Small‐fiber neuropathy: Expanding the clinical pain universe

Abstract

Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Nav1.7, Nav1.8 and Nav1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

“…Diagnosis is usually confirmed by a decrease in intra-epidermal fibre density (IDFD) in skin biopsies. Several conditions can cause SFN, and these include diabetes and autoimmune disease [52,112]. About 50% of SFN cases are idiopathic, with no obvious aetiology [112].…”

Diagnosis and management of sensory polyneuropathy

“…The most common causes include diabetes, immunologic conditions, sodium channel mutations, and vitamin B12 deficiency 29. Although immunologic conditions were found in 19% of a cohort of 921 patients with SFN, which exceeds the prevalence in the general population, the exact pathogenic role of isolated autoantibodies remains unclear 2954. In one series, the highest yield blood tests in SFN that appeared to be “initially idiopathic” were erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), C3 complement values, and autoantibodies that are associated with Sjögren’s syndrome and celiac disease 55.…”

“…In one series, the highest yield blood tests in SFN that appeared to be “initially idiopathic” were erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), C3 complement values, and autoantibodies that are associated with Sjögren’s syndrome and celiac disease 55. It has been recommended that patients are screened for glucose intolerance, vitamin B12 deficiency, and sodium channel mutations even if there is a known underlying cause 2954…”

“…QST has several limitations, such as its inability to discriminate between central nervous system and peripheral nervous system disease, the need for participant cooperation and attention, and the fact that it may be easily influenced by other factors. Therefore, it should not be used in isolation and needs to be interpreted in the clinical context and in conjunction with other studies 54171172173174…”

Evidence for Dietary Agmatine Sulfate Effectiveness in Neuropathies Associated with Painful Small Fiber Neuropathy. A Pilot Open-Label Consecutive Case Series Study

“…These include modulation of key neurotransmitter receptors [including nicotine, N-methyl-D-aspartate (NMDA), imidazoline and α2-adrenoceptors], ionic channels (including potassium and calcium channels), cell signaling pathways (by inhibiting ADP-ribosylation of proteins), nitric oxide (NO) synthesis, polyamine metabolism and extracellular protein modifications (by inhibiting matrix metalloproteases and advanced glycation end (AGE)-product formation) [20]. The spectrum of molecular mechanisms underlying painful SFN may be even broader [38]. With this body of evidence taken together with the fact that anti-inflammatory drugs are ineffective [4][5][6][7][8], the results of the present study further validate the notion that agmatine exerts its salutary action on nervous system-associated processes, rather than by acting on inflammatory mechanisms [20].…”