Background: Up to 50% of patients with diabetes develop peripheral neuropathy (DPN). DPN is associated with low intraepidermal nerve fiber density (IENFD), and morphometric degenerative changes such as axonal swellings are also observed. The relationship of swellings to DPN status has not yet been delineated.
Methods: In total 207 patients with type 2 diabetes and 24 age- and gender-matched healthy controls were included in the study. Included in the analysis were participants whose IENFD was >0.5 fiber/mm, thus allowing swelling ratio calculation (n=156). The patients underwent a rigorous DPN assessment, including a neurological examination, nerve conduction studies, skin biopsy and quantitative sensory testing. Patients were divided into three groups: without DPN (n=35), with painless DPN (n=72), and with painful DPN (n=100). Axonal swellings were defined as enlargements on nerve fibers exceeding 1.5 μm in diameter. Swelling ratio was obtained by dividing the number of swellings with IENFD.
Results: Median (IQR) IENFD was significantly different between the groups: without DPN: 6.15 (4.9;8.08) fibers/mm; painless DPN: 1.65 (1.07;2.73); painful DPN: 1.4 (0.80;2.12); controls: 5.8 (4.95;8.0), P<0.01. Median swelling ratios were also significantly different between groups: without DPN: 0.34 (0.16;0.55); painless DPN: 0.14 (0;0.55); painful DPN: 0 (0;0.31); and controls: 0 (0;0.6), p<0.01. This difference disappeared when only including patients with somewhat preserved IENFD (IENFD >2) (P=0.4). Patients with diabetes and IENFD >2 had higher swelling ratio compared with healthy controls, regardless of neuropathy status (P<0.01). Swelling ratio did not correlate with BMI, diabetes duration, pain or Toronto Clinical Neuropathy score (P>0.1), but did correlate negatively with HbA1c levels when only including all patients with IENFD >0.5 (P=0.04).
Conclusions: Axonal swellings are present in most diabetic patients with preserved IENFD and may indicate morphological changes of nerve fibers.
P. Karlsson: Advisory Panel; Self; Grünenthal. S. Gylfadottir: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical. A.S. Rice: Research Support; Self; Orion. Other Relationship; Self; Imperial College Consultants, Spinifex/Novartis. J.R. Nyengaard: None. T.S. Jensen: None. D. Bennett: Consultant; Self; Lilly Diabetes, Orion, Theranexus. A. Themistocleous: None.
Novo Nordisk Foundation (NNF14OC0011633); Danish Diabetes Academy (to P.K.)
