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Corneal Confocal Microscopy and the Nervous System
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Corneal Confocal Microscopy and the Nervous System

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (25 July 2022) | Viewed by 16901

Special Issue Editors

Dr. Stuti Misra

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Guest Editor
Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
Interests: corneal innervation; ocular surface disease; ocular imaging; dry eye disease; ophthalmic markers of diabetic neuropathy; in vivo confocal microscopy of cornea
Dr. Ioannis N. Petropoulos

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Guest Editor
Weill Cornell Medicine-Qatar of Cornell University, Research Division, Doha, Qatar
Interests: corneal confocal microscopy; biomarkers; axonal loss; neurodegenerative disease
Dr. Uazman Alam

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Guest Editor
Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
Interests: diabetes; diabetic neuropathy; neuropathic pain; small nerve fibres
Dr. Luisa H. Colorado

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Guest Editor
Anterior Eye Lab, Centre for Vision and Eye Research, Queensland University of Technology, Brisbane, Australia
Interests: corneal dendritic cell dynamics; in vivo corneal confocal microscopy; dry eye; contact lens discomfort; tear film; ocular surface biomarkers; corneal nerves; neuropathy

Special Issue Information

Dear Colleagues,

The study of human corneal nerve morphology has previously been limited by the necessity of ex vivo analysis and the rapid degeneration of corneal nerves after death. However, the advent of corneal in vivo confocal microscopy (IVCM) has enabled rapid non-invasive imaging of corneal nerve fibre bundles and allowed a correlation with peripheral nerves. IVCM is clinically used to assess corneal dystrophies, herpetic infections following corneal surgery, and other ocular surface diseases. The application of IVCM has gained traction beyond ophthalmology, including in evaluating idiopathic small fibre neuropathy, Fabry disease, Charcot–Marie–Tooth disease, auto-immune neuropathy, HIV-associated peripheral neuropathy, and diabetic peripheral neuropathy.

This Special Issue aims to highlight recent advances and explore the potential of IVCM in clinical diagnosis and monitor peripheral neuropathy due to various diseases and conditions to contribute towards clinical knowledge and informed clinical decision making. 

Dr. Stuti Misra
Dr. Ioannis N. Petropoulos
Dr. Uazman Alam
Dr. Luisa H. Colorado
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • in vivo confocal microscopy of cornea
  • peripheral neuropathy
  • corneal nerves
  • neuroimmune system
  • corneal biomarkers

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

11 pages, 293 KiB  
Editorial
Corneal Confocal Microscopy and the Nervous System: Introduction to the Special Issue
by Rayaz A. Malik and Nathan Efron
J. Clin. Med. 2022, 11(6), 1475; https://doi.org/10.3390/jcm11061475 - 08 Mar 2022
Cited by 1 | Viewed by 2463
Abstract
The heretical idea that corneal confocal microscopy (CCM)—an ophthalmic instrument—could be used to assess neurological disease emerged around the turn of the 21st century [...] Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)

