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Background and Aims: Small-fibre neuropathy (SFN) is associated with glucose dysregulation, including impaired glucose tolerance (IGT) and type 2 diabetes (T2D). Corneal confocal microscopy (CCM) offers a non-invasive tool to assess corneal nerve damage and dendritic cell density (DCD). In this study, we investigated corneal DCD in patients with SFN and glucose dysregulation, defined as IGT or T2D., Methods: We enrolled 38 patients with SFN + glucose dysregulation, 51 with SFN + non-glucose dysregulation and 20 healthy controls. All participants underwent neurological examination, neurophysiology and CCM., Results: Individuals with SFN and glucose dysregulation had higher DCD compared with healthy controls (p = .01), and mature DCD was higher in IGT SFN patients than in T2D patients., Interpretation: Higher DCD in IGT compared with controls and patients with established T2D may suggest that DCD is a biomarker of early neuropathy., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background/aims: We investigated sudomotor dysfunction, small fiber neuropathy (SFN), and their clinical significance in female fibromyalgia patients., Methods: Fibromyalgia patients and healthy controls (HCs) were recruited. Clinical and laboratory data were measured. Electrochemical skin conductance (ESC) values of hands and feet were assessed by SUDOSCAN. Additionally, several other methods were employed, including nerve conduction study (NCS), electromyography (EMG), and questionnaires. Spearman correlation coefficient was calculated to identify factors associated with ESC values of SUDOSCAN., Results: Twenty-two female fibromyalgia patients and 22 female HCs were recruited. The fibromyalgia group had lower EQ5D and higher Toronto Clinical Neuropathy scores than the HC group. Most of the EMG/NCS findings of motor and proximal sensory nerves were comparable between the fibromyalgia and HC groups, whereas sensory nerve action potential amplitudes of distal sensory nerves were significantly lower in the fibromyalgia group. Mean ESC values of hands and feet were significantly lower in the fibromyalgia group than in the HC group (57.6 ± 16.2 vs. 68.8 ± 10.3 μS, p = 0.010 for hands, 64.9 ± 11.5 vs. 72.0 ± 8.2 μS, p = 0.025 for feet, respectively). Moderate to severe SFN was more common in the fibromyalgia group (68.2%) than in the HC group (68.2 vs. 50%, p = 0.019). Fibromyalgia disease duration was significantly correlated with the ESC values of hands/feet, and tricyclic antidepressant (TCA) responders had higher ESC values than non-responders., Conclusion: SFN was commonly detected in fibromyalgia patients who had normal EMG/NCS findings and was more severe in fibromyalgia patients with longer disease duration. SUDOSCAN may predict response to TCA therapy.

Diseases reflective of multiorgan vascular injury of diverse etiology, peripheral nerve disease, dysautonomia syndromes, and intravascular lymphoma may exhibit abnormalities on a normal skin biopsy that may be instrumental in establishing a diagnosis. A retrospective review of our database was conducted to uncover cases where a normal skin biopsy was performed to rule in or out such systemic diseases as complement-driven thrombotic microvascular disease (including atypical hemolytic uremic syndrome, posttransplant thrombotic microangiopathy, and severe or critical COVID-19), systemic capillary leak syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) intravascular B cell lymphoma, small fiber neuropathy, dysautonomia syndromes, and mast cell activation syndrome. Among the special studies were immunohistochemical staining to detect C5b-9, CD56, and myxovirus resistance protein A, as well as mast cell, B and T cell markers. Characteristic patterns were critical in establishing diagnoses such as : increased C5b-9 microvascular deposition in the deltoid area (atypical hemolytic uremic syndrome, posttransplant thrombotic microangiopathy, catastrophic antiphospholipid antibody syndrome, and severe or critical COVID-19); enhanced type I interferon signaling (systemic capillary leak syndrome); ultrastructural arteriopathic changes (CADASIL); reduced cutaneous autonomic innervation in the lower extremities (small fiber neuropathy and postural orthostatic tachycardia syndrome); presence of intravascular lymphocytes on biopsy of abdominal, thigh, and buttock skin (intravascular B cell lymphoma); and a higher than normal density of mast cells in the absence of other inflammatory cell types (mast cell activation syndrome). The skin is clearly a critical window for understanding extracutaneous disease, a concept well exemplified by the myriad of diseases suggested by the microscopic and/or ultrastructural examination of clinically normal skin and therefore establishing the normal skin biopsy as an important tool for understanding certain extracutaneous reactive, neoplastic and paraneoplastic syndromes as well as small fiber neuropathy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings., Methods: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two-way mixed-effects model to evaluate inter- and intra-observer variability., Results: The automated staining system reproduced intra-epidermal nerve fibre density (IENFD) counts consistent with free-floating sections (mean ± standard deviation: free-floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at -0.00005 established non-inferiority against a margin of -0.4 (p = .08). Specifically, the inter-class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9-1), indicating excellent agreement between free-floating and automated methods. The inter- and intra-class coefficient between examiners were both 99% (95% CI: 0.9-0.1) for IENFD, demonstrating high reliability using sections stained using the automated method., Interpretation: Automated immunohistochemistry provides high-throughput reliable and reproducible intra-epidermal nerve fibre quantification. This method, although currently proof-of-concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Abstract: Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case-control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. Clinical data, quantitative sensory testing, and skin biopsies were collected from 26 selected patients with painful long-COVID syndrome. We also examined 100 individuals with past COVID-19 infection, selecting 33 patients with painless long-COVID syndrome, characterized mainly by symptoms such as brain fog and fatigue, and 30 asymptomatic post-COVID-19 controls. Demographic and clinical variables were compared among these groups. Among the 26 patients with painful long-COVID syndrome, 12 had skin biopsy and/or quantitative sensory testing abnormalities compatible with small fibre neuropathy. Demographic and clinical data did not differ across patients with small fibre neuropathy, patients with painless long-COVID syndrome, and asymptomatic post-COVID-19 controls. This case-control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post-COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy., (Copyright © 2024 International Association for the Study of Pain.)

