Small Fiber Dysfunction Research Articles

A model for in vivo analysis of sudomotor sympathetic C-fiber activation and human sweat gland output.

Quantitative assessment of small-fiber peripheral neuropathy often involves an evaluation of the interaction between the C-fiber sudomotor nerve and local sweat rate (SR). Typically, some sort of quantitative sudomotor axon reflex test (QSART) is performed to aid in diagnosing small-fiber dysfunction. The currently used QSART demonstrates only moderate test-retest reliability and therefore limits its usefulness in tracking small-fiber dysfunction. A new experimental model to examine small C-fiber function in the skin using intradermal electrical stimulation and simultaneous monitoring of SR is proposed. Using intradermal electrical stimulation (1.5 and 2.5 mA) and varying stimulus frequency from 0.2 to 64 Hz, a quantitative relationship between the area under the SR-time curve and log10 stimulus frequency is modeled using a four-parameter logistic equation, providing the following parameters: baseline, plateau, EC50, and Hill slope. The model has good to excellent repeatability within the same day (ICC = 0.98), on different days at the same skin site (ICC = 0.80), and when comparing two different skin sites (ICC = 0.78) with a small bias estimate and the line of identity always lying within the 95% limits of agreement. Atropine sulfate (0.1 mg/ml) blocked 90 ± 5% of the electrically induced sweating. Overall, the model provides control over sudomotor nerve activity and a quantitative assessment of SR. Finally, the ability to reproduce the quantitative stimulus-response curve on different days allows for a robust assessment of the relationship between the activation of a sympathetic C-fiber and local SR.NEW & NOTEWORTHY A model for quantitative assessment of C-fiber function in human skin using intradermal electrical stimulation and local sweat rate measurements has been developed. This new electrically induced sweating model is nonpainful and allows for a complete stimulus-response curve plotting the area under the local sweat rate-time curve vs. the log10 stimulus frequency. The model has good reproducibility and should provide a means of assessing the progression of small C-fiber peripheral neuropathy in humans.

Small fiber neuropathy

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

22. Laser evoked potentials, skin biopsy, somatosensory evoked potentials and electroneurography to evaluate small nerve fiber dysfunction in small fibers neuropathy: A preliminary study

Small fiber neuropathy (SFN) is characterized by a predominantly damage of small myelinated (A δ ) or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The abnormalities of these fibers may differ in SFN and the diagnostic reliability of somatic vs autonomic functions has not been well established in patients with suspected SFN. We recruited 6 patients with suspected SFN including somatic and autonomic symptoms and normal large myelinated fibers function evaluated by means of electroneurography (ENG) and somatosensory evoked potentials (2 pz). We carried out leg skin biopsy and laser evoked potentials (LEPs) to verify a possible diagnostic reliability of these tests. In all patients skin biopsy showed somatic and autonomic SFN small fiber neuropathy, 5 of them (83%) showed altered foot LEPs with absent signal of N2-P2 cortical responses. Our data demonstrated a reasonable concordance between LEP and skin biopsy in evaluating small nerve fiber loss in SFN. However these data should be considered preliminary and a larger number of patients must be recruited before to draw any definite conclusion.

Neurological Findings in Anderson-Fabry Disease

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene on chromosome Xq22, resulting in α-galactosidase A enzyme deficiency. It is characterized by progressive accumulation of lipids (e.g., globotriaosylceramide) in the lysosomes of a variety of cell types, including neural cells. Neurological manifestations, other than cerebrovascular accidents, include small fiber neuropathy and dysautonomic disorders. Small fiber peripheral neuropathy often is clinically manifested at young ages. Peripheral pain can be chronic and/or can occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with AFD often remain undiagnosed until the emergence of a more typical clinical manifestation, characterized by chronic renal and cardiac failure. Early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level, which can substantially improve the quality of these patients. Thus, it is important that physicians consider AFD in the differential diagnosis of neurological manifestations to provide an appropriate diagnostic and therapeutic workup.

Small fibre neuropathy.

To provide a review on the state-of-art of clinical features, diagnostics, genetics and treatments of small fibre neuropathy (SFN). 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. 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.

109. Laser evoked potentials and skin biopsy to evaluate small nerve fiber dysfunction in Fabry disease: A preliminary study

Fabry’s disease (FD) is caused by an X-linked mutation, and a characteristic feature is a severe loss of small myelinated fibers (AΔ) and small unmyelinated fibers (C) shown by skin biopsy. However, the pathophysiological mechanisms underlying the disease are still largely unknown. We recruited 3 patients with previously diagnosed Fabry’ disease. The specific aim of this study is to verify a possible correlation between laser evoked potentials and skin biopsy to diagnose small nerve fibers involvement in these patients. Two patients showed abnormal skin biopsy which disclosed a somatic and autonomic small fiber neuropathy and altered LEPs with increased latencies of N2-P2 and N1 cortical responses (or absence), involving both AΔ fiber responses (hand, foot and trigeminal nerve) and C-fiber responses. The third patient showed LEPs and skin biopsy normal findings. Our data demonstrated a good concordance between LEP and skin biopsy in evaluating small nerve fiber loss in FD. However these data should be considered preliminary and a larger number of patients must be recruited before to draw any definite conclusion.

