Characterization and Prediction of Early Onset Diabetic Peripheral Neuropathy (NeuroPredict)

Background

Diabetic peripheral neuropathy is the most common complication to diabetes mellitus affecting as much as 50% of the population with diabetes. Symmetrical sensory neuropathy is by far the most common pattern, which often progress slowly over many years, although some individuals experience faster and more severe courses. Despite the frequent occurrence, the causes of diabetic peripheral neuropathy are largely unknown, which is reflected in the fact that no disease-modifying treatments are available for preventing, treating or even halting the progression of the disease. The consequences can be dire, as neuropathy frequently leads to foot ulcers, amputations or intolerable neuropathic pain in the lower extremities. Sensory loss may go completely undetected in diabetes, as there often are literally no symptoms. For many individuals, the development of diabetic peripheral neuropathy can therefore proceed completely unnoticed, making regular screening the most important tool for diagnosing the condition. Unfortunately, unlike nephropathy or retinopathy, diabetic peripheral neuropathy is not easily screened for, as the condition lacks reliable markers for early- or progressing disease. Therefore, screening for diabetic peripheral neuropathy currently revolves around diagnosing loss of protective sensation, judged by the inability to feel vibration or light touch. However, in their most recent guidelines, the American Diabetes Association has included screening for small fibre neuropathy using either the cold- and heat perception thresholds or pinprick as a clinical standard. Although this acknowledgement of the importance of assessing not only large- but also small nerve fibres is a huge step towards early detection of diabetic peripheral neuropathy, the overriding issue of insensitive, unreproducible, and inaccurate bedside tests for small nerve fibres remains. While cold- and heat perception and pinprick sensation are indeed mediated by small nerve fibres, the sensitivity of these methods, outside of extreme standardization only achievable in dedicated neuropathy research-centres, remain poor and not usable on an individual level. This lack of sensitivity has also become apparent in several large clinical trials, where the methods have continuously failed as robust clinical endpoints. Due to this, the hunt for a sensitive and reproducible method for adequate assessment of the small nerve fibres have begun. Amongst several interesting methods, two have gained particular interest (corneal confocal microscopy and skin biopsies with quantification of intra-epidermal nerve fibre density), due to their diverse strengths, although clinical application is currently limited to a few specialized sites. Furthermore, both methods suffer several inherent issues including that fact that they only provide information about the structure of the nerves and not the function.

In this study, we will therefore combine established gold standards for early detection of structural changes to small nerve fibres in diabetic peripheral neuropathy with cutting-edge, experimental techniques for measuring the function of the same nerve fibres. Furthermore, we will also evaluate several advanced technologies as an alternative to the current clinical standard for large fibre evaluation (biothesiometry).

Study objectives

• To establish a prospective cohort for long-term follow-up for early detection of the development of diabetic peripheral neuropathy
• To evaluate alternative methods for screening for diabetic peripheral neuropathy in a clinical setting
• To evaluate measurements of small nerve fibre function against methods for small nerve fibre structure