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Background: Small fiber neuropathy (SFN) after both COVID-19 infection or vaccination has been reported in sporadic cases, but a detailed description and comparison are missing. We aimed to screen a large cohort of patients complaining of pain and autonomic symptoms after COVID-19 natural infection or vaccination to ascertain the presence of SFN and its correlation with autoimmune diseases., Methods: We prospectively recruited for this case-control study 66 patients: 33 developing sensory and autonomic symptoms after a natural COVID-19 infection (P-COVID) and 33 after a mRNA vaccination against COVID-19 (P-VAC). We also used 33 matched healthy controls (HC) collected before 2019 when the COVID-19 virus appeared. Patients underwent neurological examination and clinical scales, an extensive serum screening, and skin biopsy to detect small nerve fiber involvement., Results: Clinical scales showed higher scores for autonomic symptoms in P-COVID patients than in P-VAC patients, but the other scales did not differ. P-COVID and P-VAC patients showed a significant decrease in somatic small nerve fibers compared with HC, whereas autonomic innervation did not differ. SFN was more frequent in P-COVID patients (94%) than in P-VAC patients (79%). Epidermal innervation was correlated with clinical scales for pain and autonomic dysfunctions. Autoimmune abnormalities were frequent in both groups but importantly they were not correlated with SFN., Conclusions: Somatic SFN was frequently found in both P-COVID and P-VAC patients, with a higher incidence in the former group. Spared skin autonomic innervation was spared in both groups although a subtle autonomic involvement in P-COVID patients was suggested by a high COMPASS-31 scale score. SFN was not correlated with autoimmune dysfunctions, although autoimmune diseases were frequent in both groups., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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

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

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

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., Competing Interests: Conflicts of interest statement: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood., Study Purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes., Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire., Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions., Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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

Small-fiber neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ and unmyelinated C fibers. Patients generally present with neuropathic pain, while dysesthesia, allodynia, pain, burning sensations, and cold sensations are frequently present in a length-dependent pattern. Additional autonomic features of the gastrointestinal, urinary, or cardiovascular systems are frequently observed. Deep-tendon reflexes and nerve conduction tests yield normal results. Skin biopsy is useful for the diagnosis, and can demonstrate the loss of intraepidermal nerve fibers in small-fiber neuropathy and has a diagnostic sensitivity of 80%. Although many causes of small-fiber neuropathy have been reported, the cause remains unknown in 30-50% of the cases. Treatment is directed at the underlying etiology and is supported with symptomatic treatment.

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

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

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., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: To evaluate multichannel laser evoked potentials (LEPs) in patients with fibromyalgia (FM) and small fiber impairment., Methods: We recorded LEPs using 65 electrodes in 22 patients with FM and proximal denervation, 18 with normal skin biopsy, and 7 with proximal and distal intraepidermal nerve fiber density (IENFD) reduction. We considered the amplitude and topographical distribution of N1, N2 and P2 components, and habituation of N2 and P2 waves. The sLORETA dipolar analysis was also applied. We evaluated 15 healthy subjects as controls., Results: We observed reduced amplitude of the P2 component in FM group, without a topographic correspondence with the prevalent site of denervation. Decreased habituation of P2 prevailed in patients with reduced IENFD. The cingulate cortex and prefrontal cortex, were activated in the FM group, without correlation between the degree of denervation and the strength of late wave dipoles. A correlation was noted between anxiety, depression, fibromyalgia invalidity, and pain diffusion., Conclusions: The amplitude and topography of LEPs were not coherent with epidermal nerve fiber density loss. They supposedly reflected the clinical expression of pain and psychopathological factors., Significance: Multichannel LEPs are not the expression of small fiber impairment in FM. Rather, they reflect the complexity of the disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A-delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non-length-dependent (NLD) presentation that can be patchy, asymmetrical, upper limb-predominant, or diffuse. This narrative review is focused on NLD-SFN. The diagnosis of NLD-SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD-SFN. The topographic pattern of NLD-SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune-mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease-modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD-SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology., (© 2021 Wiley Periodicals LLC.)

