","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II definition and classification report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jtos.2017.05.001","article-title":"TFOS DEWS II diagnostic methodology report","volume":"15","author":"Wolffsohn","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1111\/opo.12888","article-title":"The global prevalence of dry eye disease: A Bayesian view","volume":"41","author":"Papas","year":"2021","journal-title":"Ophthalmic Physiol. Opt."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/ICO.0b013e318225415a","article-title":"Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: A retrospective study","volume":"31","author":"Lemp","year":"2012","journal-title":"Cornea"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3109\/08820538.2012.711416","article-title":"In vivo confocal microscopy in dry eye disease and related conditions","volume":"Volume 27","author":"Alhatem","year":"2012","journal-title":"Seminars in Ophthalmology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1442-9071.2009.02016.x","article-title":"In vivo confocal microscopy, an inner vision of the cornea\u2014A major review","volume":"37","author":"Guthoff","year":"2009","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"DES41","DOI":"10.1167\/iovs.17-23602","article-title":"Application of in vivo confocal microscopy in dry eye disease","volume":"59","author":"Matsumoto","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/ceo.13924","article-title":"Can in vivo confocal microscopy differentiate between sub-types of dry eye disease? A review","volume":"49","author":"Hwang","year":"2021","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sim, R., Yong, K., Liu, Y.-C., and Tong, L. (2022). In vivo confocal microscopy in different types of dry eye and meibomian gland dysfunction. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092349"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/eye.2017.3","article-title":"Corneal confocal scanning laser microscopy in patients with dry eye disease treated with topical cyclosporine","volume":"31","author":"Iaccheri","year":"2017","journal-title":"Eye"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.jfo.2023.05.024","article-title":"Evaluation of aqueous-deficient and evaporative dry eye cases with confocal microscopy","volume":"46","author":"Kasikci","year":"2023","journal-title":"J. Fr. Ophtalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jtos.2021.08.004","article-title":"Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study","volume":"22","author":"Cox","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jtos.2020.05.012","article-title":"Correlation of corneal immune cell changes with clinical severity in dry eye disease: An in vivo confocal microscopy study","volume":"19","author":"Aggarwal","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lee, O.L., Tepelus, T.C., Huang, J., Irvine, A.G., Irvine, C., Chiu, G.B., and Sadda, S.R. (2018). Evaluation of the corneal epithelium in non-Sj\u00f6gren\u2019s and Sj\u00f6gren\u2019s dry eyes: An in vivo confocal microscopy study using HRT III RCM. BMC Ophthalmol., 18.","DOI":"10.1186\/s12886-018-0971-3"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Matsumoto, Y., Ibrahim, O.M.A., Kojima, T., Dogru, M., Shimazaki, J., and Tsubota, K. (2020). Corneal in vivo laser-scanning confocal microscopy findings in dry eye patients with Sj\u00f6gren\u2019s syndrome. Diagnostics, 10.","DOI":"10.3390\/diagnostics10070497"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1167\/iovs.04-0251","article-title":"An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye","volume":"45","author":"Wasfy","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1167\/iovs.06-0127","article-title":"Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye","volume":"48","author":"Acosta","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1167\/iovs.06-1129","article-title":"The cornea in Sjogren\u2019s syndrome: An in vivo confocal study","volume":"48","author":"Villani","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1167\/iovs.02-1260","article-title":"Corneal innervation and morphology in primary Sjogren\u2019s syndrome","volume":"44","author":"Tuominen","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","first-page":"39","article-title":"In vivo confocal laser scanning microscopy of the cornea in dry eye","volume":"245","author":"Kraak","year":"2007","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.ophtha.2010.08.033","article-title":"Tear dynamics and corneal confocal microscopy of subjects with mild self-reported office dry eye","volume":"118","author":"Zhang","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/sj.eye.6701760","article-title":"Morphology of corneal nerves and corneal sensation in dry eye: A preliminary study","volume":"19","author":"Elhan","year":"2005","journal-title":"Eye"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/01.ico.0000154402.01710.95","article-title":"Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy","volume":"24","author":"Zhang","year":"2005","journal-title":"Cornea"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.exer.2008.03.002","article-title":"Alterations in corneal sensitivity and nerve morphology in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"86","author":"Tuisku","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5136","DOI":"10.1167\/iovs.10-7048","article-title":"Inflammation and the nervous system: The connection in the cornea in patients with infectious keratitis","volume":"52","author":"Cruzat","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1167\/iovs.09-3629","article-title":"Changes in corneal epithelial layer inflammatory cells in aqueous tear\u2013deficient dry eye","volume":"51","author":"Lin","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1097\/OPX.0b013e318294c184","article-title":"In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye","volume":"90","author":"Villani","year":"2013","journal-title":"Optom. