By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Acute-onset small fiber neuropathy most often is precipitated by infections, medication side effects, or vaccinations. Most cases recover spontaneously.
SOURCE: Gendre T, Lefaucheur JP, Nordine T, et al. Characterizing acute-onset small fiber neuropathy. Neurol Neuroimmunol Neuroinflamm 2024;11:e200195.
Chronic small fiber neuropathy (CSFN) affects thinly myelinated A-delta and unmyelinated C-fibers, and results in neuropathic pain and dysautonomia. It is best diagnosed by history and skin punch biopsy, the latter showing abnormal epidermal and sweat gland nerve fiber density. Associated with diabetes, vitamin B12 deficiency, autoimmune diseases, and sodium channel gene mutations, treatment generally is symptomatic and not disease-related, since often no cause is found. What are the clinical characteristics of acute-onset small fiber neuropathy (AOSFN), and how does it differ from CSFN?
Between April 2017 and April 2022, all patients referred to Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile-de-France, France, for AOSFN were included for study if they experienced maximum intensity and extension of symptoms and signs by 28 days and fulfilled NEUROdiab criteria for probable or definite small fiber neuropathy.1 Patients were excluded if signs of large fiber involvement were evident either on motor or sensory examination, or on nerve conduction studies. Extensive blood work included, but was not limited to, antinuclear antibody, antineutrophil cytoplasmic antibodies, cryoglobulins, hepatitis B and C titers, human immunodeficiency virus titer, anti-transglutaminase and anti-endomysium antibodies, anti-thyroperoxidase and antithyroglobulin antibodies, antiganglioside antibodies, onconeural antibodies, anticontactin-associated protein-2 antibodies, genetic testing for sodium channelopathies, and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. A-delta nerve fiber function was assessed using laser-evoked potentials. C-fiber function was assessed using quantitative sensory testing (QST) of the hands and feet and electrochemical skin conductance. Skin punch biopsy from the right calf and proximal right lateral thigh provided pathologic evidence of small fiber neuropathy. Amyloid was excluded using salivary gland biopsy where warranted.
Among 20 patients who satisfied study criteria, 60% were women and the median age was 44.2 years. Eighty percent (n = 16) of patients experienced a precipitating event: infectious in eight patients (flu-like syndrome, syphilis, diarrhea, or COVID-19), new pharmacotherapy in five patients (antibiotic, anti-TNF alpha, enzyme replacement therapy), and vaccination in three patients (flu, hepatitis B, diphtheria-tetanus-poliomyelitis).
Pain (85%), paresthesia (70%), and dysautonomia (60%) with faintness and tachycardia were the most common symptoms, and the clinical pattern was not length-dependent in 85% (n = 17). Laser-evoked potentials (60%) were the most sensitive test to show evidence of small fiber neuropathy, with warmth detection threshold (39%) and electrochemical skin conductance (31%) less so. Among 11 patients who underwent skin punch biopsy, epidermal nerve fiber density was reduced in six patients, allowing small fiber neuropathy to be definitively diagnosed in 90%, considering both neurophysiologic testing and skin biopsy findings.
Among the remaining studies, cerebrospinal fluid analysis was normal in five patients so tested, antifibroblast growth factor 3 antibodies were positive in 22% (four of 18 patients), anticontactin-associated protein-2 antibodies were positive in one patient, and immunoglobulin G immunoreactivity against nerve tissue was seen in 14 (70%) patients, but not in any healthy or diseased controls. Partial or complete recovery occurred in 13 (65%) patients and 3/3 improved with a short course of oral steroids. AOSFN is a non-length-dependent, painful, symmetric neuropathy, which usually improves on its own, but may have a variable course, and may possibly be immune-mediated.
COMMENTARY
Does autonomic small fiber pathology, as demonstrated by reduced nerve fiber density of dermal piloerector muscles and sweat glands on skin punch biopsy, correlate with autonomic symptomatology?
Surprisingly, it does not, at least not in fibromyalgia. Among 58 patients with fibromyalgia, 40% had small fiber pathology. All patients reported dysautonomia, as assessed by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire, usually orthostasis and gastrointestinal disturbances, but only rarely skin dryness and vasomotor symptoms. The frequency of symptoms did not differ between those with or without small fiber pathology. In fibromyalgia, reduced autonomic innervation has an uncertain effect on autonomic symptomatology, and hence the relation between skin biopsy findings and symptoms remains unclear.2
REFERENCES
- Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285-2293.
- Falco P, Galosi E, Di Stefano G, et al. Autonomic small-fiber pathology in patients with fibromyalgia. J Pain 2024;25:64-72.
