Reliable Method for Estimating Nerve Fiber Density in Epidermis Using Routine Histopathologic Tissue Preparation: A Promising Diagnostic Tool for Small Fiber Neuropathy.

Practical yet reliable diagnostic tools for small-fiber neuropathy are needed. We aimed to establish a histopathologic protocol for estimating intraepidermal nerve fiber density (eIENFD) on formalin-fixed, paraffin-embedded tissue (FFPE), evaluate its reliability through intraobserver and interobserver analyses, and provide normative reference values for clinical use. Sixty-eight healthy participants underwent nerve conduction studies and quantitative sensory testing. Skin biopsies from the distal and proximal leg were taken and processed using routine immunohistochemistry (anti-PGP9.5 antibodies) on thin 5 µm sections. eIENFD was assessed with a modified counting protocol. Interobserver and intraobserver reliabilities were excellent (ICC=0.9). eIENFD was higher in females than males (fibers/mm, 14.3±4.4 vs. 11.6±5.8, P <0.05), decreased with age ( r s =-0.47, P <0.001), and was higher proximally than distally (15.0±5.5 vs. 13.0±5.3, P =0.002). Quantile regression equations for the fifth percentile of distal and proximal eIENFD were presented: 13.125-0.161×age (y)-0.932×sex (male=1; female=0) and 17.204-0.192×age (y)-3.313×sex (male=1; female=0), respectively. This study introduces a reliable and reproducible method for estimating epidermal nerve fiber density through immunostaining on 5-µm thin FFPE tissue samples. Normative data on eIENFD is provided. Regression equations help identify abnormal decreases in small nerve fiber density.

Skin nerve phosphorylated α-synuclein in the elderly.

To determine the incidence of phosphorylated α-synuclein (p-syn) in skin nerves in very old subjects who are prone to developing incidental Lewy bodies, we prospectively performed skin biopsies on 33 elderly subjects, including 13 (>85 years old) and 20 patients (>70 years) suspected of having an acquired small fiber neuropathy. All subjects underwent neurological examination prior to the biopsy. Two screened female subjects (ages 102 and 98 years) were excluded from the study because they showed evidence of a slight bradykinetic-rigid extrapyramidal disorder on neurological examination and were not considered healthy; both showed p-syn in skin nerves. We did not identify p-syn in skin nerves in the remaining 31 subjects. A PubMed analysis of publications from 2013 to 2023 disclosed 490 healthy subjects tested for skin p-syn; one study reported p-syn in 4 healthy subjects, but the remaining subjects tested negative. Our data underscore the virtual absence of p-syn in skin nerves of healthy controls, including those who are very elderly. These data support skin biopsy as a highly specific tool for identifying an underlying synucleinopathy in patients in vivo.

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

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

Studying serum neurofilament light chain levels as a potential new biomarker for small fiber neuropathy.

BACKGROUND AND PURPOSE: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ- and C-fibers was tested. METHODS: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. RESULTS: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. CONCLUSION: Serum NfL levels cannot serve as a biomarker for small fiber damage.

Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

INTRODUCTION/AIMS: Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. METHODS: We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. RESULTS: Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. DISCUSSION: MAGNET quickly generates research-quality metrics during clinical examinations.

Corneal confocal microscopy in small and mixed fiber neuropathy-Comparison with skin biopsy and cold detection in a large prospective cohort.

BACKGROUND AND AIMS: The diagnosis of small fiber neuropathy (SFN) is supported by reduced intraepidermal nerve fiber density (IENFD). The noninvasive method corneal confocal microscopy (CCM) has the potential to be a practical alternative. We aimed to estimate the diagnostic accuracy of CCM compared with IENFD and cold detection thresholds (CDT) in SFN and mixed fiber neuropathy (MFN). METHODS: CCM was performed in an unselected prospective cohort of patients with a clinical suspicion of polyneuropathy. Predefined criteria were used to classify SFN and MFN. Neuropathy scores, including the Utah early neuropathy scale (UENS), were used to describe severity. Patients with established other diagnoses were used for diagnostic specificity calculations. RESULTS: Data were taken from 680 patients, of which 244 had SFN or MFN. There was no significant difference in sensitivities [95%CI] of CCM (0.44 [0.38-0.51]), IEFND (0.43 [0.36-0.49]), and CDT (0.34 [0.29-0.41]). CCM specificity (0.75 [0.69-0.81]) was lower (p = .044) than for IENFD (0.99 [0.96-1.00]) but not than for CDT (0.81 [0.75-0.86]). The AUCs of the ROC curves of 0.63, 0.63 and 0.74 respectively, was lower for corneal nerve fiber density (p = .0012) and corneal nerve fiber length (p = .0015) compared with IENFD. While UENS correlated significantly with IENFD (p = .0016; R2 = .041) and CDT (p = .0002; R2 = .056), it did not correlate with CCM measures. INTERPRETATION: The diagnostic utility of CCM in SNF and MFN is limited by the low specificity compared with skin biopsy. Further, CCM is less suitable than skin biopsy and CDT as a marker for neuropathy severity.

