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Zou Z, Li S, Zhang H. Advances in keratoconus animal models: From genetics to biomechanics. Exp Eye Res 2025; 254:110330. [PMID: 40081753 DOI: 10.1016/j.exer.2025.110330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/23/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]
Abstract
Keratoconus is a disorder characterized by thinning and protrusion of the cornea into a cone shape, potentially leading to decreased vision and blindness. Understanding the pathogenesis of keratoconus and developing treatment strategies is crucial. Currently, animal models of keratoconus created through gene knockout and collagenase digestion have made significant progress in studying the pathogenesis of the disease. However, these models have limitations, such as unverified long-term effects. Future research should focus on optimizing the construction methods of animal models and enhancing long-term observation and evaluation to more accurately simulate human keratoconus. This paper reviews research progress on animal models of keratoconus, examining models constructed using methods such as gene editing, drug induction, cutting of corneal stroma, and mechanical stimulation.
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Affiliation(s)
- Zongzheng Zou
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Fundamental Research on Biomechanics in Clinical Application, Capital Medical University, Beijing, 100069, China
| | - Shanshan Li
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Fundamental Research on Biomechanics in Clinical Application, Capital Medical University, Beijing, 100069, China
| | - Haixia Zhang
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Fundamental Research on Biomechanics in Clinical Application, Capital Medical University, Beijing, 100069, China.
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Kannan R, Shetty R, Panigrahi T, Koh SK, Khamar P, Deshpande V, Nuijts RMMA, Gijs M, Nishtala K, Zhou L, Ghosh A. Untargeted Tear Proteomics in a Large South-Asian Cohort Reveals Inflammatory Signaling, ECM Remodeling, and Altered Metabolism in Keratoconus. Invest Ophthalmol Vis Sci 2025; 66:60. [PMID: 39992672 PMCID: PMC11878249 DOI: 10.1167/iovs.66.2.60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Purpose Keratoconus (KC), a progressive corneal degenerative disease, is characterized by focal thinning and weakening, and the molecular pathways driving such changes are still being discovered. The progression-related pathologic molecular factors have not been identified in genetic studies from KC, and stage-specific molecular changes remain unknown in prior protein studies. We address this challenge through untargeted mass spectrometry analysis in a large KC cohort. Methods The cohort comprised 40 healthy individuals and 107 eyes with varying KC grades from 69 individuals. Quantitative proteomics using iTRAQ labeling coupled with two-dimensional nanoLC-ESI-MS/MS (TripleTOF 5600) was employed followed by validation. Results Unbiased LC-MS/MS analysis identified 1104 proteins, with 279 quantified proteins. Thirty-two proteins exhibited significant dysregulation in tear fluids compared to the control, enriched in glycolytic pathways, extra-cellular matrix (ECM) organization, reactive oxygen detoxification, and inflammatory regulation. Cystatin-S, lacritin, glutathione synthetase, and superoxide dismutase were validated to have differential expression across each KC grade. Conclusions Our data unveiled novel tear fluid proteins involved in unique biological processes such as neutrophil degranulation, autophagy, metabolic alterations, protein phosphorylation, and more, apart from the ECM modulation and inflammatory pathways. Although the newly identified progressive KC biomarkers will help in disease characterization, identified molecular pathways may serve as novel therapeutic targets.
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Affiliation(s)
- Ramaraj Kannan
- GROW Research Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India
- University Eye Clinic Maastricht, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Rohit Shetty
- University Eye Clinic Maastricht, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bengaluru, Karnataka, India
| | - Trailokyanath Panigrahi
- GROW Research Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India
| | - Siew Kwan Koh
- Ocular Proteomics, Singapore Eye Research Institute, Singapore, Singapore
| | - Pooja Khamar
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bengaluru, Karnataka, India
| | - Vrushali Deshpande
- GROW Research Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India
| | - Rudy M. M. A. Nuijts
- University Eye Clinic Maastricht, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Marlies Gijs
- University Eye Clinic Maastricht, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Krishnatej Nishtala
- GROW Research Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India
| | - Lei Zhou
- School of Optometry, Department of Applied Biology and Chemical Technology, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
- Centre for Eye and Vision Research (CEVR), Hong Kong
| | - Arkasubhra Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India
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Singh RB, Koh S, Sharma N, Woreta FA, Hafezi F, Dua HS, Jhanji V. Keratoconus. Nat Rev Dis Primers 2024; 10:81. [PMID: 39448666 DOI: 10.1038/s41572-024-00565-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 10/26/2024]
Abstract
Keratoconus is a progressive eye disorder primarily affecting individuals in adolescence and early adulthood. The ectatic changes in the cornea cause thinning and cone-like steepening leading to irregular astigmatism and reduced vision. Keratoconus is a complex disorder with a multifaceted aetiology and pathogenesis, including genetic, environmental, biomechanical and cellular factors. Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression. On the cellular level, a complex interplay of hormonal changes, alterations in enzymatic activity that modify extracellular membrane stiffness, and changes in biochemical and biomechanical signalling pathways disrupt collagen cross-linking within the stroma, contributing to structural integrity loss and distortion of normal corneal anatomy. Clinically, keratoconus is diagnosed through clinical examination and corneal imaging. Advanced imaging platforms have improved the detection of keratoconus, facilitating early diagnosis and monitoring of disease progression. Treatment strategies for keratoconus are tailored to disease severity and progression. In early stages, vision correction with glasses or soft contact lenses may suffice. As the condition advances, rigid gas-permeable contact lenses or scleral lenses are prescribed. Corneal cross-linking has emerged as a pivotal treatment aimed at halting the progression of corneal ectasia. In patients with keratoconus with scarring or contact lens intolerance, surgical interventions are performed.
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Affiliation(s)
- Rohan Bir Singh
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology, Leiden University Medical Center, Leiden, Netherlands
| | - Shizuka Koh
- Department of Innovative Visual Science, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Namrata Sharma
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Fasika A Woreta
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Farhad Hafezi
- ELZA Institute, Zurich, Switzerland
- EMAGine AG, Zug, Switzerland
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA
| | - Harminder S Dua
- Department of Ophthalmology, University of Nottingham, Nottingham, UK
| | - Vishal Jhanji
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Hao XD, Gao H, Xu WH, Shan C, Liu Y, Zhou ZX, Wang K, Li PF. Systematically Displaying the Pathogenesis of Keratoconus via Multi-Level Related Gene Enrichment-Based Review. Front Med (Lausanne) 2022; 8:770138. [PMID: 35141241 PMCID: PMC8818795 DOI: 10.3389/fmed.2021.770138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/31/2021] [Indexed: 01/20/2023] Open
Abstract
Keratoconus (KC) is an etiologically heterogeneous corneal ectatic disorder. To systematically display the pathogenesis of keratoconus (KC), this study reviewed all the reported genes involved in KC, and performed an enrichment analysis of genes identified at the genome, transcription, and protein levels respectively. Combined analysis of multi-level results revealed their shared genes, gene ontology (GO), and pathway terms, to explore the possible pathogenesis of KC. After an initial search, 80 candidate genes, 2,933 transcriptional differential genes, and 947 differential proteins were collected. The candidate genes were significantly enriched in extracellular matrix (ECM) related terms, Wnt signaling pathway and cytokine activities. The enriched GO/pathway terms of transcription and protein levels highlight the importance of ECM, cell adhesion, and inflammatory once again. Combined analysis of multi-levels identified 13 genes, 43 GOs, and 12 pathways. The pathogenic relationships among these overlapping factors maybe as follows. The gene mutations/variants caused insufficient protein dosage or abnormal function, together with environmental stimulation, leading to the related functions and pathways changes in the corneal cells. These included response to the glucocorticoid and reactive oxygen species; regulation of various signaling (P13K-AKT, MAPK and NF-kappaB), apoptosis and aging; upregulation of cytokines and collagen-related enzymes; and downregulation of collagen and other ECM-related proteins. These undoubtedly lead to a reduction of extracellular components and induction of cell apoptosis, resulting in the loosening and thinning of corneal tissue structure. This study, in addition to providing information about the genes involved, also provides an integrated insight into the gene-based etiology and pathogenesis of KC.
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Affiliation(s)
- Xiao-Dan Hao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Hua Gao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
- Shandong Eye Hospital, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wen-Hua Xu
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Chan Shan
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Zhi-Xia Zhou
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Kun Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Pei-Feng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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Santodomingo-Rubido J, Carracedo G, Suzaki A, Villa-Collar C, Vincent SJ, Wolffsohn JS. Keratoconus: An updated review. Cont Lens Anterior Eye 2022; 45:101559. [PMID: 34991971 DOI: 10.1016/j.clae.2021.101559] [Citation(s) in RCA: 304] [Impact Index Per Article: 101.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/23/2021] [Accepted: 12/12/2021] [Indexed: 02/06/2023]
Abstract
Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity. Traditionally, the condition has been described as a noninflammatory disease; however, more recently it has been associated with ocular inflammation. Keratoconus normally develops in the second and third decades of life and progresses until the fourth decade. The condition affects all ethnicities and both sexes. The prevalence and incidence rates of keratoconus have been estimated to be between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 cases per 100,000 persons/year, respectively, with highest rates typically occurring in 20- to 30-year-olds and Middle Eastern and Asian ethnicities. Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings. A family history of keratoconus, eye rubbing, eczema, asthma, and allergy are risk factors for developing keratoconus. Detecting keratoconus in its earliest stages remains a challenge. Corneal topography is the primary diagnostic tool for keratoconus detection. In incipient cases, however, the use of a single parameter to diagnose keratoconus is insufficient, and in addition to corneal topography, corneal pachymetry and higher order aberration data are now commonly used. Keratoconus severity and progression may be classified based on morphological features and disease evolution, ocular signs, and index-based systems. Keratoconus treatment varies depending on disease severity and progression. Mild cases are typically treated with spectacles, moderate cases with contact lenses, while severe cases that cannot be managed with scleral contact lenses may require corneal surgery. Mild to moderate cases of progressive keratoconus may also be treated surgically, most commonly with corneal cross-linking. This article provides an updated review on the definition, epidemiology, histopathology, aetiology and pathogenesis, clinical features, detection, classification, and management and treatment strategies for keratoconus.