Background and Objectives: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations., Methods: We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin., Results: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN., Discussion: This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated., (© 2024 Peripheral Nerve Society.)

Objectives: Corneal confocal microscopy (CCM) is a non-invasive technique that examines the corneal cellular structure. Its use in the detection of small fiber neuropathy is being researched. In our study, we examined the role of CCM in the detection of small fiber neuropathy in diabetic patients, as well as the differences between CCM findings in diabetic patients with and without overt polyneuropathy with neuropathic symptoms., Methods: 56 Diabetes Mellitus (DM) patients and 18 healthy controls were included in the study. The individuals included in the study were divided into three groups. Patients with diabetes who were found to have polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 1, patients with diabetes and neuropathic symptoms without overt polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 2, and healthy individuals were classified as Group 3. Electrophysiological examination and corneal imaging with CCM were performed in all groups., Results: The CNFD and CNFL values of individuals in the diabetic group were discovered to be lower. CNFD values differ statistically between the groups (p = 0.047). Group 1-Group 3 differs from Group 2-Group 3 (respectively; p = 0.018, p = 0.048)., Conclusion: Our study demonstrates that CCM can be used in patients with neuropathic symptoms and no polyneuropathy detected in EMG and thought to have small fiber neuropathy. CCM provides an opportunity for early diagnosis in small fiber neuropathy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objectives: Small fiber neuropathy presents a significant diagnostic and therapeutic challenge. To solve this challenge, efforts have been made to identify autoantibodies associated with this condition. Previous literature has often considered tri-sulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR3) as a singular seropositive group and/or focused primarily on symptomatic associations., Methods: One hundred seventy-two small fiber neuropathy patients with a Washington University Sensory Neuropathy panel were selected for TS-HDS seropositivity, FGFR-3 seropositivity, and seronegative controls. Data were collected to on the demographic, symptomatic, and laboratory profiles of each subgroup., Results: Percent female (P = 0.0043), frequency of neuropathic pain symptoms (P = 0.0074), and erythrocyte sedimentation rate (P = 0.0293), vitamin D (P < 0.0001), and vitamin B12 (P = 0.0033) differed between the groups. Skin biopsy was more frequently normal within both the FGFR-3 and the TS-HDS cohort (P = 0.0253)., Conclusions: TS-HDS and FGFR-3 display a distinct phenotype from both controls and one another. Immunoglobulin M (IgM) against FGFR-3 and IgM against TS-HDS may be individually valuable markers for the development of distinct clinical phenotypes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Practical yet reliable diagnostic tools for small-fiber neuropathy are needed. We aimed to establish a histopathologic protocol for estimating intraepidermal nerve fiber density (eIENFD) on formalin-fixed, paraffin-embedded tissue (FFPE), evaluate its reliability through intraobserver and interobserver analyses, and provide normative reference values for clinical use. Sixty-eight healthy participants underwent nerve conduction studies and quantitative sensory testing. Skin biopsies from the distal and proximal leg were taken and processed using routine immunohistochemistry (anti-PGP9.5 antibodies) on thin 5 µm sections. eIENFD was assessed with a modified counting protocol. Interobserver and intraobserver reliabilities were excellent (ICC=0.9). eIENFD was higher in females than males (fibers/mm, 14.3±4.4 vs. 11.6±5.8, P <0.05), decreased with age ( r s =-0.47, P <0.001), and was higher proximally than distally (15.0±5.5 vs. 13.0±5.3, P =0.002). Quantile regression equations for the fifth percentile of distal and proximal eIENFD were presented: 13.125-0.161×age (y)-0.932×sex (male=1; female=0) and 17.204-0.192×age (y)-3.313×sex (male=1; female=0), respectively. This study introduces a reliable and reproducible method for estimating epidermal nerve fiber density through immunostaining on 5-µm thin FFPE tissue samples. Normative data on eIENFD is provided. Regression equations help identify abnormal decreases in small nerve fiber density., Competing Interests: K.P. obtained funding from Region Stockholm Innovation Fund. The remaining author declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Small fiber neuropathy (SFN) is a well-defined chronic painful condition causing severe individual and societal burden. While mood disorders have been described, cognitive and behavioral profiles of SFN patients has not been investigated., Methods: Thirty-four painful SFN patients underwent comprehensive cognitive, behavioral, psychological, quality of life (QoL), and personality assessment using validated questionnaires. As control samples, we enrolled 36 patients with painful peripheral neuropathy (PPN) of mixed etiology and 30 healthy controls (HC). Clinical measures of neuropathic pain, duration, frequency, and intensity of pain at the time of assessment were recorded. Between-group and correlation analyses were performed and corrected for multiple comparisons., Results: No differences in clinical measures were found between SFN and PPN, and all groups had similar cognitive profiles. SFN patients showed higher levels of anxiety and alexithymia (p < .005) compared to PPN and HC, considering also pain intensity. Maladaptive coping strategies characterized both patient groups, but only SFN revealed higher levels of acceptance of pain (p < .05). Pain intensity and neuropathic symptoms were associated with mood, low QoL and catastrophism (p < .001), particularly, the higher the perceived pain intensity, the higher the use of maladaptive coping strategies (p < .001). The personality assessment revealed significant feelings of worthlessness and somatization