OBJECTIVECorneal 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 METHODSA 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.RESULTSThere 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.CONCLUSIONSThis 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.

This study provides normative values for HRU, and it suggests that further research with age- and gender-specific distributions must be a key priority in the development of HRU for use as a diagnostic test for peripheral nerve diseases.

Aims/hypothesisSmall 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.MethodsNine 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.ResultsType 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/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity.Conclusions/interpretationWe 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.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4653-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

BackgroundConfirmation of diabetic sensorimotor polyneuropathy (DSP) relies on standard nerve conduction studies (NCS) performed in specialized clinics. We explored the utility of a point-of-care device (POCD) for DSP detection by nontechnical personnel and a validation of diagnostic thresholds with those observed in a normative database.Research Design and Methods44 subjects with type 1 and type 2 diabetes underwent standard NCS (reference method). Two nontechnical examiners measured sural nerve amplitude potential (SNAP) and conduction velocity (SNCV) using the POCD. Reliability was determined by intraclass correlation coefficients (ICC [2], [1]). Validity was determined by Bland-Altman analysis and receiver operating characteristic curves.ResultsThe 44 subjects (50% female) with mean age 56±18 years had mean SNAP and SNCV of 8.0±8.6 µV and 41.5±8.2 m/s using standard NCS and 8.0±8.2 µV and 49.9±11.1 m/s using the POCD. Intrarater reproducibility ICC values were 0.97 for SNAP and 0.94 for SNCV while interrater reproducibility values were 0.83 and 0.79, respectively. Mean bias of the POCD was −0.1±3.6 µV for SNAP and +8.4±6.4 m/s for SNCV. A SNAP of ≤6 µV had 88% sensitivity and 94% specificity for identifying age-and height-standardized reference NCS values, while a SNCV of ≤48 m/s had 94% specificity and 82% sensitivity. Abnormality in one or more of these thresholds was associated with 95% sensitivity and 71% specificity for identification of DSP according to electrophysiological criteria.ConclusionsThe POCD demonstrated excellent reliability and acceptable accuracy. Threshold values for DSP identification validated those of published POCD normative values. We emphasize the presence of measurement bias – particularly for SNCV – that requires adjustment of threshold values to reflect those of standard NCS.

OBJECTIVEPeripheral nerve imaging by portable ultrasound (US) may serve as a noninvasive and lower-cost alternative to nerve conduction studies (NCS) for diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). We aimed to examine the association between the size of the posterior tibial nerve (PTN) and the presence and severity of DSP.RESEARCH DESIGN AND METHODSWe performed a cross-sectional study of 98 consecutive diabetic patients classified by NCS as subjects with DSP or control subjects. Severity was determined using the Toronto Clinical Neuropathy Score. A masked expert sonographer measured the cross-sectional area (CSA) of the PTN at 1, 3, and 5 cm proximal to the medial malleolus.RESULTSFifty-five patients had DSP. The mean CSA of the PTN in DSP compared with control subjects at distances of 1 (23.03 vs. 17.72 mm2; P = 0.004), 3 (22.59 vs. 17.69 mm2; P < 0.0001), and 5 cm (22.05 vs. 17.25 mm2; P = 0.0005) proximal to the medial malleolus was significantly larger. Although the area under the curve (AUC) for CSA measurements at all three anatomical levels was similar, the CSA measured at 3 cm above the medial malleolus had an optimal threshold value for identification of DSP (19.01 mm2) with a sensitivity of 0.69 and a specificity of 0.77 by AUC analysis.CONCLUSIONSThis large study of diabetic patients confirms that the CSA of the PTN is larger in patients with DSP than in control subjects, and US is a promising point-of-care screening tool for DSP.

OBJECTIVEThe prevailing hypothesis that early subclinical small-fiber injury precedes largefiber damage in diabetic sensorimotor polyneuropathy (DSP) is based on lower intraepithelial nerve fiber density in type 2 prediabetic patients despite normal nerve conduction studies (NCSs). We aimed to confirm the same hypothesis in type 1 diabetic patients by examining whether: 1) subjects without DSP include a spectrum with both normal and abnormal small-fiber measures and 2) subjects with DSP have concurrent evidence of abnormal small-fiber measures. RESEARCH DESIGN AND METHODSA healthy control population (n = 53) was used to generate threshold values for four small-fiber tests: cooling detection thresholds (CDTs), laser Doppler imaging of heat-evoked flare (LDI flare ), heart rate variability (HRV), and corneal confocal microscopy. Based on NCS results, type 1 diabetic patients (n = 131) were dichotomized according to the presence or absence of DSP. RESULTSThreshold values derived from healthy control subjects were 26.58C, 1.4 cm 2 , 13%, and 12.9 mm/mm 2 for CDT, LDI flare , HRV, and corneal nerve fiber length, respectively. Among type 1 diabetic patients, 57 of 131 had evidence of DSP, and 74 of 133 did not. Using abnormality of any small-fiber test to define small-fiber dysfunction, 55 of 57 (96.5%) DSP patients and 39 of 74 (52.7%) control subjects without DSP had concurrent small-fiber damage. The severity of small-fiber abnormalities worsened with an increasing number of NCS abnormalities (ANOVA, P < 0.01). CONCLUSIONSOur findings in type 1 diabetes support the prevailing hypothesis that small-fiber dysfunction occurs early in DSP. However, further research is required to determine which combination of small-fiber tests is most suitable as a surrogate marker in clinical trials.Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes, affecting 28-55% of patients (1). A prospective Finnish study found evidence of probable or definite neuropathy in 8.3% of diabetic patients at the time of diagnosis, 16.7% after 5 years, and 41.9% after 10 years (2). Diabetes-related peripheral neuropathy results in serious morbidity, including chronic neuropathic pain, leg

DPP-4 inhibition promotes a distal tubular natriuresis in conjunction with increased levels of intact SDF-1α. Because of the distal location of the natriuretic effect, DPP-4 inhibition does not affect tubuloglomerular feedback or impair renal hemodynamic function, findings relevant to using DPP-4 inhibitors for treating type 2 diabetes.

Single- and dual-hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out.