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"108295","DOI":"10.1016\/j.exer.2020.108295","article-title":"The cornea in keratoconjunctivitis sicca","volume":"201","author":"Pflugfelder","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1167\/iovs.05-1281","article-title":"Apical corneal barrier disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline","volume":"47","author":"Corrales","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1167\/iovs.07-0893","article-title":"Corneal involvement in rheumatoid arthritis: An in vivo confocal study","volume":"49","author":"Villani","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1167\/iovs.10-5380","article-title":"Corneal involvement in Graves\u2019 orbitopathy: An in vivo confocal study","volume":"51","author":"Villani","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.preteyeres.2007.03.003","article-title":"Contact lens-induced changes in the anterior eye as observed in vivo with the confocal microscope","volume":"26","author":"Efron","year":"2007","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1194\/jlr.R001347","article-title":"Significance of lipid mediators in corneal injury and repair","volume":"51","author":"Kenchegowda","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guerrero-Moreno, A., Baudouin, C., Melik Parsadaniantz, S., and R\u00e9aux-Le Goazigo, A. (2020). Morphological and functional changes of corneal nerves and their contribution to peripheral and central sensory abnormalities. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.610342"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.survophthal.2013.09.002","article-title":"Corneal nerves in health and disease","volume":"59","author":"Shaheen","year":"2014","journal-title":"Surv. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108243","DOI":"10.1016\/j.exer.2020.108243","article-title":"Corneal nerves anatomy, function, injury and regeneration","volume":"200","author":"Medeiros","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/00003226-200105000-00008","article-title":"Morphology of corneal nerves using confocal microscopy","volume":"20","author":"Efron","year":"2001","journal-title":"Cornea"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1136\/bjo.2008.150615","article-title":"In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: A review","volume":"93","author":"Patel","year":"2009","journal-title":"Br. J. Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1136\/bjo.2009.164780","article-title":"Corneal nerve regeneration in neurotrophic keratopathy following autologous plasma therapy","volume":"94","author":"Rao","year":"2010","journal-title":"Br. J. Ophthalmol."},{"key":"ref_42","first-page":"2915","article-title":"Corneal structure and sensitivity in type 1 diabetes mellitus","volume":"41","author":"Rosenberg","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3928\/1081-597X-20070401-05","article-title":"Dry eye and corneal sensitivity after high myopic LASIK","volume":"23","author":"Tuisku","year":"2007","journal-title":"J. Refract. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3109\/08990229309028845","article-title":"Sensory and sympathetic nerve sprouting in the rat cornea following neonatal administration of capsaicin","volume":"10","author":"Marfurt","year":"1993","journal-title":"Somatosens. Mot. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3109\/08820538.2010.518133","article-title":"In vivo confocal microscopy of corneal nerves: Analysis and clinical correlation","volume":"Volume 25","author":"Cruzat","year":"2010","journal-title":"Seminars in Ophthalmology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6569","DOI":"10.1364\/BOE.9.006569","article-title":"250 kHz, 1.5 \u00b5m resolution SD-OCT for in-vivo cellular imaging of the human cornea","volume":"9","author":"Tan","year":"2018","journal-title":"Biomed. Opt. Express"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Stachs, O., Guthoff, R.F., and Aumann, S. (2019). In vivo confocal scanning laser microscopy. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics, Springer.","DOI":"10.1007\/978-3-030-16638-0_12"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhang, X.Y., Wu, M., Chinnery, H.R., and Downie, L.E. (2022). Defining an optimal sample size for corneal epithelial immune cell analysis using in vivo confocal microscopy images. Front. Med., 9.","DOI":"10.3389\/fmed.2022.848776"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bohn, S., Stache, N., Sperlich, K., Allgeier, S., K\u00f6hler, B., Bartschat, A., Do, H.-V., George, C., Guthoff, R.F., and Stachs, A. (2022). In vivo monitoring of corneal dendritic cells in the subbasal nerve plexus during trastuzumab and paclitaxel breast cancer therapy\u2014A one-year follow-up. Diagnostics, 12.","DOI":"10.3390\/diagnostics12051180"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1038\/s41598-022-05983-5","article-title":"Real-time large-area imaging of the corneal subbasal nerve plexus","volume":"12","author":"Allgeier","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1364\/BOE.2.003037","article-title":"Micrometer axial resolution OCT for corneal imaging","volume":"2","author":"Yadav","year":"2011","journal-title":"Biomed. Opt. Express"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Chiang, J.C.B., Roy, M., Kim, J., Markoulli, M., and Krishnan, A.V. (2023). In-vivo corneal confocal microscopy: Imaging analysis, biological insights and future directions. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-05005-8"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/15\/1613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:24:00Z","timestamp":1760109840000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/15\/1613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,26]]},"references-count":52,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["diagnostics14151613"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics14151613","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,26]]}}}