[Corneal confocal microscopy detects small-fiber neuropathy in patients with amyotrophic lateral sclerosis].

Objective: To investigate small fiber neuropathy in patients with amyotrophic lateral sclerosis (ALS) by corneal confocal microscopy. Methods: A total of 57 ALS patients were consecutively enrolled in Department of Neurology between June 2015 and February 2016, including 37 men and 20 women with mean age 24-80 (52±11) years. There were 30 controls including 21 men and 9 women with mean age 23-76 (55±13) years. All subjects underwent corneal confocal microscopy (CCM), contact heat evoked potential (CHEP) and skin sympathetic reflection (SSR) to quantify small nerve fiber pathology. Four parameters, such as nerve fiber length (NFL), nerve branch density (NBD), nerve fiber density (NFD) and nerve fiber tortuosity (NFT) were assessed by corneal confocal microscopy. All statistical calculations were conducted using SPSS version 12.0. Results: Compared with control group, corneal nerve fiber length (NFL),nerve fiber density (NFD) were significantly decreased [(12.2±4.4)mm/mm2 vs.(15.1±4.5) mm/mm2,P=0.028;(50.8±24.0)/mm2 vs. (68.3±16.4)/mm2,P=0.002],and nerve fiber tortuosity (NFT) were significantly increased [(2.6±1.0)level vs.(1.0±0.5)level, P<0.01)] in SFN group, while nerve branch density (NBD) were comparable (P=0.700).The course of disease is correlated with NFT (r=0.25,P=0.030). Conclusions: CCM is a new sensitive noninvasive clinical technique that detects early small fiber nerve damage in patients with ALS.

Neuropathic pain features suggestive of small fibre neuropathy in fibromyalgia syndrome: a clinical and ultrasonographic study on female patients.

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.

Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?

OBJECTIVES: In recent years, complaints of patients about burning pain in arms and legs after the injection of gadolinium-based contrast agents (GBCAs) have been reported. In the current study, we investigated changes of small fibers in the epidermis as a potential cause of the patient complaints in a mouse model. METHODS: Six groups of 8 mice were intravenously injected with either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine) (1 mmol/kg body weight), or saline (NaCl 0.9%). Four weeks after injection, animals were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IENFD) was calculated, and the median number of terminal axonal swellings (TASs) per IENFD was determined. RESULTS: Nonparametric Wilcoxon signed-rank test revealed significantly lower IENFDs for all GBCAs compared with the control group (P < 0.0001) with the linear GBCAs showing significantly lower IENFDs than the macrocyclic GBCAs (P < 0.0001). The linear GBCAs presented significantly more TAS per IENFD than the control group (P < 0.0001), whereas no significant increase of TAS per IENFD compared with the control group was found for macrocyclic GBCAs (P < 0.237). INTERPRETATION: It is unclear whether or at what dosage the decrease of IENFDs and the increase of TAS per IENFD found in the current animal model will appear in humans and if it translates into clinical symptoms. However, given the highly significant findings of the current study, more research in this field is required.

Small fiber neuropathy in Sjögren syndrome: Comparison with other small fiber neuropathies.

INTRODUCTION: We compared histological and clinical profiles of primary Sjögren syndrome (pSS) small fiber neuropathy (SFN; pSS-SFN) with idiopathic SFN (i-SFN) and hereditary transthyretin amyloidosis SFN (hATTR-SFN) and described the evolution of pSS-SFN. METHODS: All patients with pSS-SFN, i-SFN, and hATTR-SFN confirmed by reduced intraepidermal nerve fiber density on skin biopsy were retrospectively included, and their characteristics were compared. To analyze prognosis of pSS-SFN, patients prospectively underwent a second evaluation. RESULTS: Fifteen pSS-SFN, 17 hATTR-SFN, and 11 i-SFN were included. Time to diagnosis SFN was longer in pSS-SFN and i-SFN than in hATTR-SFN. Painful and non-length-dependent patterns were more frequent in pSS-SFN than in hATTR-SFN. Twelve (80%) patients with pSS-SFN had a non-length-dependent pattern. Ten patients with pSS were reassessed after 3.1 years (1.7-4.7); none developed large fiber neuropathy linked to pSS. DISCUSSION: Primary Sjögren syndrome SFN is characterized by a more frequent non-length-dependent pattern compared with i-SFN and hATTR-SFN. Primary Sjögren syndrome SFN did not evolve through large fiber neuropathy.

