Search

Background and Purpose Methods Results Conclusions 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. [ABSTRACT FROM AUTHOR]

Although the pathophysiology of fibromyalgia syndrome has been better understood in recent decades, a unified model of its pathogenesis and an effective therapeutic approach are still far from being realized. The main aim of this article will be to delve into the fundamental mechanisms of the pathophysiology of fibromyalgia conceptualized as stress intolerance syndrome. Using the biopsychosocial model of chronic pain syndromes, we will describe the potential role of the attachment system, C-tactile fibers, and oxytocinergic system dysfunction in the pathophysiology of fibromyalgia syndrome and other central sensitivity syndromes. At the end of the article, the therapeutic implications of this new global and translational pathophysiological model will be briefly discussed. [ABSTRACT FROM AUTHOR]

Copyright of Die Dermatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the "Nicotinic acetylcholine receptor signaling pathway". Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics. [ABSTRACT FROM AUTHOR]

Small-fiber neuropathy (SFN) develops due to the impairment of fibers responsible for mediating temperature, pain, and autonomic functions. SFN complicates a number of common diseases such as diabetes mellitus, human immunodeficiency virus, and COVID-19, and is likely to be increasingly encountered. The associated pain contributes significantly to the morbidity of these diseases. Progression is slow, and most people affected by SFN do not develop large-fiber involvement over time. However, mixed polyneuropathies often start as SFN, and SFN often coexists with large fiber–predominant neuropathy. Symptoms of SFN, including painful paresthesia and dizziness, and sedative side effects of pain medications can negatively affect the quality of life. Standardized diagnostic criteria for SFN are not fully established, and skin biopsy remains the diagnostic test considered most reliable. Autonomic testing is useful when autonomic symptoms are present along with screening for associated conditions. Treatment should be individualized to control underlying causes and alleviate pain. Early diagnosis and individualized treatment are important for controlling SFN symptoms and optimizing daily functions. Here, we review the common but increasingly ignored condition, SFN, and discuss its diagnosis and management.

A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN has not been studied. This study investigated a possible relationship between SFN and patients with TN (PwTNs) using autonomic function tests (AFTs) including quantitative sudomotor axon reflex tests (QSART). We performed QSARTs and other AFTs such as the Sympathetic skin response (SSR), Valsalva ratio (VR), and heart rate variability (HRV). The QSART results, obtained at seven hospitals using same protocols, were compared between PwTNs and healthy controls. We confirmed the abnormalities in SSR, VR, and HRV in PwTNs, although those parasympathetic AFTs were not performed in healthy controls. Additionally, we checked Tinnitus handicap inventory (THI) scores for PwTNs and -50% of PwTNs had low-grade disability, whereas 9.3% had high-grade disability. Data from 57 PwTNs and 122 healthy controls were analyzed. The sweat volumes of QSART in the older age group tended to be higher in the PwTNs than in age-matched healthy controls, and significant differences between the PwTN and control groups were observed in the feet in both sexes (p < 0.001) and in the arms in women (p = 0.013). In the younger age group, the sweat volumes in the feet of men were higher in PwTNs than in healthy controls (p = 0.017). No association was observed between THI and QSART scores. In this study, the sweat volumes in QSARTs were higher in PwTNs than in healthy controls. However, abnormal SSR, HRV, and VR results were not commonly observed in PwTNs. Although the results should be interpreted with caution because of limitations in study, PwTNs might also have SFN apart from dysautonomia. This is the first study to perform QSART with other parasympathetic AFTs in PwTNs. However, larger and more rigorously controlled studies will be needed to reveal the relationship between SFN and TN in the future. [ABSTRACT FROM AUTHOR]

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the “Nicotinic acetylcholine receptor signaling pathway”. Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.

Introduction/Aims: Research has proven that epidermal and transcutaneous stimulation can identify the function of Aβ and Aδ fibers (i.e., in diabetes) individually using different electrodes. In this study we aimed to determine the stability of perception thresholds when using such electrodes. Methods: Twenty healthy volunteers participated in this study. The perception threshold of Aβ fibers (patch electrode) and Aδ fibers (pin electrode) was estimated 30 times during a period of 60 minutes. A threshold was established every other minute, alternating between the two electrodes. The stimulus duration was 1 millisecond and the interstimulus interval was 1.5 to 2.5 seconds. Linear regressions of the perception threshold as a function of time were performed. The slopes were used as an estimate of habituation and were compared between the electrodes. Results: The slope was significantly larger when assessed by the pin electrode (median: 0.020 [0.009 to 0.030] mA/trial) than when assessed by the patch electrode (median: 0.005 [0.001 to 0.018] mA/trial) (P =.017, paired t test). During the session, total increases in perception threshold of approximately 55% and 1% were seen for the pin and patch electrodes, respectively. Discussion: The two fiber types assessed showed significant perception threshold increases. The higher slope of the pin electrode indicated that the Aδ fibers were more prone to habituation than the Aβ fibers, and that habituation should be considered during prolonged experiments. This assessment is valuable for future research on nerve fiber function using the technique for long session experiments. [ABSTRACT FROM AUTHOR]

