Small Fiber Neuropathy Research Articles

Assessment of small fiber neuropathy and distal sensory neuropathy in female patients with fibromyalgia.

We investigated sudomotor dysfunction, small fiber neuropathy (SFN), and their clinical significance in female fibromyalgia patients. 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. 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. 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.

Small Fiber Neuropathy in Burning Mouth Syndrome: A Systematic Review

Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder, characterized by persistent burning sensations and pain without clear pathological causes. Recent research suggests that small fiber neuropathy (SFN) may play a significant role in the neuropathic pain and sensory disturbances associated with BMS. Following PRISMA guidelines, this systematic review aims to evaluate and synthesize current evidence supporting SFN’s involvement in BMS. The protocol is registered in PROSPERO (CRD42024555839). The results show eight studies reported reductions in nerve fiber density in tongue biopsies (ranging from 30% to 60%), along with morphological changes indicative of small fiber damage. Additionally, an increase in TRPV1-positive, NGF-positive, and P2X3-positive fibers, overexpression of Nav1.7, and slight underexpression of Nav1.9 mRNA were observed in BMS patients. Quantitative Sensory Testing in seven studies revealed sensory abnormalities such as reduced cool detection and cold pain thresholds. Blink reflex and corneal confocal microscopy also indicated peripheral and central small fiber damage, along with increased artemin mRNA expression. The evidence strongly supports SFN as a key factor in the pathophysiology of BMS, particularly due to reductions in nerve fiber density and altered sensory thresholds. However, variability across studies highlights the need for larger, standardized research to establish causal relationships and guide therapeutic strategies.

From Sudoscan to bedside: theory, modalities, and application of electrochemical skin conductance in medical diagnostics

The human body has two main types of sweat glands: apocrine and eccrine. Eccrine glands are widely distributed across the skin, including areas with hair. While the eccrine glands on palms and soles help improve grip, those on the rest of the body primarily aid in thermoregulation. Sudomotor function, which controls sweating, is regulated by the sympathetic division of the autonomic nervous system through cholinergic and adrenergic pathways. The activation of eccrine glands involves intricate processes, including neurotransmitter binding, ion channel modulation, and voltage generation. Sudoscan technology utilizes electrochemical skin conductance (ESC) to non-invasively measure sudomotor function. This method, which has been standardized for accuracy, has established normative benchmarks and has proven reliable across diverse populations. Sudoscan’s diagnostic performance is comparable to invasive methods such as intraepidermal nerve fiber density testing, making it a valuable tool for diagnosing small fiber neuropathy. Moreover, it has been shown to correlate with corneal nerve fiber length, providing insights into various neuropathic conditions. Compared to traditional sudomotor function tests, Sudoscan proves superior in terms of its accessibility, simplicity, and reliability, with the potential to replace or complement existing diagnostic methods. It is important to differentiate ESC, as measured by Sudoscan, from other skin conductance measures, such as galvanic skin response (GSR) or electrodermal activity (EDA). Although these methods share a common physiological principle, ESC is specifically designed for diagnosing sudomotor function, unlike GSR/EDA, which is typically used for continuous monitoring. Sudoscan’s success has led to its integration into consumer health devices, such as the BodyScan from Withings, showcasing its versatility beyond clinical settings. Future research may explore ESC applications in diverse medical fields, leveraging real-world data from integrated consumer devices. Collaborative efforts between researchers and engineers promise to offer new insights into sudomotor function and its implications for broader health monitoring. This study provides a comprehensive overview of ESC, including topics such as eccrine gland physiology, sudomotor function, Sudoscan technology, normative benchmarks, diagnostic comparisons, and potential future applications.