traits both in SFN and PPN (p < .002 vs HC)., Discussions: our results suggest that SFN patients had a normal-like cognitive profile, while their behavioral profile is characterized by mood disorders, alexithymia, maladaptive coping strategies, and poor QoL, as other chronic pain conditions, possibly related to pain intensity. Personality assessment suggests that somatization and feelings of worthlessness, which may worsen the neuropsychological profile, deserve clinical attention when considering patients' therapeutic approaches. At the same time, the high level of acceptance of pain is promising for therapeutic approaches based on psychological support., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Small fiber neuropathy (SFN) is a subtype of painful neuropathies defined by dysfunction of the Aδ and unmyelinated C fibers. It presents with both neuropathic pain and dysautonomia symptoms, posing a significant diagnostic and therapeutic challenge. To address this challenge, research has been conducted to identify autoantibodies and define their association with phenotypes., Methods: Eleven cases of anti-plexin-D1 seropositive SFN were reviewed, along with relevant literature, in attempt to better define anti-plexin-D1 SFN demographics, symptoms, associated medical conditions, and therapeutics., Results: Anti-plexin-D1 SFN typically presents in female patients, with neuropathic pain, normal skin biopsy findings, and normal nerve conduction studies. Anti-plexin-D1 shows an association with concurrent chronic pain, with almost half of the patients undergoing an interventional procedure., Conclusions: Anti-plexin-D1 represents a unique subgroup of SFN, defined by distinct demographics, phenotype, biopsy findings, and therapeutic management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Objectives: Small fiber neuropathy (SFN) affects the fibers involved in cutaneous and visceral pain and temperature sensation and are a crucial part of the autonomic nervous system. Autonomic dysfunction secondary to SFN and autoimmune receptor antibodies is being increasingly recognized, and gastrointestinal (GI) manifestations include constipation, early satiety, nausea, vomiting, and diarrhea. Enteric nervous system involvement may be a possible explanation of abnormal GI motility patterns seen in these patients., Methods: Children suspected to have SFN based on symptoms underwent skin biopsy at the Child Neurology clinic at Arnold Palmer Hospital for Children, which was processed at Therapath™ Neuropathology. SFN was diagnosed using epidermal nerve fiber density values that were below 5th percentile from the left distal leg (calf) as reported per Therapath™ laboratory., Results: Twenty-six patients were diagnosed with SFN. Retrospective chart review was performed, including demographic data, clinical characteristics, and evaluation. A majority of patients were white adolescent females. Autonomic dysfunction, including orthostasis and temperature dysregulation were seen in 61.5% of patients (p = 0.124). Somatosensory symptoms, including pain or numbness were seen in 85% of patients (p < 0.001). GI symptoms were present in 85% of patients (p < 0.001) with constipation being the most common symptom seen in 50% of patients. This correlated with the motility testing results., Conclusions: Pediatric patients with SFN commonly have GI symptoms, which may be the main presenting symptom. It is important to recognize and look for symptoms of small fiber neuropathy in children with refractory GI symptoms that may explain multisystemic complaints often seen in these patients., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The current study aims to characterize brain morphology of pain as reported by small fiber neuropathy (SFN) patients with or without a gain-of-function variant involving the SCN9A gene and compare these with findings in healthy controls without pain. The Neuropathic Pain Scale was used in patients with idiopathic SFN (N = 20) and SCN9A-associated SFN (N = 12) to capture pain phenotype. T1-weighted, structural magnetic resonance imaging (MRI) data were collected in patients and healthy controls (N = 21) to 1) compare cortical thickness and subcortical volumes and 2) quantify the association between severity, quality, and duration of pain with morphological properties. SCN9A-associated SFN patients showed significant (P < .017, Bonferroni corrected) higher cortical thickness in sensorimotor regions, compared to idiopathic SFN patients, while lower cortical thickness was found in more functionally diverse regions (eg, posterior cingulate cortex). SFN patient groups combined demonstrated a significant (Spearman's ρ = .44-.55, P = .005-.049) correlation among itch sensations (Neuropathic Pain Scale-7) and thickness of the left precentral gyrus, and midcingulate cortices. Significant associations were found between thalamic volumes and duration of pain (left: ρ = -.37, P = .043; right: ρ = -.40, P = .025). No associations were found between morphological properties and other pain qualities. In conclusion, in SCN9A-associated SFN, profound morphological alterations anchored within the pain matrix are present. The association between itch sensations of pain and sensorimotor and midcingulate structures provides a novel basis for further examining neurobiological underpinnings of itch in SFN. PERSPECTIVE: Cortical thickness and subcortical volume alterations in SFN patients were found in pain hubs, more profound in SCN9A-associated neuropathy, and correlated with itch and durations of pain. These findings contribute to our understanding of the pathophysiological pathways underlying chronic neuropathic pain and symptoms of itch in SFN., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences., Methods: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z -scores were calculated from reference materials to adjust for the effects of age and gender/height., Results: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z -scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z -scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST., Conclusions: Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028)., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