Lengthened Cutaneous Silent Period in Fibromyalgia Suggesting Central Sensitization as a Pathogenesis.

The pathogenesis of fibromyalgia (FM) has not been clearly elucidated, but central sensitization, which plays an important role in the development of neuropathic pain, is considered to be the main mechanism. The cutaneous silent period (CSP), which is a spinal reflex mediated by A-delta cutaneous afferents, is useful for the evaluation of sensorimotor integration at the spinal and supraspinal levels. To understand the pathophysiology of FM, we compared CSP patterns between patients with FM and normal healthy subjects. Twenty-four patients with FM diagnosed in accordance with the 1990 American College of Rheumatology classification system and 24 age- and sex-matched healthy volunteers were recruited. The CSP was measured from the abductor pollicis brevis muscle. Demographic data, number of tender points, and visual analog scale and FM impact questionnaire scores were collected. The measured CSP and clinical parameters of the patient and control groups were compared. In addition, possible correlations between the CSP parameters and the other clinical characteristics were analyzed. Mean CSP latencies did not differ between patients (55.50 ± 10.97 ms) and healthy controls (60.23 ± 11.87 ms; p = 0.158), although the mean CSP duration was significantly longer in patients (73.75 ± 15.67 ms) than in controls (63.50 ± 14.05 ms; p = 0.021). CSP variables did not correlate with any clinical variables. The significantly longer CSP duration in FM patients suggests central dysregulation at the spinal and supraspinal levels, rather than peripheral small fiber dysfunction.

Small fibre dysfunction in hypothyroidism - a prospective study using methods of small fibre function and structure

Small fibre dysfunction in hypothyroidism - a prospective study using methods of small fibre function and structure

Peripheral small fiber dysfunction and neuropathic pain in patients with Morvan syndrome

Morvan syndrome (MoS) is an autoimmune-mediated syndrome that is frequently associated with malignant thymoma and autoantibodies targeting contactin associated protein-like 2 (CASPR2-Abs). Neuropathic pain is a frequent clinical feature in MoS—encountered in 62% of patients1—but the pain mechanisms are unknown. We studied 4 patients with MoS who had neuropathic pain and investigated whether this pain could be due to a selective involvement of small nerve fibers. Written consent was obtained from all patients, and the study was approved by the institutional review board of the University Claude Bernard Lyon 1.

The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention.

Sudorimetry technology has evolved dramatically, as a rapid, non-invasive, robust, and accurate biomarker for small fibers that can easily be integrated into clinical practice. Though skin biopsy with quantitation of intraepidermal nerve fiber density is still currently recognized as the gold standard, sudorimetry may yield diagnostic information not only on autonomic dysfunction but also enhance the assessment of the small somatosensory nerves, disease detection, progression, and response to therapy. Sudorimetry can be assessed using Sudoscan™, which measures electrochemical skin conductance (ESC) of hands and feet. It is based on different electrochemical principles (reverse iontophoresis and chronoamperometry) to measure sudomotor function than prior technologies, affording it a much more practical and precise performance profile for routine clinical use with potential as a research tool. Small nerve fiber dysfunction has been found to occur early in metabolic syndrome and diabetes and may also be the only neurological manifestation in small fiber neuropathies, beneath the detection limits of traditional nerve function tests. Test results are robust, accomplished within minutes, require little technical training and no calculations, since established norms have been provided for the effects of age, gender, and ethnicity. Sudomotor testing has been greatly under-utilized in the past, restricted to specialized centers capable of handling the technically demanding and expensive technology. Yet, evaluation of autonomic and somatic nerve function has been shown to be one of the best estimates of cardiovascular risk. Evaluation of sweating has the appeal of quantifiable non-invasive determination of the integrity of the peripheral autonomic nervous system, and can now be accomplished rapidly at point of care clinics with the determination of ESC, allowing intervention for morbid complications prior to permanent structural nerve damage. We review here sudomotor function testing technology, the research evidence accumulated supporting the clinical utility of measuring ESC, the medical applications of sudorimetry now available to physicians with this device, and clinical vignettes illustrating its use in the clinical decision-making process.

Assessment of chemotherapy-induced peripheral neuropathy using the LDIFLARE technique: a novel technique to detect neural small fiber dysfunction.

