Clinical recognition of DPN is imperative for allowing timely symptom management to reduce the morbidity associated with this condition.

OBJECTIVEQuantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard.RESEARCH DESIGN AND METHODSEighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy.RESULTSManual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14).CONCLUSIONSThis study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.

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OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESEARCH DESIGN AND METHODSThirty subjects with IGT and 17 age-matched control subjects underwent an oral glucose tolerance test, assessment of neuropathic symptoms and deficits, quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) at baseline and annually for 3 years.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.

Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Aims/hypothesis The study aimed to assess the impact on neuropathy of simultaneous pancreas and kidney transplantation (SPK) in individuals with type 1 diabetes. Methods This longitudinal observational study examined neuropathic symptoms, deficits, quantitative sensory testing, neurophysiology, corneal confocal microscopy and skin biopsy results in 32 healthy (non-diabetic) control participants, 29 individuals with type 1 diabetes and severe diabetic peripheral neuropathy [DPN] and 36 individuals with type 1 diabetes after SPK. Results Following SPK, HbA 1c , eGFR, triacylglycerols and HDL improved significantly (all p < 0.05). Compared with the DPN group, which remained unchanged over the 36 month study period, corneal confocal microscopy assessments improved over 36 months following SPK, with increasing corneal nerve fibre density of 5/mm 2 (95% CI 1.8, 8.2; p = 0.003) and corneal nerve fibre length of 3.2 mm/mm 2 (95% CI 0.9, 5.5; p = 0.006). The Neuropathy Symptom Profile and peroneal nerve conduction velocity also improved significantly by 36 months compared with DPN (2.5; 95% CI 0.7, 4.3; p = 0.008 and 4.7 m/s; 95% CI 2.2, 7.4; p = 0.0004, respectively), but with a temporal delay compared with the corneal confocal microscopy assessments. Intraepidermal nerve fibre density did not change following SPK; however, mean dendritic length improved significantly at 12 ( p = 0.020) and 36 ( p = 0.019) months. In contrast, there were no changes in the Neuropathy Disability Score, quantitative sensory testing or cardiac autonomic function assessments. Except for a small decrease in corneal nerve fibre density in the healthy control group, there were no changes in any other neuropathy measure in the healthy control or DPN groups over 36 months. Conclusions/interpretation SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin, followed by an improvement in neuropathic symptoms and peroneal nerve conduction velocity. Electronic supplementary material The online version of this article (10.1007/s00125-019-4897-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Diabetic peripheral neuropathy (DPN) is a major sequela of diabetes mellitus and may have a detrimental effect on the gait of people with this complication. DPN causes a disruption in the body’s sensorimotor system and is believed to affect up to 50% of patients with diabetes mellitus, dependent on the duration of diabetes. It has a major effect on morbidity and mortality. The peripheral nervous system controls the complex series of events in gait through somatic and autonomic functions, careful balancing of eccentric and concentric muscle contractions and a reliance on the sensory information received from the plantar surface. In this literature review focussing on kinetics, kinematics and posture during gait in DPN patients, we have identified an intimate link between DPN and abnormalities in gait and demonstrated an increased risk in falls for older patients with diabetes. As such, we have identified a need for further research on the role of gait abnormalities in the development of diabetic foot ulceration and subsequent amputations.

PurposeTo assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM).MethodsIVCCM was performed in 35 participants by a single examiner. For each participant, 4 observers used a standardized protocol to select 6 central corneal nerve images to assess the inter-observer variability. Furthermore, images were selected by a single observer on two occasions to assess intra-observer variability and the effect of sample size was assessed by comparing 6 with 12 images. Corneal nerve fiber density (CNFD), branch density (CNBD) and length (CNFL) were quantified using fully automated software. The data were compared using the intra class correlation coefficient (ICC) and Bland-Altman agreement plots for all experiments.ResultsThe ICC values for CNFD, CNBD and CNFL were 0.93 (P<0.0001), 0.96 (P<0.0001) and 0.95 (P<0.0001) for inter-observer variability and 0.95 (P<0.0001), 0.97 (P<0.001) and 0.97 (P<0.0001) for intra-observer variability. For sample size variability, ICC values were 0.94 (P<0.0001), 0.95 (P<0.0001), and 0.96 (P<0.0001) for CNFD, CNBD and CNFL. Bland-Altman plots showed excellent agreement for all parameters.ConclusionsThis study shows that implementing a standardized protocol to select IVCCM images results in high intra and inter-observer reproducibility for all corneal nerve parameters and 6 images are adequate for analysis. IVCCM could therefore be deployed in large multicenter clinical trials with confidence.