A proportion of people with fibromyalgia demonstrate small fibre pathology (SFP). However, it is unclear how SFP directly relates to pain phenomenology. Thirty-three individuals with FMS and ten healthy volunteers underwent assessment of SFP and sensory phenotyping using corneal confocal microscopy, validated questionnaires and quantitative sensory testing (QST). Corneal nerve fibre length was used to stratify participants with fibromyalgia into with SFP [SFP+] and without SFP [SFP-]. SFP was detected in 50% of the fibromyalgia cohort. Current pain score and QST parameters did not differ between SFP+ and SFP-. Mechanical pain sensitivity (MPS) demonstrated a significant gain-of-function in the SFP- cohort compared to healthy-volunteers (p = 0.014, F = 4.806, η 2  = 0.22). Further stratification revealed a cohort without structural SFP but with symptoms compatible with small fibre neuropathy symptoms and a significant gain in function in MPS (p = 0.020 Chi-square). Additionally, this cohort reported higher scores for both depression (p = 0.039, H = 8.483, η 2  = 0.312) and anxiety (p = 0.022, F = 3.587, η 2  = 0.293). This study confirms that SFP is present in a proportion of people with fibromyalgia. We also show that in a proportion of people with fibromyalgia, small fibre neuropathy symptoms are present in the absence of structural SFP. Greater mechanical pain sensitivity, depression and anxiety are seen in these individuals., (© 2024. The Author(s).)

