Small Fiber Neuropathy Patients Research Articles

Comparing FGFR-3 and TS-HDS Seropositive Small Fiber Neuropathy: Unique Patient Features, Symptoms, Laboratory, and Nerve Conduction Study Findings.

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. 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. 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). 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.

Small fibre neuropathy frequently underlies the painful long-COVID syndrome

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.

Investigation of small fiber neuropathy in patients with diabetes mellitus by corneal confocal microscopy

ObjectivesCorneal 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. Methods56 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. ResultsThe 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). ConclusionOur 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.

Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide.

Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 %) FMS patients and 39/53 (73.6 %) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.

Reduced Gray Matter Volume and Cortical Thickness in Patients With Small-Fiber Neuropathy

Small-fiber neuropathy (SFN) is defined by degeneration or dysfunction of peripheral sensory nerve endings. Central correlates have been identified on the level of gray matter volume (GMV) and cortical thickness (CT) changes. However, across SFN etiologies knowledge about a common structural brain signature is still lacking. Therefore, we recruited 26 SFN patients and 25 age- and sex-matched healthy controls to conduct voxel-based- and surface-based morphometry. Across all patients, we found reduced GMV in widespread frontal regions, left caudate, insula and superior parietal lobule. Surface-based morphometry analysis revealed reduced CT in the right precentral gyrus of SFN patients. In a region-based approach, patients had reduced GMV in the left caudate. Since pathogenic gain-of-function variants in voltage-gated sodium channels (Nav) have been associated with SFN pathophysiology, we explored brain morphological patterns in a homogenous subsample of patients carrying rare heterozygous missense variants. Whole brain- and region-based approaches revealed GMV reductions in the bilateral caudate for Nav variant carriers. Further research is needed to analyze the specific role of Nav variants for structural brain alterations. Together, we conclude that SFN patients have specific GMV and CT alterations, potentially forming potential new central biomarkers for this condition. Our results might help to better understand underlying or compensatory mechanisms of chronic pain perception in the future. PerspectiveThis study reveals structural brain changes in small-fiber neuropathy (SFN) patients, particularly in frontal regions, caudate, insula, and parietal lobule. Notably, individuals with SFN and specific Nav variants exhibit bilateral caudate abnormalities. These findings may serve as potential central biomarkers for SFN and provide insights into chronic pain perception mechanisms.

Small fiber neuropathy in irritable bowel syndrome.

In this study, we intend to evaluate the occurrence of small fiber neuropathy in patients with irritable bowel syndrome (IBS). Small fiber neuropathy (SFN) is a sensory neuropathy that results from the degeneration of small Aδ and unmyelinated C fibers. SFN manifests positive symptoms, such as tingling, burning, prickling, and aching, and negative symptoms, including numbness, tightness, and coldness. The SFN coexistence with other comorbidities (e.g., fibromyalgia, inflammatory bowel disease, celiac disease) has been reported in previous studies. We conducted a cross-sectional study to assess the coexistence of SFN and IBS. Forty-two IBS patients and forty-three healthy individuals were asked to complete the Michigan Neuropathy Screening Instrument (MNSI) questionnaire. Results greater than three (>3) were considered positive. Participants with positive MNSI questionnaire results were examined for any neuropathy signs according to the Utah Early Neuropathy Scale (UENS) examination. The participants with positive results for the questionnaire and examination were checked for the sural and the superficial peroneal nerve conduction study (NCS). Normal NCS represented intact large fibers and the diagnosis of SFN. Ten participants, 7 (16.7 %) in the IBS group and 3 (6.9 %) in the healthy group, had positive results for the questionnaire. Four participants were positive for the examination, with normal NCS, and were classified as SFN-positive. All four SFN diagnoses were from the IBS group. No one in the healthy group was diagnosed with SFN. We could find a significant statistical difference (p<0.05) between the IBS and healthy groups regarding the prevalence of SFN diagnosis. The co-occurrence of SFN and IBS suggests the possibility of a generalized neuropathy syndrome characterized by widespread neuronal impairment. Thus, any peripheral neuropathy symptom in IBS patients (and potentially other chronic pain disorders) should be evaluated for SFN since timely diagnosis and proper treatment result in a better quality of life for the patients.

A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients.

Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an in-silico model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients. We analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by Hodgkin-Huxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential. Changing a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of Na-K-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect. Our study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded.

Peripheral Pain Captured Centrally: Altered Brain Morphology on MRI in Small Fiber Neuropathy Patients With and Without an SCN9A Gene Variant

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. PerspectiveCortical 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.