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Affiliation(s)
| | - Gonzalo Carracedo
- Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Asaki Suzaki
- Clinical Research and Development Center, Menicon Co., Ltd., Nagoya, Japan
| | - Cesar Villa-Collar
- Department of Pharmacy, Biotechnology, Nutrition, Optics and Optometry, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
| | - Stephen J Vincent
- Contact Lens and Visual Optics Laboratory, School of Optometry and Vision Science, Centre for Vision and Eye Research, Queensland University of Technology, Brisbane, Australia
| | - James S Wolffsohn
- School of optometry, Health and Life Sciences, Aston University, Birmingham B4 7ET, United Kingdom
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Augustin VA, Son HS, Baur I, Zhao L, Auffarth GU, Khoramnia R. Detecting subclinical keratoconus by biomechanical analysis in tomographically regular keratoconus fellow eyes. Eur J Ophthalmol 2021; 32:11206721211063740. [PMID: 34841930 DOI: 10.1177/11206721211063740] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE To analyze the tomographically non-affected second eyes of keratoconus patients using the Corvis ST to detect any biomechanical abnormalities or subclinical keratoconus. METHODS In this retrospective, single-center, consecutive case series 244 eyes of 122 keratoconus patients were analyzed between November 2020 and February 2021. Fourteen fellow eyes fulfilled the inclusion criteria and showed no clinical or tomographic signs of keratoconus. Main outcome measures included best-corrected visual acuity, tomographic and biomechanical analyses using Scheimpflug imaging: Pentacam and Corvis ST (Oculus, Wetzlar, Germany). Tomographic analyses included anterior and posterior simulated keratometry, K-Max, central corneal thickness, thinnest corneal thickness, Belin/Ambrosio Ectasia Display, and the ABCD grading system. For biomechanical analyses, the corneal biomechanical index (CBI) and tomographic biomechanical index were used. RESULTS The mean best-corrected visual acuity was 0.01 ± 0.10 logMAR. Mean K-Max was 43.79 ± 1.12 D, mean central corneal thickness 529 ± 25 µm, mean thinnest corneal thickness 524 ± 23 µm, and mean Belin/Ambrosio Ectasia Display 1.0 ± 0.32. The mean CBI was 0.30 ± 0.21. Regular CBI values were found in six of 14 patients. The mean tomographic biomechanical index was 0.47 ± 0.22 with regular values observed in only two of 14 patients. No signs of tomographic or biomechanical abnormalities were shown in only one of 14 keratoconus fellow eyes, with regular ABCD, Belin/Ambrosio Ectasia Display, CBI and tomographic biomechanical index values. CONCLUSIONS Tomographically normal fellow eyes of keratoconus patients are rare. In these cases, a biomechanical analysis of the cornea may help detect a subclinical keratoconus. The tomographic biomechanical index was the most sensitive index to verify a mild ectasia.
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Affiliation(s)
- Victor A Augustin
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
| | - Hyeck-Soo Son
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
| | - Isabella Baur
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
| | - Ling Zhao
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
| | - Gerd U Auffarth
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
| | - Ramin Khoramnia
- David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), 27178Department of Ophthalmology, 9144University of Heidelberg, Heidelberg, Germany
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Sorbara L, Lopez JCL, Gorbet M, Bizheva K, Lamarca JM, Pastor JC, Maldonado López MJ, Hileeto D. Impact of contact lens wear on epithelial alterations in keratoconus. JOURNAL OF OPTOMETRY 2021; 14:37-43. [PMID: 32376120 PMCID: PMC7752984 DOI: 10.1016/j.optom.2020.02.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/29/2019] [Accepted: 02/29/2020] [Indexed: 06/11/2023]
Abstract
PURPOSE The purpose of this study was to characterize the central epithelial thickness (CET) of penetrating keratoplasty corneal specimens obtained from patients with keratoconus (KC) and correlate the histological patterns with their clinical history. METHODS Ex vivo histological imaging was performed to measure CET and total corneal thickness (TCT) in 56 patients with KC. Microscopic slides from penetrating keratoplasty corneal specimens, stained with hematoxylin and eosin were evaluated using bright field microscopy. CET and TCT were measured, and morphological features were studied. Clinical history regarding duration of KC prior to surgery and length of and tolerance to contact lens wear were compared and analyzed. RESULTS The microscopic slides of all patients available for follow up (n=48) were analyzed and CET and TCT were measured. The histological evaluation revealed 3 distinctive epithelial patterns. Pattern 1 with central hypertrophic and hydropic changes (n=19) measured 70.89±25.88μm in CET and 308.63±100.74μm in TCT; Pattern 2 (n=14) had not changed, similar to normal epithelium CET and TCT measuring 36.5±7.02μm and 260.14±87.93μm respectively. Pattern 3 (n=15) demonstrated thinner central epithelium characterized by atrophy and focal hydropic changes measuring 19.93±4.60μm and 268.00±79.39μm in CET and TCT respectively (all p<0.0001). The presence of Pattern 2 characterized by similar to normal CET was correlated with the duration of the condition (R=0.600, p=0.030). There was a significant difference in the length of CL wear comparing those with patterns 1 and 2 versus 3 (least no. of CL years) (p=0.05 and p=0.33 respectivelly). CONCLUSIONS Patients with advanced disease have various central corneal epithelial changes detected with histology. Although each central epithelial pattern type was distinctive comparing the 3 patterns, there was no correlation with years of CL wear but only with the duration of the condition.
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Affiliation(s)
- Luigina Sorbara
- School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada.
| | | | - Maud Gorbet
- Department of System Design Engineering, University of Waterloo, Waterloo, Ontario, Canada
| | - Kostadinka Bizheva
- School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada; Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada
| | | | | | - Miguel José Maldonado López
- School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada; Department of System Design Engineering, University of Waterloo, Waterloo, Ontario, Canada; Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada; IOBA, University of Valladolid, Spain; Barraquer Ophthalmology Institute, Barcelona, Spain; Barking Havering and Redbridge University Hospitals, Romford, UK
| | - Denise Hileeto
- School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada
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Shetty R, D'Souza S, Khamar P, Ghosh A, Nuijts RMMA, Sethu S. Biochemical Markers and Alterations in Keratoconus. Asia Pac J Ophthalmol (Phila) 2020; 9:533-540. [PMID: 33323707 DOI: 10.1097/apo.0000000000000332] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Keratoconus (KC) is a corneal ectatic condition characterized by focal structural changes, resulting in progressive thinning, biomechanical weakening, and steeping of the cornea that can lead to worsening visual acuity due to irregular astigmatism and corneal scarring in more advanced cases. It is a relatively common ectatic disease of the cornea predominantly affecting the younger population. Despite its worldwide prevalence, its incidence is rather varied with a higher incidence among the Middle Eastern and South Asian population. Dysregulated corneal extracellular matrix remodeling underlies KC pathogenesis. However, a lack of absolute clarity regarding the factors that initiate and drive progression poses a significant challenge in its prevention and management. KC is a complex multifactorial disease as it is associated with a wide variety of etiological factors such as environmental stimuli/insults, oxidative stress, genetic predisposition, comorbidities, and eye rubbing. A series of studies using corneal tissues (epithelium, stroma), cultured corneal fibroblasts/keratocytes, tear fluid, aqueous humor, and blood from KC subjects has reported significant alterations in various biochemical factors such as extracellular matrix components, cellular homeostasis regulators, inflammatory factors, hormones, metabolic products, and chemical elements. It has become apparent that alterations in the biochemical mediators (related to various etiologies) could contribute to KC pathogenesis by altering the dynamics of extracellular matrix remodeling events such as collagen deposition, degradation, and cross-linking in the cornea. Determining key disease contributing biochemical mediators would aid in disease monitoring, prediction or abatement of disease progression, and development of targeted therapeutics to improve disease prognosis.
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Affiliation(s)
- Rohit Shetty
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Sharon D'Souza
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Pooja Khamar
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Arkasubhra Ghosh
- GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India
| | - Rudy M M A Nuijts
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands
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Histological Patterns of Epithelial Alterations in Keratoconus. J Ophthalmol 2020; 2020:1468258. [PMID: 32802486 PMCID: PMC7414345 DOI: 10.1155/2020/1468258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 06/23/2020] [Accepted: 07/13/2020] [Indexed: 11/18/2022] Open
Abstract
Purpose The purpose of this study was to confirm the presence of specific patterns of epithelial response in corneal buttons from keratoconus patients. Methods This was a retrospective and descriptive study. 90 penetrating keratoplasty specimens obtained from patients diagnosed with keratoconus were evaluated using bright-field microscopy. Morphologically identifiable characteristics including epithelial cell density and epithelial thickness were analyzed on hematoxylin and eosin- (H&E-) and periodic acid of Schiff- (PAS-) stained slides. Results Three distinctive patterns of epithelial alteration of the central cornea were established. Pattern 3, in which the central epithelium was as thick as peripheral epithelium, was the commonest (44.4%), followed by the pattern 2, defined as central epithelium thinner than periphery epithelium (38.9%), and the uncommonest pattern was number 1, with central epithelium thicker than the periphery (16.7%). Conclusions Three distinctive histologic patterns that could potentially have a diagnostic and prognostic value in keratoconus patients were found.
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Ferrari G, Rama P. The keratoconus enigma: A review with emphasis on pathogenesis. Ocul Surf 2020; 18:363-373. [PMID: 32234342 DOI: 10.1016/j.jtos.2020.03.006] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 02/11/2020] [Accepted: 03/19/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE To review the literature on the etiopathogenesis of keratoconus (KC). METHODS A literature search was conducted using PUBMED and Google Scholar for keratoconus. The authors analyzed epidemiology studies, reviews, and case reports. RESULTS Atopy and ocular surface inflammation are a common features of KC and should lead to a reconsideration of the traditional definition of KC as a "non inflammatory" condition. Co-morbidities suggest that KC may be the ocular manifestation of a systemic disease. Finally, KC shows higher prevalence in certain ethnicities, which calls into question the status of KC as a rare disease, at least in these communities. CONCLUSION We believe that future studies should test whether selected, high prevalence populations exhibit specific genetic background and/or ethno-specific environmental risk factors.