Background: Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies., Objectives: The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differential diagnoses. They conclude that autonomic symptoms are frequently associated, often presenting with diverse symptoms., Methods: A selective literature research to present SFN symptoms as well as differential diagnostic and therapeutic steps in the context of SFN and rare diseases focusing on the autonomic nervous system., Results: Neuropathic pain significantly reduces quality of life. To shorten the time until diagnosis and to initiate therapy, the authors recommend a structured patient history including sensory plus and minus symptoms and non-specific autonomic signs. If the initial search for the cause is not successful, rare causes such as treatable transthyretin (ATTR) amyloidosis and Fabry's disease or autoimmune causes should be considered, particularly in the case of progressive and/or autonomic symptoms., Conclusion: The diagnosis and therapy of rare SFN requires interdisciplinary collaboration and, in many cases, a referral to specialized centers to achieve the best patient care., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Small fiber neuropathy (SFN) is a condition involving the small nerve fibers of the peripheral nervous system, specifically the thinly myelinated Aδ and unmyelinated C fibers. It is an increasingly acknowledged condition within the spectrum of neuropathic pain disorders, leading to a rise in diagnosed patients. SFN is characterized by neuropathic pain, that is often described as burning, and typically presents in the hands and feet ascending proximally. Since small nerve fibers are involved in the autonomic nervous system, SFN can also lead to autonomic dysfunction. In the clinical setting, SFN diagnosis is frequently based on the Besta Criteria, which include skin biopsy and quantitative sensory testing. For clinical trials, the ACTTION criteria are also recommended. However, the diagnostic process is often complex, prompting research towards more accessible diagnostic methods. The pathophysiology of SFN remains unclear, thereby challenging therapeutic strategies. A large variety of underlying conditions has been associated with SFN, including metabolic, immune-mediated, infectious, toxic and hereditary conditions. The discovery of genetic sodium channelopathies in SFN provides insight into its underlying mechanisms. Newly discovered mutations within these genes reveal that SFN often shows overlapping clinical presentations with other sodium channelopathies. This chapter provides an in-depth look at SFN, including its clinical features, diagnostic methods, underlying conditions and possible therapeutic strategies., (Copyright © 2024. Published by Elsevier Inc.)

Introduction/aims: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non-invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis., Methods: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods., Results: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [r s ], 0.58; p < .002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (r s , 0.52; p < .001), the Neuropathy Impairment Score (r s , -0.45; p < .01), the heat-pain detection threshold (r s , -0.62; p < .0001), and the autonomic section of the Kumamoto ATTRv clinical score (r s , -0.53; p < .0001)., Discussion: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease., (© 2023 Wiley Periodicals LLC.)

Introduction: Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN., Methods: This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA., Results: Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients., Discussion: This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association., (© 2023. Fondazione Società Italiana di Neurologia.)