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease‐2019 (COVID‐19), such as Guillain–Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue. These symptoms may be associated with long COVID, also known as post–COVID‐19 conditions or postacute sequelae of SARS‐CoV‐2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health‐care providers. Recent advances have identified small‐fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post–COVID‐19 neuromuscular symptoms. [ABSTRACT FROM AUTHOR]

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3–14). Patients saw a median of three specialists (IQR = 2–3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry. [ABSTRACT FROM AUTHOR]

Background and Objectives: Sensory ganglionopathy is a rare neurological disorder caused by degeneration of the neurons composing the dorsal root ganglia. It manifests as various sensory disturbances in the trunk, proximal limbs, face, or mouth in a patchy and asymmetrical pattern. Harlequin syndrome is characterized by unilateral flushing and sweating of the face, neck, and upper chest, concurrent with contralateral anhidrosis. Here, we present and discuss a clinical case of sarcoidosis-associated ganglionopathy and Harlequin syndrome. Case presentation: A 31-year-old woman complained of burning pain in the right side of the upper chest and the feet. She also experienced episodes of intense flushing and sweating on the right side of her face, neck, and upper chest. Three years before these symptoms began, the patient was diagnosed with pulmonary sarcoidosis. On neurological examination, sensory disturbances were present. In the trunk, the patient reported pronounced hyperalgesia and allodynia in the upper part of the right chest and some patches on the right side of the upper back. In the extremities, hypoalgesia in the tips of the fingers and hyperalgesia in the feet were noted. An extensive diagnostic workup was performed to eliminate other possible causes of these disorders. A broad range of possible metabolic, immunological, and structural causes were ruled out. Thus, the final clinical diagnosis of sarcoidosis-induced sensory ganglionopathy, small-fiber neuropathy, and Harlequin syndrome was made. Initially, the patient was treated with pregabalin and amitriptyline, but the effect was inadequate for the ganglionopathy-induced pain. Therefore, therapeutic plasma exchange as an immune-modulating treatment was selected, leading to partial pain relief. Conclusions: This case report demonstrates the possible autoimmune origin of both sensory ganglionopathy and Harlequin syndrome. It suggests that an autoimmune etiology for these disorders should be considered and the diagnostic workup should include screening for the most common autoimmune conditions. [ABSTRACT FROM AUTHOR]

Background: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. Aim: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. Methods: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). Results: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. Conclusions: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach. [ABSTRACT FROM AUTHOR]

Small‐fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ‐fibers and unmyelinated C‐fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A‐gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non‐SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date‐‐‐SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health‐care providers. [ABSTRACT FROM AUTHOR]

Background: Autonomic dysfunction including sudomotor abnormalities have been reported in association with SARS-CoV-2 infection. Objective: There are no previous studies that have compared autonomic function objectively in patients pre- and post- SARS-CoV-2 infection.We aimed to identify if SARS-CoV-2 virus is triggering and/or worsening dysautonomia by comparing autonomic function tests in a group of patients pre-and post-SARS-CoV-2 infection. Design/methods: Six participants were enrolled and divided into two groups. The first group of 4 participants reported worsened autonomic symptoms post-SARS-CoV-2 infection. These individuals had their first autonomic test prior to COVID-19 pandemic outbreak (July 2019–December 2019). Autonomic function testing was repeated in these participants, 6 months to 1-year post-SARS-CoV-2 infection (June 2021).The second group of 2 participants reported new-onset autonomic symptoms post-COVID-19 infection and were also tested within 6 months post-SARS-CoV-2 infection.All participants had mild COVID-19 infection per WHO criteria. They had no evidence of large fiber neuropathy as demonstrated by normal neurophysiological studies (EMG/NCS). They were all screened for known causes of autonomic dysfunction and without risk factors of hypertension/hyperlipidemia, thyroid dysfunction, diabetes/prediabetes, vitamin deficiencies, history of HIV, hepatitis, or syphilis, prior radiation or chemical exposure or evidence of monoclonal gammopathy, or autoimmune condition. Results: Participants were female (age: 21-37y) and all endorsed orthostatic intolerance (6/6). Gastrointestinal symptoms (⅚), new-onset paresthesias, (3/6), and sexual dysfunction (2/6) were reported. Parasympathetic autonomic function remained stable 6-months to 1-year post-COVID-19 infection and no parasympathetic dysfunction was demonstrated in participants with new-onset dysautonomia symptoms. Postural orthostatic tachycardia was noted in half of the patients, being observed in one patient pre- SARS-CoV-2 infection and persisting post-SARS-CoV-2 infection; while new-onset postural tachycardia was observed in 1/3rd of patients. Sympathetic cholinergic (sudomotor) dysfunction was demonstrated in ALL participants. Worsened, or new-onset, sudomotor dysfunction was demonstrated in those with mild or normal sudomotor function on pre-COVID-19 autonomic testing. Conclusions: Sympathetic adrenergic and cholinergic dysautonomia probably account for some of the symptoms of Long COVID-19. Sudomotor dysfunction was demonstrated as consistently worsened or new-sequelae to COVID-19 infection. COVID-19 may be responsible for triggering new-onset or worsened small-fiber neuropathy in this sample, supporting previously reported studies with similar findings. However, the findings in our study are preliminary, and studies with larger sample size are needed to confirm these observations.