Aim: To investigate the diagnostic utility of corneal confocal microscopy (CCM) for small fiber neuropathy in type 2 diabetes., Materials and Methods: There were 186 participants with type 2 diabetes enrolled in this cross-sectional research. Pure small fiber neuropathy and mixed fiber neuropathy were defined using clinical examination, electromyography, and quantitative sensory testing. Demographics and clinical data, corneal confocal microscopy parameters, and other neuropathy measures were compared among the groups. The diagnostic utility of corneal confocal microscopy for small fiber neuropathy was assessed by the receiver operating curve., Results: Of the 186 patients, 24.7% had a pure small fiber neuropathy and 17.2% of patients were diagnosed with mixed fiber neuropathy. The corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) were significantly lower in subjects with pure small fiber neuropathy compared with those without diabetic peripheral neuropathy (all P < 0.05). The receiver operating curve analysis for corneal confocal microscopy diagnosing small fiber neuropathy demonstrated the area under the curve for CNFD of 0.791, CNFL of 0.778, CNBD of 0.710., Conclusions: Patients with type 2 diabetes with pure small fiber neuropathy showed more corneal nerve loss compared with those without diabetic peripheral neuropathy. It was revealed that corneal confocal microscopy can be a reasonable marker in the diagnosis of small fiber neuropathy in type 2 diabetes., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: A consistent line of investigation proposes fibromyalgia as a dysautonomia-associated neuropathic pain syndrome. Comorbid anxiety or depression amplifies fibromyalgia symptoms. The recent recognition of small fiber neuropathy in fibromyalgia patients supports the neuropathic nature of the illness. Corneal confocal microscopy accurately identifies small nerve fiber pathology. The newly developed Small-Fiber Symptom Survey captures the spectrum of small fiber neuropathy symptoms. We aimed to correlate corneal nerve density with different fibromyalgia disease severity questionnaires including the Small-Fiber Symptom Survey. We defined the possible confounding role of comorbid anxiety or depression severity in the clinical-pathological association., Methods: This is a case series of 28 women with fibromyalgia. A single ophthalmologist quantified corneal subbasal plexus nerve density. Corneal innervation was correlated (Spearman ρ) with the following clinical questionnaires scores: Small-Fiber Symptom Survey, Revised Fibromyalgia Impact Questionnaire, and COMPASS-31 (Composite Autonomic Symptom Survey 31-Item Score). Validated inquiry forms assessed the comorbid anxiety and/or depression severity., Results: There were no clinical-pathological correlations in the group as a whole. In the subgroup of fibromyalgia women without severe anxiety or depression (n = 13), there was a strong negative correlation between corneal nerve density with the Small-Fiber Symptom Survey score (ρ = -0.771, p = 0.002) and COMPASS-31 score (ρ = -0.648, p = 0.017). Patients with profound anxiety or depression (n = 15) had more intense symptoms but had not clinical-pathological correlations., Conclusions: Small fiber neuropathy and dysautonomia symptoms correlate with corneal denervation in women with fibromyalgia without severe anxiety or depression. This clinical-pathological association reinforces fibromyalgia as a dysautonomia-related neuropathic pain syndrome. Severe anxiety or depression distorts