Introduction: Peripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available., Methods: We conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN)., Results: Twenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered., Conclusion: Our results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The nociceptive flexion reflex (NFR) is a polysynaptic and multisegmental spinal reflex that develops in response to a noxious stimulus and is characterized by the withdrawal of the affected body part. The NFR possesses two excitatory components: early RII and late RIII. Late RIII is derived from high-threshold cutaneous afferent A-delta fibers, which are prone to injury early in the course of diabetes mellitus (DM) and may lead to neuropathic pain. We investigated NFR in patients with DM with different types of polyneuropathies to analyze the role of NFR in small fiber neuropathy (SFN)., Methods: We included 37 patients with DM and 20 healthy participants of similar age and sex. We performed the Composite Autonomic Neuropathy Scale-31, modified Toronto Neuropathy Scale, and routine nerve conduction studies. We grouped the patients into large fiber neuropathy (LFN), SFN, and no overt neurological symptom/sign groups. In all participants, NFR was recorded on anterior tibial (AT) and biceps femoris (BF) muscles after train stimuli on the sole of the foot, and NFR-RIII findings were compared., Results: We identified 11 patients with LFN, 15 with SFN, and 11 with no overt neurological symptoms or signs. The RIII response on the AT was absent in 22 (60%) patients with DM and 8 (40%) healthy participants. The RIII response on the BF was absent in 31 (73.8%) patients and 7 (35%) healthy participants (P = .001). In DM, the latency of RIII was prolonged, and the magnitude was reduced. Abnormal findings were seen in all subgroups; however, they were more prominent in patients with LFN compared to other groups., Conclusions: The NFR-RIII was abnormal in patients with DM even before the emergence of the neuropathic symptoms. The pattern of involvement before neuropathic symptoms was possibly related to an earlier loss of A-delta fibers., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Alcohol overconsumption is well known to cause damage to the peripheral nervous system. The aim of this study was the functional and structural evaluation of the small nerve fibers in alcohol-dependent subjects, with or without symptoms of peripheral neuropathy., Methods: Twenty-six consecutive alcohol-dependent subjects treated for detoxification voluntarily in the specialized unit of the Athens University Psychiatric Clinic were enrolled in this prospective study over 18 months. Every subject was assessed by peripheral nerve evaluation using the Neuropathy Symptoms Score (NSS) and Neuropathy Impairment Score (NIS), followed by nerve conduction studies (NCS), quantitative sensory testing (QST), and skin biopsy. Twenty-nine normal subjects, age- and gender-matched, constituted the control group., Results: Peripheral neuropathy was diagnosed in 16 subjects (61.5%). Among these 16 subjects, pure large fiber neuropathy (LFN) was found in two subjects (12.5%), pure small fiber neuropathy (SFN) was found in eight subjects (50%), and both large and small fiber neuropathy was diagnosed in six patients (37.5%). The intraepidermal nerve fiber density (IENFD) of the patients' skin biopsy was significantly lower than that of the control group. Additionally, QST results showed a statistically significant sensory impairment in the patients., Conclusions: Our study confirms small fiber neuropathy due to alcohol abuse with a high prevalence of pure SFN that might have remained undetected without QST and IENFD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2023. Published by Elsevier Inc.)

Primary erythromelalgia (PEM) is a rare condition characterized by severe burning pain, erythema, and increased temperature in the extremeties. Mutations in the Nav1.7 sodium channel encoded by the SCN9A are responsible for PEM. The pathophysiology of PEM is unclear, but the involvement of neurogenic and vasogenic mechanisms has been suggested. Here we report a case of severe PEM in a 9-year-old child with a novel SCN9A mutation and examine the distribution of nerve fibers and expression of neuropeptides in the affected skin. Gene mutation analysis revealed a novel mutation p.L951I (c.2851C>A) in the heterozygous form of the SCN9A. An immunofluorescence study showed that intraepidermal nerve fibers were decreased in the affected leg, suggesting small fiber neuropathy. There was no increase in the expression of substance P (SP) or calcitonin gene-related peptide (CGRP) in the lesional skin tissue. These findings suggest SP and CGRP do not play a major role in the pathophysiology of primary erythromelalgia., (© 2023 Japanese Dermatological Association.)

Introduction/aims: Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS-HDS and FGFR-3 autoantibodies., Methods: This was a double-blind placebo-controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR-3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra-epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo., Results: Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID-19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG-treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was -1.9 ± 2.6 in the placebo group, and - 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS)., Discussion: This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS-HDS and FGFR-3., (© 2022 Wiley Periodicals LLC.)

Sjögren's syndrome is a potentially treatable cause of Small Fiber Neuropathy (SFN)-a condition that severely affects patients' quality of life. We therefore aimed to characterize patients with SFN and Sjögren's syndrome to raise awareness of this disease and facilitate its early recognition as an essential step for appropriate treatment. In 97 SFN patients (median age 48 years, 77% female), we studied the clinical features associated with Sjögren's syndrome compared to the idiopathic SFN subtype. According to the current ACR/EULAR classification criteria (Shiboski et al., Ann Rheum Dis 76:9-16, 2017), 24/97 individuals (25%, median age 48.5 years, 75% female) were diagnosed with Sjögren's syndrome. We did not observe any differences in SFN-defining sensory plus symptoms. Furthermore, intraepidermal nerve fiber densities (IENFD) were significantly lower in patients with SFN and Sjögren's syndrome (mean 2.6 ± 1.2/mm) compared to patients with idiopathic SFN (mean 3.2 ± 1.5/mm; p = 0.048). There were no significant group differences when analyzing cerebrospinal fluid (CSF) parameters. We conclude that Sjögren's syndrome-associated SFN is difficult to distinguish from idiopathic forms based on initial clinical symptoms and CSF results. However, lower IENFD values in patients with Sjögren's syndrome-associated SFN might indicate a distinct different pathomechanism in this entity compared to idiopathic SFN., (© 2022. The Author(s).)

