Abstract:A dense nerve plexus in the clear outer window of the eye, the cornea, can be imaged in vivo to enable non-invasive monitoring of peripheral nerve degeneration in diabetes. However, a limited field of view of corneal nerves, operator-dependent image quality, and subjective image sampling methods have led to difficulty in establishing robust diagnostic measures relating to the progression of diabetes and its complications. Here, we use machine-based algorithms to provide wide-area mosaics of the cornea’s subbas… Show more
“…Scale bar = 0.5 mm. The entire set of original high-resolution images of sub-basal plexi from the cohort is freely available 32 . Figure 4 Sub-basal nerve plexus mosaic from the central cornea taken from the left eye of a subject with NGT.…”
Section: Resultsmentioning
confidence: 99%
“…As part of ophthalmic examinations in 2014, the central cornea in both eyes of all study subjects was imaged by in vivo confocal microscopy (IVCM) using a Heidelberg Retinal Tomograph 3 with Rostock cornea module (HRT3-RCM, Heidelberg Engineering, Heidelberg, Germany). Details of the imaging procedure have been described elsewhere 32 . Briefly, a drop of ophthalmic tear gel (Tear Gel carbomer 0.3%, Thea Pharmaceuticals, France) was used as coupling medium between the microscope objective lens and the corneal surface.…”
Section: Methodsmentioning
confidence: 99%
“…Raw data from the IVCM examination were sorted to exclude images not containing the sub-basal plexus, and the plexus images served as input to an automated mosaicking algorithm that assembled the raw images taken in three dimensions into a two-dimensional mosaic with the maximal projection of sub-basal nerves 32 . One hundred sixty-two mosaics (bilateral eye data from 81 subjects) were assembled, with a mean mosaic assembly time of 7 minutes on a standard dual-core Windows PC.…”
Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.
“…Scale bar = 0.5 mm. The entire set of original high-resolution images of sub-basal plexi from the cohort is freely available 32 . Figure 4 Sub-basal nerve plexus mosaic from the central cornea taken from the left eye of a subject with NGT.…”
Section: Resultsmentioning
confidence: 99%
“…As part of ophthalmic examinations in 2014, the central cornea in both eyes of all study subjects was imaged by in vivo confocal microscopy (IVCM) using a Heidelberg Retinal Tomograph 3 with Rostock cornea module (HRT3-RCM, Heidelberg Engineering, Heidelberg, Germany). Details of the imaging procedure have been described elsewhere 32 . Briefly, a drop of ophthalmic tear gel (Tear Gel carbomer 0.3%, Thea Pharmaceuticals, France) was used as coupling medium between the microscope objective lens and the corneal surface.…”
Section: Methodsmentioning
confidence: 99%
“…Raw data from the IVCM examination were sorted to exclude images not containing the sub-basal plexus, and the plexus images served as input to an automated mosaicking algorithm that assembled the raw images taken in three dimensions into a two-dimensional mosaic with the maximal projection of sub-basal nerves 32 . One hundred sixty-two mosaics (bilateral eye data from 81 subjects) were assembled, with a mean mosaic assembly time of 7 minutes on a standard dual-core Windows PC.…”
Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.
“…29 The diagnostic ability of IVCCM may be further enhanced by assessing the inferior whorl or using wide-area mosaics, which take into account both proximal and distal corneal nerve morphology. 30,31 Multiple pathogenetic mechanisms, including advanced glycation, increased flux through the sorbitol pathway, and oxidative stress, have been implicated in the development of diabetic neuropathy. 32 Experimental studies using a combination of menhaden oil, a-lipoic acid, and enalapril have been shown to ameliorate oxidative and inflammatory stress and improve distal corneal nerve morphology.…”
PURPOSE. We have previously used in vivo corneal confocal microscopy (IVCCM) to demonstrate significant alterations in the corneal epithelial cells, stromal keratocytes, and subbasal nerves in young patients with type 1 diabetes mellitis (T1DM), especially those with diabetic retinopathy (DR). We have evaluated the change in corneal cellular and subbasal nerve morphology over 2 years in young patients with T1DM with or without DR. METHODS. A total of 19 patients with T1DM, without (n ¼ 12) and with (n ¼ 7) DR and 19 ageand sex-matched healthy control subjects underwent quantification of corneal cellular and subbasal nerve plexus morphology by using IVCCM at baseline and after 2 years. RESULTS. There was no significant change in corneal basal epithelial, posterior stromal keratocyte, or endothelial cell densities over 2 years. However, there was a significant reduction in corneal nerve branch (P ¼ 0.03) and total nerve branch density (P ¼ 0.04) in patients without DR and a significant reduction in corneal nerve fibre density (P ¼ 0.004) in those with DR. CONCLUSIONS. IVCCM can detect a progressive loss of corneal nerve fibers in young patients with T1DM and may allow the identification of individuals at risk of neuropathy progression for more active risk factor reduction.
“…First, CCM parameters were estimated on a CCM mosaic of images generated by custom‐made software, rather than single images as per previously validated methodology. It is unknown if the approach is of diagnostic value, especially in cross‐sectional observational studies . Second, the CCM mosaic was compared to single skin biopsy sections, which may have introduced an estimation bias.…”
Section: Corneal Confocal Microscopy For Peripheral Neuropathiesmentioning
Corneal confocal microscopy is a non-invasive ophthalmic imaging modality, which was initially used for the diagnosis and management of corneal diseases. However, over the last 20 years it has come to the forefront as a rapid, non-invasive, reiterative, cost-effective imaging biomarker for neurodegeneration. The human cornea is endowed with the densest network of sensory unmyelinated axons, anywhere in the body. A robust body of evidence shows that corneal confocal microscopy is a reliable and reproducible method to quantify corneal nerve morphology. Changes in corneal nerve morphology precede or relate to clinical manifestations of peripheral and central neurodegenerative conditions. Moreover, in clinical intervention trials, corneal nerve regeneration occurs early and predicts functional gains in trials of neuroprotection. In view of these findings, it is timely to summarise the knowledge in this area of research and to explain why the case for corneal confocal microscopy is sufficiently compelling to argue for its inclusion as a Food and Drug Administration endpoint in clinical trials of peripheral and central neurodegenerative conditions.
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