Background & Aims

In a recent longitudinal study (Tsilingiris et al., 2023) using quantitative sensory testing (QST) we found that progression of diabetic sensorimotor polyneuropathy (DSPN) was reflected by transitions from a “healthy” phenotype to “thermal hyperalgesia”, to “mechanical hyperalgesia”, and finally to “sensory loss”. This sequence suggests that loss of heat pain sensitivity precedes impairment of mechanical pain. We used slow depolarizing electrical stimuli preferentially activating C-nociceptors to assess their axonal excitability in patients independent of sensory transduction mechanisms.

Methods

66 individuals with diabetes mellitus (DM) were examined (63.6% type 2 DM). Among them, 51 individuals exhibited varying stages of DSPN. Slow depolarizing transcutaneous currents of low-intensity (maximum 1 mA) with 4 Hz sinusoidal stimulation profile as well as single 500 ms half sine wave pulses were used to stimulate C-nociceptors. Pain perception was quantified using (0-10)-Numeric-Rating-Scale. Findings were cross-referenced with QST Z-scores to investigate levels of sensory impairment and also correlated to serum levels of neurofilament light chain (NfL) as biomarker of neuropathy.

Results

Patients with “sensory loss” phenotype had significantly reduced sensitivity to all sensory test compared to each other phenotype. However, no significant differences were found between the phenotypes “thermal hyperalgesia” and “mechanical hyperalgesia” in heat pain thresholds, mechanical pain sensitivity or electrically induced pain. Interestingly, we found a significant heat hypoalgesia (z=-0.65; -0.35/-0.94, 95%CI) and mechanical hyperalgesia (z=1.16; 0.68/1.15, 95%CI) not only in the thermal and mechanical hyperalgesia phenotype, but also in patients phenotyped as “healthy”. Correlation analysis of NRS at low electrical stimulus intensities indicate reduced heat pain sensitivity was even linked to increased pain ratings in about 50% of the patients, confirming intact terminal axons of polymodal nociceptors despite impaired transduction of noxious heat. For most of our sensory tests, higher levels of NfL correlated to impaired sensory function. The only exception was pain ratings to

Conclusions

C-fiber specific electrical stimulation can differentiate between impaired transduction and actual denervation in small fiber neuropathy. Loss of noxious heat transduction precedes functional axonal loss in the course of diabetic small fiber neuropathy supporting the concept that sensory phenotypes reflect severity of neuropathy. Hypersensitivity to slow depolarizing stimuli may provide new aspects into diabetic neuropathy’s natural course. The nearly complete overlap in pain sensitivity parameters between “healthy”, “thermal hyperalgesia” and “mechanical hyperalgesia” contest their value for meaningful mechanistic stratification of patients.

References

Tsilingiris D, Schimpfle L, von Rauchhaupt E, Sulaj A, Seebauer L, Herzig S, Szendroedi J, Kopf S, Kappaender Z. 2024. Sensory Phenotypes Provide Insight Into the Natural Course of Diabetic Polyneuropathy. Diabetes 73:135-146

Presenting Author

Martin Schmelz

Poster Authors

Martin Schmelz

MD

Heidelberg University, Dept. Exp. Pain Research, MCTN Mannheim

Lead Author

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Omar Eldesouky

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

Lead Author

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Lukas Seebauer MD

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

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Roman Rukwied

Dept. Exp. Pain Research, MCTN, Med. Faculty Mannheim, Heidelberg University, Mannheim, Germany

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Richard Carr

Dept. Exp. Pain Research, MCTN, Med. Faculty Mannheim, Heidelberg University, Mannheim, Germany

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Mani Roshan MD

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

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Dimitrios Tsilingiris MD

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

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Julia Szendroedi PhD

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

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Zoltan Kender MD PhD

Dept Int. Medicine 1 & Clin. Chemistry, Univ. Hosp. Heidelberg, Heidelberg, Germany

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Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral