Reduction of skin innervation is associated with a severe fibromyalgia phenotype

Abstract

Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MD-P: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS.

Reduced activity, reactivity and functionality of the sympathetic nervous system in fibromyalgia: An electrodermal study

“…Small (intraepidermal unmyelinated nerve fibers) and even large peripheral nerve fiber neuropathy, usually in distal body parts, has been observed in a proportion of FMS patients, leading to a lower density of these fibers in comparison with healthy individuals [ 5 , 6 , 45 – 48 ]. A recent study in a large cohort of patients with FMS applied different tests for multidimensional characterization of neuropathy, observing indications of widespread small nerve fiber dysfunction and damage and identifying patient subgroups in relation to the extent and pattern of this damage [ 49 ]. The reduced small fiber density is congruent with the increased rate of neurologic symptoms like numbness, tingling, and increased heat and cold sensorial thresholds in FMS patients [ 50 ].…”

Juvenile primary Fibromyalgia Syndrome: epidemiology, etiology, pathogenesis, clinical manifestations and diagnosis

“…This has been demonstrated in adult studies using objective testing methods, such as pain-related evoked potentials, quantitative sensory evaluations and examination of skin biopsies using electron microscopy [21,22]. A metaanalysis indicates a 49% prevalence of small nerve fiber pathology in adult patients with FM [23] and recent evidence suggests that this may be related to symptom severity [24]. Aberrant expression of systemic and cutaneous microRNAs (which regulate molecular factors determining nerve de-and re-generation) were found to correlate with reduced density of small nerve fibers in patients with FM [25].…”

Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome

“…In recent studies, small nerve fiber pathology was found in subgroups of patients with fibromyalgia syndrome (FMS) . Applying corneal confocal microscopy (CCM), corneal denervation was also reported in FMS patients …”