Evidence of Abnormal Epidermal Nerve Fiber Density in Fibromyalgia: Clinical and Immunologic Implications

Abstract

Objective. A subset of patients with fibromyalgia (FM) exhibit a large fiber demyelinating peripheral polyneuropathy akin to that seen in chronic inflammatory demyelinating polyneuropathy (CIDP). It has been suggested that this demyelinating process is likely to be immune mediated. Because it is known that similar large fiber neuropathic lesions may be associated with a cutaneous small fiber neuropathy, we sought to determine the prevalence of small fiber neuropathy, as measured by epidermal nerve fiber density (ENFD), in a series of patients with FM and clinically healthy control subjects.Methods. Forty-one consecutive patients with FM and 47 control subjects underwent a 3-mm punch skin biopsy at the proximal thigh and distal leg near the ankle, for analysis of the ENFD. Patients with FM who had clinical evidence of a disorder known to be associated with small fiber neuropathy were excluded. The patients with FM also underwent pinwheel testing and vibratory testing for hypesthesia and serologic testing for a series of cytokine, circulating immune complex, and complement measurements.Results. All patients with FM had evidence of stocking hypesthesia. The ENFD of patients with FM was lower than that of control subjects at both the calf (mean ؎ SD 5.8 ؎ 2.8 versus 7.4 ؎ 1.9; P ‫؍‬ 0.0002) and thigh (9.3 ؎ 3.2 versus 11.3 ؎ 2.0; P ‫؍‬ 0.0007). There was an inverse correlation between calf ENFD and age at the time of skin biopsy in patients with FM (r ‫؍‬ ؊0.29, P ‫؍‬ 0.03) but not in control subjects; however, analysis of covariance showed that this relationship could not be explained by aging alone. Serologic evaluation showed an inverse correlation between calf ENFD in patients with FM and the interleukin-2 receptor (IL-2R) level (r ‫؍‬ ؊0.28, P ‫؍‬ 0.04). However, an inverse correlation between thigh ENFD and serum IL-2R levels did not reach significance (P ‫؍‬ 0.08). Analysis of thigh-to-calf ENFD ratios suggested that the ENFD decline in FM is affected by both a diffuse and a length-dependent process.Conclusion. The calf and thigh ENFD in patients with FM is significantly diminished compared with that in control subjects. Advancing age alone cannot explain this finding. Calf ENFD was inversely correlated, although weakly, with serum levels of IL-2R. These findings suggest that small fiber neuropathy is likely to contribute to the pain symptoms of FM; that pain in this disorder arises, in part, from a peripheral immunemediated process; and that measurement of ENFD may be a useful clinical tool in FM.

Evidence of peripheral large nerve involvement in fibromyalgia: a retrospective review of EMG and nerve conduction findings in 55 FM subjects

“…Further, they support the concept of a connection between FM and CIDP, at least in a subgroup of these patients. As the immune system is known to be instrumental in the genesis of CIDP, we reason that a subgroup of FM is likely to have a significant immune mediated element to its pathogenesis as well (7,9,30). Finally, we believe that our findings may be of considerable interest to students of FM, to those investigating the origin of immune mediated neuropathic pain, and to clinicians who deal with FM on a daily basis.…”

“…The laboratory and clinical screening of our FM participants paralleled that used by us previously (9). Only records from those subjects who lacked evidence of any disorder known to be associated with LFN were included in our final FM study cohort.…”

Fibromyalgia: A Critical and Comprehensive Review

“…The results demonstrated that ENFD was reduced in a subset of patients with FMS [463][464][465][466][467]. Several other findings in these patients were consistent with a small fiber polyneuropathy, including elevated scores on neuropathic pain questionnaires [464,535], a high frequency of paresthesias [466], stocking hypesthesia [465], and some abnormal results of sensory testing [463,467], and autonomic function testing [464]. More specifically, Üceyler et al [463] provided evidence of deficits in Aδ and C fiber function in the overall cohort of patients they investigated.…”

“…In view of the growing evidence that FMS is associated with signs and symptoms of small-fiber neuropathy in a substantial subset of patients [463][464][465][466][467], the SCN9 gene is of particular interest since 8/28 (29 %) of patients who met stringent criteria for idiopathic small fiber neuropathy were demonstrated to harbor seven different gain of function mutations in this gene [468]. The SCN9 gene encodes the sodium channel Nav1.7 and has been the target of intense research since the discovery that loss of function mutations result in complete insensitivity to pain, whereas gain of function mutations cause severe chronic pain conditions like inherited erythromelalgia and paroxysmal extreme pain disorder.…”

Clinical presentation and diagnosis of neuropathic pain

“…Distal leg SB with quantification of intradermal small fibers density using established rules is considered an effective technique for the diagnosis of small fibers neuropathy 29,30 . With SB it was possible to detect evidences of small fibers neuropathy in a variety of conditions 31 , including fibromyalgia patients 32,33 . So, SB has been recommended as important part of diagnostic tests for small fibers neuropathy in fibromyalgia patients 34 .…”