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Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136(Pt 6):1857-67. PMID 23474848

One-paragraph summary

Twenty-five patients with fibromyalgia syndrome (FMS) underwent comprehensive neurological and neurophysiological assessment, quantitative sensory testing, pain-related evoked potentials (PREP), and skin punch biopsies of the lower leg and upper thigh, with two comparison groups: 10 patients with monopolar depression without pain, and healthy subjects matched for age and sex. Neurological and standard neurophysiological examination was normal in all FMS patients, excluding large-fibre polyneuropathy. FMS patients scored higher on neuropathic pain questionnaires than both depression patients and controls (p < 0.001 each). Compared with controls — and unlike the depression group — FMS patients showed impaired small-fibre function with increased cold and warm detection thresholds (p < 0.001). PREP showed increased N1 latency on foot stimulation (p < 0.001) and reduced amplitudes on face, hand and foot stimulation (p < 0.001). In skin biopsies, total (p < 0.001) and regenerating (p < 0.01) intraepidermal nerve fibres were reduced at both leg and thigh, and dermal unmyelinated nerve fibre bundles were reduced relative to both comparison groups, while myelinated fibres were spared. All three methods converged on impaired small-fibre function, which the authors read as pointing toward a neuropathic nature of FM pain.

Key findings

  • Three independent methods — QST, pain-related evoked potentials, skin biopsy morphometry — converged on small-fibre dysfunction and loss.
  • Reduction was present proximally as well as distally (upper thigh as well as lower leg), i.e. not a classical length-dependent pattern.
  • Depression controls were normal on the small-fibre measures, which rules out chronic distress or inactivity as a sufficient explanation.
  • Myelinated fibres and standard neurophysiology were normal — the deficit is selective to small fibres.

Limitations

  • n = 25 FMS patients, single centre; the depression comparison group was 10 patients.
  • Cross-sectional: order of events between small-fibre loss and pain is not established. Later work showed patient IgG can induce loss of intraepidermal innervation in mice (Goebel 2021, PMID 34196305), which would place denervation downstream.
  • Association with symptom severity was not the focus here; other series found no correlation between IENFD and neuropathic pain scores (Kosmidis 2014, PMID 25304055), and cortical laser-evoked potentials do not track the denervation (Vecchio 2022, PMID 35074721).
  • Prevalence estimates vary widely across the literature that followed — 32.6% (Kosmidis 2014, PMID 25304055), 41% (Oaklander 2013, PMID 23748113), 63% (Evdokimov 2019, PMID 31376174), pooled 49% (95% CI 38–60%) (Grayston 2019, PMID 30314675) — so "FM has small-fibre pathology" is a statement about a subgroup, not the syndrome.
  • FM small-fibre morphology is not identical to classical small-fibre neuropathy: mean unmyelinated axon diameter is reduced in FM relative to both SFN and controls (Doppler 2015, PMID 26164586), and activity-dependent conduction slowing differs (Serra 2014, PMID 24243538).

Why it matters

Published alongside Oaklander's independent 2013 report (PMID 23748113), this paper reopened the peripheral question in fibromyalgia after two decades in which the field had concluded, on muscle-biopsy, MR-spectroscopy and EMG grounds, that there was no peripheral lesion to find (Simms 1996, PMID 8860798). It established that a substantial minority of FM patients have objectively demonstrable small-fibre pathology, that the finding is not an artifact of depression or deconditioning, and that it is not length-dependent. Everything in the current periphery-versus-centre debate — subgroup hypotheses, corneal confocal microscopy as a screening tool, the autoimmune model in which denervation is a consequence of circulating IgG — descends from this result and the Oaklander paper.

Cited by wiki pages

  • pathophysiology-peripheral