Functional and structural markers of peripheral microvascular autonomic neuropathy.

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.

Expanding the genetic causes of small-fiber neuropathy: SCN genes and beyond.

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.

Small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and small-fibre neuropathy.

BACKGROUND: In this clinical and psychophysical study, we aimed to verify whether patients with fibromyalgia with and without small-fibre pathology and patients with pure small-fibre neuropathy share common sensory phenotypes. METHODS: Using an algorithm based on quantitative sensory testing variables, we grouped 64 consecutive patients with fibromyalgia (20 with small-fibre pathology, 44 without) and 30 patients with pure small-fibre neuropathy into different sensory phenotypes: sensory loss, thermal hyperalgesia, mechanical hyperalgesia and healthy phenotypes. RESULTS: We found that the frequency of the different sensory phenotypes differed markedly between patients with fibromyalgia and patients with small-fibre neuropathy. In patients with fibromyalgia, with and without small-fibre pathology, healthy and hyperalgesia phenotypes (both thermal and mechanical) were similarly represented, whilst sensory loss and mechanical hyperalgesia phenotypes were the most frequent phenotypes in patients with small-fibre neuropathy. CONCLUSIONS: Our findings indicate that small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and in patients with small-fibre neuropathy. The lack of phenotype differences between patients with fibromyalgia with and without small-fibre pathology and the relatively high frequency of the healthy phenotype in these patients highlight a complex relationship between small-fibre pathology and pain in patients with fibromyalgia.

Autoantibodies Against Trisulfated Heparin Disaccharide and Fibroblast Growth Factor Receptor-3 May Play a Role in the Pathogenesis of Neuropathic Corneal Pain.

PURPOSE: The aim of this study was to describe cases of patients with presumable dysimmune small-fiber neuropathy (SFN)-related neuropathic corneal pain (NCP), presenting with autoantibodies against trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor-3 (FGFR-3). METHODS: This study was a case series of 3 patients with NCP with positive anti-TS-HDS and/or anti-FGFR-3 autoantibodies and systemic SFN as confirmed by positive skin biopsy results. RESULTS: All 3 patients were women with a mean age of 34.3± 6.1 years. They suffered from moderate to severe persistent chronic ocular discomfort (10/10, 10/10, and 9/10 on a visual analogue scale, respectively). Although 1 patient suffered from ocular pain and photophobia alone, the other 2 patients experienced additional non-ocular pain. One of the patients had pain on her face and head, and 1 patient reported neck and lower back pain. Two patients had high anti-TS-HDS IgM titers, whereas 1 patient had both high anti-TS-HDS IgM and anti-FGFR-3 IgG titers. Skin biopsy confirmed the presence of SFN in all patients by demonstrating decreased intraepidermal nerve fiber density. CONCLUSIONS: The presence of anti-TS-HDS and anti-FGFR-3 autoantibodies in patients with NCP with positive skin biopsy findings for SFN highlights the potential role of dysimmune SFN in the pathogenesis of this disease.

The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy.

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non-specialist centers are warranted to identify patients who require second-level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN-SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN-SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN-SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second-level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials.

Small fiber neuropathies: expanding their etiologies.

PURPOSE OF REVIEW: Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN. RECENT FINDINGS: In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood. SUMMARY: The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Increased Epidermal Nerve Growth Factor without Small-Fiber Neuropathy in Dermatomyositis.

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.

Acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination: A report of three cases and review of the literature.

Small fiber neuropathy usually presents with gradual and progressive chronic length-dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford-AstraZeneca ChAdOx1-S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra-epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination are described. At follow up, neuropathic pain was present in two of the patients.

Role of skin punch biopsy in diagnosis of small fiber neuropathy-A review for the neuropathologist.

Over the last three decades, skin punch biopsy has become the gold standard for diagnosis of small fiber neuropathies, including autonomic neuropathies commonly seen in diabetics, patients with HIV, and children with hereditary sensory autonomic neuropathies and toxin-induced neuropathy. Clinical, biochemical, electrophysiological tests are inconclusive, making it difficult to diagnose and initiate treatment. A skin punch biopsy is easy to perform in the outpatient clinic, is highly sensitive, and provides an objective diagnosis. Importantly, it helps avoid performing invasive nerve biopsy in patients with small fiber neuropathy, thereby preventing complications such as non-healing of the biopsy site, which is common in these patients. Secondly, the greatest advantage of skin punch biopsies is that they can be repeated any number of times, unlike a nerve biopsy, and are useful to evaluate disease progression and therapeutic response. More recently, its use has been expanded to the diagnosis of large fiber neuropathies, inherited demyelinating neuropathies, etc., obviating the need for a nerve biopsy. The European Federation of Neurological Societies has published guidelines for evaluation to ensure uniformity with regard to the site of biopsy, processing, and quantification. The evaluation of the skin biopsy involves morphometric assessment of the intraepidermal nerve fiber density using PGP 9.5 immunostained sections by bright-field microscopy. This review focuses on the practical aspects of skin punch biopsy and its utility for the practicing pathologist.