Introduction/Aims: Autonomic dysfunction is a common complication of small‐fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment. Methods: Fifteen patients with confirmed SFN (idiopathic neuropathy [n = 10], chemotherapy‐induced peripheral neuropathy [n = 2], impaired glucose tolerance [n = 1], hereditary transthyretin amyloidosis (hATTR) [n = 1], pulmonary sarcoidosis [n = 1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART). Results: We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function. Discussion: Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system. [ABSTRACT FROM AUTHOR]

Small‐fiber neuropathy (SFN), a pathology caused by severe loss of free‐endings of unmyelinated sensory nerves, is difficult to diagnose and monitor. The use of cutaneous electrical stimulation as a diagnostic tool is hampered by the fact that the injected current penetrates deep into the skin and stimulates many other receptors. Interdigitated electrodes are recently proposed to control the depth of current penetration and selectively address small‐fibers. Here, flexible and adhesive interdigitated electrodes made of Au coated with poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) are developed, that conform comfortably and reliably to human skin. It is shown that the PEDOT:PSS coating improves safety by significantly reducing the voltage required to inject current. The selectivity of the device is assessed by showing that it elicits a significantly slower reaction time than commercial cutaneous electrophysiology electrodes, as it exclusively activates unmyelinated fibers. The device is further evaluated on volunteers that undergo local capsaicin treatment to induce temporary loss of the nerve endings of small‐fibers. Pre‐ and post‐treatment electrical stimulation of the affected area with the device reveals impaired sensory detection that is not observed with commercial cutaneous electrophysiology electrodes. These results represent a significant step towards the use of electrical stimulation as a diagnostic and monitoring tool for SFN. [ABSTRACT FROM AUTHOR]

COVID-19 has caused several neurological complications by affecting the central and peripheral nervous systems (PNS). Studies on the PNS involvement in COVID-19 are limited. These complications are likely unreported, given the difficulty of obtaining further diagnostic information, such as expert neurologist evaluation, electrodiagnostic testing, and skin biopsy. Herein, we report 2 cases of possible COVID-19-related small-fiber neuropathy (SFN). These cases are reported to increase awareness of a possible link between COVID-19 and SFN. Additional investigation, including neurology consultation, nerve conduction studies, and skin biopsy, should be considered in patients who develop paresthesia during and after COVID-19 infection. Further research is also needed to determine a possible underlying neuropathology mechanism and the role of immunomodulatory treatment, such as intravenous immunoglobulin, in COVID-19-related SFN.

Background: Previous researchers have used a 30-min eutectic mixture of local anesthetic (EMLA) test, which assesses the sympathetically mediated vasomotor function, in diagnosing carpal tunnel syndrome (CTS). However, its specificity was low, limiting its clinical diagnostic utility. In this study, we assessed the efficiency of 90-min extended EMLA-induced stimulated skin-wrinkling (SSW) test in CTS diagnosis. Methods: A cross-sectional study was designed among patients clinically diagnosed with CTS. Hands of healthy volunteers and the asymptomatic hands of selected patients served as control. The Boston symptom severity scale (SSS) and the neuropathic pain severity inventory (NPSI) were used to assess symptom severity, and nerve conduction study (NCS) was used to assess electrophysiological severity. EMLA-induced SSW was visually graded after 90 min of application and correlated with symptom and NCS severities. Results: Forty-two symptomatic hands and 30 asymptomatic hands were enrolled as cases and controls, respectively. The diagnostic efficiency of the extended EMLA test was found to be 83.4% for digit 2 and 87.3% for the lateral 4 digits (mean), whereas the diagnostic efficiency of standard NCS was 88.1%. Boston SSS and NPSI were better correlated with EMLA positivity than NCS positivity. A linear regression analysis showed negative correlation of wrinkling grade with NCS grade. Conclusion: With its improved diagnostic efficiency, the 90-min extended EMLA test can feasibly be used as an alternative to NCS, especially in general practice settings. Its potential clinical utility should be explored in a large population of CTS patients showing varying clinical and electrophysiological severities.