Objective: Autonomic small fibre neuropathy is described in patients with autoimmune autonomic neuropathy (AAN). Few data are available on somatosensory function and skin biopsies in AAN., Methods: Retrospective analysis of 17 patients (51.2 ± 6.8 years, n = 7 males) with AAN, including autoantibodies, quantitative sensory testing (QST, n = 13) and intraepithelial nerve fibre density (IENFD) in skin biopsy (n = 16). QST was performed according to the DFNS protocol over hands and feet dorsum. QST data were compared to healthy controls. Comparison of antibody-positive and antibody-negative cases., Results: 70.6% of patients were antibody positive. 82.4% described at least one episode with sensory symptoms. Skin biopsies revealed reduced IENFD in 58.8% of patients, whereas neuropathic pain was only present in 41.2%. QST showed a nonregional increase for nonpainful thermal and mechanical detection rather than for mechanical pain thresholds. Compared to healthy controls, sensory loss for cold and warm detection thresholds and for the thermal sensory limen-the temperature difference between alternating warm and cold stimuli-was found on hands and feet (all p < 0.05). For nonpainful mechanical stimuli, the vibration detection threshold on the hand was increased (p < 0.05). Of all pain thresholds, only the mechanical pain threshold was elevated for pinprick stimuli to the feet (p < 0.05)., Interpretation: Findings are consistent with a sensory small fibre more than large fibre neuropathy in AAN. Sensory loss was comparably distributed across hands and feet, indicating that nerve fibre dysfunction was rather generalized. Serostatus was not a significant predictor of the small fibre deficit present in AAN., (© 2022. The Author(s).)

Objective: Small fiber neuropathy (SFN) is characterized by chronic neuropathic pain and autonomic dysfunction. Currently, symptomatic pharmacological treatment is often insufficient and frequently causes side effects. SFN patients have a reduced quality of life. However, little is known regarding whether psycho-social variables influence the development and maintenance of SFN-related disability and complaints. Additional knowledge may have consequences for the treatment of SFN. For example, factors such as thinking, feeling, and behavior are known to play roles in other chronic pain conditions. The aim of this study was to obtain further in-depth information about the experience of living with SFN and related chronic pain., Methods: Fifteen participants with idiopathic SFN participated in a prospective, semi-structured, qualitative, focus group interview study. The focus groups were audio-recorded, transcribed, and analyzed cyclically after each interview., Results: The following main themes were identified: "pain appraisal", "coping", "social, work, and health environment", and "change in identity". Catastrophic thoughts and negative emotions were observed. Living with SFN resulted in daily limitations and reduced quality of life., Conclusions: Given the results, it can be concluded that an optimal treatment should include biological, psychological, and social components.

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., Competing Interests: L. A. Zeidman has received honoraria for participating on scientific advisory boards for Akcea Therapeutics and Takeda, for being on the CIDP speaker's bureau for Grifols, has received fees for expert medicolegal consulting, and has received royalties from Oxford University Press. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Competing interests: David Cornblath is an Editorial Board Member at Journal of Neurology, Neurosurgery and Psychiatry.

Small-fiber neuropathy (SFN) is suggested to be involved in the pathogenesis of some types of autoimmune connective tissue diseases. SFN with a reduction in epidermal nerve fibers might affect sensory fibers and cause neuropathic symptoms, such as pruritus and pain, which are common in both dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Nerve growth factor (NGF) has been recognized as important in nociception by regulating epidermal nerve fiber density and sensitizing the peripheral nervous system. The present study aimed to investigate whether SFN was associated with the cutaneous manifestations of DM and CLE. We also investigated the relationship between SFN and axon guidance molecules, such as NGF, amphiregulin (AREG), and semaphorin (Sema3A) in DM and CLE. To explore the molecular signaling, interleukin (IL)-18 and IL-31, which have been implicated in the cutaneous manifestation and neuropathic symptoms in DM, were examined in keratinocytes. Our results revealed that intraepidermal nerve fiber density (IENFD) was unchanged in patients with DM, but significantly reduced in IENFD in patients with CLE compared with healthy control. Increased epidermal expression of NGF and decreased expression of Sema3A were demonstrated in patients with DM. Furthermore, IL-18 and IL-31 both induced the production of NGF from keratinocytes. Taken together, IL-18 and IL-31 mediated epidermal NGF expression might contribute to the cutaneous neuropathic symptoms in DM, while SFN might be important for CLE.

