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

Background Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Na v 1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Na v 1.3, Na v 1.7, and Na v 1.8, and stabilizes channels in the slow-inactivation state. Since multiple Na v 1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective. Methods/design The Lacosamide-Efficacy-‘N’-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A- associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum pain score, the Small Fiber Neuropathy Symptoms Inventory Questionnaire, sleep quality and the quality of life assessment, patients’ global impressions of change, and safety and tolerability measurements. Sensitivity analyses will include assessing the proportion of patients having ≥ 2 points average pain improvement compared to the baseline Pain Intensity Numerical Rating Scale scores. Discussion This is the first study that will be evaluating the efficacy, safety, and tolerability of lacosamide versus placebo in patients with SCN9A- associated small fiber neuropathy. The findings may increase the knowledge on lacosamide as a potential treatment option in patients with painful neuropathies, considering the central role of Na v 1.7 in pain. Trial registration ClinicalTrials.gov, NCT01911975 . Registered on 13 July 2013.

Small fibre neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ-fibres and unmyelinated C-fibres. Although multiple causes of small nerve fibre degeneration have been reported, including via genetic mutations, the cause of small fibre neuropathy remains unknown in up to 50% of cases. The typical clinical presentation of small fibre neuropathy is that of a symmetrical, length-dependent polyneuropathy associated with sensory or autonomic symptoms. More rarely, the clinical presentation is characterised by non-length-dependent, focal, or multifocal symptoms. The diagnostic tests to identify small fibre neuropathy include skin biopsy, quantitative sensory, and autonomic testing. Additional tests, such as those measuring small fibre-related evoked potentials and corneal confocal microscopy, might contribute to a better understanding of these neuropathies. Biochemical markers can also help in screening patients for the presence of small fibre neuropathy and to assess disease progression.

Background and Purpose Small fiber neuropathy (SFN), resulting from dysfunction and loss of peripheral unmyelinated and thinly myelinated nerve fibers, is traditionally characterized by distal skin pain and sensory loss. Patients often report additional symptoms, including muscle cramps, myalgias, fatigue, subjective weakness, and neuropathic itch, but the prevalence and intensity of these symptoms remain poorly defined. Current treatments—focused primarily on pain—are often ineffective, possibly due to substantial between‐patient heterogeneity. This study aimed to characterize the symptomatic variability of SFN and determine whether patients can be stratified into clinically meaningful subgroups. Methods Demographic, clinical, and laboratory data were analyzed from patients with skin biopsy‐confirmed SFN (n = 203) and healthy controls (n = 30). SFN patients were clustered based on clinical features using unsupervised machine learning. Results Fatigue—not neuropathic pain—was the most prevalent and intense symptom among patients with SFN. Muscle symptoms were as common and severe as neuropathic pain, while neuropathic itch was rare. Three distinct phenotypic clusters were identified: (1) an “algesic” group (~20%) with severe neuropathic pain and co‐occurring intense symptoms; (2) a “myalgic” group (~60%) with prominent fatigue, myalgias, and subjective weakness but milder neuropathic pain; and (3) a “pauci‐symptomatic” group with few, mild to moderate symptoms. Clusters differed by symptom profiles, disease duration, intraepidermal nerve fiber density, sex, and body mass index. Conclusion Fatigue and muscle symptoms are highly prevalent in SFN and may rival pain in clinical importance. Identifying patient subgroups provides a foundation for stratified treatment approaches and improved disease management.

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

Background Fibromyalgia (FM) is a complex chronic pain disorder characterized by widespread musculoskeletal pain and symptoms suggesting autonomic dysfunction. Small fiber neuropathy (SFN) has been described in a subgroup of patients. We aimed to explore the value of structured symptom assessment to identify patients with SFN or autonomic neuropathy. Methods Forty‐six female FM patients were assessed in a cross‐sectional study including clinical examinations, validated questionnaires (modified neuropathic pain symptom inventory (m‐NPSI), PainDETECT and the composite autonomic symptom score (COMPASS 31)) and diagnostic tests (intraepidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and quantitative sudomotor axon reflex test (QSART)). m‐NPSI > 58, PainDETECT > 18, and COMPASS 31 > 16 were defined as suggestive of neuropathic pain and dysautonomia, respectively. SFN was defined as negative findings (hypoalgesia and reduced thermal sensation) and an abnormal diagnostic test (IENFD, thermal detection thresholds or QSART). Cardiovascular autonomic neuropathy (CAN) was defined as two abnormal cardiovascular reflex tests. Symptom scores were compared with patient controls and patients with an established diagnosis of neuropathy. Results Among FM patients, one had SFN, while two had definite CAN. Thirty‐two, 20, and 43 of the FM patients had NPSI, PainDETECT, and COMPASS 31 scores suggesting neuropathy/dysautonomia. NPSI was higher in FM than in neuropathy patients. Increased mechanical pain sensitivity (15/46) and paradoxical heat sensation (23/46) were frequent QST findings in the FM group. Conclusion SFN or autonomic neuropathy was infrequent in FM patients and not related to symptom scores, which were higher than those for patients with neuropathy.