IntroductionSmall fiber neuropathies (SFNs) are disorders of skin nerve endings inducing pruritus, burning pain, numbness, and paresthesia. The aims of this study were to search for putative etiologies of SFN and their occurrence in a cohort of patients and to compare patients with SFN to a group of patients without SFN to highlight potential factors associated with SFN.MethodsThis study was observational, retrospective, and monocentric. All patients with symptoms of SFN who underwent skin biopsies with intraepidermal nerve density counts were included. Patients with a count lower than 5 percentiles were considered to be in the SFN group. Other patients were considered to be the control group.ResultsA total of 162 patients with SFN and 161 controls were included. No cause was identified for 108 patients (61.7%). The established causes were autoimmune diseases (9.1%), diabetes or glucose intolerance (8%), medication (4%), liver disease (3.4%), and monoclonal gammopathy of undetermined significance (2.9%). Current or former smokers were more numerous in the SFN group (26.5%) than in the control group (16.1%), while vitamin D amounts were significantly lower in the SFN group than in the control group.DiscussionHence, tobacco smoking and vitamin D deficiency might be new putative causes of SFN.

Background and Objectives: Sensory ganglionopathy is a rare neurological disorder caused by degeneration of the neurons composing the dorsal root ganglia. It manifests as various sensory disturbances in the trunk, proximal limbs, face, or mouth in a patchy and asymmetrical pattern. Harlequin syndrome is characterized by unilateral flushing and sweating of the face, neck, and upper chest, concurrent with contralateral anhidrosis. Here, we present and discuss a clinical case of sarcoidosis-associated ganglionopathy and Harlequin syndrome. Case presentation: A 31-year-old woman complained of burning pain in the right side of the upper chest and the feet. She also experienced episodes of intense flushing and sweating on the right side of her face, neck, and upper chest. Three years before these symptoms began, the patient was diagnosed with pulmonary sarcoidosis. On neurological examination, sensory disturbances were present. In the trunk, the patient reported pronounced hyperalgesia and allodynia in the upper part of the right chest and some patches on the right side of the upper back. In the extremities, hypoalgesia in the tips of the fingers and hyperalgesia in the feet were noted. An extensive diagnostic workup was performed to eliminate other possible causes of these disorders. A broad range of possible metabolic, immunological, and structural causes were ruled out. Thus, the final clinical diagnosis of sarcoidosis-induced sensory ganglionopathy, small-fiber neuropathy, and Harlequin syndrome was made. Initially, the patient was treated with pregabalin and amitriptyline, but the effect was inadequate for the ganglionopathy-induced pain. Therefore, therapeutic plasma exchange as an immune-modulating treatment was selected, leading to partial pain relief. Conclusions: This case report demonstrates the possible autoimmune origin of both sensory ganglionopathy and Harlequin syndrome. It suggests that an autoimmune etiology for these disorders should be considered and the diagnostic workup should include screening for the most common autoimmune conditions.

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3–14). Patients saw a median of three specialists (IQR = 2–3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

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. [ABSTRACT FROM AUTHOR]

Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In mice, inflammation was induced focally by subcutaneous adjuvant injection to one paw and systemically by intraperitoneal lipopolysaccharides (LPS) administration. One day following injection, thrombin activity increased in the skin of the injected compared with the contralateral and non-injected control paws (p = 0.0009). One week following injection, thrombin increased in both injected and contralateral paws compared with the controls (p = 0.026), coupled with increased heat-sensitivity (p = 0.009). Thrombin activity in the footpad skin was significantly increased one week after systemic administration of LPS compared with the controls (p = 0.023). This was not accompanied by increased heat sensitivity. In human skin, a correlation was found between nerve fiber density and thrombin activity. In addition, a lower thrombin activity was measured in patients with evidence of systemic inflammation compared with the controls (p = 0.0035). These results support the modification of skin thrombin activity by regional and systemic inflammation as well as a correlation with nerve fiber density. Skin thrombin activity measurments may aid in the diagnosis and treatment of SFN. [ABSTRACT FROM AUTHOR]

