Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy

Abstract

IMPORTANCE Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.OBSERVATIONS Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.CONCLUSIONS AND RELEVANCE Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

“…It is also possible that there is impact of pirenzepine on select sub-types of IENF that is not discriminated when all IENF are quantified using the pan-neuronal marker PGP9.5 (Beiswenger et al, 2008). Diabetic neuropathy is frequently described as a small fiber neuropathy due to the early appearance of positive and negative symptoms of small fiber dysfunction (Oaklander and Nolano, 2019). However, indices of large myelinated fiber dysfunction, such as sensory and motor nerve conduction slowing, are also early features of human diabetic neuropathy (Bril, 2016), albeit of less immediate concern to the patient, while large fiber demyelination, axonal degeneration and loss are established pathological features (Malik, 2014).…”

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

“…Treatment with an anticonvulsant combined with an antidepressant, both at lower doses, may be more efficacious than either alone [15]. This also indicates that the combination treatment targets more mechanisms that may underlie the complex disease pathology [16].…”

Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants

“…Recent reviews and the expected 2020 publication of the first global consensus case definition of SFN are increasing its visibility. 1,8 This case definition and diagnostic criteria for "definite," "probable," and "possible" cases, although intended for research use, will inform medical practice as well.…”

“…Diabetes is the most common cause of SFN in developed countries, with cancer chemotherapies and other toxic exposures also well recognized. 1 However, such common causes of neuropathy are usually quickly diagnosed by history, exam, or basic testing and then managed by ameliorating the cause when possible. Yet, 20% to 50% of patients with objectively confirmed SFN have no recognized medical risks; this is known as "cryptogenic" or "initially idiopathic" SFN.…”

“…Primary Sjögren's syndrome (often seronegative 21 ) is the most common systemic autoimmune disease associated with SFN, and efficacy of treatment with pooled intravenous immunoglobulins was recently reported. 22 Other iiSFN appears to develop as part of ill-defined systemic dysimmune/inflammatory conditions, with selective immunoglobulin deficiencies particularly common, 1 and reports have associated autoantibodies with dysautonomic SFN symptoms including POTS. 23,24 In a small passive transfer study that injected sera from patients with "idiopathic" painful small fiber polyneuropathy to reproduce symptoms, physiology and pathology in mice provided direct support of the hypothesis that some cases of iiSFN are B cell mediated.…”