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Affiliation(s)
- Giulio Ferrari
- San Raffaele Hospital, Cornea and Ocular Surface Unit, Eye Repair Lab, Italy.
| | - Paolo Rama
- San Raffaele Hospital, Cornea and Ocular Surface Unit, Eye Repair Lab, Italy
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Pradhan KR, Reinstein DZ, Vida RS, Archer TJ, Dhungel S, Dhungana P, Carp GI. Femtosecond Laser-Assisted Small Incision Sutureless Intrastromal Lamellar Keratoplasty (SILK) for Corneal Transplantation in Keratoconus. J Refract Surg 2020; 35:663-671. [PMID: 31610008 DOI: 10.3928/1081597x-20190826-01] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/26/2019] [Indexed: 11/20/2022]
Abstract
PURPOSE To describe a femtosecond laser-assisted small incision sutureless intrastromal lamellar keratoplasty in an eye with severe keratoconus and report on the outcome with a 1-year follow-up. METHODS A 20-year-old man with a history of keratoconus presented for evaluation at the Tilganga Institute of Ophthalmology, Kathmandu, Nepal. The patient had previously undergone a deep anterior lamellar keratoplasty in the left eye. Examination of the right eye revealed an uncorrected distance visual acuity (UDVA) of counting fingers with a manifest refraction of -5.00 -3.50 × 170, giving a corrected distance visual acuity (CDVA) of 20/80. Thinnest pachymetry was 425 µm and progression of both anterior and posterior corneal elevation tomography and maximum keratometry was noted compared to examination 2 years prior. The VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany) was used to prepare the donor and recipient cornea. The donor graft was inserted into the recipient through the 3-mm small incision. No sutures were applied. RESULTS At 2 weeks postoperatively, UDVA was 20/50 with a manifest refraction of -1.00 -5.00 × 145 (20/32). One year postoperatively, UDVA was 20/80 with a manifest refraction of -2.50 -3.50 × 125 (20/40-2), with the maximum keratometry decreasing from 64.08 to 56.74 diopters. CONCLUSIONS This femtosecond laser-assisted sutureless intrastromal corneal transplantation technique may provide an option to improve the quality of vision for some patients with keratoconus, affording a simpler postoperative follow-up course compared to traditional anterior lamellar or full-thickness corneal transplantation. [J Refract Surg. 2019;35(10):663-671.].
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Wadhwa H, Ismail S, McGhee JJ, Van der Werf B, Sherwin T. Sphere-forming corneal cells repopulate dystrophic keratoconic stroma: Implications for potential therapy. World J Stem Cells 2020; 12:35-54. [PMID: 32110274 PMCID: PMC7031758 DOI: 10.4252/wjsc.v12.i1.35] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/11/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Keratoconus is a degenerative corneal disease characterised by aberrant cell behaviour and loss of matrix that can result in vision loss. Cells extracted from peripheral corneas can form stem cell-enriched spheres, which have shown the potential to repopulate the normal peripheral corneal stroma in vitro upon sphere implantation but have not been previously studied in keratoconic tissue. AIM To investigate the therapeutic potential of stem cell-enriched spheres formed from extracted peripheral human corneal cells when introduced to keratoconic tissue. METHODS Stem cell-enriched spheres were formed from extracts of normal cadaveric human peripheral corneal cells. These spheres were implanted into incisions created in full thickness and onto the surface of 10 µm thin sections of keratoconic and normal stromal tissues in vitro. Tissue sections were used to maximise use of limited keratoconic tissue available for research. Living cells were stained with Calcein-AM and visualised with stereo and fluorescence microscopy to assess survival and behaviours between the time of implantation day 0 and 14 d (D14) from implantation. Sphere cells in implanted tissues were characterised for stem cell and differentiation markers using immunohistochemistry and droplet digital PCR to assess the potential implications of these characteristics in the use of spheres in keratoconus treatment. RESULTS Spheres were successfully implanted into full-thickness central corneal tissue and onto the surface of 10 µm thin en face tissue sections. No observable differences were seen in sphere migration, proliferation or differentiation in keratoconic tissue compared to normal between day 0 and D14. Spheres stained positively with Calcein-AM up to D14. Cell migration increased from day 0 to D14, occurring radially in three dimensions from the sphere and in alignment with tissue edges. Cell proliferation marker, EdU, was detected at day 10. Implanted spheres stained positively for putative stem cell markers ∆Np63α and ABCB5, while ABCG2, ABCB5, ∆Np63 and p63α were detectable by droplet digital PCR up to D14. Double immunolabelling revealed absence of ABCB5 staining in migrated cells but positive staining of alpha smooth muscle actin (myofibroblast marker) in some migrated cells. Droplet digital PCR showed similar expression patterns of differentiation markers but a reduction in stem cell markers between normal and keratoconic tissue with an increase in stromal cell markers and a reduction in epithelial cell markers, indicating an appropriate response to repopulating diseased tissue. CONCLUSION Cells from implanted stem cell-enriched spheres can repopulate a keratoconic corneal stromal surface in a directed manner and exhibit migratory stromal cell phenotypes.
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Affiliation(s)
- Himanshu Wadhwa
- Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Salim Ismail
- Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Jennifer J McGhee
- Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Bert Van der Werf
- Department of Epidemiology and Biostatistics, School of Population Health, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Trevor Sherwin
- Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand.
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Peng H, Hulleman JD. Prospective Application of Activity-Based Proteomic Profiling in Vision Research-Potential Unique Insights into Ocular Protease Biology and Pathology. Int J Mol Sci 2019; 20:ijms20163855. [PMID: 31398819 PMCID: PMC6720450 DOI: 10.3390/ijms20163855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
Activity-based proteomic profiling (ABPP) is a powerful tool to specifically target and measure the activity of a family of enzymes with the same function and reactivity, which provides a significant advantage over conventional proteomic strategies that simply provide abundance information. A number of inherited and age-related eye diseases are caused by polymorphisms/mutations or abnormal expression of proteases including serine proteases, cysteine proteases, and matrix metalloproteinases, amongst others. However, neither conventional genomic, transcriptomic, nor traditional proteomic profiling directly interrogate protease activities. Thus, leveraging ABPP to probe the activity of these enzyme classes as they relate to normal function and pathophysiology of the eye represents a unique potential opportunity for disease interrogation and possibly intervention.
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Affiliation(s)
- Hui Peng
- Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9057, USA
| | - John D Hulleman
- Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9057, USA.
- Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
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Loukovitis E, Sfakianakis K, Syrmakesi P, Tsotridou E, Orfanidou M, Bakaloudi DR, Stoila M, Kozei A, Koronis S, Zachariadis Z, Tranos P, Kozeis N, Balidis M, Gatzioufas Z, Fiska A, Anogeianakis G. Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities. Ophthalmol Ther 2018; 7:263-292. [PMID: 30191404 PMCID: PMC6258591 DOI: 10.1007/s40123-018-0144-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Keratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC. METHODS The PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of "keratoconus," "risk factor(s)," "genetics," "genes," "genetic association(s)," and "cornea" were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches. RESULTS An association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed. CONCLUSION Twenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.
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Affiliation(s)
| | - Konstantinos Sfakianakis
- Division of Surgical Anatomy, Laboratory of Anatomy, Medical School, Democritus University of Thrace, University Campus, Alexandroupolis, Greece
| | - Panagiota Syrmakesi
- AHEPA University Hospital, Thessaloníki, Greece
- Ophthalmica Eye Institute, Thessaloníki, Greece
| | - Eleni Tsotridou
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Myrsini Orfanidou
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Dimitra Rafailia Bakaloudi
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Maria Stoila
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Athina Kozei
- Ophthalmica Eye Institute, Thessaloníki, Greece
- School of Pharmacology, University of Nicosia, Makedonitissis, Nicosia, Cyprus
| | | | | | | | | | | | - Zisis Gatzioufas
- Department of Ophthalmology, Cornea, Cataract and Refractive Surgery, University Hospital Basel, Basel, Switzerland
| | - Aliki Fiska
- Laboratory of Anatomy, Medical School, Democritus University of Thrace, University Campus, Alexandroupolis, Greece
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You J, Corley SM, Wen L, Hodge C, Höllhumer R, Madigan MC, Wilkins MR, Sutton G. RNA-Seq analysis and comparison of corneal epithelium in keratoconus and myopia patients. Sci Rep 2018; 8:389. [PMID: 29321650 PMCID: PMC5762683 DOI: 10.1038/s41598-017-18480-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/12/2017] [Indexed: 12/12/2022] Open
Abstract
Keratoconus is a common degenerative corneal disease that can lead to significant visual morbidity, and both genetic and environmental factors have been implicated in its pathogenesis. We compared the transcriptome of keratoconus and control epithelium using RNA-Seq. Epithelial tissues were obtained prior to surgery from keratoconus and myopia control patients, undergoing collagen cross-linking and photorefractive keratectomy, respectively. We identified major differences in keratoconus linked to cell-cell communication, cell signalling and cellular metabolism. The genes associated with the Hedgehog, Wnt and Notch1 signaling pathways were down-regulated in keratoconus. We also identified plasmolipin and Notch1 as being significantly reduced in keratoconus for both gene and protein expression (p < 0.05). Plasmolipin is a novel protein identified in human corneal epithelium, and has been demonstrated to have a key role in epithelial cell differentiation in other tissues. This study shows altered gene and protein expression of these three proteins in keratoconus, and further studies are clearly warranted to confirm the functional role of these proteins in the pathogenesis of keratoconus.
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Affiliation(s)
- Jingjing You
- Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia.