Background: Small‐fiber neuropathy is a disorder clinically dominated by neuropathic pain and autonomic symptoms. In >50% of patients, no etiology can be identified. and some evidence suggests a possible role of the immune system. Among the most common manifestations of hypereosinophilic syndrome, neurological lesions have been described in the central and peripheral nervous systems. No correlation between idiopathic hypereosinophilia with systemic involvement and small‐fiber neuropathy has been described before. Case presentation: We present the case of a 21‐year‐old woman with large‐ and small‐fiber neuropathy associated with systemic idiopathic hypereosinophilic syndrome. The patient manifested a subacute itchy rash to the limbs and trunk with painless lymphadenopathy of the neck and groin, persistent lack of appetite, vomiting, and subsequent painful dysesthesia on the feet. At blood test, eosinophilic leukocytosis was detected, electrophysiological studies showed axonal sensory neuropathy on the sural nerve bilaterally, cerebrospinal fluid analysis showed a cytological–albumin dissociation, and skin biopsy was decisive in confirming a severe picture of the small fibers pathology and lymphocytic infiltrates with eosinophils in the dermis. The in‐depth diagnostic investigations excluded other significant alterations and pathologies. After steroid and immunoglobulin therapies, the patient progressively improved with resolution of the rash and vomiting episodes, resuming regular nutrition and obtaining important reduction of painful dysesthesia. Conclusions: In the present case, we hypothesized that idiopathic hypereosinophilic syndrome was the likely cause of the atopic dermatitis and small‐fiber neuropathy, consistent with pain and dysautonomic symptoms. [ABSTRACT FROM AUTHOR]

Introduction/Aims: 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. Methods: 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. Results: 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. Discussion 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. [ABSTRACT FROM AUTHOR]

Background and ObjectivesPatients frequently complain of mild, transient, unpleasant skin sensations that cannot be diagnosed as common neuropathies. Dermatologists have termed these symptoms “sensitive skin syndrome.” This narrative review was performed for a better knowledge by other specialists.Databases and Data TreatmentPublications on pain in sensitive skin syndrome were obtained from PubMed.ResultsThere is a growing body of data supporting the concept that sensitive skin is a type of small-fiber neuropathy. The arguments are based on clinical data, a decrease in intra-epidermal nerve fiber density, quantitative sensory testing abnormalities and an association with irritable bowel syndrome and sensitive eyes. Sensitive skin is triggered by environmental factors. Sensitive skin is a frequent condition, with a lifetime prevalence of ~50% according to self-reports.ConclusionsMild levels of skin pain or itch are frequently experienced by patients, who rarely report them. There is a need for a better knowledge of sensitive skin because it can be the first level of small-fiber neuropathies.

COVID-19 has caused several neurological complications by affecting the central and peripheral nervous systems (PNS). Studies on the PNS involvement in COVID-19 are limited. These complications are likely unreported, given the difficulty of obtaining further diagnostic information, such as expert neurologist evaluation, electrodiagnostic testing, and skin biopsy. Herein, we report 2 cases of possible COVID-19-related small-fiber neuropathy (SFN). These cases are reported to increase awareness of a possible link between COVID-19 and SFN. Additional investigation, including neurology consultation, nerve conduction studies, and skin biopsy, should be considered in patients who develop paresthesia during and after COVID-19 infection. Further research is also needed to determine a possible underlying neuropathology mechanism and the role of immunomodulatory treatment, such as intravenous immunoglobulin, in COVID-19-related SFN. [ABSTRACT FROM AUTHOR]

Background: Previous researchers have used a 30-min eutectic mixture of local anesthetic (EMLA) test, which assesses the sympathetically mediated vasomotor function, in diagnosing carpal tunnel syndrome (CTS). However, its specificity was low, limiting its clinical diagnostic utility. In this study, we assessed the efficiency of 90-min extended EMLA-induced stimulated skin-wrinkling (SSW) test in CTS diagnosis. Methods: A cross-sectional study was designed among patients clinically diagnosed with CTS. Hands of healthy volunteers and the asymptomatic hands of selected patients served as control. The Boston symptom severity scale (SSS) and the neuropathic pain severity inventory (NPSI) were used to assess symptom severity, and nerve conduction study (NCS) was used to assess electrophysiological severity. EMLA-induced SSW was visually graded after 90 min of application and correlated with symptom and NCS severities. Results: Forty-two symptomatic hands and 30 asymptomatic hands were enrolled as cases and controls, respectively. The diagnostic efficiency of the extended EMLA test was found to be 83.4% for digit 2 and 87.3% for the lateral 4 digits (mean), whereas the diagnostic efficiency of standard NCS was 88.1%. Boston SSS and NPSI were better correlated with EMLA positivity than NCS positivity. A linear regression analysis showed negative correlation of wrinkling grade with NCS grade. Conclusion: With its improved diagnostic efficiency, the 90-min extended EMLA test can feasibly be used as an alternative to NCS, especially in general practice settings. Its potential clinical utility should be explored in a large population of CTS patients showing varying clinical and electrophysiological severities. [ABSTRACT FROM AUTHOR]