Small fiber neuropathy (SFN) is a common feature of many inflammatory diseases, often presenting with pain and disability. SFN is diagnosed using symptoms, thermal threshold testing, and intra-epidermal nerve fiber quantification. Corneal confocal microscopy (CCM) is an ophthalmic imaging technique which non-invasively quantifies corneal nerve fiber (CNF) density, branch density and length, and has comparable diagnostic and superior ability to identify nerve regeneration compared to skin biopsy. CNF size (width and area) depends upon the number of fibers within each nerve, as well as pathology (e.g., swelling), and may provide additional sensitivity to diagnose SFN and identify nerve repair. We have compared the utility of the standard CCM variables employed to CNF size in patients with diabetic sensorimotor polyneuropathy or sarcoidosis-associated SFN, and in patients with SFN following cibinetide administration, an agent which promotes nerve repair. The results show that: 1) CNF width distribution and area depend upon neuropathy severity; 2) CNF area, density, branch density and length possess comparable discriminatory power for diagnosing neuropathy; 3) CNF area is related to length by a quadratic function which is predictive for both healthy subjects and those with SFN; 4) CNF area is a useful variable for quantifying change in CNF morphology.

Background Patients with post‐COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience symptoms potentially associated with small fiber neuropathy (SFN). Methods A sample of 90 participants, comprising 30 PCC patients, 30 ME/CFS patients, and 30 healthy controls (HC), matched by sex and age, was assessed. Neuropathic, autonomic, and fatigue symptoms were measured with TaskForce Monitor, the Sudoscan, heat and cold evoked potentials, In Vivo Corneal Confocal Microscopy (IVCCM), and specialized questionaries. Results PCC and ME/CFS patients demonstrated significantly higher levels of autonomic symptoms (H = 39.89, p < 0.001), neuropathic symptoms (H = 48.94, p < 0.001), and fatigue (H = 49.29, p < 0.001) compared to HC. Quantitative sensory testing revealed significant differences in heat detection thresholds between PCC patients and HC (F = 4.82; p < 0.01). Regarding corneal small fiber tortuosity, there were statistically significant differences between patients and HC (F = 6.80; p < 0.01), indicating pathological responses in patients. Small fiber tortuosity in IVCCM was identified as the main discriminator between patients and HC (AUC = 0.720; p < 0.01). Conclusion PCC and ME/CFS patients demonstrated sensory SFN, as evidenced by impaired heat detection and increased tortuosity of small fibers in the central corneal subbasal plexus. The findings underscore the importance of a multimodal approach to comprehensively detect and characterize SFN. This study provides valuable scientific insights into the neuropathic manifestations associated with these conditions.

INTRODUCTION Neuronal intranuclear inclusion disease (NIID) manifests as dementia combined with other neurological symptoms. However, small fiber neuropathy (SFN) and pathology remain unknown in NIID. METHODS A total of 294 subjects, including patients with NIID, Parkinson's disease, Alzheimer's disease, diabetic peripheral neuropathy, and healthy controls (HCs), were included. Clinical scales, sensory and autonomic function testing, and skin biopsy were performed. RESULTS NIID patients had more severe sensory and autonomic dysfunction than other groups. Substantial reductions in intraepidermal, sweat gland, and pilomotor nerve fiber densities were observed in NIID patients, with a non–length dependent pattern. Detailed analysis revealed marked reductions in noradrenergic, cholinergic, peptidergic, and regenerative nerve fibers. Small fiber densities showed high diagnostic accuracy in distinguishing NIID from HCs and other diseases. DISCUSSION This study is the first to reveal wide and severe loss of small fibers in NIID, suggesting the involvement of SFN in the pathogenesis of NIID. Highlights Our study is the first to identify wide and severe non–length dependent small fiber neuropathy in neuronal intranuclear inclusion disease (NIID) patients. Approximately 50% of NIID patients exhibited pure small fiber neuropathy without large fiber or mixed neuropathy. NIID patients showed a significant reduction in noradrenergic, cholinergic, peptidergic, and regenerative fiber innervation. Small fiber densities, especially intraepidermal nerve fiber density, demonstrated high diagnostic accuracy in distinguishing NIID patients from healthy controls and other disease groups. Findings suggest that small fiber neuropathy may play a role in the pathogenesis of NIID.