- School of Optometry and Vision Science, University of New South Wales, New South Wales, Australia.
| | - Susan M Corley
- School of Biotechnology and Biomolecular Science, NSW System Biology Initiative, University of New South Wales, New South Wales, Australia
| | - Li Wen
- Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Chris Hodge
- Lions NSW Eye Bank, Sydney, Australia
- Vision Eye Institute, Chatswood, New South Wales, Australia
| | - Roland Höllhumer
- University of the Witwatersrand, Johannesburg, South Africa
- The Cornea Foundation, Johannesburg, South Africa
| | - Michele C Madigan
- Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia
- School of Optometry and Vision Science, University of New South Wales, New South Wales, Australia
| | - Marc R Wilkins
- School of Biotechnology and Biomolecular Science, NSW System Biology Initiative, University of New South Wales, New South Wales, Australia
| | - Gerard Sutton
- Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia
- Lions NSW Eye Bank, Sydney, Australia
- Vision Eye Institute, Chatswood, New South Wales, Australia
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A Study for Parametric Morphogeometric Operators to Assist the Detection of Keratoconus. Symmetry (Basel) 2017. [DOI: 10.3390/sym9120302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Naderan M, Jahanrad A, Balali S. Histopathologic findings of keratoconus corneas underwent penetrating keratoplasty according to topographic measurements and keratoconus severity. Int J Ophthalmol 2017; 10:1640-1646. [PMID: 29181305 DOI: 10.18240/ijo.2017.11.02] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 07/13/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To investigate the histopathologic and morphological changes of the corneas with keratoconus (KC) undergoing penetrating keratoplasty (PKP) according to topographic findings and severity of KC. METHODS The corneal tissue of 35 samples with KC was retrospectively evaluated with conventional light microscopy. Topographic and pachymetric parameters of keratoconus corneas by means of Pentacam such as mean keratometry (K) and central corneal thickness (CCT) were recorded. Severity of KC was graded according to Amsler-Krumeich classification. RESULTS Epithelial thinning and breaks in Bowman's layer are the most common findings in keratoconus corneas (94.3% and 82.9% corneas, respectively). The results revealed statistically significant higher mean K value and lower CCT in the keratoconus corneas that were affected by epithelial thinning, breaks in the Bowman's layer, folds in the Descemet's membrane, epithelial scars, breaks in Descemet's membrane, and stromal scars than those corneas without these findings (P<0.05). Moreover, those corneas with epithelial thinning, breaks in the Bowman's layer, folds in Descemet's membrane, epithelial scars, and stromal scars had significantly more severe disease than those corneas without these findings (P<0.05). The presence of the stromal and epithelial scars were associated with the higher KC severity, in which, respectively, 87.5% and 80.0% of the corneas with stromal and epithelial scars had stage 4 of the KC severity. CONCLUSION It seems that there are some specific patterns in histologic changes of the keratoconus corneas. The presence of pathologic findings was correlated with thinner and steeper corneas. Epithelial or stromal scars were associated with the highest disease severity. The description of histopathologic findings of KC may help in elucidating the pathogenesis of the disease and help pathologist in differentiating KC from other corneal diseases.
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Affiliation(s)
- Mohammad Naderan
- School of Medicine, Tehran University of Medical Sciences, Tehran 1417653761, Iran
| | - Ali Jahanrad
- School of Medicine, AJA University of Medical Sciences, Tehran 1411718541, Iran
| | - Siavash Balali
- School of Medicine, AJA University of Medical Sciences, Tehran 1411718541, Iran
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Mas Tur V, MacGregor C, Jayaswal R, O'Brart D, Maycock N. A review of keratoconus: Diagnosis, pathophysiology, and genetics. Surv Ophthalmol 2017; 62:770-783. [PMID: 28688894 DOI: 10.1016/j.survophthal.2017.06.009] [Citation(s) in RCA: 287] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 06/26/2017] [Accepted: 06/29/2017] [Indexed: 12/11/2022]
Abstract
We discuss new approaches to the early detection of keratoconus and recent investigations regarding the nature of its pathophysiology. We review the current evidence for its complex genetics and evaluate the presently identified genes/loci and potential candidate gene/loci. In addition, we highlight current research methodologies that may be used to further elucidate the pathogenesis of keratoconus.
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Affiliation(s)
- Veronica Mas Tur
- Eye Department, Queen Alexandra Hospital, Portsmouth, Hants, United Kingdom
| | - Cheryl MacGregor
- Eye Department, Queen Alexandra Hospital, Portsmouth, Hants, United Kingdom
| | - Rakesh Jayaswal
- Eye Department, Queen Alexandra Hospital, Portsmouth, Hants, United Kingdom
| | - David O'Brart
- Department of Ophthalmology, St Thomas' Hospital, London, United Kingdom
| | - Nicholas Maycock
- Department of Ophthalmology, St Thomas' Hospital, London, United Kingdom.
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Molecular and Histopathological Changes Associated with Keratoconus. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7803029. [PMID: 28251158 PMCID: PMC5303843 DOI: 10.1155/2017/7803029] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/16/2016] [Accepted: 01/04/2017] [Indexed: 12/13/2022]
Abstract
Keratoconus (KC) is a corneal thinning disorder that leads to loss of visual acuity through ectasia, opacity, and irregular astigmatism. It is one of the leading indicators for corneal transplantation in the Western countries. KC usually starts at puberty and progresses until the third or fourth decade; however its progression differs among patients. In the keratoconic cornea, all layers except the endothelium have been shown to have histopathological structural changes. Despite numerous studies in the last several decades, the mechanisms of KC development and progression remain unclear. Both genetic and environmental factors may contribute to the pathogenesis of KC. Many previous articles have reviewed the genetic aspects of KC, but in this review we summarize the histopathological features of different layers of cornea and discuss the differentially expressed proteins in the KC-affected cornea. This summary will help emphasize the major molecular defects in KC and identify additional research areas related to KC, potentially opening up possibilities for novel methods of KC prevention and therapeutic intervention.
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Xu Z, Jiang J, Yang C, Huang S, Peng M, Li W, Cui L, Wang J, Lu F, Shen M. Value of corneal epithelial and Bowman's layer vertical thickness profiles generated by UHR-OCT for sub-clinical keratoconus diagnosis. Sci Rep 2016; 6:31550. [PMID: 27511620 PMCID: PMC4980663 DOI: 10.1038/srep31550] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 07/19/2016] [Indexed: 11/22/2022] Open
Abstract
Ultra-high resolution optical coherence tomography (UHR-OCT) can image the corneal epithelium and Bowman’s layer and measurement the thicknesses. The purpose of this study was to validate the diagnostic power of vertical thickness profiles of the corneal epithelium and Bowman’s layer imaged by UHR-OCT in the diagnosis of sub-clinical keratoconus (KC). Each eye of 37 KC patients, asymptomatic fellow eyes of 32 KC patients, and each eye of 81 normal subjects were enrolled. Vertical thickness profiles of the corneal epithelium and Bowman’s layer were measured by UHR-OCT. Diagnostic indices were calculated from vertical thickness profiles of each layer and output values of discriminant functions based on individual indices. Receiver operating characteristic curves were determined, and the accuracy of the diagnostic indices were assessed as the area under the curves (AUC). Among all of the individual indices, the maximum ectasia index for epithelium had the highest ability to discriminate sub-clinical KC from normal corneas (AUC = 0.939). The discriminant function containing maximum ectasia indices of epithelium and Bowman’s layer further increased the AUC value (AUC = 0.970) for sub-clinical KC diagnosis. UHR-OCT-derived thickness indices from the entire vertical thickness profiles of the corneal epithelium and Bowman’s layer can provide valuable diagnostic references to detect sub-clinical KC.
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Affiliation(s)
- Zhe Xu
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jun Jiang
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chun Yang
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shenghai Huang
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mei Peng
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weibo Li
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lele Cui
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianhua Wang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
| | - Fan Lu
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Meixiao Shen
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Transepithelial Versus Epithelium-Off Corneal Collagen Cross-Linking for Progressive Keratoconus: A Prospective Randomized Controlled Trial. Cornea 2016; 34 Suppl 10:S53-6. [PMID: 26266436 DOI: 10.1097/ico.0000000000000547] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE To compare the safety and efficacy of transepithelial with epithelium-off corneal cross-linking for progressive keratoconus. METHODS In a prospective clinical trial, 70 patients with progressive keratoconus were randomized to undergo corneal cross-linking with intact epithelium (n = 34) or after deepithelialization (n = 36). The main outcome measure was a change in the maximum K reading (K(max)). RESULTS With 3-year follow-up, K(max) decreased in the epithelium-off group with a mean of 2.4 D and no patient showed evidence of progression. In the transepithelial group, K(max) increased by a mean of 1.1 D, and 20 patients (55%) showed progression of keratoconus. CONCLUSIONS In this study, epithelium-off was significantly more effective than transepithelial corneal cross-linking in halting the progression of keratoconus (P < 0.0001).
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Galvis V, Sherwin T, Tello A, Merayo J, Barrera R, Acera A. Keratoconus: an inflammatory disorder? Eye (Lond) 2015; 29:843-59. [PMID: 25931166 PMCID: PMC4506344 DOI: 10.1038/eye.2015.63] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 03/08/2015] [Indexed: 02/06/2023] Open
Abstract
Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.
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Affiliation(s)
- V Galvis
- Centro Oftalmologico Virgilio Galvis, Floridablanca, Colombia
- Faculty of Health Sciences, Universidad Autonoma de Bucaramanga, Floridablanca, Colombia
| | - T Sherwin
- Faculty of Medical and Health Sciences, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
| | - A Tello
- Centro Oftalmologico Virgilio Galvis, Floridablanca, Colombia
- Faculty of Health Sciences, Universidad Autonoma de Bucaramanga, Floridablanca, Colombia
| | - J Merayo
- Instituto Oftalmologico Fernandez-Vega, Oviedo, Spain
| | - R Barrera
- Centro Oftalmologico Virgilio Galvis, Floridablanca, Colombia
| | - A Acera
- Bioftalmik Applied Research, Derio, Spain
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Abstract
Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. It is the single most common reason for keratoplasty in the developed world. The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. Various strategies have been employed to address the gap in our understanding of this complex disease, with the expectation that over time more sophisticated therapies will be developed. In this review we summarise our current knowledge of the aetiology and risk factors associated with KC.
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Hasby EA, Saad HA. Immunohistochemical expression of Fas ligand (FasL) and neprilysin (neutral endopeptidase/CD10) in keratoconus. Int Ophthalmol 2013; 33:125-131. [PMID: 23065018 DOI: 10.1007/s10792-012-9651-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Accepted: 10/03/2012] [Indexed: 02/05/2023]
Abstract
Recent evidence demonstrated a correlation between apoptosis and neprilysin expression. The aim of this study was to investigate the immunohistochemical expression of Fas ligand (FasL) and neprilysin in keratoconic corneas in comparison to normal cadaver corneas to evaluate if such molecules play a role in the pathogenesis of keratoconus. We studied the expression of FasL and neprilysin in corneal specimens removed during penetrating keratoplasty in 15 cases with keratoconus and compared them with 5 normal cadaver corneas. In keratoconus, FasL was expressed in epithelium, endothelium and sub-Bowman's stroma only, while neprilysin was expressed in epithelium, endothelium and all stromal layers. All normal corneas showed weak expression of both markers in basal epithelial layer only. In keratoconus, corneal epithelium with higher expression of FasL may evoke apoptosis in keratocytes, while neprilysin could prevent possible rescue of keratocytes from apoptosis.