Research

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11 pages, 2656 KiB  
Article
Impact of Chronic Kidney Disease on Corneal Neuroimmune Features in Type 2 Diabetes
by Kofi Asiedu, Maria Markoulli, Shyam Sunder Tummanapalli, Jeremy Chung Bo Chiang, Sultan Alotaibi, Leiao Leon Wang, Roshan Dhanapalaratnam, Natalie Kwai, Ann Poynten and Arun V. Krishnan
J. Clin. Med. 2023, 12(1), 16; https://doi.org/10.3390/jcm12010016 - 20 Dec 2022
Cited by 4 | Viewed by 2643
Abstract
Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes [...] Read more.
Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes with chronic kidney disease (T2DM-CKD) (n = 29) and those with type 2 diabetes without chronic kidney disease (T2DM-no CKD) (n = 29), along with 30 healthy controls. Corneal dendritic cell densities were compared between people with T2DM-CKD and those with T2DM-no CKD. The groups were matched for neuropathy status. Results: There was a significant difference in corneal nerve fiber density (p < 0.01) and corneal nerve fiber length (p = 0.04) between T2DM-CKD and T2DM-no CKD groups. The two diabetes groups had reduced corneal nerve parameters compared to healthy controls (all parameters: p < 0.01). Immature central dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group ((7.0 (3.8–12.8) and 3.5 (1.4–13.4) cells/mm2, respectively, p < 0.05). Likewise, central mature dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group (0.8 (0.4–2.2) and 0.4 (0.6–1.1) cells/mm2, respectively, p = 0.02). Additionally, total central dendritic cell density was increased in the T2DM-CKD group compared to T2DM-no CKD group (10.4 (4.3–16.1) and 3.9 (2.1–21.0) cells/mm2, respectively, p = 0.03). Conclusion: The study showed that central corneal dendritic cell density is increased in T2DM-CKD compared to T2DM-no CKD, with groups matched for peripheral neuropathy severity. This is accompanied by a loss of central corneal nerve fibers. The findings raise the possibility of additional local factors exacerbating central corneal nerve injury in people with diabetic chronic kidney disease. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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13 pages, 1663 KiB  
Article
Trigeminal Nerve Affection in Patients with Neuro-Sjögren Detected by Corneal Confocal Microscopy
by Tabea Seeliger, Marten A. Gehlhaar, Irene Oluwatoba-Popoola, Franz F. Konen, Melanie Haar, Emilia Donicova, Marija Wachsmann, Amelie Pielen, Stefan Gingele, Nils K. Prenzler, Diana Ernst, Torsten Witte, Carsten Framme, Anna Bajor and Thomas Skripuletz
J. Clin. Med. 2022, 11(15), 4484; https://doi.org/10.3390/jcm11154484 - 01 Aug 2022
Cited by 3 | Viewed by 1767
Abstract
Background: Patients with Sjögren’s syndrome and polyneuropathy more frequently develop cranial nerve affection when compared to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We therefore aimed to analyze trigeminal corneal nerve fibre characteristics in both patient groups. Methods: A total of 26 patients [...] Read more.
Background: Patients with Sjögren’s syndrome and polyneuropathy more frequently develop cranial nerve affection when compared to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We therefore aimed to analyze trigeminal corneal nerve fibre characteristics in both patient groups. Methods: A total of 26 patients with Sjögren’s syndrome associated neuropathy and 29 patients with CIDP were recruited at our university hospital and compared to 6 healthy controls. Dry eye symptoms and signs were assessed via clinical examination and the Ocular Disease Surface Index questionnaire. Trigeminal corneal nerve fibres were analyzed via corneal confocal microscopy (CCM) as a non-invasive in vivo microscopy. Results: CCM revealed significantly reduced corneal nerve fibre density and corneal nerve fibre main branch density in the Neuro-Sjögren group when compared with healthy controls. There were no significant group differences between the Neuro-Sjögren and the CIDP group for any of the microscopic parameters. Dry eye assessment showed similarly reduced scores for both patient groups, while healthy controls showed better results for objective dry eye signs. There was no correlation between microscopic parameters of the corneal confocal microscopy and parameters of dry eye assessment. Conclusions: Our data revealed trigeminal corneal nerve affection in patients with neuropathy associated with Sjögren’s syndrome and patients with CIDP detected by CCM. No difference was found between both neuropathy groups indicating that CCM is not able to distinguish between both entities. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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18 pages, 5508 KiB  
Article
Corneal Confocal Microscopy Features and Tear Molecular Profile in Study Participants with Discordance between Ocular Surface Disease Clinical Signs and Discomfort
by Sharon D’Souza, Rohit Shetty, Archana Padmanabhan Nair, Ruchika Agrawal, Mor M. Dickman, Pooja Khamar, Rudy M. M. A. Nuijts, Arkasubhra Ghosh and Swaminathan Sethu
J. Clin. Med. 2022, 11(9), 2407; https://doi.org/10.3390/jcm11092407 - 25 Apr 2022
Cited by 9 | Viewed by 1743
Abstract
Various ocular surface conditions such as dry eye disease can present with severe discomfort and pain. However, it is clinically challenging to establish etiology and prescribe correct treatment in patients who have a lot of discordance between symptoms and signs. To understand the [...] Read more.
Various ocular surface conditions such as dry eye disease can present with severe discomfort and pain. However, it is clinically challenging to establish etiology and prescribe correct treatment in patients who have a lot of discordance between symptoms and signs. To understand the basis of such discordance, we stratified subjects with ocular surface pain based on concordance between the severity of signs and symptoms and evaluated corneal structural features and tear molecular factors. All subjects underwent slit lamp examination, dry eye evaluation, and ocular surface disease index (OSDI) scoring. Subjects were stratified into group 1—without symptoms or clinical signs; group 2—without symptoms but with signs; group 3—with similar severity of symptoms and signs; and group 4—with symptom severity greater than that of the signs. Laser scanning in vivo confocal microscopy (IVCM) and tear fluid analysis for soluble factors by multiplex ELISA was performed for all subjects. Patients with a higher grade of symptoms and signs showed increased corneal dendritic cell (cDC) density (p < 0.05) which was more pronounced in subjects with discordance between the symptoms and signs (group 4). A significantly higher proportion of microneuroma-like structures and cDC were observed in group 4. IL-17A levels were significantly elevated in the tears of subjects with more discomfort. Our results demonstrate that corneal IVCM and the measurement of tear film factors can help clinicians improve diagnosis and treatment choice. Stratifying patients with ocular surface discomfort on the basis of discordance between symptoms and clinical signs may help identify patients who need additional adjunctive targeted therapy to resolve their condition. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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12 pages, 1139 KiB  
Article
Using Corneal Confocal Microscopy to Identify Therapeutic Agents for Diabetic Neuropathy
by Corinne G. Jolivalt, May Madi Han, Annee Nguyen, Fiona Desmond, Carlos Henrique Alves Jesus, Daniela C. Vasconselos, Andrea Pedneault, Natalie Sandlin, Sage Dunne-Cerami, Katie E. Frizzi and Nigel A. Calcutt
J. Clin. Med. 2022, 11(9), 2307; https://doi.org/10.3390/jcm11092307 - 21 Apr 2022
Cited by 1 | Viewed by 2045
Abstract
Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy [...] Read more.
Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy and neurodegenerative disease is less clear but may be supported by preclinical studies of investigational agents. We, therefore, used diverse investigational agents to assess concordance of efficacy against corneal nerve loss and peripheral neuropathy in a mouse model of diabetes. Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy. Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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Review