Small fiber neuropathy and related factors in patients with systemic lupus erythematosus; the results of cutaneous silent period and skin biopsy

Abstract 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.(AU)

Male sexual dysfunction in obesity: The role of sex hormones and small fibre neuropathy.

CONTEXT: Multiple factors contribute to sexual dysfunction in men with obesity. Sex hormone levels are commonly abnormal in men with obesity and this abnormality is often the focus of management in clinical practice. The role of small fibre neuropathy in obesity-related sexual dysfunction is not well established. OBJECTIVE: We aimed to investigate the relationship between sexual function, sex hormone levels and small nerve fibre morphology in men with severe obesity. MATERIALS AND METHODS: A prospective study of 29 men with severe obesity was undertaken. Sexual function was assessed using the European Male Ageing Study Sexual Function Questionnaire. Small nerve fibre morphology was quantified using corneal confocal microscopy. Sex hormone levels were measured by mass spectrophotometry. RESULTS: Erectile dysfunction was present in 72% of the cohort with a higher prevalence of diabetes among the symptomatic group (88% vs 38%, p = 0.006). Corneal nerve fibre length (CNFL) and corneal nerve fibre density (CNFD) were both significantly lower in participants with erectile dysfunction compared to those without (p = 0.039 and p = 0.048 respectively). The erectile function score correlated with CNFL (r = -0.418, p = 0.034) and CNFD (r = -0.411, p = 0.037). Total testosterone and calculated free testosterone levels did not differ significantly between men with or without erectile dysfunction (median 8.8 nmol/L vs 9.0 nmol/L, p = 0.914; and median 176 pmol/L vs 179 pmol/L, p = 0.351 respectively), infrequent sexual thoughts (median 8.1 nmol/L vs 9.2 nmol/L, p = 0.650; and median 184 pmol/L, vs 176 pmol/L, p = 0.619 respectively) and decreased morning erections (median 9.0 nmol/L vs 8.8 nmol/L, p = 0.655; and median 170 pmol/L vs 193 pmol/L, p = 0.278 respectively). CONCLUSION: Sexual dysfunction is highly prevalent in men with severe obesity. We found an association between small fibre neuropathy with erectile dysfunction with presence of diabetes a likely a significant contributing factor. We found no associations between testosterone levels with sexual symptoms (including frequency of sexual thoughts). The influence of small nerve fibre neuropathy on response to therapeutic interventions and whether interventions that improve small fibre neuropathy can improve erectile function in this population merits further study.

Small fibre neuropathy.

PURPOSE OF REVIEW: To provide a review on the state-of-art of clinical features, diagnostics, genetics and treatments of small fibre neuropathy (SFN). RECENT FINDINGS: The spectrum of clinical features has been widened from the classical presentation of burning feet as length-dependent SFN to that of small fibre dysfunction and/or degeneration associated with focal, diffuse and episodic neuropathic pain syndromes. The involvement of small nerve fibres in neurodegenerative diseases has been further defined, challenging the relationship between neuropathic pain symptoms and small fibre loss. The clinical reliability of skin biopsy has been strengthened by the availability of normative values for both the immunohistochemistry techniques used and their comparison, and by side and short-term follow-up analyses. Corneal confocal microscopy has implemented its diagnostic potentiality because of the availability of age-adjusted and sex-adjusted normative values. Genetic studies expanded the panel on genes involved in SFN because of the discovery of new mutations in SCN10A and SCN11A, besides the first found in SCN9A, and identification of mutations in COL6A5 in patients with itching. SUMMARY: In the last 5 years, the chapter of SFN has been widened by new clinical and genetics descriptions leading to a more comprehensive approach to patients in clinical practice and research.