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Affiliation(s)
- Eiman Adel Hasby
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
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Patel D, McGhee C. Understanding keratoconus: what have we learned from the New Zealand perspective? Clin Exp Optom 2012; 96:183-7. [PMID: 23278718 DOI: 10.1111/cxo.12006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Revised: 08/24/2012] [Accepted: 08/27/2012] [Indexed: 11/27/2022] Open
Abstract
Although first described more than 150 years ago, keratoconus is still an enigmatic disease that remains an area of wide-ranging, dynamic, international research. This review considers data from New Zealand/Aotearoa, where keratoconus is both relatively common and extensively studied. New Zealand researchers have made several significant contributions to the international literature in this field, including identifying a higher prevalence of keratoconus in New Zealand per se and within Maori and Polynesian populations compared to many international studies. As reported in other studies, a higher proportion of asthma, allergy and eczema as potential risk co-factors are present in New Zealand subjects with keratoconus compared with estimates from the general population. The rates of family history of keratoconus are typically higher than those reported internationally, with higher rates in Asian, Pacific and Maori ethnicities. Interestingly, such a positive family history has been associated with less severe keratoconus on computerised topographic analysis. Investigations of corneal microstructure have revealed dramatic alterations in the keratoconic cornea, with reduced density and abnormal morphology of the corneal sub-basal nerve plexus and decreased keratocytic density. Laboratory studies of keratoconic corneal buttons have also furthered our understanding of the pathophysiology of this disease, demonstrating elevated levels of cathepsin enzymes and localised disruptions in Bowman's layer with incursion of cellular processes from anterior keratocytes. Over the past two decades keratoconus has consistently remained the leading indication for corneal transplantation in New Zealand, accounting for over 40 per cent of cases. Indeed, New Zealand appears to have the highest reported proportion of transplantation surgery for keratoconus worldwide. Current and future studies of keratoconus in New Zealand highlight an emphasis on elucidating the genetics of, and investigating novel therapeutic interventions for, this relatively common corneal disease.
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Affiliation(s)
- Dipika Patel
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
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Yadav R, Kottaiyan R, Ahmad K, Yoon G. Epithelium and Bowman's layer thickness and light scatter in keratoconic cornea evaluated using ultrahigh resolution optical coherence tomography. JOURNAL OF BIOMEDICAL OPTICS 2012; 17:116010. [PMID: 23117805 PMCID: PMC3484266 DOI: 10.1117/1.jbo.17.11.116010] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 10/09/2012] [Accepted: 10/10/2012] [Indexed: 05/20/2023]
Abstract
A custom-developed ultrahigh resolution optical coherence tomography with an axial resolution of 1.1 μm in corneal tissue was used to characterize thickness and light scatter of the epithelium and Bowman's layer in keratoconic (KC) cornea noninvasively. A 4-mm wide vertical corneal section around the apex in nine KC and eight normal eyes was imaged in vivo. The epithelium and Bowman's layer were visualized and their thickness profiles were quantified. Scatter was quantified based on the sensitivity normalized mean signal intensity distribution. Average mean thickness of the epithelium and Bowman's layer in KC eyes was significantly smaller (p<0.05) than the normal eyes. The epithelium thickness variation across a central 3-mm cornea was significantly larger in KC eyes than in normal eyes. The scatter in KC eyes was significantly increased only for Bowman's layer. The changes observed in this study could improve our understanding of the underlying disease mechanism of KC and can provide new indications for early disease diagnosis.
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Affiliation(s)
- Rahul Yadav
- University of Rochester, The Institute of Optics, 275 Hutchinson Road, Rochester, New York 14627
| | - Ranjini Kottaiyan
- University of Rochester, Flaum Eye Institute, 210 Crittenden Boulevard, Rochester, New York 14642
| | - Kamran Ahmad
- University of Rochester, Center for Visual Science, 274 Meliora Hall, Rochester, New York 14627
| | - Geunyoung Yoon
- University of Rochester, The Institute of Optics, 275 Hutchinson Road, Rochester, New York 14627
- University of Rochester, Flaum Eye Institute, 210 Crittenden Boulevard, Rochester, New York 14642
- University of Rochester, Center for Visual Science, 274 Meliora Hall, Rochester, New York 14627
- Address all correspondence to: Geunyoung Yoon, University of Rochester Eye Institute, 601 Elmwood Avenue, Box 314 Rochester, New York 14642. Tel: 585-273-4998; Fax: 585-276-2432; E-mail:
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Abstract
AIMS The aims of this study were to re-assess the histopathology of the disease by introducing more modern measuring techniques and to determine if axial stromal thinning, which is the most apparent change, is related to the other alterations observed. METHODS Recipient keratoconic corneas from 36 patients following corneal transplantation were studied. Haematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were used to identify breaks in Bowman's layer and Descemet's membrane. Thickness of corneal layers was measured by Leica QWin software. Epithelial and stromal thickness were measured in each sample at the periphery of the corneal button and at the area of maximal stromal thinning. The presence of apoptotic cells in Bowman's layer breaks was detected by terminal deoxynucleotidyl transferase mediated dUTP-X nick end labelling. RESULTS In all 36 corneal samples the central stroma, at the apex of the cone, was thinner than the peripheral. There was a negative correlation between central stromal and central epithelial thickness (p = 0.009). Bowman's layer breaks were found in 92% of corneas. Apoptotic cells were detected at the level of Bowman's breaks membrane. We found a positive correlation between epithelial thickness and the number of Bowman's layer breaks (p = 0.009 for central epithelial thickness and p = 0.003 for peripheral epithelial thickness). Descemet's membrane deformities were observed in 19% of corneas and central stromal thickness of these corneas was significantly less than corneas without breaks (p = 0.006). CONCLUSIONS There are various different histopathological features associated with keratoconus and some of them are very subtle and not very well studied. Accurate measurements also suggest some correlations between them. Stromal thinning is associated with the number of breaks in Descemet's membrane, but it is the thickening of the epithelium which is associated with breaks in Bowman's layer.
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Mannion LS, Tromans C, O'Donnell C. Reduction in corneal volume with severity of keratoconus. Curr Eye Res 2011; 36:522-7. [PMID: 21501083 DOI: 10.3109/02713683.2011.553306] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE To compare the corneal volume in keratoconic and normal eyes to improve our understanding of the tissue distribution associated with the disease. MATERIALS AND METHOD The Oculus Pentacam tomographer (Oculus Inc., Wetzlar, Germany) was used to analyze the corneal volume contained within discs with diameters of 3, 5, 7, and 10 mm in 21 patients with keratoconus and 21 matched healthy control subjects. RESULTS Corneal volume was significantly decreased in the keratoconus group (keratoconus vs. control group: 3.44 ± 0.39 vs. 4.05 ± 0.29 mm(3), 10.34 ± 0.95 vs. 11.79 ± 0.84 mm(3), 22.80 ± 1.73 vs. 25.26 ± 1.74 mm(3), and 57.17 ± 3.94 vs. 61.90 ± 4.12 mm(3) for the 3-, 5-, 7-, and 10-mm diameter discs, respectively; p < 0.001). As the corneal disc diameter analyzed increased, fewer differences were found between the control corneas and keratoconic corneas at different stages of the disease. Within the 3-mm and 5-mm diameter discs, significant differences were detected between the control group, moderate keratoconus, and the severe keratoconus groups (p < 0.05). However, within the 10-mm discs, differences were only detected between the control group and the severe keratoconus group (p = 0.005). CONCLUSIONS Corneal volume was significantly decreased in keratoconus, particularly in the central and paracentral area. The decrease in corneal volume in moderate and severe keratoconus as detected by the Pentacam tomographer, may be explained by loss of corneal tissue. In the early stages of the disease, the altered metabolic activity may cause tissue stretching and, as the disease progresses, this stretching is then accompanied by tissue loss.
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Affiliation(s)
- Luisa Simo Mannion
- Department of Optometry, Dublin Institute of Technology, Dublin, Ireland
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Akhtar S, Bron AJ, Hayes AJ, Meek KM, Caterson B. Role of keratan sulphate (sulphated poly -N-acetyllactosamine repeats) in keratoconic cornea, histochemical, and ultrastructural analysis. Graefes Arch Clin Exp Ophthalmol 2011; 249:413-20. [PMID: 20853116 DOI: 10.1007/s00417-010-1512-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 08/30/2010] [Accepted: 09/01/2010] [Indexed: 11/26/2022] Open
Abstract
AIMS Keratan sulphate (KS) is the predominant glycosaminoglycan (GAG) present in the corneal stroma where it is thought to regulate collagen fibril diameter. In this study we investigated the distribution of KS in normal and keratoconic corneas. METHODS Four normal, one mild, and four severe keratoconic corneas were used for the study. Distribution of keratan sulphate proteoglycans (KS-PG) was investigated using a primary monoclonal antibody (5-D-4) that recognizes disulphated disaccharides in the poly-N-acetyllactosamine repeats of KS. The immuno-reactivity of 5-D-4 was analyzed by immunohistochemistry and immuno-electron microscopy. RESULTS Immuno-histochemistry showed diffuse 5-D-4 staining in keratoconic cornea compared to the punctuate staining in normal corneas. In the single cornea with mild keratoconus, immunogold microscopy revealed a very high density of KS-PG staining, especially in the posterior stroma, compared to severe keratoconic and normal cornea. The amount of KS-PG in the stroma in severe keratoconus was slightly less compared to the normal cornea. In the mild keratoconic cornea, a higher quantity of KS-PG was present around the keratocytes. In severe keratoconic corneas, a higher quantity of KS-PG was present within the keratocytes compared to normal cornea. CONCLUSIONS The finding of an altered expression of KS in our keratoconic corneas, in particular the strong expression of KS in keratocytes, is in keeping with reports of an altered expression of proteoglycan metabolism in keratoconus. KS-PG plays an important role in stromal collagen fibril assembly and a dysregulation of KS-PG synthesis or catabolism could explain changes in collagen fibril spacing and diameter, which we have reported elsewhere.
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Affiliation(s)
- S Akhtar
- Department of Optometry, College of Applied Medical Sciences, King Saud University, PO Box 10219, Riyadh, 11433, Saudi Arabia.