fibromyalgia symptoms., Practical Point: Corneal confocal microscopy may become a useful procedure to study fibromyalgia patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Fibromyalgia and small fibre neuropathy are two diseases leading to chronic widespread pain, and it is difficult to differentiate them in order to provide appropriate care. In this review, we will describe the pathophysiological and clinical differences between fibromyalgia and small fibre neuropathy. In fibromyalgia, pain is increased by dysregulation of central pain processing while small fibre neuropathy pain is related to loss or dysfunction of intraepidermal small nerve fibres. Higher pain intensity; stabbing pain and paraesthesia; allodynia; dry eyes/mouth; changed pattern or sweating on body; skin colour alterations/modifications; reduced hair/nail growth on lower extremities; warm or cold hypoesthesia could be more common in small fibre neuropathy whereas headache or temporo-mandibular disorder point toward fibromyalgia. Length-dependent distribution of pain is common in small fibre neuropathy but can also affect the whole body. Anxiety or depression are common in these two diseases, but post-traumatic stress disorder and physical or sexual abuse in childhood or adulthood suggest fibromyalgia. Inflammatory disease or musculoskeletal disease is frequently reported with fibromyalgia whereas metabolic disorders (especially diabetes mellitus), neurotoxic exposure, Sjogren's syndrome, sarcoidosis, HIV are the main diseases associated with small fibre neuropathy. Skin biopsy, quantitative sensory testing, laser evoked potentials, confocal corneal microscopy or electrochemical skin conductance can help to discriminate between fibromyalgia and small fibre neuropathy., (Copyright © 2021 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the performance of two screening tools, respectively Pain Detect Questionnaire (PDQ) and Douleur Neuropathique 4 questions (DN4), and the optimal cut-off point of the sural nerve cross-sectional area (CSA), in identifying the neuropathic pain features suggestive of a small fiber neuropathy (SFN), in patients with fibromyalgia syndrome (FM)., Methods: Consecutive adult female FM patients fulfilling the American College of Rheumatology (ACR) 2016 criteria have been enrolled. Patients underwent a clinical assessment and ultrasound examination of the sural nerve CSA. In each patient was established the presence of neuropathic pain features suggestive of the presence of SFN. The performance of PDQ versus DN4 was compared to the clinical judgment of SFN as external criterion analysing the area under the receiver operating characteristic curve (AUCROC). The optimal sural nerve CSA cut-off was established with the ROC curve analysis versus the clinical judgment of SFN., Results: The study involved 80 patients (mean age 49.5±10.5 years, mean disease duration 5.2±4.9 years, mean revised FIQR score 60.9±19.6). Comparing the AUC-ROCs of the screening tools with clinical judgment of SFN, a better AUC was documented, although not significantly (p=0.715), for DN4 (0.875) compared to PDQ (0.857). A sural nerve CSA of 3 mm2 identifies neuropathic pain features with a sensitivity of 70% and a specificity of 90%., Conclusions: Screening tools have a good concordance in identifying neuropathic pain features suggestive of SFN in FM patients, although a better performance is provided by DN4. Determining the CSA sural nerve with an ultrasound examination may provide some information about the possible presence of SFN.

