Intraepidermal Nerve Fiber Density as Measured by Skin Punch Biopsy as a Marker for Small Fiber Neuropathy: Application in Patients with Fibromyalgia

Abstract

Small fiber neuropathy (SFN) is a type of peripheral neuropathy that occurs from damage to the small A-delta and C nerve fibers that results in the clinical condition known as SFN. This pathology may be the result of metabolic, toxic, immune-mediated, and/or genetic factors. Small fiber symptoms can be variable and inconsistent and therefore require an objective biomarker confirmation. Small fiber dysfunction is not typically captured by diagnostic tests for large-fiber neuropathy (nerve conduction and electromyographic study). Therefore, skin biopsies stained with PGP 9.5 are the universally recommended objective test for SFN, with quantitative sensory tests, autonomic function testing, and corneal confocal imaging as secondary or adjunctive choices. Fibromyalgia (FM) is a heterogenous syndrome that has many symptoms that overlap with those found in SFN. A growing body of research has shown approximately 40–60% of patients carrying a diagnosis of FM have evidence of SFN on skin punch biopsy. There is currently no clearly defined phenotype in FM at this time to suggest whom may or may not have SFN, though research suggests it may correlate with severe cases. The skin punch biopsy provides an objective tool for use in quantifying small fiber pathology in FM. Skin punch biopsy may also be repeated for surveillance of the disease as well as measuring response to treatments. Evaluation of SFN in FM allows for better classification of FM and guidance for patient care as well as validation for their symptoms, leading to better use of resources and outcomes.

In vitro characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease

“…Determination of IENFD with low inter- and intra-observer variability [ 65 ] is frequently used in patients with suspected small fiber neuropathy [ 35 , 40 ], however, reduction of skin innervation as a typical finding is not specific [ 19 , 71 ]. Given the reduced distal IENFD in our patient, we analyzed the in vitro excitability of sensory neurons carrying the S126G variant.…”

No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action

“…32 About 50% of fibromyalgia patients have concomitantly a small fiber neuropathy, which has been confirmed with skin biopsy. 33,34 The pain reducing effect of phenytoin cream in fibromyalgia patients could be explained due to dampening the coexistent small fiber neuropathic pain, and reduction of peripheral input, resulting in silencing central sensitization.…”

Etiology and pathophysiology of fibromyalgia

“…A recent study provided evidence supporting the peripheral neurological origin of the symptoms. According to the authors, there is a significant overlapping of symptoms between fibromyalgia and small fiber neuropathy, in addition to the objective presence of small fiber neuropathy in individuals with fibromyalgia [33][34][35] . This compatibility suggests chronic pain of neurological origin, challenging the concept of fibromyalgia as part of a central nervous system disease because it involves mechanisms of peripheral origin 36 .…”

“…In turn, multiple methods allow the assessment of autonomic function, such as sympathetic microneurography, QT-RR slope, post-exercise heart rate recovery, heart rate turbulence, baroreflex sensitivity, heart rate variability (HRV), tilt table test, reflex test sudomotor axon, and others 34,49 . Among these methods, HRV analysis is one of the most used in research, which allows for assessing the dynamics of the sympathetic and parasympathetic nervous systems 45 .…”