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OBJECTIVE Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2–7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1–5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70–5.11; P < 0.001) for new-onset DPN. CONCLUSIONS CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future.

The measurement of corneal nerve fibre length (CNFL) by in vivo corneal confocal microscopy serves as a biomarker for the presence of diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the threshold for abnormal CNFL change, its prevalence in T1D and T2D, and if this biomarker could predict DSP progression. Data from 622 diabetes patients (424 T1D and 198 T2D) and 204 nondiabetic controls were examined as part of a 5-centre multinational consortium study. Patients had at least 1-year of follow-up data and were classified with Rapid CNFL (RCNFL) loss if the change in CNFL was beyond the 5thpercentile of the controls. Controls were 38±20 y, had a median of 3 follow-up visits over a median of 3.0 y, baseline CNFL of 16±4 mm/mm2, and a mean annual change in CNFL of -0.1%[90% CI, -5.9-5.0%]. RCNFL loss was defined by the 5th percentile value of -6% or greater loss. T1D patients were 40±19 y, had a median of 3 visits over a median of 4.4 y, baseline CNFL of 13.5±4.3 mm/mm2 and had a mean annual change in CNFL of -0.8%[90% CI, -14.0-9.9%]. T2D patients were 60±8 y, had a median of 3 visits over a median of 5.3 y, baseline CNFL of 13.8±4.4 mm/mm2 and a mean annual change in CNFL of -0.2%[90% CI, -14.1-14.3%]. Prevalence of RCNFL loss was similar between T1D (64(16.0%)) and T2D (37(19.4%), p=0.31). Baseline CNFL was not different between cases with RCNFL loss (14.3±4.2 mm/mm2) and diabetes controls (13.5±4.3 mm/mm2) (p=0.073). Cases were more likely to have DSP at baseline (47, (47%) vs. 144, (30%), p=0.001). During follow-up, CNFL decreased in cases (-3.5 mm/mm2[-5.7, -1.5] vs. 0.59 mm/mm2 [-1.3, 2.4], p>0.001). Cases showed DSP progression measured by changes in sural nerve conduction velocity (0.0 m/s [-1.2, 2.4] vs. 0.2 m/s [-1.1, 5.0]. p=0.027) and peroneal conduction velocity (-1.1 m/s [-3.6, 0.9] vs. -0.6 [-2.8, 1.5], p=0.001) compared to diabetes controls. Rapid CNFL loss occurs in over 16% of diabetes patients and appears to predict those at highest risk for DSP progression. Disclosure E.J.H. Lewis: Board Member; Spouse/Partner; Nutarniq Corp. Employee; Self; Nutarniq Corp. L. Lovblom: None. M. Ferdousi: None. M. Jeziorska: None. D. Pacaud: Other Relationship; Self; Novo Nordisk A/S, Sandoz, TOLMAR. N. Pritchard: None. R.M. Shtein: None. N. Efron: None. M. Tavakoli: None. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. R.A. Malik: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. Funding National Institutes of Health (1DP3DK104386-01)

Corneal Nerve Fibre Length (CNFL) reasonably identifies the presence of neuropathy in patients with T1D and T2D. In this longitudinal diagnostic study, we aimed to determine its ability to predict future neuropathy. Among 998 participants with diabetes, we examined the 387 who did not have neuropathy at baseline and who had follow-up in a 5-centre multinational consortium study. Participants underwent corneal nerve quantification and clinical and electrophysiological examination for neuropathy at baseline and in scheduled follow-up. Predictive validity and diagnostic thresholds were determined using time-dependent receiver operating characteristic (ROC) curves that accounted for censoring, and used baseline and time-updated CNFL. Estimates were derived in the T1D subcohort and validated in the T2D subcohort. The 387 participants had mean follow-up of 4.8 years (interquartile range 3-7y). 288 had T1D (baseline mean age 35±17 years and A1c 8.2±1.5%) and 99 had T2D (baseline age 59±8 years and A1c 7.3±1.1%). New onset neuropathy occurred in 85 participants (22%; incidence rate 5.05 events per 100 person years). The crude area under the ROC curve (AUC) for CNFL was 0.64 (95% CI 0.56-0.73, p=0.001) in the T1D derivation set, which was confirmed in the T2D validation set (AUC 0.69, 95% CI 0.57-0.81, p=0.002). In the combined cohort, time-dependent ROC curves were generated for 2, 4, 6, and 8 years; AUC ranged from 0.67 to 0.71 for baseline CNFL, and 0.66 to 0.68 for time-updated CNFL. The optimal diagnostic threshold for baseline CNFL was 14.1mm/mm2 (sensitivity 67%, specificity 63%, 1ikelihood ratio (LR) positive 1.8, LR negative 0.5, Cox proportional hazard rate ratio 2.79, p Disclosure B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. L. Lovblom: None. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. M. Ferdousi: None. A. Orszag: None. K. Edwards: None. N. Pritchard: None. A.W. Russell: None. C. Dehghani: None. D. Pacaud: Other Relationship; Self; Novo Nordisk A/S, Sandoz, TOLMAR. K. Romanchuk: None. J. Mah: None. M. Jeziorska: None. A. Marshall: None. R.M. Shtein: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. S.I. Lentz: None. A.J. Boulton: None. M. Tavakoli: None. N. Efron: None. R.A. Malik: None. Funding National Institutes of Health