Small fiber neuropathy is common and prevalent in the elderly. The disease can be associated with many medical conditions. It often has a negative impact on quality of life due to painful paresthesia, dizziness, and sedative side effects of pain medications. Skin biopsy is the gold standard diagnostic test. Screening for associated conditions is important, because etiology-specific treatment can slow down disease progression and ameliorate symptoms. Adequate pain control can be challenging due to safety and tolerability of pain medications in the elderly. Treatment should be individualized with the goals of controlling underlying causes, alleviating pain, and optimizing daily function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Small fiber neuropathy (SFN) causes damage to small-calibre nerve fibers (unmyelinated C fibers and myelinated A-delta fibers). The symptoms of SFN usually are sensitive including paresthesia, dysesthesia or burning pain, and protopathic deficits, sometimes associated with dysautonomia. The causes of SFN can be classified in six main groups: idiopathic, toxic, metabolic, immunological, infectious and hereditary. In this article, we present the diagnostic approach to SFN, the most common autoimmune aetiologies, as well as elements of their therapeutic management., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose., (© 2020 Peripheral Nerve Society.)

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation., (© 2020 American Academy of Neurology.)

Aim: To investigate the frequency of foot sudomotor dysfunction determined by the electrochemical skin conductance test (ESC) and its independent predictors in individuals with type 1 diabetes mellitus (T1D) and no clinical evidence of diabetic peripheral neuropathy (DPN)., Methods: Adults with T1D for longer than 5 years and without DPN defined by the Michigan Neuropathy Screening Instrument and Neuropathy Disability Score were assessed for foot sudomotor dysfunction by ESC. Multivariate logistic regression analysis was used to examine the association between foot sudomotor dysfunction (ESC < 70 µS) and demographic, clinical, and biochemical variables., Results: A total of 61 individuals with T1D were included. Their mean age was 29.5 ± 8.6 years, and mean diabetes duration was 17.8 ± 7.9 years. Foot sudomotor dysfunction was present in 16 (26.2%) participants, despite no clinical evidence of DPN. Retinopathy, hand sudomotor dysfunction and glycated haemoglobin (HbA1c) levels were identified as independent predictors of foot sudomotor dysfunction by multivariate logistic regression analysis. Retinopathy, hand sudomotor dysfunction, and every 1% increase of HbA1c increased the odds of foot sudomotor dysfunction by 2.48, 2.82, and 1.24-fold, respectively., Conclusion: Our findings indicate a high frequency of foot sudomotor dysfunction among individuals with T1D and no overt DPN. Factors associated with DPN, including retinopathy and higher HbA1c levels, independently predicted the occurrence of sudomotor dysfunction, suggesting that ESC assessment is a useful tool in the clinical setting to identify early small-fiber neuropathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The most common peripheral nervous system manifestations in Sjogren's syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies. Currently, treatment in small fiber neuropathy is mainly symptomatic and based on anti-depressors and anti-epileptics. The benefit of treatment with polyvalent immunoglobulins for SFPN has been reported in small series of patients, although transient in several cases. The medium-to-long-term effects of polyvalent immunoglobulins (Ig) in SFPN in patients with Sjogren's syndrome who are refractory to conventional treatments remain an unmet medical need. We present our experience related to the persistent improvement of Ig in a case series of SFPN in Sjogren's syndrome and relevant data in the literature regarding the benefits of immunoglobulins, for this indication.

Introduction: Small fiber neuropathy (SFN) is a heterogeneous group of disorders affecting thin myelinated Aδ and unmyelinated C fibers. Common symptoms include neuropathic pain and autonomic disturbances, and the typical clinical presentation is that of a length-dependent polyneuropathy, although other distributions could be present., Area Covered: This review focuses on several aspects of SFN including etiology, clinical presentation, diagnostic criteria and tests, management, and future perspectives. Diagnostic challenges are discussed, encompassing the role of accurate and standardized assessment of symptoms and signs and providing clues for the clinical practice. The authors discuss the evidence in support of skin biopsy and quantitative sensory testing as diagnostic tests and present an overview of other diagnostic techniques to assess sensory and autonomic fibers dysfunction. The authors also suggest a systematic approach to the etiology including a set of laboratory tests and genetic examinations of sodium channelopathies and other rare conditions that might drive the therapeutic approach based on underlying cause or symptoms treatment., Expert Opinion: SFN provides a useful model for neuropathic pain whose known mechanisms and cause could pave the way toward personalized treatments.

Purpose: We aimed at describing for the first time peripheral small-fiber neurotoxicity and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation (SCT)., Methods: In a cross-sectional, retrospective, single-center study, we assessed 25 relapse-free long-term survivors (median age at SCT: 11 ± 4.9 years; median time between SCT and testing: 8.25 years, 19 males) using a reduced version of the pediatric-modified total neuropathy score for clinical assessment and Quantitative Sensory Testing (QST)., Inclusion Criteria: [Formula: see text] 6 years old at testing, [Formula: see text] 18 years old at time of SCT, [Formula: see text] 1 year between SCT and testing., Results: Nine patients (36%) had peripheral neuropathy as defined by the clinical red-pmTNS (≥ 4). The QST parameters mechanical pain sensitivity, mechanical detection threshold, thermal sensory limen, vibration detection threshold and pressure pain threshold were significantly abnormal in the survivor cohort (p < 0.0038). Except for one, all survivors showed at least one abnormal QST parameter. When using QST, signs of small and large fiber dysfunction were present in 22 (88%) and 17 (68%) survivors, respectively. More than half of all survivors were found to experience pathologic sensitization to pain., Conclusions and Implications for Cancer Survivors: Survivors of pediatric acute lymphoblastic leukemia after SCT are at high risk for long-term peripheral neuropathy with a dominating small-fiber and pain sensitization pattern.