The Evolving Landscape of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) belongs to a heterogeneous group of disorders in which thinly myelinated Aδ and unmyelinated C-fibers are primarily affected, leading to neuropathic pain and autonomic symptoms. SFN can be associated with systemic conditions such as diabetes, autoimmune diseases, exposure to drugs and toxins, and infection, with the list of associated diseases continuing to expand. Variants in the SCN9A, SCN10A, and SCN11A genes encoding Nav 1.7, Nav 1.8, and Nav 1.9 sodium channel subunits, as well as in the TRPA1 gene, have been found in SFN patients, expanding the spectrum of underlying conditions and enhancing our understanding of pathophysiological mechanisms. There is also growing interest in immune-mediated forms that could help identify potentially treatable subgroups. According to international criteria, diagnosis is established through clinical examination, the assessment of intraepidermal nerve fiber density, and/or quantitative sensory testing. Autonomic functional tests allow for a better characterization of dysautonomia in SFN, which can be subclinical. Other tests can support the diagnosis. Currently, the management of SFN prioritizes treating the underlying condition, if identified, within a multidisciplinary approach that combines symptomatic pain therapy, lifestyle changes, and biopsychological interventions. Emerging insights from the molecular characterization of SFN channelopathies hold promise for improving diagnosis, potentially leading to the discovery of new drugs and refining trial designs in the future. This article reviews the clinical presentation, diagnostic workup, and advancing knowledge of associated conditions and interventional management of SFN.

Comparison of intraepidermal nerve fiber density and confocal corneal microscopy for neuropathy.

Compare the diagnostic characteristics of intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM) for distal symmetric polyneuropathy (DSP) and small fiber neuropathy (SFN). Participants with obesity were recruited from bariatric surgery clinics and testing was performed prior to surgery. DSP and SFN were determined using the Toronto consensus definitions of probable neuropathy. IENFD was assessed from 3 mm punch biopsies of the distal leg and proximal thigh. CCM was performed on both eyes with manual and automated counting. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was also completed. Diagnostic capability was determined using areas under the receiver operating characteristics curve (AUC) from logistic regression. We enrolled 140 participants (mean [standard deviation [SD]] age: 50.3 years [7.1], 77.1% female, BMI: 44.4 kg/m2 [6.7]). In this population, 22.9% had DSP and 14.3% had SFN. Distal leg IENFD had the largest AUC (95% confidence interval) for DSP (0.78, 0.68-0.89) and SFN (0.85, 0.75-0.96). Proximal thigh IENFD (DSP: AUC: 0.59, 0.48-0.69, SFN: AUC: 0.59, 0.46-0.73) and CCM metrics (DSP: AUC range: 0.55-0.60, SFN: AUC range: 0.45-0.62) had poorer diagnostic capability than distal leg IENFD for DSP/SFN (P < 0.05). MNSIq had similar diagnostic capability to distal leg IENFD for both DSP/SFN (DSP: AUC: 0.76, 0.68-0.85, SFN: AUC: 0.81, 0.73-0.88). More participants (52%) preferred skin biopsies to CCM. Distal leg IENFD was the best quantitative measure of DSP/SFN. CCM had poor diagnostic characteristics and fewer patients preferred this test to IENFD. The MNSIq had similar diagnostic characteristics to distal leg IENFD, indicating its value as a diagnostic tool in the clinical setting. clinicaltrials.gov: NCT03617185.

SMALL FIBER NEUROPATHY DIAGNOSIS IN PARKINSON'S DISEASE PATIENTS: A CASE SERIES

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Motor impairments, particularly in gait and balance, significantly reduce the quality of life in patients, increasing the risk of falls. Non-motor symptoms, including autonomic dysfunctions and peripheral neuropathy, are prevalent as the disease progresses. Peripheral neuropathy, present in 55% of PD patients, manifests with sensory loss, postural instability, and pain, further impairing motor function and increasing fall risk. This study aimed to adapt and test a simple method to identify small fiber neuropathy in PD patients, specifically using the Skin Wrinkling Test (SWT), and to correlate its findings with autonomic dysfunctions. Four PD patients were evaluated using questionnaires (Non-Motor Symptoms Questionnaire, COMPASS-31) and SWT. All patients showed alterations in the SWT, suggesting the presence of small fiber neuropathy, regardless of disease duration or comorbid conditions such as diabetes. Despite the small sample size, our findings support the SWT as a practical tool for assessing small fiber neuropathy in clinical practice. Further large-scale studies are needed to validate these results and their implications for diagnosing peripheral neuropathy in PD patients.

NaV1.8/NaV1.9 double deletion mildly affects acute pain responses in mice.