Background: The transition from pediatric to adult diabetes care is a vulnerable period for youth with diabetes. During transition, youth with diabetes are at high risk for loss to follow-up, worsening glycemic control, and increased hospitalizations. Objective: Our objective was to assess the effect of a technology enhanced transition coordinator on loss to follow-up in youth with diabetes transitioning from pediatric to adult diabetes care. Methods: This open label, pre-post pragmatic clinical trial, assessed the effect of a technology enhanced transition coordinator in transitioning young adults with diabetes from pediatric to adult diabetes care. Our primary outcome was the rate of loss to follow-up defined as no outpatient diabetes appointments in the one year following transfer. The usual care (control) cohort were youth with diabetes who received usual care (i.e., transition preparation during pediatric diabetes appointments prior to transfer). The intervention cohort received the usual care and had a transition coordinator who assisted them through the transition period with regular, per protocol contact, by texting, emailing, Twitter®, and/or postings on a private Facebook® page. Results: Baseline average hemoglobin A1c was not different between the intervention cohort [number (n) = 101, 47.5% females] versus the usual care cohort (n= 209, 49.3% female) [8.9 ± 2.0 standard deviation (SD) versus 9.1 ± 2.4 SD, p=0.28] in the year prior to transfer. In the year following transfer, 49.3% of young adults in the usual care cohort versus 11.8% of young adults in the intervention group did not attend any outpatient diabetes appointments (p< 0.01) in the year following transfer. Conclusions: Our technology enhanced transition coordinator intervention was successful in reducing loss to follow-up in transitioning young adults with diabetes. Importantly, this program used simple readily accessible technologies which increases the transferability and sustainability of this intervention. Disclosure S. Butalia: None. A. McGuire: None. S. Crawford: None. D. Dyjur: None. J. Mercer: None. D. Pacaud: Other Relationship; Self; Novo Nordisk A/S, Sandoz, TOLMAR. Funding Lawson Foundation

The measurement of corneal nerve fibre length (CNFL) by in vivo corneal confocal microscopy is a biomarker for the presence of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, its prevalence in T1D and T2D, and its clinical predictors. We examined longitudinal data from 94 nondiabetic controls and 297 diabetes participants (224 T1D and 73 T2D) from an ongoing multi-centre NIH-funded study of IVCCM in diabetes. Participants were included if they had at least 1-year of follow-up data and were classified as progressors with “rapid corneal nerve fibre loss” (RCNFL) if the loss of CNFL was beyond the 5th percentile (-14%/y) of the nondiabetic controls. Nondiabetic controls were 43.0±15.8 y, had a median of 2 follow-up visits over a median of 2 y, baseline CNFL of 15.4±4.2 mm/mm2, and the median annual change in CNFL was -1.7%[90% CI, -14.3 to 30.9%]. Diabetes participants were 49.6±15.5 y, had a median of 3 visits over a median of 2 y, baseline CNFL of 14.3±4.4 mm/mm2 and the median annual change in CNFL was 1.8%[90% CI, -26.1 to 25.0%]. There were 33(11.1%) cases of RCNFL in the diabetes sub-cohort, which was comparable between T1D (26(11.6%)) and T2D (7(9.6%)). Progressors did not differ from non-progressors for baseline levels of age, sex, BMI, HbA1c or CNFL levels. However, progressors were more likely to have baseline DSP (16(50%) vs. 83(32%), p=0.048), lower cooling detection threshold (21.3 C±8.5 vs. 25.3 C±7.2, p=0.048) and lower heart rate variability (26.3±13.1 vs. 38.2±25.4, p=0.036). A more rapid loss of CNFL (RCNFL) exceeding 14%/y occurs in ∼11% of diabetes patients. This more rapid of corneal nerves may identify patients at highest risk for the development or progression of DSP. Disclosure E.J.H. Lewis: Employee; Self; Nutarniq Corp. M. Tavakoli: None. L. Lovblom: None. E.M. Halpern: None. M. Jeziorska: None. D. Pacaud: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Versartis, Inc. N. Pritchard: Other Relationship; Self; JDRF, NHMRC. R.M. Shtein: None. N. Efron: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc.. R.A. Malik: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc..

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./mm2 per year for men, P < 0.01, and −0.161 no./mm2 per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm2 per year for men, P = 0.26, and −0.050 no./mm2 per year for women, P = 0.78). CNFL decreased in men (−0.045 mm/mm2 per year, P = 0.07) and women (−0.060 mm/mm2 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.