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Objective: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables., Research Design and Methods: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes., Results: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA 1c or its change over follow-up., Conclusions: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP., (© 2020 by the American Diabetes Association.)

Corneal confocal microscopy (CCM) has been used to identify corneal nerve damage and increased Langerhans cell (LC) density in adults with Type 1 diabetes mellitus (T1DM). The purpose of this study was to evaluate whether corneal confocal microscopy can identify early corneal nerve damage and change in LC density in children and adolescents with T1DM. 64 participants with T1DM (age-14.6 ± 2.5 years, duration of diabetes-9.1 ± 2.7 years, HbA1c-75.66 ± 2.53 mmol/mol [9.1 ± 1.8%]) and 48 age-matched healthy control subjects underwent CCM. Sub-basal corneal nerve morphology and the density of mature and immature LCs was quantified. Corneal nerve fibre length and branch density were lower, whilst fibre density and tortuosity did not differ and both immature and mature LC density was significantly higher in T1DM compared to control subjects. There was no association between HbA1c and duration of diabetes with nerve fibre parameters or LC's density. Children and adolescents with T1DM demonstrate early immune activation and nerve degeneration.

Aims/hypothesis: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP., Methods: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard., Results: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm 2 in type 1 diabetes and 12.3 mm/mm 2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm 2 to rule in DSP and an upper value of 15.3 mm/mm 2 to rule out DSP were associated with 88% specificity and 88% sensitivity., Conclusions/interpretation: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Purpose: To assess the image and patient level interrater agreement and repeatability within 1 month for corneal nerve fiber length (CNFL) measured using in vivo corneal confocal microscopy (IVCCM) in children., Methods: Seventy-one subjects (mean [SD] age 14.3 [2.6] years, range 8-18 years; 44 with type 1 diabetes and 27 controls; 36 males and 35 females) were included. 547 images (∼6 images per subject) were analyzed manually by two independent and masked observers. One-month repeat visit images were analyzed by a single masked observer in 21 patients. Automated image analysis was then performed using a specialized computerized software (ACCMetrics)., Results: For CNFL, the ICC (95% CI) were 0.94 (0.93-0.95) for image-level, 0.86 (0.78-0.91) for patient-level, and 0.88 (0.72-0.95) for the 1-month repeat assessment, and the Bland-Altman plots showed minimal bias between observers. Although there was excellent agreement between manual and automated analysis according to an ICC 0.89 (0.82-0.93), the Bland-Altman plot showed a consistent bias with manual measurements providing higher readings., Conclusions: In vivo corneal confocal microscopy image analysis shows good reproducibility with excellent intraindividual and interindividual variability in pediatric subjects. Since the image-level reproducibility is stronger than the patient-level reproducibility, refinement of the method for image selection will likely further increase the robustness of this novel, rapid, and noninvasive approach to detect early neuropathy in children with diabetes. Further studies on the use of IVCCM to identify early subclinical neuropathy in children are indicated.

Objective: Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters., Research Design and Methods: A total of 1,965 corneal nerve images from 343 healthy volunteers were pooled from six clinical academic centers. All subjects underwent examination with the Heidelberg Retina Tomograph corneal confocal microscope. Images of the central corneal subbasal nerve plexus were acquired by each center using a standard protocol and analyzed by three trained examiners using manual tracing and semiautomated software (CCMetrics). Age trends were established using simple linear regression, and normative corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) reference values were calculated using quantile regression analysis., Results: There was a significant linear age-dependent decrease in CNFD (-0.164 no./mm(2) per year for men, P < 0.01, and -0.161 no./mm(2) per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm(2) per year for men, P = 0.26, and -0.050 no./mm(2) per year for women, P = 0.78). CNFL decreased in men (-0.045 mm/mm(2) per year, P = 0.07) and women (-0.060 mm/mm(2) per year, P = 0.02). CNFT increased with age in men (0.044 per year, P < 0.01) and women (0.046 per year, P < 0.01). Height, weight, and BMI did not influence the 5th percentile normative values for any corneal nerve parameter., Conclusions: This study provides robust worldwide normative reference values for corneal nerve parameters to be used in research and clinical practice in the study of diabetic and other peripheral neuropathies., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)