Peripheral neuropathy in sarcoidosis.

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

[Small fiber neuropathy diagnosis]. / Diagnostiquer une neuropathie des petites fibres.

Small fiber neuropathies affect small, poorly myelinated sensory Aδ and amyelinated C autonomic fibers. Neuropathic pain is often the main symptom. Positive diagnosis is based on the presence of deficient thermo-algesic sensory signs and/or dysautonomic signs with normal neurography. Several tests help to confirm the involvement of small fibers, ranging from simple tests such as the sympathetic skin response to skin biopsy, which measures the density of intraepidermal nerve fibers. The availability of these different tests varies greatly from one center to another. There are multiple etiologies, from rare genetic causes to the more frequent acquired dysimmune or metabolic causes. However, in more than half of the cases, no etiology is identified.

Les neuropathies des petites fibres touchent les petites fibres peu myélinisées sensitives Aδ et amyéliniques C autonomes. La douleur neuropathique est souvent le symptôme principal. Le diagnostic positif repose sur la présence de signes sensitifs thermo-algiques déficitaires et/ou de signes dysautonomiques avec des neurographies normales. Plusieurs examens aident à confirmer l'atteinte des petites fibres, allant de tests simples comme la réponse cutanée sympathique à la biopsie de peau qui mesure la densité des fibres nerveuses intra-épidermiques. L'accessibilité de ces différents examens est très variable d'un centre à l'autre. Les étiologies sont variées, des causes génétiques rares aux causes acquises dysimmunes ou métaboliques plus fréquentes. Toutefois, dans plus de la moitié des cas, aucune étiologie n'est retrouvée.

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

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.

Small Fiber Neuropathy in Patients with Chronic Pain and a Previous Diagnosis of Multiple Chemical Sensitivity Syndrome.

Small fiber neuropathy (SFN) is characterized by the involvement of Aδ and C fibers leading to sensory, mainly pain, and/or autonomic symptoms. Multiple chemical sensitivity syndrome (MCS) is an incompletely defined condition characterized by the onset of various symptoms in patients after exposure to several chemical substances. Pain is a common symptom in these patients. In this study, we report the histological and clinical data of a cohort of 21 patients who had been diagnosed as having MCS and who were referred to us with the suspicion of SFN because of chronic pain. All patients underwent neurological clinical examination, (including scales for pain and autonomic disorders), and a skin biopsy. Age-matched healthy subjects were used as controls for the skin biopsies. Nerve conduction studies and serum screening to exclude possible causes of peripheral neuropathy were also performed. Skin biopsies disclosed a somatic SFN in all patients. Although the majority (18 out of 21) of patients also had autonomic symptoms. we found sparing of autonomic innervation in the biopsies. These observations suggest that chronic pain in MCS could be secondary to the presence of somatic SFN, although more data are needed to confirm these observations.

Small fiber neuropathy: Swiss cohort characterization.

INTRODUCTION/AIM: There is currently insufficient clinical and epidemiological data concerning small fiber neuropathy (SFN). This research analyzes data from medical records to determine epidemiology, demographics, clinical characteristics and etiology of SFN. METHODS: This is a retrospective, observational study of sequential patients diagnosed with definite SFN (typical clinical features, normal nerve conduction studies, abnormal epidermal nerve fiber density) from the end of November 2016 to the middle of July 2019 at the Cantonal Hospital Lucerne, central Switzerland. RESULTS: A total of 84 patients (64.3% female) with a mean age of 54.7 y were analyzed. Symptoms had been present in patients for an average of 4.8 y when entering the study. A length dependent clinical pattern was seen in 79.8%. All patients had sensory discomfort. Etiology could not be determined in 35.7% of patients, who were diagnosed with idiopathic SFN; 34.5% of patients had an apparently autoimmune SFN, followed by14.3% of patients with metabolic causes. The estimated incidence was at least 4.4 cases/100.000 inhabitants/y. The minimum prevalence was 131.5 cases/100.000 inhabitants. DISCUSSION: This study indicates significant incidence and prevalence rates of SFN in Switzerland. SFN can vary greatly in its symptoms and severity. Extensive work-up resulted in two thirds of the patients being assigned an etiological association. The largest group of patients could not be etiologically defined, underlining the importance of further research on etiologic identification. We expect increased awareness of the developing field of SFN.