Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies.

OBJECTIVES: To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. METHODS: In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. RESULTS: Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). CONCLUSIONS: IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.

Limbic Connectivity Underlies Pain Treatment Response in Small-Fiber Neuropathy.

OBJECTIVE: Small-fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small-diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain-related brain changes after skin nerve degeneration. METHODS: Diffusion-weighted and resting-state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain-related network was assessed using network-based statistic (NBS) analysis. RESULTS: Compared with age- and sex-matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti-neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition-integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition-integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. INTERPRETATION: Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655-667.

Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin.

OBJECTIVES: Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. METHODS: An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. RESULTS: In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P = 0.014). Facial involvement was more common in seropositive patients (P = 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P = 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P = 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P = 0.052), and prior erroneous diagnosis (P = 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%. CONCLUSIONS: TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers. They are often misdiagnosed but may respond subjectively and objectively to IVIG.

[Small Fiber Neuropathy with Inadequate Response to Medical Therapy: Diagnosis and Treatment of Small Fiber Neuropathy].

Small-fiber neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ and unmyelinated C fibers. Patients generally present with neuropathic pain, while dysesthesia, allodynia, pain, burning sensations, and cold sensations are frequently present in a length-dependent pattern. Additional autonomic features of the gastrointestinal, urinary, or cardiovascular systems are frequently observed. Deep-tendon reflexes and nerve conduction tests yield normal results. Skin biopsy is useful for the diagnosis, and can demonstrate the loss of intraepidermal nerve fibers in small-fiber neuropathy and has a diagnostic sensitivity of 80%. Although many causes of small-fiber neuropathy have been reported, the cause remains unknown in 30-50% of the cases. Treatment is directed at the underlying etiology and is supported with symptomatic treatment.

Small Fiber Neuropathy in the Elderly.

Small fiber neuropathy is common and prevalent in the elderly. The disease can be associated with many medical conditions. It often has a negative impact on quality of life due to painful paresthesia, dizziness, and sedative side effects of pain medications. Skin biopsy is the gold standard diagnostic test. Screening for associated conditions is important, because etiology-specific treatment can slow down disease progression and ameliorate symptoms. Adequate pain control can be challenging due to safety and tolerability of pain medications in the elderly. Treatment should be individualized with the goals of controlling underlying causes, alleviating pain, and optimizing daily function.

Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

OBJECTIVE: This is the first double-blind randomized controlled trial evaluating the efficacy and safety of IV immunoglobulin (IVIG) vs placebo in patients with idiopathic small fiber neuropathy (I-SFN). METHODS: Between July 2016 and November 2018, 60 Dutch patients with skin biopsy-proven I-SFN randomly received a starting dose of IVIG (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIG (1 g/kg) or placebo were administered at 3-week intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale score at 12 weeks compared to baseline. RESULTS: Thirty patients received IVIG, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIG, the mean average pain was decreased by at least 1 point compared to 30% of the patients receiving placebo (p = 0.588, odds ratio 1.56, 95% confidence interval 0.53-4.53). No significant differences were found on any of the other prespecified outcomes, including general well-being, autonomic symptoms, and overall functioning and disability. CONCLUSIONS: This randomized controlled trial showed that IVIG treatment had no significant effect on pain in patients with painful I-SFN. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02637700, EudraCT 2015-002624-31. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with painful I-SFN, IVIG did not significantly reduce pain compared to placebo.

Pain behavior in SCN9A (Nav1.7) and SCN10A (Nav1.8) mutant rodent models.

The two voltage gated sodium channels Nav1.7 and Nav1.8 are expressed in the peripheral nervous system and involved in various pain conditions including inflammatory and neuropathic pain. Rodent models bearing deletions or mutations of the corresponding genes, Scn9a and Scn10a, were created in order to understand the role of these channels in the pathophysiological mechanism underlying pain symptoms. This review summarizes the pain behavior profiles reported in Scn9a and Scn10a rodent models. The complete loss-of-function or knockout (KO) of Scn9a or Scn10a and the conditional KO (cKO) of Scn9a in specific cell populations were shown to decrease sensitivity to various pain stimuli. The Possum mutant mice bearing a dominant hypermorphic mutation in Scn10a revealed higher sensitivity to noxious stimuli. Several gain-of-function mutations were identified in patients with painful small fiber neuropathy. Future knowledge obtained from preclinical models bearing these mutations will allow understanding how these mutations affect pain. In addition, the review gives perspectives for creating models that better mimic patients' pain symptoms in view to developing novel analgesic strategies.