Characterizing Acute-Onset Small Fiber Neuropathy

Abstract

Background and objectives: Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable.

Methods: We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected.

Results: Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course.

Discussion: AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

Figure 1. Individual Distribution of Sensory Symptoms at the Peak and the Last Follow-Up

Body diagrams representing the regional distribution of sensory symptoms at the peak (A) and last follow-up (B) for the front (left) and back (right) of 20 patients with acute-onset small fiber neuropathy. The numbers on the top left of each figure correspond to the patient numbers in Tables 1–3.

Figure 2. Patterns of Nerve Fiber Staining

This figure shows teased fibers from mouse sciatic nerves immunostained with patient IgG (green), goat anti-contactin-1 IgG (CNTN1; red) to localize to the node of Ranvier (A, B, C, D, F), or chicken antiperipherin IgG (red) to localize unmyelinated axons (E). IgG deposition was observed on Schwann cells (A), at the juxtaparanodes in patients with circulating anti-CASPR2 antibodies (B), on the surface of Schwann cells near the paranodal region (C), at paranodes (D), or on unmyelinated fibers (E). IgG deposition was not observed in some patients (F). Scale bar: 10 µm.

Figure 3. Patterns of Cultured Dorsal Root Ganglion Staining

Live dorsal root ganglia (DRG) were incubated with patient sera, fixed, and immunostained for human IgG (green) and antibodies against neurofilament heavy (NF-H; red) to stain DRG. Some patients did not show reactivity toward the DRG (A). Other patients showed strong IgG reactivity against surface antigens expressed by both large and small cells in DRG (B-C). Patient No. 10, who presented with circulating anti-CASPR2 antibodies, showed strong reactivity against the soma and axons of the DRG (B). Patient No. 8, without any identified antibody target, also showed strong reactivity against the DRG soma and axons (C). Scale bar: 10 µm.