Diagnosis and prevalence of diabetic polyneuropathy: a cross‐sectional study of Danish patients with type 2 diabetes

Gylfadottir, Sandra Sif; Itani, Mustapha; Krøigård, Thomas; Kristensen, Alexander Gramm; Christensen, Diana Hedevang; Nicolaisen, Sia Kromann; Karlsson, Páll; Callaghan, Brian C.; Bennett, David L.H.; Andersen, Henning; Tankisi, Hatice; Nielsen, Jens Steen; Andersen, Niels Trolle; Jensen, Troels Staehelin; Thomsen, Reimar Wernich; Sindrup, Søren Hein; Finnerup, Nanna Brix

doi:10.1111/ene.14469

Cited by 40 publications

(55 citation statements)

References 35 publications

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“…Study participants underwent nerve conduction studies, skin biopsy for IENFD assessment, quantitative sensory testing and diabetes-related biochemistry testing including a single HbA 1c test at the time of study. The clinical examination is described in detail elsewhere [10,15]. The Toronto Clinical Scoring System (TCSS) score was calculated for all participants [16].…”

Section: Study Protocolmentioning

confidence: 99%

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

et al. 2021

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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

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Section: Study Protocolmentioning

confidence: 99%

“…This study investigates whether the axonal swelling ratio (axonal swellings/intraepidermal nerve fibres) is related to DSP, neuropathic pain and clinical variables in a wellcharacterised and comprehensively phenotyped cohort of study participants with type 2 diabetes mellitus and HC participants [10,15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…This study was a nested cross-sectional study based on a previous clinical study 19 of patients from the Danish Center for Strategic Research in Type 2 Diabetes (DD2) cohort. 11,20 DD2 is an ongoing cohort of patients with recently diagnosed type 2 DM that currently comprises more than 8000 patients.…”

Section: Design Setting and Participantsmentioning

confidence: 99%

“…A total of 389 patients from the DD2 cohort agreed to be enrolled during a 2-year period, from October 2016 until October 2018 in a previous clinical study. 21 A subsample of the 389 patients was included in this study based on the following inclusion criteria: (a) no clinical evidence of DPN, or (b) a clinical diagnosis of either probable or definite DPN according to the Toronto Consensus Criteria. 17 Patients with possible DPN, subclinical DPN, neuropathy due to other causes than DM, and patients with symptoms due to other neurological disease than neuropathy were excluded from this study.…”

Section: Design Setting and Participantsmentioning

confidence: 99%

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Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes

Itani

Gylfadottir

Krøigård

et al. 2020

J Peripheral Nervous Sys

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Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose. K E Y W O R D S diabetic polyneuropathy, large fiber neuropathy, mixed fiber neuropathy, small fiber neuropathy, type 2 diabetes mellitus Mustapha Itani and Sandra Sif Gylfadottir are Combined authorship.

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Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy‐Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study

Themistocleous

Kristensen

Solà³

et al. 2022

Annals of Neurology

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Objective: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy-induced distal symmetrical polyneuropathy. Methods: Two hundred thirty-nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy-induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). Results: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength-duration time constant, and current-threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy-induced polyneuropathy. Interpretation: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapyinduced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between

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Diagnosis and prevalence of diabetic polyneuropathy: a cross‐sectional study of Danish patients with type 2 diabetes

Cited by 40 publications

References 35 publications

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

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

Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes

Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy‐Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study

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