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

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.

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Intraepidermal Nerve fiber Density in healthy Subjects with Diabetic Family History. ¿Is Neuropathy an early Biomarker? A Pilot study

Neuroscience and Neurological Surgery ◽

10.31579/2578-8868/169 ◽

2021 ◽

Vol 8 (3) ◽

pp. 01-08

Author(s):

Ildefonso Leyva

Keyword(s):

Pilot Study ◽

Family History ◽

Nerve Fiber ◽

Healthy Subjects ◽

Nerve Fibers ◽

Diabetic Patients ◽

Fiber Density ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

Objective: Evaluate the intraepidermal nerve fiber density in healthy subjects with diabetic family history compared with diabetic patients and controls. Introduction: Neuropathy is the most prevalent chronic complication of diabetes, presenting various symptoms that interfere with daily living activities, psychosocially disability, and reducing life quality. The skin biopsy is recognized as a minimally invasive procedure that allows morphometric quantification of intraepidermal nerve fibers and has made possible the study of peripheral neuropathies involving thin fibers that traditional methods cannot diagnose. Methods: Analytical cross-sectional observational pilot study with seven patients per group including healthy, diabetic, and healthy with diabetic family history subjects. For the statistical analysis, we used the R package, R software version 3.3.2, with a confidence level of 95%. The research was performed with ANOVA and Kruskal-Wallis test to test the primary objective. Results: The density of intraepidermal nerve fibers is similar between the group with diabetic family history 6.8 ± 2.1 (3.5 - 10.1) and diabetic patients 6.3 ± 2.9 (3.5 - 7.05) while the control group reported a density in parameters of normality of 10± 1.2 (8.2 - 10.1) with a p= 0.01 between the three groups. The decrease of intraepidermal nerve fibers showed a tendency to decrease with increasing age and BMI with a ratio coefficient for age of r= -0.342, 95% CI (-0.67 - 0.106), p= 0.129; and for BMI of r= -0.36, 95% CI (-0.685 - 0.0847), p= 0.109. Conclusion: Intraepidermal nerve fiber density is decreased in subjects with a family history of diabetes mellitus type 2 and even more so in diabetics, with no statistical difference.

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

Journal of Endocrinology ◽

10.1530/joe-16-0284 ◽

2016 ◽

Vol 231 (2) ◽

pp. 147-157 ◽

Cited By ~ 8

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.

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

Frontiers in Pain Research ◽

10.3389/fpain.2021.725363 ◽

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.

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Effect of Diabetes Mellitus Type 1 Diagnosis on the Corneal Cell Densities and Nerve Fibers

Physiological Research ◽

10.33549/physiolres.933899 ◽

2018 ◽

pp. 963-974

Author(s):

M. ČESKÁ BURDOVÁ ◽

M. KULICH ◽

D. DOTŘELOVÁ ◽

G. MAHELKOVÁ

Keyword(s):

Diabetes Mellitus ◽

Nerve Fiber ◽

Cell Density ◽

Nerve Fibers ◽

Diabetic Patients ◽

Fiber Density ◽

Corneal Cell ◽

Fiber Damage ◽

Corneal Confocal Microscopy

Relation of diabetes mellitus (DM) to the various stages of corneal nerve fiber damage is well accepted. A possible association between changes in the cornea of diabetic patients and diabetic retinopathy (DR), DM duration, and age at the time of DM diagnosis were evaluated. The study included 60 patients with DM type 1 (DM1) and 20 healthy control subjects. The density of basal epithelial cells, keratocytes and endothelial cells, and the status of the subbasal nerve fibers were evaluated using in vivo corneal confocal microscopy. Basal epithelial cell density increased with age (p=0.026), while stromal and endothelial cell density decreased with age (p=0.003, p=0.0005, p<0.0001). After the DM1 diagnosis was established, this association with age weaken. We showed nerve fiber damage in DM1 patients (p˂0.0001). The damage correlated with the degree of DR. DM1 patients with higher age at DM1 diagnosis had a higher nerve fiber density (p=0.0021). These results indicated that age at DM1 diagnosis potentially has an important effect on final nerve fiber and corneal cell density.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-01072 ◽

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.

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

Molecular Medicine ◽

10.2119/molmed.2013.00122.erratum ◽

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

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Neurophysiology and Intraepidermal Nerve Fiber Density in Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1) (P03.202)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.p03.202 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. P03.202-P03.202

Author(s):

W. David ◽

A. L. Oaklander ◽

J. Pan ◽

P. Novak ◽

R. Brown ◽

...

Keyword(s):

Nerve Fiber ◽

Autonomic Neuropathy ◽

Fiber Density ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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

TECHNOLOGY ◽

10.1142/s2339547813500039 ◽

2013 ◽

Vol 01 (01) ◽

pp. 20-26 ◽

Cited By ~ 6

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.

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

Scientific Reports ◽

10.1038/s41598-021-01226-1 ◽

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.

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