scholarly journals Corneal Confocal Microscopy to Image Small Nerve Fiber Degeneration: Ophthalmology Meets Neurology

2021 ◽  
Vol 2 ◽  
Author(s):  
Ioannis N. Petropoulos ◽  
Gulfidan Bitirgen ◽  
Maryam Ferdousi ◽  
Alise Kalteniece ◽  
Shazli Azmi ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Diabetic Neuropathy ◽  
Nerve Fiber ◽  
Clinical Intervention ◽  
Nerve Fibers ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Intraepidermal Nerve Fiber Density ◽  
Corneal Nerve ◽  
Small Nerve

Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases.

scholarly journals Early detection of diabetic neuropathy by investigating CNFL and IENFD in thy1-YFP mice

2016 ◽  
Vol 231 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Janine Leckelt ◽  
Pedro Guimarães ◽  
Annett Kott ◽  
Alfredo Ruggeri ◽  
Oliver Stachs ◽  
...  
Keyword(s):  
Diabetic Neuropathy ◽  
Nerve Fiber ◽  
Blood Glucose Concentration ◽  
Ex Vivo ◽  
Surrogate Marker ◽  
Nerve Fibers ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Intraepidermal Nerve Fiber Density ◽  
Corneal Nerve

Small fiber neuropathy is one of the most common and painful long-term complications of diabetes mellitus. Examination of the sub-basal corneal nerve plexus is a promising surrogate marker of diabetic neuropathy. To investigate the efficacy, reliability and reproducibility of in vivo corneal confocal microscopy (IVCCM), we used thy1-YFP mice, which express yellow fluorescence protein (YFP) in nerve fibers. 4 weeks after multiple low-dose injections of streptozotocin, thy1-YFP mice showed manifest diabetes. Subsequent application of insulin-releasing pellets for 8 weeks resulted in a significant reduction of blood glucose concentration and HbA1c, a significant increase in body weight and no further increase in advanced glycation end products (AGEs). IVCCM, carried out regularly over 12 weeks and analyzed both manually and automatically, revealed a significant loss of corneal nerve fiber length (CNFL) during diabetes manifestation and significant recovery after insulin therapy. Ex vivo analyses of CNFL by YFP-based microscopy confirmed the IVCCM results (with high sensitivity between manual and automated approaches) but demonstrated that the changes were restricted to the central cornea. Peripheral areas, not accessible by IVCCM in mice, remained virtually unaffected. Because parallel assessment of intraepidermal nerve fiber density revealed no changes, we conclude that IVCCM robustly captures early signs of diabetic neuropathy.

scholarly journals Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Michael Fleischer ◽  
Inn Lee ◽  
Friedrich Erdlenbruch ◽  
Lena Hinrichs ◽  
Ioannis N. Petropoulos ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Confocal Microscopy ◽  
Diabetic Neuropathy ◽  
Nerve Fiber ◽  
Cell Density ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Basal Layer ◽  
Nerve Fibers ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve

Abstract Background Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes. Methods In this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified. Results Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes. Conclusions An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.

scholarly journals Corneal confocal microscopy demonstrates axonal loss in different courses of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioannis N. Petropoulos ◽  
Kathryn C. Fitzgerald ◽  
Jonathan Oakley ◽  
Georgios Ponirakis ◽  
Adnan Khan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Confocal Microscopy ◽  
Nerve Fiber ◽  
Clinically Isolated Syndrome ◽  
Axonal Loss ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Segmentation Methods ◽  
Relapsing Remitting ◽  
Corneal Nerve

AbstractAxonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm2, 95% CI − 8.94 to − 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm2, 95% CI − 9.55 to − 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI − 0.09 to − 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% − 0.13 to − 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome.

scholarly journals Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy

2019 ◽  
Vol 104 (12) ◽  
pp. 6220-6228
Author(s):  
Sonja Püttgen ◽  
Gidon J Bönhof ◽  
Alexander Strom ◽  
Karsten Müssig ◽  
Julia Szendroedi ◽  
...  
Keyword(s):  
Nerve Fiber ◽  
Rating Scale ◽  
Nerve Fibers ◽  
Control Group ◽  
Fiber Density ◽  
Nerve Branch ◽  
Perception Threshold ◽  
Cross Sectional ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve

AbstractContextThe factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.ObjectiveWe hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.Design and MethodsIn this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.ResultsAfter adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.ConclusionDespite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.

scholarly journals Assessment and comparison of the morphology and function of the corneal sub-basal nerve plexus in type-1 diabetes mellitus patients and in healthy subjects

2016 ◽  
Vol 1 (1) ◽  
pp. 51-63
Author(s):  
Irmante Derkac ◽  
Ingrida Januleviciene ◽  
Kirwan Asselineau ◽  
Dzilda Velickiene
Keyword(s):  
Nerve Fiber ◽  
Healthy Subjects ◽  
Nerve Fibers ◽  
Corneal Sensitivity ◽  
Fiber Density ◽  
Corneal Confocal Microscopy ◽  
Corneal Nerve ◽  
Type 1 Dm ◽  
Nerve Fiber Density

