Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves

Lagali, Neil; Poletti, Enea; Patel, Dipika V.; McGhee, Charles N J; Hamrah, Pedram; Kheirkhah, Ahmad; Tavakoli, Mitra; Petropoulos, Ioannis N.; Malik, Rayaz A.; Utheim, Tor Paaske; Zhivov, Andrey; Stachs, Oliver; Falke, Karen; Peschel, Sabine; Guthoff, Rudolf; Chao, Cecilia; Golebiowski, Blanka; Stapleton, Fiona; Ruggeri, Alfredo

doi:10.1167/iovs.15-17284

Cited by 31 publications

(25 citation statements)

References 23 publications

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“…71 Tortuosity is becoming extensively used as a feature to describe subbasal nerves in healthy and pathological corneas. 139 Lagali et al performed an interesting study, focusing on the perception of experts and definitions of tortuosity, and concluded that reproducibility in tortuosity analysis can be subject to sampling bias regardless of the definition used and that further efforts are required to develop standardized quantification strategies. 139 …”

Section: Corneal Nerves In Normal Subjects With and Without Contacmentioning

confidence: 99%

In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease

2017

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In vivo confocal microscopy (IVCM) is becoming an indispensable tool for studying corneal physiology and disease. Enabling the dissection of corneal architecture at a cellular level, this technique offers fast and noninvasive in vivo imaging of the cornea with images comparable to that of ex vivo histochemical techniques. Corneal nerves bear substantial relevance to clinicians and scientists alike, given their pivotal roles in regulation of corneal sensation, maintenance of epithelial integrity, and proliferation and promotion of wound healing. Thus, IVCM offers a unique method to study corneal nerve alterations in a myriad of conditions, such as ocular and systemic diseases and following corneal surgery, without altering the tissue microenvironment. Of particular interest has been the correlation of corneal subbasal nerves to their function, which has been studied in normal eyes, contact lens wearers, and patients with keratoconus, infectious keratitis, corneal dystrophies, and neurotrophic keratopathy. Longitudinal studies have applied IVCM to investigate the effects of corneal surgery on nerves, demonstrating their regenerative capacity. IVCM is increasingly important in the diagnosis and management of systemic conditions such as peripheral diabetic neuropathy and, more recently, in ocular diseases. In this review, we outline the principles and applications of IVCM in the study of corneal nerves in various ocular and systemic diseases.

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Section: Corneal Nerves In Normal Subjects With and Without Contacmentioning

confidence: 99%

In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease

2017

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“…Previous studies used manual and automated tracing to define the tortuosity mostly on the basis of the individual standard. 22, 24, 27, 30, 31, 36–38 We used a different grading scale (Figure 1) because of the different presentation and severe nerve drop out in LSCD. The degrees of tortuosity of the nerve differed significantly among the early, intermediate, and late stages of LSCD and increased in the more severe stages.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Corneal Subbasal Nerve Plexus in Limbal Stem Cell Deficiency

Chuephanich

Supiyaphun

Aravena

et al. 2016

Cornea

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Purpose To quantify the changes of subbasal nerve plexus in patients with limbal stem cell deficiency (LSCD) using in vivo laser scanning confocal microscopy. Design: Retrospective cross-sectional comparative study Methods Confocal images of 51 eyes of 37 patients with LSCD collected between 2010 and 2015 by the Heidelberg Retina Tomograph III Rostock Corneal Module Confocal Microscope. Two independent observers evaluated the scans of the central cornea. Seventeen normal eyes of 13 patients served as controls. Total subbasal nerve density (SND), density of long nerves (i.e., nerves 200 μm or longer) and the degree of tortuosity were quantified. Results The mean (± SD) total SND and long nerve density were 48.0 ± 34.2 nerves/mm2 and 9.7 ± 10.9 nerves/mm2, respectively, in all eyes with LSCD and 97.3 ± 29.9 nerves/mm2 and 35.3 ± 25.3 nerves/mm2, respectively, in eyes of the control group (P<0.001 for both comparisons). Compared with SND in control subjects, SND was reduced by 34.9% in the early stage, 54.0% in the intermediate stage, and 73.5% in the late stage of LSCD. The degrees of nerve tortuosity were significantly greater in patients with LSCD than in control subjects and differed among the early, intermediate, and late stages of LSCD. Reductions in total SND and long nerve density were positively correlated with the severity of LSCD. Conclusions Reductions in total SND and long nerve density were accompanied by increases in nerve tortuosity in eyes with LSCD. These parameters could be used as quantifiable measures of LSCD severity.

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“…In normal corneas, sensory nerve regeneration is robust, starting near the limbus with newly formed sensory nerve fibers and endings arranged in parallel and extending radially toward the center of the cornea (16,18,19). Diabetic mouse corneas exhibit changes similar to those observed in diabetic human corneas, with fewer nerve insertion sites near the limbus, and severely delayed regeneration of sensory nerve endings that exhibit a tortuous, fragmented appearance (20). Neurotrophins expressed by the developing cornea, including nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin-3, have been shown to play a critical role in attracting sensory nerves (21).…”

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confidence: 88%

Opposing Effects of Neuropilin-1 and -2 on Sensory Nerve Regeneration in Wounded Corneas: Role of Sema3C in Ameliorating Diabetic Neurotrophic Keratopathy

et al. 2019

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The diabetic cornea exhibits pathological alterations, such as delayed epithelial wound healing and nerve regeneration. We investigated the role of semaphorin (SEMA) 3C in corneal wound healing and reinnervation in normal and diabetic B6 mice. Wounding induced the expression of SEMA3A, SEMA3C, and their receptor neuropilin-2 (NRP2), but not NRP1, in normal corneal epithelial cells; this upregulation was suppressed for SEMA3C and NRP2 in diabetic corneas. Injections of Sema3C- specific small interfering RNA and NRP2-neutralizing antibodies in wounded mice resulted in a decrease in the rate of wound healing and regenerating nerve fibers, whereas exogenous SEMA3C had opposing effects in diabetic corneas. NRP1 neutralization, on the other hand, decreased epithelial wound closure but increased sensory nerve regeneration in diabetic corneas, suggesting a detrimental role in nerve regeneration. Taken together, epithelium-expressed SEMA3C plays a role in corneal epithelial wound closure and sensory nerve regeneration. The hyperglycemia-suppressed SEMA3C/NRP2 signaling may contribute to the pathogenesis of diabetic neurotrophic keratopathy, and SEMA3C might be used as an adjunctive therapeutic for treating the disease.

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Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves

Cited by 31 publications

References 23 publications

In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease

In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease

Characterization of the Corneal Subbasal Nerve Plexus in Limbal Stem Cell Deficiency

Opposing Effects of Neuropilin-1 and -2 on Sensory Nerve Regeneration in Wounded Corneas: Role of Sema3C in Ameliorating Diabetic Neurotrophic Keratopathy

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