Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

Abstract

Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN-associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN-diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively.

Keywords: Autonomic function testing; Chronic pain; Human-subject research; Peripheral nerve; Peripheral neuropathy; Skin biopsy.

Figure 1

Enrollment and Outcomes

Figure 2

Immunohistochemical visualization of sensory nerve endings in distal-leg skin biopsy by anti-PGP9.5-immunoreactivity. Arrows depict labeled axons. Panel A: Biopsy from 44-year old Caucasian, female, control subject with normal density of epidermal innervation (337 neurites/mm² skin surface area; at the 76^th centile of predicted value). Panel B: Biopsy from 47-year old Caucasian, female, fibromyalgia subject with reduced density of epidermal innervation diagnostic for small-fiber polyneuropathy (135 neurites/mm² skin surface area; at the 3^rd centile of predicted value). Bars represent 50 micrometers.

Figure 3

Evidence of SFPN from neuropathy symptom scales. (A) Comparison of Michigan Neuropathy Screening Instrument scores for FMS and control subjects by questionnaire category. Sensory comprised MNSI questions 1, 7, 13; Pain comprised questions 2, 3, 5, 6, 12; Trophic comprised questions 8, 14, 15; Other comprised questions 4, 9, 10, 11. (B) Comparison of Utah Early Neuropathy Scale scores for FMS and control subjects by examination category: Motor (great toe extension); Pin (absent and reduced sensation); Allodynia (in toes and foot); Large Fiber Sensation (vibration and great toe position); and Reflexes (deep tendon at the ankle). * P < 0.05, ** P < 0.01, *** P < 0.001.