Peripheral nerve disorders in sarcoidosis consist of granulomatous neuropathy and non-granulomatous small fiber neuropathy (SFN), which differ in their underlying pathology, diagnostic methods and treatment. While granulomatous nerve involvement is rare in sarcoidosis, SFN is reported in over 40% of systemic cases. Distal symmetric polyneuropathy and asymmetric polyradiculoneuropathy are the most common presentations of granulomatous neuropathy, which typically responds to corticosteroids. In contrast, SFN is often manifested as non-length dependent pain and paresthesias that may improve with intravenous immune globulin or infliximab. Early recognition and treatment of sarcoidosis neuropathy can lead to improved outcomes and patient quality of life., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose of Review: This narrative review aims to summarize advances in the field of small fiber neuropathy made over the last decade, with emphasis on novel research highlighting the distinctive features of SFN., Recent Findings: While the management of SFNs is ideally aimed at treating the underlying cause, most patients will require pain control via multiple, concurrent therapies. Herein, we highlight the most up-to-date information for diagnosis, medication management, interventional management, and novel therapies on the horizon. Despite the prevalence of small fiber neuropathies, there is no clear consensus on guidelines specific for the treatment of SFN. Despite the lack of specific guidelines for SFN treatment, the most recent general neuropathic pain guidelines are based on Cochrane studies and randomized controlled trials (RCTs) which have individually examined therapies used for the more commonly studied SFNs, such as painful diabetic neuropathy and HIV neuropathy. The recommendations from current guidelines are based on variables such as number needed to treat (NNT), safety, ease of use, and effect on quality of life., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 (SFN) has few significant laboratory findings and is difficult to diagnose. In 70% of the cases, the cause of SFN is unknown. Among the cases with known etiology, 50% are associated with diabetes, and the causes are autoimmune, amyloidosis, or multifactorial. In recent years, a specific autoantibody-positive group has been identified and has attracted attention because immunotherapy was successful in the autoantibody-positive SFN groups. In the cases reporting to our department, abnormalities could not be detected by various tests, including nerve conduction studies, and the response to symptomatic treatment was poor. An abnormality was identified in the current perception threshold test result, and a positive blood anti-plexin D1 antibody was detected via enzyme-linked immunosorbent assay. Therefore, autoimmune SFN was diagnosed, and plasma exchange therapy was remarkably effective. Subsequently, we aim to introduce general treatments for SFN and COVID-19-related SFN.

Small fiber neuropathy (SFN) is a peripheral nervous system disease due to affection of A-delta or C-fibers in a proximal, distal, or diffuse distribution. Selective SFN (without large fiber affection) manifests with pain, sensory disturbances, or autonomic dysfunction. Though uniform diagnostic criteria are unavailable, most of them request typical clinical features and reduced intra-epidermal nerve fiber density on proximal or distal skin biopsy. Little consensus has been reached about the treatment of SFN, why this narrative review aims at summarizing and discussing treatment options for SFN. Treatment of SFN can be classified as symptomatic, pathophysiologic, or causal. Prerequisites for treating SFN are an established diagnosis, knowledge about the symptoms and signs, and the etiology. Pain usually responds to oral/intravenous pain killers, antidepressants, anti-seizure drugs, or topical, transdermal specifications. Some of the autonomic disturbances respond favorably to symptomatic treatment. SFN related to Fabry disease or hATTR are accessible to pathogenesis-related therapy. Immune-mediated SFN responds to immunosuppression or immune-modulation. Several of the secondary SFNs respond to causal treatment of the underlying disorder. In conclusion, treatment of SFN relies on a multimodal concept and includes causative, pathophysiologic, and symptomatic measures. It strongly depends on the clinical presentation, diagnosis, and etiology, why it is crucial before initiation of treatment to fix the diagnosis and etiology. Due to the heterogeneous clinical presentation and multi-causality, treatment of SFN should be individualized with the goal of controlling the underlying cause, alleviating pain, and optimizing functionality., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)