A role for pathogenic autoantibodies in small fiber neuropathy?

The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen's syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Serum Neurofilament Light Chain Levels in Small Fiber Neuropathy Patients with Skin Denervation and Ongoing Neuropathic Symptoms (P14-8.004)

<h3>Objective:</h3> To identify active axonal damage by measurement of serum neurofilament light chain (sNfL) levels in patients with small fiber neuropathy (SFN) and ongoing neuropathy symptoms. <h3>Background:</h3> SFN is associated with sensory symptoms and is evident by skin biopsy which show a reduction of the intraepidermal nerve fiber density (IENFD) indicating skin denervation. SFN patients may complain of prolonged/worsening symptoms, but it is not clear if this is associated with continuous axonal damage. <h3>Design/Methods:</h3> Blood samples were collected from 95 consecutive patients that were referred for a skin biopsy due to suspected SFN. All patients had symptoms that were consistent with a clinical diagnosis of SFN. Patients were excluded if they had clinical or imaging evidence for a central nervous system disorder, electrodiagnostic abnormalities or absence of electrodiagnostic evaluation. Following these exclusions, 34 patients were included for analysis. Skin biopsy was performed 2–3 months from symptoms onset by 4 patients, 4–12 months by 7, and after more than 12 months by 23. Severe skin denervation was defined by an intraepidermal nerve fiber density (IENFD) below the 5^th percentile per age, mild denervation when the IENFD was at the 5–20^th percentiles, and above the 20^th percentile was considered normal. <h3>Results:</h3> The majority of patients (29/34; 85%) showed normal sNfL levels and almost half of the patients showed skin denervation (15/34; 44%). Two patients with skin denervation (2/15; 13.3%) showed elevated sNfL, after 7 and more than 12 months from symptoms onset. The skin biopsy was normal in the other 3 patients with elevated sNfL, obtained 2, 8 and more than 12 months from symptoms onset. All patients with elevated sNfL had a history of chemotherapy treatment or immune-mediated disorders. <h3>Conclusions:</h3> In this cohort, a small portion of patients with SFN and skin denervation showed increased sNfL which indicated ongoing axonal damage. <b>Disclosure:</b> Dr. Zohar has nothing to disclose. Miss Qassim has nothing to disclose. Dr. Eltity has nothing to disclose. Dr. Keren has nothing to disclose. Efrat Shavit has nothing to disclose. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mapi Pharma. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merk Serono. The institution of Dr. Chapman has received research support from Ministry Of Industry. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TEVA. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda . Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medison Pharma. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medison Pharma. The institution of Dr. Dori has received research support from Biogen. The institution of Dr. Dori has received research support from Pfizer. The institution of Dr. Dori has received research support from Alnylam therapeutics. Dr. Dori has received intellectual property interests from a discovery or technology relating to health care.

Cytokine expression profiles in white blood cells of patients with small fiber neuropathy

BackgroundThe role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls.MethodsWe prospectively recruited 52 patients and 21 age- and sex-matched healthy controls. Study participants were characterized in detail and underwent complete neurological examination. Venous blood was drawn for routine and extended laboratory tests, and for WBC isolation. Systemic RNA expression profiles of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-2, IL-8, tumor necrosis factor-alpha (TNF) and the anti-inflammatory cytokines IL-4, IL-10, transforming growth factor beta-1 (TGF) were analyzed. Protein levels of IL-2, IL-8, and TNF were measured in serum of patients and controls. Receiver operating characteristic (ROC)-curve analysis was used to determine the accuracy of IL-2, IL-8, and TNF in differentiating patients and controls. To compare the potential discriminatory efficacy of single versus combined cytokines, equality of different AUCs was tested.ResultsWBC gene expression of IL-2, IL-8, and TNF was higher in patients compared to healthy controls (IL-2: p = 0.02; IL-8: p = 0.009; TNF: p = 0.03) and discriminated between the groups (area under the curve (AUC) ≥ 0.68 for each cytokine) with highest diagnostic accuracy reached by combining the three cytokines (AUC = 0.81, sensitivity = 70%, specificity = 86%). Subgroup analysis revealed the following differences: IL-8 and TNF gene expression levels were higher in female patients compared to female controls (IL-8: p = 0.01; TNF: p = 0.03). The combination of TNF with IL-2 and TNF with IL-2 and IL-8 discriminated best between the study groups. IL-2 was higher expressed in patients with moderate pain compared to those with severe pain (p = 0.02). Patients with acral pain showed higher IL-10 gene expression compared to patients with generalized pain (p = 0.004). We further found a negative correlation between the relative gene expression of IL-2 and current pain intensity (p = 0.02). Serum protein levels of IL-2, IL-8, and TNF did not differ between patients and controls.ConclusionsWe identified higher systemic gene expression of IL-2, IL-8, and TNF in SFN patients than in controls, which may be of potential relevance for diagnostics and patient stratification.

