Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Abstract

The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiberpredominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of small-fiber neuropathy.

Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy

“…Autoimmune small-fiber-predominant ganglionopathies/neuronopathies are also recognized, particularly in patients with SS or cancer [41]. It is logical that small-fiber-predominant autoimmune axonopathies should also exist, and we and others have reported cases, although these are not yet well-characterized [12, 43, 48, 57].…”

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

“…The neuropathological characteristics of neurogenic‐inflammation‐mediated SFN include pain hypersensitivity and inflammatory responses of extremities [1]. Tumor necrosis factor‐α (TNFα) is a pleiotropic cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1) [2,3], and targeting TNFα/TNFR1 signaling is a newly developed therapeutic strategy for inflammatory diseases and is particularly advantageous in alleviating injury‐induced neuropathic pain [1,4–6]. For clinical use, several lines of anti‐inflammatory drugs are available; however, the mechanism underlying the effect of these anti‐inflammatory agents on SFN remains elusive.…”

“…Small fiber neuropathy (SFN) is onset by peripheral inflammation, specifically neurogenic inflammation, which is associated with neuropathic manifestations. The neuropathological characteristics of neurogenic-inflammationmediated SFN include pain hypersensitivity and inflammatory responses of extremities [1]. Tumor necrosis factor-a (TNFa) is a pleiotropic cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1) [2,3], and targeting TNFa/TNFR1 signaling is a newly developed therapeutic strategy for inflammatory diseases and is particularly advantageous in alleviating injury-induced neuropathic pain [1,4e6].…”

Small‐fiber neuropathy associated with autoinflammatory syndromes in children and adolescents

“…The sparse data available in children point to metabolic, infectious, autoimmune, and toxic causes in addition to a possible relationship with human papillomavirus vaccine . Preliminary evidence, including serological markers, has provided evidence of organ‐specific dysimmunity in some cases …”