Painful and Non-painful Diabetic Neuropathy, Diagnostic Challenges and Implications for Future Management

Troels S. Jensen; Pall Karlsson; Sandra S. Gylfadottir; Signe T. Andersen; David L. Bennett; Hatice Tankisi; Nanna B. Finnerup; Astrid J. Terkelsen; Karolina Khan; Andreas C. Themistocleous; Alexander G. Kristensen; Mustapha Itani; Søren H. Sindrup; Henning Andersen; Morten Charles; Eva L. Feldman; Brian C. Callaghan


Brain. 2021;144(6):1632-1645. 

In This Article

Abstract and Introduction


Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30–40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies.

The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential.

Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain.

Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.


Peripheral neuropathies represent a heterogeneous group of neurological disorders that affect the peripheral nerves, causing sensory, motor, or autonomic symptoms or signs, or most frequently, a combination thereof. Neuropathies are present in 1–8% of the general population[1–4] and vary in aetiologies, including metabolic, toxic, nutritional, inflammatory, and hereditary.[5–9] The cause is unknown in up to 40% of patients with neuropathy. Unless treated, neuropathies are associated with an increase in morbidity, with pain, frequent falls, and, in more severe cases, a high risk for foot ulcers, Charcot arthropathy, and amputations, which increase mortality.[10] It is therefore important to carefully screen for an underlying aetiology in all patients suspected of having neuropathy.

The most common causes of peripheral neuropathy are type 2 diabetes and prediabetes. Neuropathy occurs in approximately half of all patients with diabetes, of which 30–40% develop neuropathic pain, such that approximately one in five diabetic patients develop painful neuropathy.[11] Diabetes gives rise to different types of nerve damage and clinical presentations, which includes distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies.[12,13] By far the most common form of diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, and encompasses small and large fibre neuropathy. DN is usually characterized by a sensory disturbance involving the feet, which ascends to the calves over time, and, in more advanced cases, also eventually involves the upper limbs. This review will focus on DN, while the other neuropathy subtypes, including autonomic neuropathy, will not be discussed in any depth.

DN accounts for 80–90% of diabetic neuropathies and is thus termed typical diabetic neuropathy, while other less common diabetic neuropathies are called atypical diabetic neuropathies.[14,15] In contrast to other major diabetes complications, such as retinopathy and nephropathy, no single gold standard diagnostic test exists for DN. In some instances, damage occurs solely as a pure small fibre neuropathy (SFN), which also lacks a gold diagnostic standard. Further, improved glycaemic control is the only DN therapy, which is more effective in type 1 than type 2 diabetes. Therefore, definitive diagnosis can be challenging and therapy is often limited to symptomatic treatment of pain in patients with painful DN. With diabetes and prediabetes burden continuing to rise worldwide, it is anticipated that DN incidence and prevalence will also increase dramatically within the next decades. As a result, there is a critical need to address the major diagnostic challenges for this diabetic complication, by identifying the best strategies for diagnosing DN early in the disease course. Following DN progression will also generate useful prospective data for evaluating preventive and therapeutic DN interventions in future clinical studies.