Small-fibre neuropathy in a patient with dermatomyositis and severe scalp pruritus.

Dermatomyositis (DM) is commonly associated with scalp pruritus that can be severe. In addition, significant crawling and burning sensations have been reported in these cases. The aetiology of these scalp sensations in the context of DM is not fully understood. We report a 42-year-old female with treatment-resistant DM and structural changes in scalp epidermal and dermal nerve fibres. The patient presented with characteristic skin manifestations (Gottron's papules and poikiloderma), severely pruritic scalp, intermittent muscle weakness on neurological exam with electrodiagnostically confirmed myositis, and joint pain. Structural changes in scalp epidermal and dermal nerve fibres were discovered in a skin biopsy, suggesting that small-fibre neuropathy associated with scalp pruritus may be a manifestation of the DM syndrome. Further clinical experience combined with selective skin biopsy in patients with DM and symptomatic scalp will help determine the frequency of coexistent small nerve fibre involvement. Based on our limited findings, we suggest that pruritus in DM may be associated with abnormal epidermal and dermal nerve fibre structure.

Laser Doppler Flare Imaging and Quantitative Thermal Thresholds Testing Performance in Small and Mixed Fiber Neuropathies.

INTRODUCTION: Small fiber neuropathy might be a part of typical mixed small and large fiber neuropathy, or a distinct entity, affecting exclusively small nerve fibers. OBJECTIVES: Explore the utility of small nerve fiber testing in patients with clinical presentation suggesting small fiber neuropathy, with and without evidence for concomitant large fiber neuropathy. METHODS: Patients attending the neuromuscular clinic from 2012 to 2015 with a clinical presentation suggesting small nerve fiber impairment, who had Laser Doppler flare imaging (LDIFlare) and quantitative thermal testing (QTT) were evaluated for this study. Patients with clinical or electrophysiological evidence for concomitant large fiber neuropathy were not excluded. RESULTS: The sensitivities of LDIFlare, cooling and heat threshold testing were 64%, 36%, and 0% respectively for clinically highly suggestive small fiber neuropathy, 64%, 56%, and 19% respectively for mixed fiber neuropathy, and 86%, 79%, and 29% respectively for diabetic mixed fiber neuropathy. DISCUSSION: LDIFlare and cooling thresholds testing are non-invasive small nerve fiber testing modalities, with moderate performance in patients with small and mixed fiber neuropathy, and excellent performance in diabetic mixed fiber neuropathy.

Evidence for small fiber neuropathy in early Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is neurodegenerative movement disorder affecting primarily the central nervous system with several recognized non-motor symptoms that can occur at various stages of the disease. Recently it has been shown that patients with PD may be prone to peripheral nervous system pathology in the form of a peripheral neuropathy (PN). It is unclear if PN is an inherent feature of PD or if it is an iatrogenic effect of the mainstay PD treatment Levodopa. METHODS: To determine if peripheral neuropathy occurs in early untreated PD we employed a case-control study design using gold standard tests for PN, including neurological examination according to the Utah Early Neuropathy Scale (UENS) and nerve conduction studies, as well as new, more sensitive and informative tests for PN including the skin biopsy and corneal confocal microscopy (CCM). RESULTS: We studied 26 patients with PD and 22 controls using the neurological examination and nerve conduction studies (NCS) and found no significant difference between groups except for some reduced vibration sense in the PD group. Epidermal nerve densities in the skin biopsies were similar between our cohorts. However, using CCM - a more sensitive test and a surrogate marker of small fiber damage in PN, we found that patients with PD had significantly reduced corneal nerve fiber densities and lengths as compared to controls. CONCLUSIONS: We conclude that our positive CCM results provide evidence of preclinical PN in newly diagnosed PD patients.