The 2 tetrodotoxin-resistant (TTXr) voltage-gated sodium channel subtypes NaV1.8 and NaV1.9 are important for peripheral pain signaling. As determinants of sensory neuron excitability, they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and the release of neurotransmitters from sensory neuron terminals. NaV1.8 and NaV1.9, which are encoded by SCN10A and SCN11A, respectively, are predominantly expressed in pain-sensitive (nociceptive) neurons localized in the dorsal root ganglia (DRG) along the spinal cord and in the trigeminal ganglia. Mutations in these genes cause various pain disorders in humans. Gain-of-function missense variants in SCN10A result in small fiber neuropathy, while distinct SCN11A mutations cause, i. a., congenital insensitivity to pain, episodic pain, painful neuropathy, and cold-induced pain. To determine the impact of loss-of-function of both channels, we generated NaV1.8/NaV1.9 double knockout (DKO) mice using clustered regularly interspaced short palindromic repeats/Cas-mediated gene editing to achieve simultaneous gene disruption. Successful knockout of both channels was verified by whole-cell recordings demonstrating the absence of NaV1.8- and NaV1.9-mediated Na+ currents in NaV1.8/NaV1.9 DKO DRG neurons. Global RNA sequencing identified significant deregulation of C-LTMR marker genes as well as of pain-modulating neuropeptides in NaV1.8/NaV1.9 DKO DRG neurons, which fits to the overall only moderately impaired acute pain behavior observed in DKO mice. Besides addressing the function of both sodium channels in pain perception, we further demonstrate that the null-background is a very valuable tool for investigations on the functional properties of individual human disease-causing variants in NaV1.8 or NaV1.9 in their native physiological environment.

Correlation Between Orofacial Pain and Sensory and Autonomic Neuropathies.

Orofacial Pain (OFP) affects 15% of the general population. OFP conditions can be myofascial, also known as temporomandibular disorders (TMDs) or neuropathic. The underlying pathophysiology in several chronic OFP conditions, is unknown. Small fiber neuropathy (SFN) is a disorder of thinly myelinated A-delta and non-myelinated C-fibers and can manifest as sensory and autonomic neuropathies. SFN has been demonstrated in some OFP conditions. Our study aims to assess the presence of OFP in patients with sensory and autonomic neuropathies and assess the correlation between OFP, skin biopsy and autonomic dysfunction. This is a retrospective study (2018-2020) of patients from the SFN registry, Massachusetts General Hospital, Boston, USA, for the presence of OFP. All patients were included. Primary outcome: Prevalence of OFP in patients with chronic neuropathies. Secondary outcomes: Correlation between OFP and skin biopsy, dysautonomia, headaches, chronic nociceptive pain, psychological conditions, and patient factors, such as mean age and BMI. Charts of 450 patients with sensory and autonomic neuropathies were reviewed. 22.67% (n=102) had OFP. The mean (range) age at biopsy in patients with OFP was 48.36 (20-81) years, female: male ratio 3.25:1. More OFP patients had negative skin biopsy results (p value<0.05) than those with sensory neuropathies. Patients with OFP had significantly higher prevalence of psychological conditions (p value 0.000), and higher BMI >30 (p value 0.025). Dysautonomia was significantly higher in patients with TMDs when compared to the ones without TMDs (p value 0.030). There was no significant difference in mean age, gender predilection, presence of headaches, peripheral neuropathies, and nociceptive pain between patients with and without OFP. OFP and sensory neuropathies can be overlapping conditions. Patients presenting with concomitant TMD and dysautonomia can be further tested for SFN. This can further help us understand a correlation if any, between idiopathic TMD/OFP conditions and SFN and further our understanding of the pathophysiology of these conditions.

567P A prospective observational study on the effect of intravenous immunoglobulin on small fiber neuropathy after SARS-CoV-2 infection or vaccination

567P A prospective observational study on the effect of intravenous immunoglobulin on small fiber neuropathy after SARS-CoV-2 infection or vaccination

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy.

Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

Correlates and predictors of symptom severity over time in people under investigation for postural orthostatic tachycardia syndrome (POTS).