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Recurrence of keratoconic pathology in penetrating keratoplasty buttons originally transplanted for keratoconus. Cornea 2009; 28:688-93. [PMID: 19512900 DOI: 10.1097/ico.0b013e3181967024] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Study aimed to examine buttons removed from patients originally grafted for KC (group 1) for signs of recurrence at a cellular level and compare them with buttons removed from patients originally grafted for other conditions (group 2). The study further aimed to compare buttons from group 1 exhibiting high astigmatism (group 3) with the other buttons in the study (group 4). METHODS Together with clinical data, corneal buttons were collected at repeat penetrating keratoplasty and labeled immunohistochemically with a panel of antibodies to structural proteins to assist microanatomical interpretation. Image analysis of montaged images of many individual sections was performed using custom software. The resulting data were analyzed statistically for significant differences between groups 1/2 and 3/4. RESULTS Little evidence of KC recurrence could be found despite statistically significant differences between groups 1/2 in corneal thinning at both graft-host junction (GHJ) (P = 0.035) and within the graft (P = 0.001), epithelial thickening at the GHJ only (P < 0.001), high astigmatism (P = 0.028), and history of high intraocular pressure (P = 0.032) or rejection (P = 0.002) and between groups 3/4 in corneal thinning at both GHJ (P = 0.002) and within the graft (P = 0.003), epithelial thickening at the GHJ only (P = 0.003), and high astigmatism (P < 0.001). CONCLUSION This study has highlighted the rarity of recurrence of KC in transplanted donor corneas and the corresponding difficulty in detecting early signs of the disease.
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Raecker ME, Erie JC, Patel SV, McLaren JW, Hodge DO, Bourne WM. Long-term keratometric changes after penetrating keratoplasty for keratoconus and Fuchs Endothelial dystrophy. Am J Ophthalmol 2009; 147:227-33. [PMID: 18834579 DOI: 10.1016/j.ajo.2008.08.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Revised: 07/30/2008] [Accepted: 08/01/2008] [Indexed: 11/30/2022]
Abstract
PURPOSE To compare long-term keratometric changes after penetrating keratoplasty (PK) for keratoconus and Fuchs endothelial dystrophy. DESIGN Retrospective, comparative case series. METHODS We retrospectively analyzed 168 corneas after PK for keratoconus (85 eyes of 63 subjects) and Fuchs dystrophy (83 eyes of 60 subjects). Patients were examined after final suture removal at 12 months after PK to 30 years after surgery. Operations were performed by one surgeon (W.M.B.) using the same suturing technique in all cases. Eyes were excluded from further analysis after regrafting or after relaxing incisions. Mean keratometric corneal power and astigmatism were measured by manual keratometry. Data were assessed by using generalized estimating equation models to determine change over time. RESULTS Mean keratometric corneal power and astigmatism increased through 30 years after PK for keratoconus (P < .001 and P < .001), but did not change through 20 years after PK for Fuchs dystrophy (P = .55 and P = .55) The change in keratometric corneal power and astigmatism after PK in keratoconus patients only differed from the change in Fuchs dystrophy patients 10 or more years after PK (P = .002 and P = .003). CONCLUSIONS Corneal curvature and regular astigmatism increase progressively after PK for keratoconus, but remain stable after PK for Fuchs dystrophy. Our data suggest that keratometric instability after PK for keratoconus is attributable to delayed, progressive ectasia in the host corneal rim.
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Akhtar S, Bron AJ, Salvi SM, Hawksworth NR, Tuft SJ, Meek KM. Ultrastructural analysis of collagen fibrils and proteoglycans in keratoconus. Acta Ophthalmol 2008; 86:764-72. [PMID: 18422999 DOI: 10.1111/j.1755-3768.2007.01142.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
PURPOSE To investigate ultrastructural alterations in the distribution of collagen fibrils (CFs) and proteoglycans (PGs) in the keratoconus cornea. METHODS Four normal corneas (donor age 24-75 years) and four severe and one mild keratoconus corneas (donor age 24-47 years) were fixed in 2.5% glutaraldehyde containing 0.05% cuprolinic blue dye for electron microscopy. Analyses were carried out on approximately 39 000 CF and 66 000 PG filaments in the anterior, middle and posterior stroma, using analySIS soft imaging software. RESULTS In severe keratoconus, stromal lamellae were seen to undulate in most regions, whereas in mild keratoconus only the middle and posterior lamellae were affected. In keratoconus corneas the mean diameter and interfibrillar spacing of CFs was reduced in all zones (p < 0.0001) and the CF and PG number density and area fractions were significantly increased (p < 0.0001) compared with in normal corneas and were higher (p < 0.0001) in the corneas with severe keratoconus than in that with mild keratoconus. The lamellae contained microfibrils (8-9 nm wide) and, in addition, PGs embedded within CFs. Degenerate keratocytes containing PGs were found in all keratoconus corneas. CONCLUSIONS These studies suggest that as keratoconus progresses, the PG content of the stroma increases, whereas fibril diameter is reduced. The altered stromal content of PGs may influence CF diameters and their organization in keratoconus, weakening lateral cohesion and resulting in significant disorder of CF packing.
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Affiliation(s)
- Saeed Akhtar
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK.
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Ku JYF, Niederer RL, Patel DV, Sherwin T, McGhee CNJ. Laser Scanning In Vivo Confocal Analysis of Keratocyte Density in Keratoconus. Ophthalmology 2008; 115:845-50. [PMID: 17825419 DOI: 10.1016/j.ophtha.2007.04.067] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2006] [Revised: 04/02/2007] [Accepted: 04/04/2007] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Keratoconus is a form of progressive noninflammatory corneal ectasia. Although abnormalities have been documented at every level of the keratoconic cornea, the exact underlying pathophysiologic process remains unknown. This study aimed to determine the keratocyte density in human corneas with keratoconus imaged by laser scanning in vivo confocal microscopy. DESIGN Prospective cross-sectional study. PARTICIPANTS Thirty-six eyes of 26 subjects with keratoconus compared with 33 eyes of 33 control subjects. METHODS Subjects were assessed via ophthalmic examination, computed topography, and laser scanning in vivo confocal microscopy. MAIN OUTCOME MEASURES Anterior and posterior stromal keratocyte density. RESULTS Mean age was 34.7+/-12.1 years in the control group, 38.4+/-11.0 years in the keratoconic with no contact lens wear group, and 38.5+/-10.3 years in the keratoconic with contact lens wear group. No significant difference was noted in age or gender between the groups. Mean keratocyte density in the control group was 786+/-244 cells/mm(2) in the anterior stroma and 293+/-35 cells/mm(2) in the posterior stroma. Anterior keratocyte density was higher than posterior keratocyte density (P<0.001). Anterior keratocyte density was significantly lower in contact lens-wearing keratoconic subjects in comparison with controls (463 vs. 786 cells/mm(2); P<0.001). Posterior keratocyte density was significantly lower in keratoconic subjects with no contact lens wear (236 vs. 293 cells/mm(2); P<0.001) and in keratoconic subjects with contact lens wear (208 vs. 293 cells/mm(2); P<0.001). In subjects with keratoconus, anterior keratocyte density correlated with central corneal thickness (r = 0.426, P = 0.012) and inversely with steepest keratometry values (r = -0.383, P = 0.028). CONCLUSIONS Keratocyte density is significantly lower in subjects with keratoconus, and the decline in keratocyte density correlates with indices of disease severity. In vivo confocal microscopy offers the opportunity to study early microstructural changes in the keratoconic cornea.
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Affiliation(s)
- Judy Y F Ku
- Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Abstract
PURPOSE To investigate corneal nerve structure and function in a 24-year-old patient with keratoconus and prominent corneal nerves. METHODS Corneal nerve appearance was assessed by using a corneal confocal microscope, and corneal nerve function was assessed by using a Cochet-Bonnet aesthesiometer. Findings were compared to those of an age-matched control subject without keratoconus. RESULTS The patient with keratoconus was found to have thicker nerve fiber bundles in the stroma (keratoconus vs. control, 9.8 +/- 5.0 microm vs. 5.4 +/- 2.7 microm) and reduced nerve fiber density in the subepithelial plexus (keratoconus vs. control, 269.7 +/- 145.6 microm vs. 1,258 +/- 254.8 mum) compared to the control subject. The patient with keratoconus was found to have reduced corneal sensitivity compared to the control subject (keratoconus vs. control 0.39 gr/mm2 vs. 1.59 gr/mm2). CONCLUSIONS Corneal confocal microscopy proved to be a useful in vivo technique for assessing corneal nerve structure in this patient with keratoconus. Although the total number of stromal nerve fiber bundles was reduced in the patient with keratoconus versus the control subject, the increased tortuosity and increased nerve fiber diameter may explain why the corneal nerves appear more visible in this patient with keratoconus.
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Hayes S, Boote C, Tuft SJ, Quantock AJ, Meek KM. A study of corneal thickness, shape and collagen organisation in keratoconus using videokeratography and X-ray scattering techniques. Exp Eye Res 2007; 84:423-34. [PMID: 17178118 DOI: 10.1016/j.exer.2006.10.014] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2006] [Revised: 10/16/2006] [Accepted: 10/18/2006] [Indexed: 10/23/2022]
Abstract
In keratoconus, the cornea becomes progressively ectactic resulting in severe visual impairment. Here, we use a combination of videokeratography and synchrotron X-ray diffraction to investigate the relationship between corneal shape and thickness, and the distribution and predominant orientation of stromal fibrillar collagen in five keratoconus corneas. In all but the least advanced case, the thinning and ectasia measured in vivo using corneal videokeratography was accompanied by corresponding changes in the relative distribution and orientation of stromal collagen in the excised corneal buttons. Although the most severe case of keratoconus possessed the most pronounced stromal collagen alterations, and only a minor disruption to stromal collagen arrangement was seen in the least advanced case, a variability in the extent of stromal collagen alteration was seen between these clinical extremes. The observed abnormalities in collagen distribution and orientation are consistent with a mechanism of keratoconus progression that involves inter-fibrillar or inter-lamellar slippage causing a redistribution of tissue within the cornea.
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Affiliation(s)
- Sally Hayes
- Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, United Kingdom.
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Im E, Kazlauskas A. The role of cathepsins in ocular physiology and pathology. Exp Eye Res 2006; 84:383-8. [PMID: 16893541 DOI: 10.1016/j.exer.2006.05.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Revised: 05/19/2006] [Accepted: 05/23/2006] [Indexed: 11/21/2022]
Abstract
Cathepsins are proteases that were originally identified in the lysosome, where they participate in house keeping tasks such as degradation of phagocytosed photoreceptors. More recently, cathepsins have been detected outside of the lysosome, and associated with numerous diseases (keratoconus, retinal detachment, age related macular degeneration, and glaucoma). The most likely mechanism by which cathepsins contribute to ocular pathologies is via degradation of the extracellular matrix, and/or regulation of angiogenesis.