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

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. 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. 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. 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.

Small-fibre Neuropathy in Patients with Familial Amyotrophic Lateral Sclerosis Type 8.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the nervous system that primarily affects motor neurons. ALS type 8 (ALS8) is a familiar form with predominant involvement of lower motor neurons, tremor, and slow progression. The aim of this study was to describe sensory involvement in a cohort of ALS8 patients and compare it with the characteristics of sporadic ALS (sALS) patients and controls. We compared data from 40 ALS8 and 10 sALS patients assessed by neurological evaluation and electrophysiological study. Skin biopsies were performed in these patients and 12 controls for analysis of intraepidermal nerve fiber (IENF) density by protein gene product 9.5 (PGP 9.5) immunohistochemistry. The ALS8 group was younger than the sALS group at the onset of symptoms (p < 0.05) and had a longer disease evolution (p < 0.01). Sensory abnormalities were evident in 35% of the ALS8 and 30% of the sALS patients by neurological examination, and all ALS patients presented normal sensory nerve action potentials. Despite being similar in the ALS8 and sALS groups, IENF density in the ALS8 group was lower than that in the controls (p < 0.0005). In the ALS8 group, IENF density was significantly lower in patients with impairment of vibratory sensation than in those without this finding (p < 0.05) and in females than in males (p < 0.05). Sensory impairment and decreased IENF density are present in ALS8 patients at a frequency and intensity similar to that in the sALS group.

Clinical and paraclinical features of small fiber neuropathy in Sjögren’s syndrome

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.

Living with small fiber neuropathy: insights from qualitative focus group interviews.

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. 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. 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. Given the results, it can be concluded that an optimal treatment should include biological, psychological, and social components.

S577 Comparison of Gastrointestinal Symptoms and Gastric Emptying Scintigraphy Between Postural Orthostatic Tachycardia Patients With and Without Small Fiber Neuropathy