Introduction: Evaluating small nerve fibers in patients with systemic lupus erythematosus (SLE) using cutaneous silent period (CSP) and skin biopsy and assesssing the relationship between clinical signs, autoantibodies and neuropathic pain score., Objective - Methods: Fifty one SLE patients and 46 healthy volunteers were included in this study. Nerve conduction studies and CSP were performed both on upper and lower limbs in subjects. Skin biopsy was performed and the number of epidermal nerve density and IL-6 staining were evaluated., Results: In SLE patients, CSP latencies were significantly prolonged both in lower and upper limbs and lower and upper extremity CSP durations were significantly shorter when compared to controls (p < 0.001). The number of epidermal nerve was significantly lower in SLE patients when compared to healthy controls (p < 0.001)., Conclusion: We detected marked small nerve fiber damage in both lower and upper limbs in SLE patients using CSP. Decreased epidermal nerve density also supports this finding.

Background: Peripheral neuropathy is a common neurological complication in uremic patients, and quantitative sensory testing (QST) is effective for diagnosis of small fiber neuropathy. Malnutrition and arterial stiffness are prevalent in patients undergoing hemodialysis (HD). The associations of small fiber neuropathy with nutritional status and arterial stiffness remain uncertain in maintenance HD patients., Methods: A total of 152 HD patients were included. Geriatric nutritional risk index (GNRI), an indicator of nutritional status, was calculated by serum albumin and actual and ideal body weight. Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) > 1400 cm/s. Small fiber neuropathy was assessed by an abnormal QST threshold of cold and warm sensation in patients' hands or feet. Multivariate forward logistic regression analysis was performed to examine the associations among abnormal QST threshold, GNRI, and arterial stiffness., Results: baPWV and prevalence of abnormal QST threshold were significantly higher in diabetic patients. Multivariate logistic analyses revealed that older age (OR, 1.081; 95% CI, 1.026-1.139, p = 0.003) and male gender (OR, 4.450; 95% CI, 1.250-15.836, p = 0.021) were associated with abnormal warm threshold of hands. Furthermore, diabetes (OR, 3.966; 95% CI, 1.351-11.819, p = 0.012) and lower GNRI (per 1 unit increase, OR, 0.935, 95% CI, 0.887-0.985, p = 0.012) were associated with abnormal cold threshold of feet. Arterial stiffness (OR, 5.479, 95% CI, 1.132-22.870, p = 0.020) and higher calcium-phosphorus product (OR, 1.071, 95% CI, 1.013-1.132, p = 0.015) were associated with abnormal warm threshold of feet., Conclusions: Lower GNRI and arterial stiffness were significantly associated with small fiber neuropathy in patients undergoing HD. Malnutrition risk and vascular factors might play important roles in small fiber neuropathy among patients undergoing HD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Mei-Chuan Kuo et al.)

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/mm 3 )., Discussion: Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients., (© 2019 Wiley Periodicals, Inc.)

Aim: To assess if latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy., Methods: Participants with LADA (n=31), Type 2 diabetes (n=31) and healthy control participants without diabetes (n=31) underwent a detailed assessment of neurologic deficits, quantitative sensory testing, electrophysiology, skin biopsy and corneal confocal microscopy., Results: The groups were matched for age (healthy control without diabetes: 53.5±9.1 vs. Type 2 diabetes: 58.0±6.5 vs. LADA: 53.2±11.6 years), duration of diabetes (Type 2 diabetes: 10.0±8.3 vs. LADA: 11.0±9.1 years) and blood pressure. However, BMI (P=0.01) and triglycerides (P=0.0008) were lower and HbA 1c (P=0.0005), total cholesterol (P=0.01) and HDL (P=0.002) were higher in participants with LADA compared with Type 2 diabetes. Peroneal motor nerve conduction velocity (P=0.04) and sural sensory nerve conduction velocity (P=0.008) were lower in participants with latent autoimmune diabetes in adults compared with Type 2 diabetes. Intra-epidermal nerve fibre density (P=0.008), corneal nerve fibre density (P=0.003) and corneal nerve branch density (P=0.006) were significantly lower in participants with LADA compared with Type 2 diabetes. There were no significant differences in the other neuropathy parameters., Conclusions: Despite comparable age and duration of diabetes, participants with LADA demonstrate more severe neuropathy and particularly small fibre neuropathy, compared with participants with Type 2 diabetes., (© 2018 Diabetes UK.)