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Affiliation(s)
- Eunok Im
- Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
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Mackiewicz Z, Määttä M, Stenman M, Konttinen L, Tervo T, Konttinen YT. Collagenolytic proteinases in keratoconus. Cornea 2006; 25:603-10. [PMID: 16783151 DOI: 10.1097/01.ico.0000208820.32614.00] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE To study the proteolytic phenomena contributing to the pathogenesis of keratoconus, corneal enzymes with potential to cleave fibrillar collagen were studied. METHODS Immunohistochemical labeling was undertaken of conventional and novel mammalian collagenases (MMP-1, -2, -8, -13, and -14) of the matrix metalloproteinase (MMP) family and other collagenolytic proteinases of the serine (human trypsin-2) and cysteine (cathepsin K) endoproteinase families. The results were analyzed using a semiquantitative scoring system. RESULTS Labeling of MMP-8 was moderate in healthy controls, but weak in keratoconus. Moderate MMP-2 and weak MMP-14 expressions were similar in controls and keratoconus. MMP-1 was slightly overexpressed in keratoconus. In contrast, MMP-13 was weak in controls compared to moderate in keratoconus and human trypsin-2 and cathepsin K were moderate in controls and strong in keratoconus. CONCLUSIONS The collagenolytic milieu of human cornea is more complex than expected. Mesenchymal isoform of MMP-8 (ie, collagenase-2) participates in normal tissue remodeling, which may be impaired in keratoconus. MMP-2 (gelatinase A with interstitial collagenase activity) and MMP-14 (membrane-type MMP type I with collagenolytic potential) seem to be constitutively expressed and probably play a role in normal corneal remodeling. The most prominent changes in keratoconic cornea were observed in collagenase MMP-13 (ie, collagenase-3), and particularly, in cathepsin K and human trypsin-2, which were strongly expressed in keratoconus suggesting a role in intra- and extracellular pathological collagen destruction, respectively. This may contribute to stromal thinning characteristic for keratoconus.
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Määttä M, Väisänen T, Väisänen MR, Pihlajaniemi T, Tervo T. Altered expression of type XIII collagen in keratoconus and scarred human cornea: Increased expression in scarred cornea is associated with myofibroblast transformation. Cornea 2006; 25:448-53. [PMID: 16670484 DOI: 10.1097/01.ico.0000183537.45393.1f] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Type XIII collagen (ColXIII) is a transmembrane protein thought to be involved in cell-cell and cell-matrix interactions. We report here on its presence in the normal human cornea and compare the results for keratoconus and scarred corneas. METHODS Immunohistochemistry and in situ hybridization were applied to human corneal samples obtained by penetrating keratoplasty. RESULTS In the normal human cornea, ColXIII was immunolocalized to the corneal epithelial cells, and to a lesser degree to the stromal keratocytes. The keratoconus cases showed otherwise similar results, but in areas containing Bowman membrane disruptions showed thinned epithelial cells reduced immunostaining for ColXIII, whereas occasionally pronounced immunoreactivity was seen in the stromal keratocytes. The corneal scar samples contained highly increased ColXIII immunostaining by stromal cells in the fibrotic foci, whereas the peripheral areas showed less intense immunostaining. In situ hybridization confirmed that the corneal epithelium and keratocytes actively synthesize the transcript. Immunostaining with alphaSMA revealed that a substantial proportion of the ColXIII mRNA-expressing cells in the stromal scar tissues was myofibroblasts and that these areas lack CD34 immunoreactivity. CONCLUSIONS The results indicate that ColXIII, which is predominantly confined to the basal corneal cells in the normal cornea, may have a role in the adhesion of corneal epithelial cells to each other and to the underlying basement membrane. Additionally, highly increased expression in scarred corneas suggests that it participates in the corneal wound healing process.
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Affiliation(s)
- Marko Määttä
- Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.
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Määttä M, Heljasvaara R, Sormunen R, Pihlajaniemi T, Autio-Harmainen H, Tervo T. Differential Expression of Collagen Types XVIII/Endostatin and XV in Normal, Keratoconus, and Scarred Human Corneas. Cornea 2006; 25:341-9. [PMID: 16633037 DOI: 10.1097/01.ico.0000178729.57435.96] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE This study was designed to clarify the expression of 2 closely related collagen (Col) types XVIII and XV, and the proteolytically derived endostatin fragment of ColXVIII in normal, keratoconus, and scarred human corneas. METHODS Immunohistochemistry, in situ hybridization, immunoelectron microscopy, and Western immunoblotting were used for human corneal samples obtained from penetrating keratoplasty. RESULTS In the normal cornea, ColXVIII was immunolocalized to the corneal and conjunctival epithelial basement membrane (EBM), Descemet s membrane, and the limbal and conjunctival capillaries. Immunoreaction for endostatin was otherwise similar, but it also was present in corneal epithelial cells. Western immunoblotting showed that normal cornea contains several endostatin fragments ranging from 20 to 100 kDa. ColXV was present in the EBM of the limbus and conjunctiva, but not in EBM of the clear cornea. In situ hybridization revealed that corneal basal epithelial cells were responsible for the synthesis of ColXVIII mRNA. Keratoconus cases were characterized by an irregular EBM immunoreactivity for ColXVIII and endostatin and patchy immunoreactivity beneath EBM. In scarred corneas, highly increased immunoreactivity for ColXVIII, endostatin, and ColXV was present within stroma. CONCLUSIONS The results indicate that ColXVIII and ColXV are differentially expressed in normal human corneas. Constant expression of ColXVIII by corneal EBM suggests that it is an important structural molecule. Aberrant expression of ColXVIII, endostatin, and ColXV in keratoconus and scarred corneas emphasizes the active role these molecules in the wound healing process.
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Affiliation(s)
- Marko Määttä
- Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.
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Simo Mannion L, Tromans C, O'Donnell C. An evaluation of corneal nerve morphology and function in moderate keratoconus. Cont Lens Anterior Eye 2005; 28:185-92. [PMID: 16332504 DOI: 10.1016/j.clae.2005.10.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2005] [Revised: 10/25/2005] [Accepted: 10/25/2005] [Indexed: 11/20/2022]
Abstract
PURPOSE To investigate corneal nerve morphology and corneal sensitivity in keratoconus. METHODS The central cornea of 13 subjects with keratoconus and 13 age-matched control subjects was assessed using in vivo confocal microscopy and corneal aesthesiometry. RESULTS Significant differences in corneal nerve fibre density were found between the subjects with keratoconus and the control subjects (keratoconus versus control; 1018.3+/-489.6 microm versus 1820.7+/-789.5 microm; p = 0.006). The mean diameter of nerve fibres in the stroma was found to be greater in subjects with keratoconus compared to control subjects (keratoconus versus control; 10.2+/-4.6 microm versus 5.5+/-1.9 microm; p = 0.007). The orientation of corneal nerve fibres in the subjects with keratoconus appeared to be altered from the predominantly vertical orientation seen in the control subjects. Corneal touch threshold was found to be similar in the two groups, although the subjects with keratoconus using contact lens correction had reduced corneal sensitivity compared to the contact lens-wearing control subjects (keratoconus with contact lenses versus controls with contact lenses; 1.18+/-0.19 g/mm2 versus 0.98+/-0.05 g/mm2; p = 0.03). CONCLUSION This study reveals significant reductions in nerve density in the keratoconic cornea. The thickened stromal nerve fibres observed in the keratoconic corneas may explain why prominent corneal nerves are often seen using slit lamp biomicroscopy in keratoconic patients.
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Affiliation(s)
- Luisa Simo Mannion
- Optometry and Neuroscience, Moffat Building, The University of Manchester, PO Box 88, Manchester, M60 1QD, UK.
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Wassélius J, Johansson K, Håkansson K, Abrahamson M, Ehinger B. Cystatin C uptake in the eye. Graefes Arch Clin Exp Ophthalmol 2004; 243:583-92. [PMID: 15614539 PMCID: PMC7087865 DOI: 10.1007/s00417-004-1055-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Revised: 09/02/2004] [Accepted: 09/20/2004] [Indexed: 10/31/2022] Open
Abstract
BACKGROUND As a secreted protein, cystatin C is assumed to play its role in the extracellular compartment, where it can inhibit virtually all cysteine proteases of families C1 (cathepsin B, L, S) and C13 (mammalian legumain-related proteases). Since many of its potential target enzymes in the eye reside in intracellular compartments, we sought evidence for a cellular uptake of the inhibitor in ocular tissues. METHODS Fluorescence-labeled human cystatin C was injected intravitreally into normal rat eyes. Ocular tissues were subsequently examined using ELISA, fluorescence microscopy, and immunohistochemistry. Cystatin C uptake was additionally studied in an in vitro retina model. RESULTS Cystatin C administered intravitreally in vivo is taken up into cells of the corneal endothelium and epithelium, the epithelial cells lining the ciliary processes, and into cells in the neuroretina (mostly ganglion cells) and the retinal pigment epithelium. The uptake is demonstrable also in vitro and was, in the neuroretina, found to be a high-affinity system, inhibited by cooling the specimens or by adding the microfilament polymerization inhibitor, cytochalasin D, to the medium. CONCLUSIONS There is an active, temperature-dependent uptake system for cystatin C into several cell types in the cornea, ciliary body, and retina. The cell types that take up cystatin C are generally the same that contain endogenous cystatin C, suggesting that much or all cystatin C seen intracellularly in the normal eye may have been taken up from the surrounding extracellular space. The uptake indicates that the inhibitor may exert biological functions in intracellular compartments. It is also possible that this uptake system may regulate the extracellular levels of cystatin C in the eye.