Chronic itch is a frequent and debilitating condition that greatly affects the quality of life of those affected. In a subset of patients, damage to the peripheral or central nervous system constitutes the cause of the itch. Small-fiber neuropathy, nerve compression syndromes, post-herpetic neuralgia, scars and burns are possible conditions affecting the peripheral nervous system potentially causing itch, whereas space-occupying lesions affecting the spinal cord and stroke are examples of conditions that may induce central itch. Neuropathic itch starts on normal appearing skin, is often accompanied by pain sensations and other dysesthesias, and usually relieved by local cold application. Its distribution depends on the affected site of the somatosensory system. A comprehensive medical history is paramount to reach the diagnosis, while complementary diagnostics with skin biopsies for the investigation of cutaneous neuromorphological alterations or medical imaging to rule out nerve impingement may be advised in selected cases. Topical agents such as capsaicin or local anesthetics as well as systemic drugs such as gabapentinoids, antidepressants and opioid receptor modulators are used in the treatment of neuropathic itch. This review article provides an overview of the clinical features, underlying causes, diagnostic workup and therapeutic approach in neuropathic itch., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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. PERSPECTIVE: This 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., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

To assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). Thirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). While 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. Peripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. The association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN. We created 2 independent knock-in mouse lines carrying the Nav1.7 I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multielectrode array recordings show that Nav1.7 I228M knock-in DRG neurons are hyperexcitable compared with wild-type littermate-control neurons, but despite this, Nav1.7 I228M mice do not display mechanical or thermal hyperalgesia or intraepidermal nerve fiber loss in vivo. Therefore, although these 2 Nav1.7 I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of-function mutations in Nav1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyperexcitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice. [ABSTRACT FROM AUTHOR]

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.

Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In mice, inflammation was induced focally by subcutaneous adjuvant injection to one paw and systemically by intraperitoneal lipopolysaccharides (LPS) administration. One day following injection, thrombin activity increased in the skin of the injected compared with the contralateral and non-injected control paws (p = 0.0009). One week following injection, thrombin increased in both injected and contralateral paws compared with the controls (p = 0.026), coupled with increased heat-sensitivity (p = 0.009). Thrombin activity in the footpad skin was significantly increased one week after systemic administration of LPS compared with the controls (p = 0.023). This was not accompanied by increased heat sensitivity. In human skin, a correlation was found between nerve fiber density and thrombin activity. In addition, a lower thrombin activity was measured in patients with evidence of systemic inflammation compared with the controls (p = 0.0035). These results support the modification of skin thrombin activity by regional and systemic inflammation as well as a correlation with nerve fiber density. Skin thrombin activity measurments may aid in the diagnosis and treatment of SFN.

Abstract: Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration. [ABSTRACT FROM AUTHOR]

Neuropathic itch occurs due to damage of neurons of the peripheral or central nervous system. Several entities, including metabolic, neurodegenerative, orthopedic, infectious, autoimmune, malignant, and iatrogenic conditions, may affect the somatosensory system and induce neuropathic itch. Due to the complex nature of neuropathic itch, particularly concerning its clinical presentation and possible etiological factors, diagnostic work-up of this condition is challenging. A detailed medical history, especially in regard to the itch, and a comprehensive physical examination are relevant to detect characteristic signs and symptoms of neuropathic itch and to rule out other possible causes for chronic itch. Complementary diagnostic exams, especially laboratory tests, determination of the intraepidermal nerve fiber density via a skin biopsy and radiological examinations may be indicated to confirm the diagnosis of neuropathic itch and to identify underlying etiological factors. Functional assessments such as quantitative sensory testing, nerve conduction studies, evoked potentials, or microneurography may be considered in particular cases. This review article provides a comprehensive overview of the diagnostic work-up recommended for patients with neuropathic itch.

Background and purpose: Small‐fiber nerves are the first to be involved in transthyretin familial amyloid polyneuropathy (TTR‐FAP) patients. In vivo corneal confocal microscopy (CCM) is a noninvasive technique to detect small‐fiber polyneuropathy (SFN) by quantifying corneal nerve morphology. The characteristic whorl‐like pattern of the corneal nerve provides a static landmark for observation. We aimed to evaluate whether CCM images of the whorl‐like plexus can sensitively evaluate and monitor disease progression in FAP patients. Methods: Fifteen FAP patients and 15 controls underwent neurological evaluation and CCM observation. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) detected by conventional method and inferior whorl length (IWL), inferior whorl fiber density (IWFD), and inferior whorl branch density (IWBD) were compared in controls and patients. The Langerhans cell (LC) density in each image was calculated. Results: All CCM parameters were significantly reduced with disease progression. Preclinical patients had significantly lower IWL (P = 0.008) than age‐matched controls. IWL (P = 0.006), CNFL (P = 0.005), CNBD (P = 0.008), and CNFD (P = 0.014) were significantly lower in early‐phase patients. LC density was significantly increased around the central whorl in early‐phase patients and was relatively lower in progressive patients. Both IWL and CNFL correlated with the severity of neuropathy, and IWL was more significantly reduced. The area under the receiver operating characteristic (ROC) curve for FAP with CNFL and IWL was 88.0% (95% CI, 70.9%–96.9%) and 89.3% (95% CI, 72.6%–97.6%), respectively, exceeding other parameters. Conclusions: IWL is a more sensitive surrogate to detect preclinical SFN in FAP and can best discriminate patients from controls. The clustering of immature LCs at the inferior whorl area might reflect the inflammatory response of small‐fiber nerves at the early stage. [ABSTRACT FROM AUTHOR]

