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Reduction of Skin Innervation Is Associated With a Severe Fibromyalgia Phenotype
TAKE-HOME MESSAGE
- The authors of this study examined neurophysiological and pathological correlates of small-fiber neuropathy in 117 female patients with fibromyalgia. They found that reduced intraepidermal nerve fiber density has statistically significant correlations with pain intensity, impairment, paresthesias, and anxiety (P<.05). The authors identified four patterns of skin innervation in patients with fibromyalgia: normal, distally reduced, proximally reduced, and both distally and proximally reduced.
- This is the first-large scale study showing comprehensive neurophysiological small-nerve fiber pathology correlating with disease severity in patients with fibromyalgia. This study will be important for diagnosis and management of this very challenging disease.
– Kyle Binder, MD
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
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.
Additional Info
Disclosure statements are available on the authors' profiles:
Reduction of Skin Innervation Is Associated With a Severe Fibromyalgia Phenotype
Ann. Neurol 2019 Oct 01;86(4)504-516, D Evdokimov, J Frank, A Klitsch, S Unterecker, B Warrings, J Serra, A Papagianni, N Saffer, C Meyer Zu Altenschildesche, D Kampik, RA Malik, C Sommer, N ÜçeylerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The latest (biopsychosocial) model emphasized the brain, positing that central sensitization of unspecified origin caused its signature deep pain and exertional intolerance. However, since 2013, a rising tide of papers now link fibromyalgia to SFN, a neuropathy in which the small unmyelinated pain and autonomic axons misfire and degenerate. There has been increasing scientific evidence that fibromyalgia is linked to SFN by neuropathology and electrophysiology. Recently, a 2018 review calculated that, overall, 49% of studied fibromyalgia patients were reported to have small-fiber neuropathology.1
This 2019 study seals the deal. A German-led European consortium studied 117 female fibromyalgia patients with best-available objective tests of small-fiber pathology and physiology. The most widely accepted epidermal neurite density (END) measurements from skin biopsies showed 63% meeting criteria for SFN, with supportive results from evoked potentials, noninvasive corneal-confocal microscopy, and microneurography recordings confirming unprovoked firing of pain-transmitting axons. The study identified new patterns of denervation and correlations between pain and symptom intensity and extent of small-fiber losses.
Earlier pathology studies from Pestronk’s and Rice’s labs had already explicated exertional intolerance and deep aching as consequences of microcirculatory denervation preventing local blood flow augmentation during peak need,2,3 and imaging studies from multiple labs reported similar brain imaging abnormalities in SFN as fibromyalgia.4
Together, these papers change the clinical paradigm. Pain management is no longer enough. Detecting SFN, when present, moves these lucky patients onto conventional pathways for establishing its causes and selecting more effective and disease-modifying therapies.5 Has skin biopsy become the single most important suggestion for fibromyalgia?
References