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Affiliation(s)
- Johan Wassélius
- Department of Ophthalmology, University Hospital, Lund University, 221 85 Lund, Sweden
| | - Kjell Johansson
- Department of Ophthalmology, University Hospital, Lund University, 221 85 Lund, Sweden
| | - Katarina Håkansson
- Department of Clinical Chemistry, University Hospital, Lund University, Lund, Sweden
| | - Magnus Abrahamson
- Department of Clinical Chemistry, University Hospital, Lund University, Lund, Sweden
| | - Berndt Ehinger
- Department of Ophthalmology, University Hospital, Lund University, 221 85 Lund, Sweden
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Avitabile T, Franco L, Ortisi E, Castiglione F, Pulvirenti M, Torrisi B, Castiglione F, Reibaldi A. Keratoconus staging: a computer-assisted ultrabiomicroscopic method compared with videokeratographic analysis. Cornea 2004; 23:655-60. [PMID: 15448489 DOI: 10.1097/01.ico.0000127486.78424.6e] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE The aim of this study was to introduce a new paradigm for keratoconus assessment, the keratoconus index (KI), generated from the ratio of peripheral corneal thickness (PCT) to the thinnest corneal thickness (TCT), and calculated by a computer-assisted procedure after ultrabiomicroscope (UBM) examination. Then we compared KI and the keratoconus severity index (KSI), obtained by videokeratography in patients with different stages of keratoconus. METHODS We studied 60 eyes with different forms of keratoconus using the TMS-3 autotopographer, provided with a keratoconus screening program (using Smolek-Klyce methods) and the commercial version of the ultrasound biomicroscope (Paradigm UBM Plus Model P45) equipped with a 50-MHz probe, which was provided with our computer-assisted program. The proportion test Z and the correlation coefficient R were applied to the outcomes. RESULTS The keratoconus severity index, KSI, obtained by color-coded videokeratographic maps, was in the range 95% to 32% (mean 52.22%). By means of UBM examination, we obtained 60 images and found values of TCT 0.278-0.592 mm and PCT 0.475-0.704 mm. Applying the computer-assisted method, we obtained values for KI of 1.112-2.159 (mean 1.428). CONCLUSIONS KI is correlated as well as KSI with the severity of the keratoconus (R = 0.76, P < 0.0001). It can be used as a similar parameter to measure the evolution of the disease, on the basis of corneal thickness rather than the curvature.
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Abstract
Keratoconus was first discriminated from other corneal ectatic diseases in 1854. Since that time the morphological characteristics of keratoconic progression have been invaluable in the diagnosis of the condition. The key clinical features used to identify keratoconus have remained essentially the same since the introduction of the slit-lamp biomicroscope. Only relatively recently has the development of computerized corneal topography revolutionized the diagnosis of early keratoconus. Analysis of peer-reviewed literature databases revealed a steady chronological increase in pathological research into the progress of keratoconus. This overview describes the recent advances in our understanding of keratoconic pathology and highlights the interactions within the cornea that may be important in the pathogenesis of this condition.
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Affiliation(s)
- Trevor Sherwin
- Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
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Szczotka-Flynn L, McMahon TT, Lass JH, Sugar J, Weissman BA, Stiegemeier MJ, Reinhart WJ. Late-Stage Progressive Corneal Astigmatism After Penetrating Keratoplasty for Keratoconus. Eye Contact Lens 2004; 30:105-10. [PMID: 15260360 DOI: 10.1097/01.icl.00000118526.35929.0f] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Progressive corneal astigmatism occurring at least 10 years after penetrating keratoplasty for keratoconus is a late-phase complication of surgery. This report characterizes this condition in a series of patients from three corneal referral centers in the United States. METHODS Charts were retrospectively reviewed which met the following criteria: penetrating keratoplasty performed for keratoconus at least 10 years ago, keratometry or simulated keratometry from topography as well as manifest refraction recorded at least 6 months after the last suture removal ("baseline"), and an increase in corneal astigmatism of at least three D over baseline recorded at least 5 years later. Patients who had any other corneal or intraocular surgery performed were excluded. RESULTS Data from 15 patients (11 males and 4 females) who had penetrating keratoplasties performed by 8 different surgeons are included in this descriptive series. Postoperative follow-up averaged 17.27 years (range 11-24 years). The average donor button size was 7.83 mm (range 7.25-8.5 mm). Baseline corneal astigmatism was obtained an average of 5.2 years after penetrating keratoplasty (range 1.5-16 years) and was on average 3.57 +/- 1.8 D (10 with-the-rule [WTR], 3 against-the-rule [ATR], 2 oblique). Corneal astigmatism significantly increased to an average of 11.23 +/- 3.56 D (range 8.00-19.37 D, P < 0.0001) and most astigmatism was regular and WTR (9 WTR, 3 ATR, 3 oblique) 15.3 years (range 10-22 years) after surgery. Inferior steepening on topography was often noted, even those with oblique and ATR axes. CONCLUSIONS High, late-stage, regular astigmatism after penetrating keratoplasty for keratoconus is described in a series of patients occurring at least 10 years after surgery. Possible mechanisms of this progressive astigmatism are recurrence of keratoconus in the graft, progressive corneal thinning of the host cornea, or progressive misalignment of the graft-host interface over time.
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Wassélius J, Wallin H, Abrahamson M, Ehinger B. Cathepsin B in the rat eye. Graefes Arch Clin Exp Ophthalmol 2003; 241:934-42. [PMID: 14586591 DOI: 10.1007/s00417-003-0782-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2003] [Revised: 09/02/2003] [Accepted: 09/03/2003] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Cathepsin B is a mammalian cysteine protease. The enzyme has been suggested to participate in the patophysiological processes of keratoconus as well as in the corneal response to infectious agents. This study describes the localization of cathepsin B in the rat eye. METHODS Cathepsin B was identified in rat ocular tissues by Western blotting and immunohistochemistry. Cathepsin B mRNA levels were analyzed in the tissues by quantitative real-time cDNA amplification (QRT-PCR). RESULTS Cathepsin B is present in the epithelium, in stromal cells and in the endothelium of the cornea. It is also present in the epithelium lining the ciliary processes, in occasional stromal cells in the iris, in the anterior subcapsular lens epithelium and in various cell types in the retina. At all locations cathepsin B is present in cytoplasmic granules, presumably lysosomes. QRT-PCR analysis detected cathepsin B mRNA in all these tissues in amounts correlating to the immunodetection results, suggesting that the enzyme detected is locally produced. CONCLUSIONS Cathepsin B is present in several tissues and cell types throughout the rat eye. It is localized to cytoplasmic granules, presumably lysosomes. Our results suggest that it is probably also produced in the same cell types.
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Affiliation(s)
- Johan Wassélius
- Department of Ophthalmology, University of Lund, 221 85, Lund, Sweden.
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Brookes NH, Loh IP, Clover GM, Poole CA, Sherwin T. Involvement of corneal nerves in the progression of keratoconus. Exp Eye Res 2003; 77:515-24. [PMID: 12957150 DOI: 10.1016/s0014-4835(03)00148-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Keratoconus is a debilitating corneal thinning disease that principally develops in the second and third decades of life. Our group previously developed a novel approach to studying keratoconus, based on the observation that there is a gradient of damage across the keratoconic cone. We identified a number of cellular characteristics of keratoconus such as discrete incursions of fine cellular processes from the anterior keratocytes in association with localised indentation of the basal epithelium, and increased levels of the lysosomal enzymes Cathepsin B and G in aberrant keratocytes, located beneath compromised regions of Bowman's layer, but also deeper in the stroma. Enzyme activity by these cells seemed to be causing localised structural degradation of the anterior stroma, leading to near-complete destruction of both Bowman's layer and the stroma, often necessitating a full-thickness corneal graft for sight restoration. This current study extends our initial findings by investigating the role of corneal nerves passing between the stroma and epithelium at the sites of early degradative change observed previously, and may be facilitating the keratocyte-epithelial interactions in this disease. Cells in sections of normal and keratoconic human corneas were labelled with the fixable fluorescent viability dye 5-chloromethylfluorescein diacetate, antibodies to alpha-tubulin (nerves), alpha3beta1 integrin, Cathepsin B and G, and the nuclear dye DAPI, and then examined with a confocal microscope. Anterior keratocyte nuclei were seen wrapping around the nerves as they passed through the otherwise acellular Bowman's layer, and as the disease progressed and Bowman's layer degraded, these keratocytes were seen to express higher levels of Cathepsin B and G, and become displaced anteriorly into to the epithelium. Localised nerve thickenings also developed within the epithelium in association with Cathepsin B and G expression, and appeared to be very destructive to the cornea. Insight into the molecular mechanisms of keratoconic disease pathogenesis and progression can be gained from the process of extracellular matrix remodelling known from studies of connective tissues other than the cornea, and wound healing studies in the cornea. Further studies are required to determine how well this model fits the actual molecular basis of the pathogenesis of keratoconus.
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Affiliation(s)
- N H Brookes
- Department of Ophthalmology, Faculty of Medicine and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
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de Toledo JA, de la Paz MF, Barraquer RI, Barraquer J. Long-term progression of astigmatism after penetrating keratoplasty for keratoconus: evidence of late recurrence. Cornea 2003; 22:317-23. [PMID: 12792474 DOI: 10.1097/00003226-200305000-00008] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To study changes in astigmatism throughout a 20-year period using keratometry and refraction in patients who underwent penetrating keratoplasty (PKP) for keratoconus. METHODS We reviewed the charts of patients who underwent PKP for keratoconus from 1975 to 1979 and recorded preoperative refraction, stage of keratoconus, laterality of surgery, graft size, suture technique, time of suture removal, keratometry, subjective refraction at 1, 3, 5, 7, 10, 15, 20, and 25 years after suture removal, and slit-lamp findings. RESULTS Eighty eyes with a mean follow-up of 20 years (range, 15-25) were included in the study. Graft size, suture technique, and time of suture removal had no significant influence on the astigmatism at the last examination. We observed a stabilization of keratometric astigmatism in the first 7 years (4.05 +/- 2.29 D 1 year after suture removal, 3.90 +/- 2.28 D at year 3, 4.03 +/- 2.49 D at year 5, 4.39 +/- 2.48 D at year 7) followed by a progressive increase from 10 years after suture removal until the last follow-up visit (5.48 +/- 3.11 D at year 10, 6.43 +/- 4.11 D at year 15; 7.28 +/- 4.21 D at year 20, and 7.25 +/- 4.27 D at year 25). The mean absolute value of the difference vector (DV) calculated by vector analysis was 7.17 +/- 4.35 D (0-18.33). In 70% of cases, progression of the astigmatism was evident with mean absolute DV of 9.10 +/- 3.65 D. There was a significant correlation between the preoperative and final axis of astigmatism (Pearson r = 0.39, p = 0.0008). There was also a slight positive correlation coefficient between the DV of the eyes in bilateral cases, but it was not significant (Spearman's r = 0.2226, p = 0.34). The major late slit-lamp finding was a peripheral crescent-shaped thinning at the graft-host junction with absence of Bowman's layer on histopathology. CONCLUSION In spite of refractive stability obtained during the first years after PKP for keratoconus, increasing astigmatism thereafter suggests that there is a progression of the disease in the host cornea.
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