Background: We aimed at evaluating the differential involvement of large myelinated Aβ‐, small myelinated Aδ‐, and unmyelinated C‐fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. Methods: We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aβ‐fiber mediated nerve conduction study, Aδ‐fiber mediated laser‐evoked potentials and skin biopsy mainly assessing unmyelinated C‐fibers. Results: Pure large‐fiber and small‐fiber polyneuropathy were relatively uncommon; conversely mixed‐fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small‐fiber related variables. Conclusions: Diabetic polyneuropathy mainly manifests as a mixed‐fiber polyneuropathy, simultaneously involving Aβ‐, Aδ‐, and C‐fibers. In most patients, neuropathic pain is distinctly associated with small‐fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large‐, pure small‐, and mixed‐fiber polyneuropathy, raises the possibility that in patients with pure large‐fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques. [ABSTRACT FROM AUTHOR]

Label-free imaging methodologies for nerve fibers rely on spatial signal continuity to identify fibers and fail to image free intraepidermal nerve endings (FINEs). Here, we present an imaging methodology-called discontinuity third harmonic generation (THG) microscopy (dTHGM)-that detects three-dimensional discontinuities in THG signals as the contrast. We describe the mechanism and design of dTHGM and apply it to reveal the bead-string characteristics of unmyelinated FINEs. We confirmed the label-free capability of dTHGM through a comparison study with the PGP9.5 immunohistochemical staining slides and a longitudinal spared nerve injury study. An intraepidermal nerve fiber (IENF) index based on a discontinuous-dot-connecting algorithm was developed to facilitate clinical applications of dTHGM. A preliminary clinical study confirmed that the IENF index was highly correlated with skin-biopsy-based IENF density (Pearson's correlation coefficient R = 0.98) and could achieve differential identification of small-fiber neuropathy (p = 0.0102) in patients with diabetic peripheral neuropathy., Competing Interests: Declaration of interests The disclosed protocol is under patent applications entitled “A METHOD AND APPARATUS FOR NON-INVASIVE IMAGE-OBSERVING DENSITY OF INTRAEPIDERMAL NERVE FIBER OF HUMAN SKIN.”, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract Objectives Sjögren's syndrome (SS) is a chronic inflammatory disease with an autoimmune background with possible complications from peripheral (PNS) and central nervous system (CNS). The aim of this study was to assess the prevalence and to describe the phenotype of peripheral neuropathies in patients with SS. Materials & Methods We studied fifty patients with primary Sjögren's syndrome for peripheral nervous system involvement. All patients underwent neurological and rheumatological examination followed by nerve conduction studies (NCS) of nine peripheral nerves. Results Thirty‐six patients (72%) fulfilled the criteria for the diagnosis of neuropathy. Carpal tunnel syndrome (54%) and axonal sensorimotor neuropathy (22%) were the most common. Neurological symptoms preceded the diagnosis of SS in eight patients. Conclusions Peripheral neuropathies are frequent in SS patients. Neurologists should be aware of possible autoimmune causes of neuropathies because clinical manifestations of neuropathy may precede the development of other symptoms of the autoimmune disease.

The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling—the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia. [ABSTRACT FROM AUTHOR]

Objectives: Sjögren's syndrome (SS) is a chronic inflammatory disease with an autoimmune background with possible complications from peripheral (PNS) and central nervous system (CNS). The aim of this study was to assess the prevalence and to describe the phenotype of peripheral neuropathies in patients with SS. Materials & Methods: We studied fifty patients with primary Sjögren's syndrome for peripheral nervous system involvement. All patients underwent neurological and rheumatological examination followed by nerve conduction studies (NCS) of nine peripheral nerves. Results: Thirty‐six patients (72%) fulfilled the criteria for the diagnosis of neuropathy. Carpal tunnel syndrome (54%) and axonal sensorimotor neuropathy (22%) were the most common. Neurological symptoms preceded the diagnosis of SS in eight patients. Conclusions: Peripheral neuropathies are frequent in SS patients. Neurologists should be aware of possible autoimmune causes of neuropathies because clinical manifestations of neuropathy may precede the development of other symptoms of the autoimmune disease. [ABSTRACT FROM AUTHOR]