Aim/purpose: It is believed that small nerve bundles are damaged in the earliest stages of neuropathy caused by diabetes mellitus (DM). Our goal was to evaluate and compare anatomical characteristics of corneal nerve fibers and corneal sensitivity in type-1 DM patients and in healthy control subjects.Design: A prospective, masked, controlled cross-sectional clinical study.Method: Thirty patients with type-1 DM and ten non-diabetic healthy subjects underwent a corneal confocal microscopy to evaluate the corneal sub-basal nerve fibers (density, number of nerves and branches, total nerve length) and contact corneal esthesiometry.Results: Diabetic patients had significantly lower corneal nerve fiber density density (14.32 ± 5.87 vs. 19.71 ± 5.59 mm/mm2; p = 0.023 ) nerve branches number (4.57 ± 3,91 vs. 9.90 ± 5.8 n°/image; p = 0.006) , nerve fiber length (2.28 ± 0.94 vs. 3.13 ± 0.89 mm; p = 0.032) and corneal sensitivity (1.13 ± 0.29 vs. 0.98 ± 0.058 gr/mm2 p = 0.02), as compared with controls. A negative correlation was found between corneal nerve fiber length, corneal nerve number, corneal nerve fiber density and disease duration (p < 0.05).Conclusion: Corneal confocal microscopy and corneal sensitivity evaluation are noninvasive techniques helping to detect early changes in the sub-basal nerve plexus characteristic for diabetic neuropathy (DN) in patients with type-1 DM. Further studies are required to investigate the role of corneal neuropathy assessment using these novel techniques as a toll to detect early DN. 

scholarly journals Erratum to: ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

2016 ◽  
Vol 22 (1) ◽  
pp. 674-674
Author(s):  
Albert Dahan ◽  
Ann Dunne ◽  
Maarten Swartjes ◽  
Paolo L. Proto ◽  
Lara Heij ◽  
...  
Keyword(s):  
Nerve Fiber ◽  
Fiber Density ◽  
Corneal Nerve ◽  
Nerve Fiber Density ◽  
Small Nerve

Corneal nerve quantification predicts the severity of symptoms in sarcoidosis patients with painful neuropathy

TECHNOLOGY ◽  
2013 ◽  
Vol 01 (01) ◽  
pp. 20-26 ◽  
Author(s):  
M. Brines ◽  
M. Swartjes ◽  
M.R. Tannemaat ◽  
A. Dunne ◽  
M. van Velzen ◽  
...  
Keyword(s):  
Nerve Fiber ◽  
Adult Population ◽  
Brief Pain Inventory ◽  
The United States ◽  
Fiber Density ◽  
Painful Neuropathy ◽  
Small Fiber ◽  
Corneal Confocal Microscopy ◽  
Fiber Number ◽  
Corneal Nerve

Small fiber neuropathy (SFN) is a debilitating condition characterized by chronic pain as well as sensory and autonomic dysfunction. SFN is an increasingly recognized component of a large number of diseases, including sarcoidosis. Although affecting an estimated 2–3% of the adult population in the United States, it often remains undiagnosed. Skin biopsy for evaluating intra-epidermal nerve fiber density (IENFD) and more recently corneal confocal microscopy (CCM) have been used to identify small fiber damage in patients with neuropathy. We demonstrate a significant reduction in IENFD, corneal nerve fiber number and length, with no change in the number of branches in patients with painful sarcoid neuropathy. Moreover, unlike IENFD, corneal nerve fiber number and length inversely correlate with the degree to which pain interferes with activities of daily living as assessed by the Brief Pain Inventory questionnaire. CCM thus constitutes an accurate, non-invasive assessment technique to aid in the diagnosis of SFN, as well as an objective marker of symptoms in patients with painful sarcoid neuropathy.

scholarly journals Combining In Vivo Corneal Confocal Microscopy with Deep Learning-based Analysis Reveals Sensory Nerve Fiber Loss in Acute SIV Infection

2020 ◽  
Author(s):  
Megan E. McCarron ◽  
Rachel L. Weinberg ◽  
Jessica M. Izzi ◽  
Suzanne E. Queen ◽  
Stuti L. Misra ◽  
...  
Keyword(s):  
Fractal Dimension ◽  
Deep Learning ◽  
Confocal Microscopy ◽  
Nerve Fiber ◽  
Fiber Length ◽  
Sensory Nerve ◽  
Corneal Confocal Microscopy ◽  
Siv Infection ◽  
Corneal Nerve

AbstractPurposeTo characterize corneal subbasal nerve plexus morphologic features using in vivo corneal confocal microscopy (IVCM) in normal and SIV-infected macaques and to implement automated assessments using novel deep learning-based methods customized for macaque studies.MethodsIn vivo corneal confocal microscopy images were collected from both male and female age-matched specific-pathogen free rhesus and pigtailed macaques housed at the Johns Hopkins University breeding colony using the Heidelberg HRTIII with Rostock Corneal Module. We also obtained repeat IVCM images of 12 SIV-infected animals including pre-infection and 10 day post-SIV infection time-points. All IVCM images were analyzed using a novel deep convolutional neural network architecture developed specifically for macaque studies.ResultsDeep learning-based segmentation of subbasal nerves in IVCM images from macaques demonstrated that corneal nerve fiber length (CNFL) and fractal dimension measurements did not differ between species, but pigtailed macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques (P = 0.005). Neither sex nor age of macaques was associated with differences in any of the assessed corneal subbasal nerve parameters. In the SIV/macaque model of HIV, acute SIV infection induced significant decreases in both corneal nerve fiber length and fractal dimension (P= 0.01 and P= 0.008 respectively).ConclusionsThe combination of IVCM and objective, robust, and rapid deep-learning analysis serves as a powerful noninvasive research and clinical tool to track sensory nerve damage, enabling early detection of neuropathy. Adapting the deep-learning analyses to human corneal nerve assessments will refine our ability to predict and monitor damage to small sensory nerve fibers in a number of clinical settings including HIV, multiple sclerosis, Parkinson’s disease, diabetes, and chemotherapeutic neurotoxicity.

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