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19 pages, 1521 KiB  
Review
Artificial Intelligence and Corneal Confocal Microscopy: The Start of a Beautiful Relationship
by Uazman Alam, Matthew Anson, Yanda Meng, Frank Preston, Varo Kirthi, Timothy L. Jackson, Paul Nderitu, Daniel J. Cuthbertson, Rayaz A. Malik, Yalin Zheng and Ioannis N. Petropoulos
J. Clin. Med. 2022, 11(20), 6199; https://doi.org/10.3390/jcm11206199 - 20 Oct 2022
Cited by 8 | Viewed by 2588
Abstract
Corneal confocal microscopy (CCM) is a rapid non-invasive in vivo ophthalmic imaging technique that images the cornea. Historically, it was utilised in the diagnosis and clinical management of corneal epithelial and stromal disorders. However, over the past 20 years, CCM has been increasingly [...] Read more.
Corneal confocal microscopy (CCM) is a rapid non-invasive in vivo ophthalmic imaging technique that images the cornea. Historically, it was utilised in the diagnosis and clinical management of corneal epithelial and stromal disorders. However, over the past 20 years, CCM has been increasingly used to image sub-basal small nerve fibres in a variety of peripheral neuropathies and central neurodegenerative diseases. CCM has been used to identify subclinical nerve damage and to predict the development of diabetic peripheral neuropathy (DPN). The complex structure of the corneal sub-basal nerve plexus can be readily analysed through nerve segmentation with manual or automated quantification of parameters such as corneal nerve fibre length (CNFL), nerve fibre density (CNFD), and nerve branch density (CNBD). Large quantities of 2D corneal nerve images lend themselves to the application of artificial intelligence (AI)-based deep learning algorithms (DLA). Indeed, DLA have demonstrated performance comparable to manual but superior to automated quantification of corneal nerve morphology. Recently, our end-to-end classification with a 3 class AI model demonstrated high sensitivity and specificity in differentiating healthy volunteers from people with and without peripheral neuropathy. We believe there is significant scope and need to apply AI to help differentiate between peripheral neuropathies and also central neurodegenerative disorders. AI has significant potential to enhance the diagnostic and prognostic utility of CCM in the management of both peripheral and central neurodegenerative diseases. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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19 pages, 3240 KiB  
Review
Corneal Confocal Microscopy as a Quantitative Imaging Biomarker of Diabetic Peripheral Neuropathy: A Review
by Eleonora Cosmo, Giulia Midena, Luisa Frizziero, Marisa Bruno, Michela Cecere and Edoardo Midena
J. Clin. Med. 2022, 11(17), 5130; https://doi.org/10.3390/jcm11175130 - 31 Aug 2022
Cited by 7 | Viewed by 2024
Abstract
Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly [...] Read more.
Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly due to their high subjectivity, invasiveness, and non-repeatability. Corneal confocal microscopy (CCM) is an in vivo, non-invasive, and reproducible diagnostic technique for the study of all corneal layers including the sub-basal nerve plexus, which represents part of the peripheral nervous system. We reviewed the current literature on the use of CCM as an instrument in the assessment of diabetic patients, particularly focusing on its role in the study of sub-basal nerve plexus alterations as a marker of DPN. CCM has been demonstrated to be a valid in vivo tool to detect early sub-basal nerve plexus damage in adult and pediatric diabetic patients, correlating with the severity of DPN. Despite its great potential, CCM has still limited application in daily clinical practice, and more efforts still need to be made to allow the dissemination of this technique among doctors taking care of diabetic patients. Full article
(This article belongs to the Special Issue Corneal Confocal Microscopy and the Nervous System)
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