Therapeutic plasma exchange for peripheral neuropathy associated with trisulfated heparan disaccharide IgM antibodies: A case series of 17 patients.

BACKGROUND: Small fiber neuropathy (SFN) can be associated with autoantibodies, including those of IgM class with specificity for the trisulfated heparan disaccharide (TS-HDS) antigen. We hypothesized that, as an IgM autoantibody-mediated disorder, TS-HDS-associated SFN symptoms may be reduced with therapeutic plasma exchange (TPE). STUDY METHODS: This was an observational analysis of all patients referred for TPE from 2018 to 2020 following laboratory confirmation of SFN with TS-HDS autoantibodies; a loading course of 3 to 5 procedures over 2 weeks was completed, with some patients returning for monthly procedures. The following data were collected: demographics, symptoms and duration, TS-HDS levels, skin biopsy results, reported responses to TPE, and TPE-associated adverse events. RESULTS: Of the 17 subjects, 12 (71%) were female and the mean age was 57.5 years (range 27-94). The most common reported symptom was lower extremity paresthesia (88% of subjects). The mean number of TPE procedures completed per subject was 9 (range 3-18), with 71% (12/17) reporting symptomatic improvement or slowed disease progression. About 15% of procedures were associated with an adverse event, with vasovagal reactions being the most common; 53% of patients had at least one adverse event. CONCLUSIONS: Given a reported symptomatic response rate of more than 70%, TPE may be a treatment option for individuals with autoimmune-mediated SFN associated with increased titers of TS-HDS IgM autoantibodies. Since TPE-associated adverse events appear common in this population, close monitoring during procedures is warranted.

Novel Autoantibodies in Idiopathic Small Fiber Neuropathy.

OBJECTIVE: Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state. METHODS: Sera from 58 SFN patients and 20 age- and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts. RESULTS: Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). Further subgroup analysis into iSFN and SFN by secondary causes (secondary SFN) in the main cohort showed that MX1 is higher in iSFN compared to secondary SFN (FC = 1.61 vs 0.106, p = 0.009). INTERPRETATION: Novel autoantibodies MX1, DBNL, and KRT8 are found in iSFN. MX1 may allow diagnostic subtyping of iSFN patients. ANN NEUROL 2022;91:66-77.

Antiplexin D1 Antibodies Relate to Small Fiber Neuropathy and Induce Neuropathic Pain in Animals.

OBJECTIVES: To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo. METHODS: We developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection. RESULTS: The ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG. CONCLUSIONS: Plexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.

Antibody Testing for Suspected Autoimmune Autonomic Dysfunction and Small Fiber Neuropathies.

SUMMARY: Autonomic dysfunction and small fiber neuropathies are heterogeneous disorders with a wide array of potential etiologies. As with other neurologic diseases, autoantibodies specific to neural tissue, either in the setting of cancer or systemic autoimmunity, may cause autonomic abnormalities. Given the complex and varied functions of the autonomic nervous system, however, the presentation of these conditions may be quite variable. This, in addition to pitfalls of autonomic testing especially for the novice, can lead to inaccuracies in recognizing and characterizing these conditions. We now have a large number of autoantibodies available for testing with more in the pipeline thanks to unprecedented developments in the field of neuroimmunology. Those have been very helpful in uncovering potentially treatable mechanisms of autonomic disease, but also pose a challenge to the clinician given their multiplicity and variable specificity. Growing knowledge regarding autoimmune autonomic implications and the autonomic specificities of each antibody, in addition to the increasing attention to the relevance of antibody titers are of utmost importance for clinicians concerned with autonomic neurology. This review attempts to shed a light on the frequently encountered antibodies in relation to autonomic dysfunction.

Utility of salivary gland biopsy in diagnosing Sjogren's syndrome in a POTS patient population.

PURPOSE: POTS patients undergo labial salivary gland biopsies (LSGB) for histologic confirmation of Sjogren's syndrome (SS). Predictive features of positive results are unknown. METHODS: 161 POTS patients underwent LSGB. Their charts were reviewed for antibody and diagnostic testing results. RESULTS: Only 11% (17/161) of POTS patients were SS positive. There were more positive ANA antibodies in those with positive LSGB (65% v 28%, p = .0026). Positive skin nerve biopsy for small fiber neuropathy (SFN) was associated with positive LSGB (p = .046). CONCLUSION: A positive ANA and skin biopsy for SFN are two helpful features in selecting POTS patients for LSGB.

Cryptogenic small-fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor-3.

INTRODUCTION: Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. METHODS: One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. RESULTS: Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. DISCUSSION: Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

Biopsy-Proven Small-Fiber Neuropathy in Primary Sjögren's Syndrome: Neuropathic Pain Characteristics, Autoantibody Findings, and Histopathologic Features.

OBJECTIVE: Painful small-fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large-fiber involvement. SFN can be diagnosed by punch skin biopsy results that identify decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves. METHODS: We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh). RESULTS: There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti-Ro 52 (P = 0.01) and anti-Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking-and-glove pain, and 12 patients had nonstocking-and-glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients). CONCLUSION: SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking-and-glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies.

The incidental finding of elevated anti GQ1B antibodies in a patient with selective small fiber neuropathy.

Small fiber neuropathy (SFN) selectively affects small diameter sensory and/or autonomic axons. Pain and autonomic dysfunctions are the most common symptoms. SFN occurs in several autoimmune diseases and autoantibodies against neuronal proteins may play a role in SFN pathophysiology. Anti-GQ1b antibody has been associated with Miller Fisher syndrome, Bickerstaff's brainstem encephalitis, acute ophthalmoplegia, pharyngeal-cervical-brachial weakness and peripheral neuropathy involving large fibers. Isolated SFN associated with anti-GQ1b antibodies has not been previously reported. Here we report a 45-year-old woman presenting with highly positive anti-GQ1b titer and selective SFN without central nervous system or peripheral large nerve involvement. She improved upon administration of adalizumab. Further studies will clarify a possible pathogenetic role of antiganglioside antibodies in SFN. Moreover, the recognition of antiganglioside antibodies in SFN may have therapeutic consequences with patients who would benefit from immunotherapy.

A prospective, observational study of patients with uncommon distal symmetric painful small-fiber neuropathy.

OBJECTIVE: To investigate the clinical characteristics of patients with uncommon distal symmetric painful small-fiber neuropathy (DSPSFN). METHODS: From September 2012 to September 2014, participants between 18-70 years of age that had DSPSFN defined by clinical signs/symptoms and ID pain > 2 or DN4 > 4 on questionnaires for more than 1 month were included. Participants who had previous historical or laboratory evidence of common etiologies of DSPSFN were excluded. Enzyme activity and genetic studies for Fabry diseaseand familial amyloid polyneuropathy were performed after participants fulfilled the inclusion and exclusion criteria. The cryoglobulin test, autoantibodies studies and electrophysiological studies were performed in these participants. RESULTS: In total, 100 cases were enrolled in the current study. Three cases of subclinical diabetes mellitus and two cases of fibromyalgia were found. Fabry disease (1%) and familial amyloid polyneuropathy (3%) with Ala97Ser transthyretin (TTR) mutations were also detected. The cryoglobulin test was positive in 30% of participants, and these participants had higher DN4 scores than the negative group. In the autoantibodies studies, 59% of the participants had abnormal anti-Ro/SSA and/or anti-La/SSB antibodies. CONCLUSIONS: Cryoglobulinemia is not a rare etiology of uncommon DSPSFN. The long-term prognosis is quite good in these participants. From our structuralized protocol, Fabry disease and familial amyloid polyneuropathy could be easily detected in these cases of uncommon DSPSFN.