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ABSTRACT & COMMENTARY
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
SYNOPSIS: In a detailed clinical analysis of patients with fibromyalgia compared to normal controls, patients with fibromyalgia had significantly lower epidermal nerve fiber density in the distal leg skin biopsies, and distal hypesthesia, compared to normal controls.
SOURCE: Caro XJ, Winter EF. Evidence of abnormal epidermal nerve fiber density in fibromyalgia. Arthritis Rheumatol 2014;66:1945-1954.
Fibromyalgia (FM) — a controversial illness of undetermined cause, characterized by widespread musculoskeletal pain and fatigue, six times more common in females, and one in which the role of organic illness is itself questioned — is surprisingly the most common cause of generalized, musculoskeletal pain in women between the ages of 20 and 55 years, with a prevalence in the United States of approximately 2% and increasing with age. Patients appear well, no objective abnormalities are found on physical examination, and routine laboratory and radiologic studies are normal. Alterations in central nervous system pain processing have been hypothesized to explain its pathophysiology, but evidence now points to a peripheral nervous system etiology.
Forty-one consecutive outpatients with clinical features of FM, presenting to a private, consultative rheumatology practice in Northridge, CA, between January 2007 and August 2011, and satisfying American College of Rheumatology 1990 criteria for FM, underwent bilateral Wartenberg pinwheel and 128-Hz tuning fork sensory testing of the legs and blood studies, including erythrocyte sedimentation rate, C-reactive protein, extensive autoimmune testing, serum protein electrophoresis, spectrophotometry, capillary electrophoresis, and thyroid function testing. To determine epidermal nerve fiber density (ENFD), all underwent skin punch biopsies, taken from the proximal anterolateral thigh at the level of the pubis and the distal anterolateral leg, 10 cm proximal to the lateral malleolus. Forty-seven normal persons served as controls and underwent similar testing, including skin punch biopsy. Exclusionary criteria included any disorder possibly associated with neuropathy including diabetes, lupus, sarcoidosis, Sjögren’s syndrome, active hepatitis C virus infection, or a history of cancer within 5 years of the study. Statistical analysis comprised the one-tailed t-test and one-way analysis of covariance, with P values ≤ 0.05 (one-tailed) considered significant.
Stocking hypesthesia was found in all FM patients, who also demonstrated a significantly lower ENFD compared to normal controls. Distal calf, but not thigh, ENFD was inversely correlated to interleukin-2 receptor levels in FM patients and, based on thigh-to-calf ENFD ratios, FM appears to be affected by both a diffuse and length-dependent process. Advancing age did not explain these findings, which support the notion that pain in FM is due to the presence of a small fiber neuropathy.
Abnormal peripheral C-nociceptor function may also contribute to the pain in FM and is found in the majority of such patients.1 Microneurographic recording of C-nociceptors in 30 women with FM, 17 with small fiber neuropathy, and 9 normal controls revealed that 76.6% of FM patients demonstrated abnormal silent, but not mechanosensitive, nociceptor behavior, with spontaneous activity seen in 31% of FM patients, 34% of small fiber neuropathy patients, and 2.2% of controls. Given that small fiber neuropathy is present in many FM patients, it is not surprising that hyperexcitability of silent nociceptors present in the former resembles that in the latter. Abnormal peripheral C-nociceptor activity may be the common denominator underlying pain in both these conditions.