Introduction: Autonomic dysfunction is common in patients with postural orthostatic tachycardia syndrome (POTS) and affects multiple systems, including the gastrointestinal (GI) tract. Various subtypes of POTS exist: autoimmune, hyperadrenergic, and neuropathic. While these subtypes share features of common autonomic symptoms; it remains unclear how symptom presentation amongst other affected systems, such as the GI tract, differ across subtypes. We aimed to compare gastrointestinal symptom presentation and gastric emptying scintigraphy (GES) between POTS patients with and without small fiber neuropathy (SFN). Methods: We conducted a retrospective case series of all POTS patients at our institution who underwent autonomic testing between 2013-2021. Patients were divided into those with SFN (abnormal QSART test) and those without SFN (normal QSART). Demographics, comorbidities, and reported GI symptoms were extracted. GES results were also extracted with percentage emptying at 60-minute intervals (4-hour study). Chi2 and glmnet testing were used to compare the groups. Results: 97 POTS patients (14 men), who underwent autonomic testing for SFN were included. Median age was 36 (21-67). Common comorbidities included hypermobile Ehlers Danlos Syndrome (44%), and chronic fatigue syndrome (22%). POTS patients with SFN were more likely to have nausea (75% vs 55%, p=0.03), poor oral intake (32% vs 9%, p=0.01), parenteral nutrition dependence (9% vs 0%, p=0.01), and early satiety (36% vs 18%, p=0.05) (Table). Most demographics and GI symptoms did not show significance as predictors for SFN. Of the 97 patients, a total of 33 underwent GES for evaluation of reported GI symptoms. The percentage of patients with delayed GES was numerically higher but not statistically significant in POTS patients with SFN (45% vs 23%, p=0.21). There were no significant differences in mean gastric emptying between groups (Table). Conclusion: Our data affirms the high prevalence of GI symptoms in patients with POTS independent of SFN. Patient with SFN were more likely to have upper GI symptoms of nausea, poor oral intake and early satiety despite similarities in GES. This suggests that symptoms may be due to sensory rather than motor dysfunction. While some GI symptoms were more common in those with SFN, there was a lack of predictability of symptoms and demographics for SFN. This suggests the need to have a high clinical suspicion for diagnosing SFN in patients with POTS whose GI symptoms do not respond to conventional therapy. Table 1. - Baseline Demographics and Gastrointestinal Symptom Presentation across POTS patients with and without SFN and Gastric Emptying Results Variable All (n=97) POTS with SFN (n=53) POTS w/o SFN (n=44) p-value Basic Demographics Age: Median (IQR) 36 (30-46) 37 (32-48) 35 (27-40) 0.12 Sex, n (%) 0.59 Female 83 (86) 45 (85) 39 (89) Male 14 (14) 8 (15) 5 (11) Race, n (%) 0.17 White 83 (86) 43 (81) 40 (91) Other 14 (14) 10 (19) 4 (9) Co-morbidities Hypermobile EDS 43 (44) 23 (43) 20 (45) 0.84 CSF Leak 19 (20) 13 (25) 6 (14) 0.18 Chronic Fatigue Syndrome 21 (22) 14 (26) 7 (16) 0.21 Fibromyalgia 15 (15) 9 (17) 6 (14) 0.27 Diabetes 2 (2) 1 (2) 1 (2) 0.89 Hypothyroidism 14 (14) 5 (9) 9 (20) 0.12 Chronic Narcotic Use 7 (7) 1 (2) 6 (14) 0.03 Gastrointestinal Symptoms Abdominal pain, n (%) 63 (65) 37 (70) 26 (59) 0.27 Bloating, n (%) 44 (45) 26 (49) 18 (41) 0.42 Nausea, n (%) 64 (66) 40 (75) 24 (55) 0.03 Vomiting, n (%) 28 (29) 19 (36) 9 (20) 0.10 Dyspepsia, n (%) 9 (9) 7 (13) 2 (5) 0.09 Constipation, n (%) 57 (59) 35 (66) 22 (50) 0.11 Diarrhea, n (%) 34 (35) 23 (43) 11 (25) 0.06 Early Satiety, n (%) 27 (28) 19 (36) 8 (18) 0.05 Dysphagia, n (%) 11 (11) 6 (11) 5 (11) 0.99 Weight Loss, n (%) 26 (27) 16 (30) 10 (23) 0.41 Poor oral intake, n (%) 21 (22) 17 (32) 4 (9) 0.01 Enteral nutrition dependence, n (%) 4 (4) 3 (6) 1 (2) 0.40 Parenteral nutrition dependence, n (%) 5 (5) 5 (9) 0 (0) 0.04 Gastric Emptying Delayed Gastric Emptying, n (%) 12 (36) 9 (45) 3 (23) 0.21 Percentage Emptying at Various Durations 60 minutes: Mean (SD) 32.1 (22.3) 28.9 (24.6) 37.0 (18.2) 0.35 120 minutes: Mean (SD) 57.3 (27.3) 53.3 (29.4) 62.5 (24.6) 0.37 180 minutes: Mean (SD) 74.3 (24.9) 68.7 (26.8) 83.3 (19.2) 0.15 240 minutes: Mean (SD) 85.8 (17.4) 84.1 (18.4) 88.2 (16.6) 0.55

Small-fibre Neuropathy in Patients with Type 2 Diabetes Mellitus and its Relationship with Diabetic Itch: Preliminary Results.

Abstract is missing (Short communication)

Subepidermal Schwann cell counts correlate with skin innervation - an exploratory study.

Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype. Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined. Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n=13; median age, 53[range, 19-73]years) and normal distal (n=15, median age, 54 [range, 43-68]years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics. Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.

Modified collision study to isolate and study small fibre neuropathy in patients with Type 2 diabetes.

Introduction:Diabetic distal symmetrical polyneuropathy (DSPN) can be categorized as small fibre, large fibre, and mixed neuropathy. Even though small fibre neuropathy is the most prevalent, unfortunately it is usually not recognized by routine electrophysiologic studies. In this study, we intend to examine the slow velocity small fibres responsible for small fibre DSPN, by isolating them using collision technique principle in patients with diabetes.Methods:This is an observational case-control study designed to compare nerve conduction values with application of collision technique in 60 patients with T2D and in 60 age and sex matched controls.Results:The collision study in patients with Type 2 Diabetes showed mean Latency of 10.5 ± 1.7 ms and mean Amplitude of 3.4 ± 2.3 mV on the right side and mean Latency of 10.5 ± 1.7 ms and the mean Amplitude of 3.5 ± 2.2 mV on the left side. There was a statistically significant difference (P value < 0.001) in the amplitute and latency of CNAPs of small fibres in median nerve innervated APBs of both arms between those with T2D and controls.Discussion and Conclusion:Collision study helps to examine the slower conducting fibres of the larger nerves. Our study suggests that the Collision Technique can be used to identify early peripheral neuropathy regardless of the diabetes status, thus making it more practically feasible and cost-effective.