Postural Orthostatic Tachycardia Syndrome (POTS) is a poorly understood chronic disorder characterised by an unexplained excessive increase in heartbeat upon standing. The aim of this study was to investigate psychosocial and physiological correlates and predictors of symptom severity over time in patients presenting with POTS-like symptoms. Longitudinal cohort study of patients under investigation for POTS ( n = 149). Patients completed questionnaires at one month pre-clinic appointment and 6 months later. Diagnosis, blood pressure (BP) and heart rate (HR) measures were collected from medical records. Data were analysed using hierarchical linear multiple regression. Orthostatic and small fibre neuropathy (SFN) symptoms remained stable over time and were significantly correlated with distress, cardiac anxiety, threatening views of the illness, and cognitive-behavioural responses to symptoms, but not with emotional reactivity or social support. Baseline psychosocial factors collectively explained 48% (F = 5.37, p < .001) of the variance in orthostatic symptoms, and 35% (F = 3.49, p < .001) of the variance of SFN symptoms at baseline, but a non-significant amount of variance in symptoms at 6 months when controlling for baseline symptoms. Haemodynamic measures explained a significant 4% (F = 3.37, p = .026) of variance of orthostatic symptoms at 6 months. Symptom burden in patients with suspected POTS remained high over 6 months. Psychosocial factors explained a large amount of the variance in symptoms at baseline. As symptoms did not change/improve over time, baseline symptoms accounted for most of the variance in symptoms at 6 months. An integrated approach addressing psychosocial factors alongside medical treatments may promote adjustment to the condition and lessen symptom burden for this group.

Nociplastic Pain: A Critical Paradigm for Multidisciplinary Recognition and Management.

Our understanding of chronic pain has evolved significantly, shifting from a focus on peripheral damage to recognizing the central mechanisms underlying pain perception. This perspective article explores the concept of nociplastic pain, a term introduced by the International Association for the Study of Pain (IASP) in 2017, which describes pain arising from altered pain modulation within the central nervous system, without clear evidence of tissue damage or inflammation. The historical progression from fibrositis to fibromyalgia, and now to nociplastic pain, underscores the complexity of chronic pain syndromes and the need for a multidisciplinary approach to management. Nociplastic pain is characterized by central sensitization, leading to heightened pain sensitivity and often accompanied by comorbidities such as fatigue, sleep disturbances, and cognitive difficulties. Advances in neuroimaging have revealed altered connectivity within key brain networks, such as the default mode and salience networks, in patients with nociplastic pain, providing insights into the neural underpinnings of this condition. The article also addresses controversies surrounding the role of small fiber neuropathy and autonomic dysfunction in nociplastic pain, highlighting the ongoing debates in the field. The practical importance of recognizing nociplastic pain across various medical disciplines-including primary care, orthopedics, neurology, psychiatry, and rheumatology-is emphasized, with recommendations for integrating this knowledge into clinical practice. Emerging therapies, such as neurofeedback, hyperbaric oxygen therapy, and neuromodulation, offer new avenues for treatment, particularly for patients who do not respond to conventional approaches. The article calls for continued research into the mechanisms of nociplastic pain, the development of reliable diagnostic tools, and the exploration of novel therapeutic strategies to improve patient outcomes. The recognition and management of nociplastic pain are crucial for advancing the care of patients with chronic pain, necessitating interdisciplinary collaboration and a patient-centered approach.

A study of PGP 9.5 immunohistochemical labeling on formalin-fixed paraffin embedded tissues for epidermal nerve fiber density testing

ABSTRACT There have been several methods established for immunohistochemical labeling of the PGP 9.5 antigen in human tissue for the assessment of epidermal nerve fiber density, none of which uses neutral-buffered formalin as the preferred fixative for paraffin-embedded tissue. The literature maintains that formalin-fixed paraffin embedded tissues are unable to be used for this purpose and that other fixatives must be used due to the cross-linkages caused by formalin fixation. This study was undertaken to develop a standardized method for the use of formalin-fixed paraffin embedded tissues for immunohistochemical labeling and assessment of epidermal nerve fiber density. Formalin-fixed paraffin embedded tissues from the punch biopsies of patients suspected to have small fiber neuropathy were prepared for immunohistochemical labeling using heat-induced epitope retrieval for one hour at 92°C. The tissues were then stained with a polyclonal rabbit anti-human PGP 9.5 primary antibody. The resulting stains were then evaluated by a licensed pathologist who counted the number of epidermal nerve fibers stained and recorded the epidermal length in millimeters. Human foreskin was used as the tissue control in these studies. Satisfactory immunohistochemical labeling of epidermal nerve fibers was achieved from formalin-fixed paraffin embedded tissues through the use of heat-induced epitope retrieval. The authors of this paper have concluded that formalin-fixed paraffin embedded tissues may be used to achieve satisfactory immunohistochemical labeling for the assessment of epidermal nerve fiber density.