Purpose of Review: The current review discusses the diagnosis and management of nonorgan-related symptoms that commonly arise in the setting of systemic sarcoidosis. Fatigue, small fiber neuropathy (SFN) and neuropsychological symptoms are highlighted., Recent Findings: The debilitating effects of chronic nonorgan-based symptoms in sarcoidosis have led to recent studies focusing on incidence rates, contributing factors and potential therapeutic strategies. In a web-based survey of over 1000 sarcoidosis patients, the most common symptom was fatigue, which was reported by over 90% of participants, whereas memory loss and concentration problems were reported in 50%. SFN was also common, and may be diagnosed with tools such as skin biopsy measurement of intraepidermal nerve fibers and corneal confocal microscopy. In a recent cohort study of SFN patients, serologic evaluation demonstrated other contributing causes such as diabetes and vitamin B12 deficiency, which warrant-specific treatment. Finally, physical inactivity in patients with sarcoidosis correlated with lower quality-of-life (QOL) scores and possibly fatigue. Multidisciplinary programs that include physical therapy, patient education and psychological support were found to improve fatigue and mood disorders., Summary: Recognition of nonorgan-related symptoms and their impact on patient QOL is essential to optimal treatment of the sarcoidosis patient.

Objectives : The commonest types of peripheral neuropathy in the context of Coeliac Disease (CD) and gluten sensitivity (GS) are length-dependent symmetrical sensorimotor neuropathies and sensory ganglionopathies. In patients with such neuropathy, (gluten neuropathy), peripheral neuropathic pain is prevalent suggesting involvement of small fibers. The purpose of this report was to describe the clinical characteristics of patients with CD or GS and pure small fiber neuropathy (SFN). Methods : We reviewed the records of all patients that had been referred to the Gluten-Related Neurological Disorders clinic who had clinical and neurophysiological evidence of SFN. All patients had serological evidence of gluten sensitivity (GS) prior to commencing GFD. All patients were offered a duodenum biopsy. Patients with comorbidities that could cause SFN were excluded. Results : We identified 13 patients (9 males) with SFN and gluten sensitivity. Of 11 patients who underwent duodenal biopsy 10 had evidence of enteropathy (CD). Mean age at onset of pain was 53.5 ± 11.4 years (range 34-72) and mean age of CD/GS diagnosis was 50.8 ± 10.4 years (range 34-68). In 8 patients (61.5%) pain was the presenting feature. Neurophysiological assessment suggested a length-dependent small fiber neuropathy in 11 patients, whereas in 2, a non-length dependent pattern was identifying suggesting that the predominant pathology lies in the dorsal root ganglia. Conclusion : SFN can be a presenting feature of CD and GS and, therefore, screening for CD and GS should be included in the diagnostic workup of patients with idiopathic SFN.

Objective: Painful small-fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large-fiber involvement. SFN can be diagnosed by punch skin biopsy results that identify decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves., Methods: We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh)., Results: There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti-Ro 52 (P = 0.01) and anti-Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking-and-glove pain, and 12 patients had nonstocking-and-glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients)., Conclusion: SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking-and-glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies., (© 2018, American College of Rheumatology.)

