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

Clinical Scaling of DN

An important issue for clinically evaluating patients with suspected or established DN is early detection and subsequent follow-up of progression. A wide range of clinical scales exist to detect and track DN progression. These scales often combine symptom assessments with bedside evaluations of clinical DN signs, and they are mostly validated against NCS or IENFD. Recently, Gewandter and colleagues[42] reviewed a series of clinical scales for distal symmetric axonal polyneuropathies, which revealed a large variation in motor and sensory examination items used in the different test measures, as well as great variability in the proportion of tests devoted to assess reflexes and motor, sensory, and autonomic functions. A particular problem in assessing the usefulness of a specific test concerns its validity (Box 1). Table 1 presents an overview of the most frequently used DN scales, along with a description of the potential overlap in measures between the diagnostic and reference test. Most of the tests include clinical signs and fewer symptoms or confirmatory tests, possibly because clinical signs are easier to quantify and follow than symptoms.[20] Some of the clinical scales contain disproportionate tests of motor function, despite the late clinical appearance in the course of DN.

The clinical scales also highlight the large variation in symptoms and clinical signs that qualify for the different classification grades using the Toronto classification. This is demonstrated in Figure 4, where three different clinical scales, MNSI, Toronto Clinical Neuropathy Score, Utah Early Neuropathy Scale, are plotted against the Toronto Consensus definition of DN in a population of recently diagnosed type 2 diabetes patients.[78] There is a positive correlation between increasing certainty of neuropathy from possible to definite with increasing scores on the neuropathy scales, but also a large variation. This Toronto hierarchical system has good criterion validity, but there is considerable variation and overlap between the DN groups on all three of these clinical scales. Currently, challenges exist in the diagnosis of DN, whether painful or non-painful, with a need to develop an easy and more uniform method to diagnose DN both for clinical and research purposes.

DN Severity

Assessing DN severity presents its own challenges. Dyck and colleagues[17] proposed a method to determine DN severity by successively adding signs and then symptoms to different electrophysiological abnormalities, generating five degrees of severity. An alternative approach is to determine severity based on different sum scores or composite scores, as presented in questionnaires or different assessment scales.[16,18–20,103–105] Since few long-term prospective studies have been performed, the usefulness of these composite scores to grade severity is limited. However, using this principle of composite scoring, Dyck and colleagues[104] showed worsening of DN status using the Neuropathy Impairment Score of the Lower Limbs [NIS (LL)] +7 tests in a longitudinally monitored patient cohort. Whether these changes associated with clinically relevant outcomes, such as falls, ulcerations, and quality of life, remained unclear. More studies are needed to investigate the best way to evaluate DN severity, including direct comparisons between approaches and associations of changes in severity with clinically relevant outcomes. Such studies could potentially lead to consensus definitions of DN severity, which could be used consistently across studies, facilitating better comparisons.