Beyond pain: Using Unsupervised Machine Learning to Identify Phenotypic Clusters of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is characterized by dysfunction and loss of peripheral unmyelinated and thinly myelinated nerve fibers, resulting in a phenotype that includes varying combinations of somatosensory and dysautonomia symptoms, which can be profoundly disabling and lead to decreased quality of life. Treatment aimed mainly at pain reduction, which may not target the underlying pathophysiology, is frequently ineffective. Another impediment to the effective management of SFN may be the significant between-patient heterogeneity. Accordingly, we launched this study to gain insights into the symptomatic variability of SFN and determine if SFN patients can be sub-grouped based on clinical characteristics. To characterize the phenotype and investigate how patients with SFN differ from those with large fiber involvement, 105 patients with skin-biopsy proven SFN and 45 with mixed fiber neuropathy (MFN) were recruited. Using unsupervised machine learning, SFN patients were clustered based upon symptom concurrence and severity. Demographics, clinical data, symptoms, and skin biopsy- and laboratory findings were compared between the groups. MFN- as compared to SFN patients, were more likely to be male, older, had a lower intraepidermal nerve fiber density at the ankle and more frequent abnormal immunofixation. Beyond these differences, symptom prevalence and intensities were similar in the two cohorts. SFN patients comprised three distinct phenotypic clusters, which differed significantly in symptom severity, co-occurrence, localization, and skin biopsy findings. Only one subgroup, constituting about 20% of the patient population, was characterized by intense neuropathic pain, which was always associated with several other SFN symptoms of similarly high intensities. A pauci-symptomatic cluster comprised patients who experienced few SFN symptoms, generally of low to moderate intensity. The largest cluster was characterized by intense fatigue, myalgias and subjective weakness, but lower intensities of burning pain and paresthesia. This data-driven study introduces a new approach to subgrouping patients with SFN. Considering both neuropathic pain and pernicious symptoms beyond pain, we identified three clusters, which may be related to distinct pathophysiological mechanisms. Although additional validation will be required, our findings represent a step towards stratified treatment approaches and, ultimately, personalized treatment.

Nonamyloidogenic TTR gene variants c.76G>A and c.337-18G>C are not associated with idiopathic small-fiber neuropathy.

Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.

New phenotyping questionnaire for diagnosing sarcoidosis-associated small fiber neuropathy.

Small fiber neuropathy is a common complication in patients with sarcoidosis and its prevalence is estimated at 40-86%. The underlying mechanism influences the presentation of small fiber neuropathy. For example, patients with metabolic diseases are often associated with a classic length-dependent small fiber neuropathy pattern, while patients with inflammatory diseases are more often present with a non-length-dependent small fiber neuropathy. Detailed phenotyping may be useful to improve diagnostic efficiency, as a clue to underlying mechanisms and as a precondition for personalized medicine. This study examined four phenotypes distinguishing between length-dependent and non-length-dependent presentation with a new subdivision for continuous and intermittent presentation. Forty-eight sarcoid patients with symptoms and at least two clinical signs of small fiber neuropathy and normal nerve conduction studies were classified as having probable small fiber neuropathy. A new small fiber neuropathy phenotyping questionnaire has been developed that allows patients to mark the anatomical locations of pain at three different levels: the skin, muscles, and joints. The location of symptoms was used to define length dependence, and two colors were used to distinguish continuous (red) from intermittent (blue) symptoms. In addition, skin biopsy, corneal confocal microscopy, Sudoscan and water immersion skin wrinkling were used to investigate a correlation between the four phenotypes, sensory function, nerve fiber density, and autonomic nerve function. Overall, 35% of patients with probable small fiber neuropathy showed length-dependent symptoms and 44% showed non-length-dependent symptoms while 21% suffered from non-neuropathic musculoskeletal pain. The distinction between intermittent and continuous symptoms showed significantly less continuous than intermittent non-length-dependent symptoms (odds ratio = 0.3, P = 0.01). Moreover, continuous length-dependent symptoms were the only phenotype that correlated with thermal threshold testing (R = 0.3; P = 0.02) and the small fiber neuropathy screening list (R = 0.3; P = 0.03). In addition, thermal threshold testing (TTT) also correlated with the small fiber neuropathy (SFN) screening list (R = 0.3; P = 0.03). Other diagnostic methods showed no correlation with any of the four defined phenotypes. A novel finding is that TTT is only associated with continuous length-dependent pain, suggesting that TTT could result in more false negatives in patients with other pain phenotypes. Determining the pathophysiologic mechanisms could help develop new diagnostic methods. If patients suspected of SFN show symptoms without a length-dependent continuous presentation, the diagnosis should focus less on the diagnostic methods used.

