Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy

Abstract

Aims/hypothesis Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. Methods A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP−; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. Results Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2–9.2) for healthy control participants; 6.2 (4.4–7.3) for DSP−; 1.3 (0.5–2.2) for painless DSP+; and 0.84 (0.4–1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP− and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. Conclusions/interpretation In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes. Graphical abstract

Joint European Academy of Neurology–European Pain Federation–Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment

“…In some of these patients, microneurography or genetics is needed to make the final diagnosis [42]. Another approach has been to increase the sensitivity by using more parameters in skin biopsy than merely the intraepidermal nerve fibre density, for example, assessing dermal nerve fibres [43] or nerve fibre swellings [44], or the quantification of nerve fibre subtypes [45,46]. Recent skin biopsy studies investigating possible pathological biomarkers of pain found that peptidergic and regenerating fibre immunostaining in patients with diabetic neuropathy is closely associated with neuropathic pain [45,47].…”

Involvement of Cutaneous Sensory Corpuscles in Non-Painful and Painful Diabetic Neuropathy

“…The Toronto Consensus (2011) [ 2 ] defined DDSP pain as “ pain that is a direct consequence of abnormalities in the peripheral somatosensory nervous system in diabetic individuals ”. Diagnostic of DSSN is frequently delayed due to the scarcity of early diagnostic tests, and recently, axonal swellings in cutaneous biopsies have been proposed as an early marker of sensory nerve injury in type 2 diabetes mellitus [ 4 , 5 ]. Consequently, there is a high risk of ulceration with subsequent distal amputation in lower limbs [ 6 , 7 ].…”

Identification of corneal and intra‐epidermal axonal swellings in amyotrophic lateral sclerosis

“…), blinded to the origin and clinical features of the subjects, performed the entire process based on published data. 25 Axonal swellings were defined as the enlargements greater than 1.5 μm, as per previous publications e.g., [26][27][28] Swellings smaller than 1.5 μm were considered normal. The dimensions of axonal swellings were measured using stereological software NewCast (Horesholm, Denmark).…”