Objective: To determine whether clinical features of neuropathic pain differ with respect to the presence of small-fiber neuropathy (SFN) in patients with primary Sjögren's syndrome (pSS)., Methods: We compared the clinical presentation of neuropathic pain between 15 patients with pSS and SFN detected by neurophysiological tests (laser-evoked potentials, cold and warm detection thresholds, sympathetic skin responses, and electrochemical skin conductance) and 15 patients with pSS but no neurophysiological evidence of SFN., Results: The patients with SFN had more intense squeezing and pressure sensations and more frequent dynamic mechanical allodynia (pain provoked by brushing) than the patients without SFN. Restless leg syndrome was also more frequently observed in patients with SFN, who had pain aggravated at rest that improved by moving., Conclusions: These findings are in favor of the sensitization of relatively spared large Aβ-fibers and second-order nociceptive neurons in patients with SFN. On the other hand, burning sensations, which rather reveal sensitization of small nociceptive fibers, were observed whether SFN was present or not. Thus, some discriminating clinical features may help to suggest the presence of SFN in patients with pSS and chronic neuropathic pain., (© 2018 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We attempted to determine whether clinical features could differentiate painful small-fiber neuropathy related to primary Sj€ogren's syndrome (pSS-SFN) from idiopathic SFN (idio-SFN)., Methods: Validated clinical questionnaires and neurophysiological investigations specific for pain and SFN assessment were performed in 25 patients with pSS-SFN and 25 patients with idio-SFN., Results: Patients with idio-SFN had more frequent severe burning sensations and higher mean anxiety scores and daily pain intensity compared to patients with pSSSFN. Conversely, patients with pSS-SFN had reduced electrochemical skin conductance measured by Sudoscan&#95;, and almost half of them had the sensation of walking on cotton wool., Conclusion: Our results suggest that idio-SFN more specifically involved small sensory fibers than pSS-SFN, in which subtle dysfunction of larger sensory fibers and damage of distal autonomic sudomotor innervation may occur. A practical algorithm is proposed to help to differentiate SFN associated with pSS from idio-SFN, based on information very easy to obtain by clinical interview., (© 2019 World Institute of Pain.)

Objective: To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients., Methods: FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non-length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method., Results: A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P = 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P = 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P = 0.06)., Conclusions: This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.

Objectives: To examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction., Methods: This single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored., Results: 10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv., Conclusions: SFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Novak is advisor - independent Contractor for Dysimmune Diseases Foundation. Dr. Novak received speaker’s honoraria from KabaFusion. All other authors report no disclosures. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

This cross-sectional multicentre study aimed at investigating frequency and features of painful diabetic polyneuropathy. We consecutively enrolled 816 patients attending hospital diabetic outpatient clinics. We first definitely diagnosed diabetic polyneuropathy and pure small-fibre polyneuropathy using clinical examination, nerve conduction study, and skin biopsy or quantitative sensory testing. Adhering to widely agreed criteria, we then identified neuropathic pain and diagnosed painful polyneuropathy using a combined approach of clinical examination and diagnostic tests. Of the 816 patients, 36% had a diabetic polyneuropathy associated with male sex, age, and diabetes severity; 2.5% of patients had a pure small-fibre polyneuropathy, unrelated to demographic variables and diabetes severity. Of the 816 patients, 115 (13%) suffered from a painful polyneuropathy, with female sex as the only risk factor for suffering from painful polyneuropathy. In this large study, providing a definite diagnosis of diabetic polyneuropathy and pure small-fibre polyneuropathy, we show the frequency of painful polyneuropathy and demonstrate that this difficult-to-treat complication is more common in women than in men.

Background: Sensitive skin syndrome (SSS) is defined as the occurrence of unpleasant sensations (itch, pain, burning, prickling) in response to stimuli that should not normally cause such sensations. Previous studies show that SSS could be a small fibre neuropathy, but quantitative sensory testing (QST) is lacking., Objectives: Using QST, to determine the presence or absence of tactile sensitivity disorder, mainly heat pain threshold (HPT), in patients with SSS., Methods: This monocentric case-control study included 21 patients with SSS and 21 controls. The patients underwent QST. Neuropathic pain was assessed by two questionnaires: the Douleur Neuropathique 4 (DN4) and the Neuropathic Pain Symptom Inventory (NPSI)., Results: Forty-two patients were included in the study. The HPT was significantly lower in the cases (14·5 ± 2·8) than in the controls (17·8 ± 2·5) (P < 0·001). Intermediate pain (HPT 5·0) was also significantly decreased in patients with SSS. The DN4 and NPSI scores were significantly higher in the cases than in the controls., Conclusions: The decrease in HPT in patients with SSS compared with controls suggests the presence of hyperalgesia, probably due to the damage of C-fibres. These findings, as well as the increased DN4 and NPSI scores, strengthen the neuronal hypothesis of SSS and are new arguments for consideration of SSS as small fibre neuropathy., (© 2018 British Association of Dermatologists.)