Painful stimulation increases functional connectivity between supplementary motor area and thalamus in patients with small fibre neuropathy.

The lead symptom of small fibre neuropathy (SFN) is neuropathic pain. Recent functional magnetic resonance imaging (fMRI) studies have indicated central changes in SFN patients of different etiologies. However, less is known about brain functional connectivity during acute pain processing in idiopathic SFN. We conducted fMRI with thermal heat pain application (left volar forearm) in 32 idiopathic SFN patients and 31 healthy controls. We performed functional connectivity analyses with right supplementary motor area (SMA), left insula, and left caudate nucleus (CN) as seed regions, respectively. Since pathogenic gain-of-function variants in voltage gated sodium channels (Nav) have been linked to SFN pathophysiology, explorative connectivity analyses were performed in a homogenous subsample of patients carrying rare heterozygous missense variants. For right SMA, we found significantly higher connectivity with the right thalamus in SFN patients compared to controls. This connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. We found significantly reduced connections between right SMA and right middle frontal gyrus in patients with Nav variants. Likewise, connectivity between left CN and right frontal pole was decreased. Aberrant functional connectivity in SFN is in line with previous research on other chronic pain syndromes. Functional connectivity changes may be linked to SFN, highlighting the need to determine if they result from peripheral changes causing abnormal somatosensory processing. This understanding may be crucial for assessing their impact on painful symptoms and therapy response. We found increased functional connectivity between SMA and thalamus during painful stimulation in patients with idiopathic SFN. Connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. Our findings emphasize the importance of investigating functional connectivity changes as a potential feature of SFN.

Automated immunohistochemistry of intra-epidermal nerve fibres in skin biopsies: A proof-of-concept study.

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. 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. 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. 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.

Navigating Complexity in Postural Orthostatic Tachycardia Syndrome.

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes.

Tear neuropeptide Y as a non-invasive marker of peripheral microvascular complications in type 1 diabetes

AimsTo investigate tear neuropeptide Y (NPY) and substance P concentrations in individuals with type 1 diabetes, comparing those with and without both diabetic retinopathy (DR) and peripheral neuropathy. MethodsThis cross-sectional study involved 41 participants with type 1 diabetes and none to moderate DR, and 22 healthy controls. Assessments included clinical ocular surface parameters, quantification of corneal nerve attributes (based on in vivo confocal microscopy imaging), DR grading, and evaluation for small and large fibre neuropathy. Concentrations of NPY and substance P in tear samples were measured using enzyme-linked immunosorbent assay. ResultsMean (± standard deviation) tear NPY concentrations in participants with type 1 diabetes and length-dependent small fibre neuropathy (SFN) was lower than in controls (10.84 ± 4.10 ng/mL vs 14.72 ± 3.12 ng/mL; p=0.004), but not significantly different from type 1 diabetes participants without SFN (13.39 ± 4.66 ng/mL; p=0.11). Tear NPY levels were lower in individuals with type 1 diabetes and mild/moderate non-proliferative DR (10.44 ± 3.46 ng/mL) compared to none/minimal DR (13.79 ± 4.76 ng/mL; p=0.0005) and controls. In separate linear regression models, both the presence of SFN (β = −0.75, p=0.02) and the presence of mild/moderate DR (β = −0.84, p=0.009) were significantly associated with tear NPY levels relative to controls, after adjusting for participant age, sex, and dry eye disease. There were no inter-group differences for tear substance P concentrations. ConclusionsTear NPY has potential utility as an indicator of peripheral microvascular complications associated with type 1 diabetes.