Introduction: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology.Methods: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center.Results: Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial.Discussion: The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available. [ABSTRACT FROM AUTHOR]

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

Treatment-induced neuropathy of diabetes (TIND) is an acute painful autonomic small-fiber neuropathy that develops following an abrupt improvement in glycaemia control. Recent reports suggest TIND is a significant problem in tertiary neuropathy clinics. TIND in hospitalized patients with poor initial glycaemia control, that we refer to as nosocomial TIND, has not been well-studied. We describe the demographic, clinical features and indices of glycaemia control in 5 consecutive nosocomial TIND patients. TIND was defined using recently published criteria. Pre-meal capillary blood glucose recordings performed during the period of HbA1c decline was used to calculate glycaemic variability. All the nosocomial TIND patients were hospitalized for prolonged periods for serious medical conditions that warranted good glycaemia control, namely severe sepsis, diabetic ketoacidosis, stroke, heart failure and traumatic head injury. They had raised, double-digit, HbA1c levels at admission that subsequently dropped precipitously with tight in-patient glycaemia control protocols. These patients had multiple, largely asymptomatic, hypoglycaemic episodes. Glycaemic variability also appeared to be high in this cohort. TIND may be a significant cause of morbidity in hospitalized diabetic patients with poor glycaemia control. Not all patients developed both autonomic and painful neuropathies, raising the possibility of forme-fruste TIND. [ABSTRACT FROM AUTHOR]

Introduction: Large-fiber neuropathy is rare in neurofibromatosis type 1, but small-fiber neuropathy has not been studied.Methods: Patients with neurofibromatosis type 1 underwent nerve conduction studies for large-fiber assessment. Small-fiber tests included quantitative thermal thresholds, laser Doppler flare imaging, intraepidermal nerve fiber density, and corneal nerve fiber length.Results: Of the 52 patients enrolled, 31 (60%) were female and the mean age was 33.0 ± 12.3 years. Four (8%) patients had abnormal nerve conduction studies. Small-fiber tests were frequently abnormal: thermal thresholds in 7 (13%); laser Doppler flare imaging in 10 (19%); intraepidermal nerve fiber density in 11 (22%); and corneal nerve fiber length in 27 (52%). The mean corneal nerve fiber length was below normative level (10.1 ± 2.7 mm/mm3 ).Discussion: Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients. [ABSTRACT FROM AUTHOR]

Postural Orthostatic Tachycardia Syndrome (POTS) presents with a range of poorly delineated symptoms across several domains. There is an urgent need for standardized symptom reporting in POTS, but a lack of validated symptom burden instruments. Our aim was to evaluate the psychometric properties of two symptom burden measures: the Orthostatic Grading Scale (OGS) and the Symptom Screen for Small-Fiber Polyneuropathy (SSS), in patients under investigation for suspected POTS. Psychometric validation study. Confirmatory factor analysis (CFA) tested the factor structure of the SSS and OGS completed by 149 patients under investigation for POTS. Scale reliability and validity were assessed. The uni-dimensionality of the SSS was assessed through principal component analysis (PCA). CFA of the OGS revealed that a 1-factor structure had adequate fit. CFA of the SSS revealed that a 5-factor structure had generally appropriate fit supporting the originally proposed 5 factors (1: Gastrointestinal, 2: Somatosensory, 3: Miscellaneous, 4: Microvascular, and 5: Urological). In addition, the SSS demonstrated sufficient uni-dimensionality in the PCA, warranting use of a single total score. Omega coefficients of both measures indicated satisfactory internal reliability (0.668–0.931). Correlations with related constructs (distress (K10 score), r = 0.317–0.404, p < 0.001) and heart rate indices (with the OGS, r = 0.211–0.294, p < 0.05) suggested sound convergent and divergent validity. Initial evidence suggests that the OGS and SSS have good psychometric properties for use in populations with suspected and confirmed POTS. • More standardized symptom reporting is needed in Postural Orthostatic Tachycardia Syndrome (POTS) • The Orthostatic Grading Scale (OGS) has been used in POTS studies but not validated • The Symptom Screen for Small-Fiber Neuropathy (SSS) has not previously been specifically used in POTS • The current study assessed the psychometric properties of the OGS and SSS in populations with suspected POTS • Both the OGS and the SSS are valid and reliable measures of symptom burden in POTS [ABSTRACT FROM AUTHOR]