IntroductionThe diagnosis and quantification of chemotherapy-induced peripheral neuropathy (CIPN) remains a challenge. Conventional methods including quantitative sensory testing (QST), nerve conduction tests, and biopsy are unable to detect subclinical changes, and do not consistently correlate with severity of patients' symptoms and functional impairment. This study aims to determine the utility of the LDI (laser Doppler imager) FLARE technique in the diagnosis of CIPN and whether it correlates with symptom severity.Materials and MethodsWe assessed 24 patients with established CIPN [12 due to platinum analogs (PA) and 12 to Taxanes (TX)] and 24 matched healthy controls (HC). All underwent neurophysiological examination including vibration perception threshold (VPT), sural nerve amplitude (SNAP) and conduction velocity (SNCV), LDIFLARE, and fasting biochemistry. The QLQ-CIPN20 questionnaire was used to assess symptom severity.ResultsHC, combined chemotherapy (CG), PA, and TX groups were matched for age, sex, BMI, and blood pressure. The LDIFLARE was significantly reduced in CG compared to HC (P =< 0.0001), whereas SNAP (P = 0.058) and SNCV (P = 0.054) were not. The LDIFLARE correlated with the QLQ-CIPN20 symptom scores in all three categories namely, CG (P =< 0.0001), PA (P = 0.001) and TX (P = 0.027) whilst, VPT, SNAP, and SNCV did not.ConclusionOur findings suggest that the LDIFLARE technique is more helpful in confirming the diagnosis of CIPN in patients with distal sensory symptoms than current commonly used methods. Moreover, this novel test fulfils the unmet need for a diagnostic test that relates to the severity of symptoms. This may be useful in quantifying early changes in small fibre function indicating early CIPN.

Characterization of nerve and microvessel damage and recovery in type 1 diabetic mice after permanent femoral artery ligation.

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.

Pharmacological and Nonpharmacological therapies in the Management of Diabetic Peripheral Neuropathy in Type 2 Diabetes :A Comprehensive Review

Diabetes is a form of chronic illness usually requiring glycemic monitoring, self-management education and support to prevent acute complications and to reduce the risk of long-term complications. Diabetic peripheral neuropathy (DPN) implies damage or loss of function of the peripheral nerves. Though there are a number of theories trying to postulate the exact mechanism for DPN, still there remains a dearth in literature as to the exact cause for DPN. Two main problems can result from loss or damage to the sensory nerve fibers. The first problem is loss of the sensation for pain. This increases the likelihood of ulcers in diabetic population. The second problem is a small fiber dysfunction seen in DPN which exhibits itself clinically as heightened sensation of pain and burning sensations that can be quite uncomfortable for the patient suffering from type 2 diabetes. This review discusses about the available pharmacological and non-pharmacological therapies for glycemic control and management of painful (small fiber dysfunction) neuropathy in type 2 diabetes. Key Words: Drug therapy, pharmacological therapy, pathogenesis, Diabetic peripheral neuropathy, exercise, diet. Key Message: Diabetic Peripheral Neuropathy is a debilitating disease in type 2 disease. A need for early comprehensive management is emphasized using both pharmacological and non-pharmacological therapy to reduce the complications in Diabetic Peripheral Neuropathy.

100. Sensory and autonomic small fiber involvement in CMT 1A

Sensory symptoms in CMT1A are generally attributed to large fiber. However, an involvement of small fibers has been recently brought up. We performed an extensive clinical, morphological and functional study of cutaneous somatic and autonomic innervation in 10 patients affected by CMT 1A, in order to assess small fiber involvement in this condition. We used a 13 items questionnaire and QST to evaluate symptoms and function of somatic small fibers, DST, SSR and Ewing tests to evaluate autonomic function. Morphological analysis of cutaneous innervation included lENF density and sudomotor nerves assessment. Twenty age-and-sex-matched healthy subjects were used as controls for morphological data. All patients complained of at least 2 symptoms related to small fiber dysfunction. Nine out of ten patients had an increase in thermal/pain thresholds indicating an impairment of both C and A-delta fibers. DST revealed hypoidrosis in all patients (41.8 ± 22.8 vs 83.7 ± 17.3 sweat drops/cm2). SSR amplitude at feet was significantly lower (p < 0.05) in patients compared to controls (1.6 ± 0.7 versus 4.2 ± 3.2 mV). One patient showed a cardiac dysautonomia. Density of ENFs sudomotor nerves was significantly lower (p < 0.01) compared to age-and-sex-matched control subjects. Our findings confirm a sensory and autonomic small fiber damage in CMT 1A patients.

Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy

Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction and impaired stress signalling, as well as protein nitration. In this study, we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes. C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/day) or protein nitration inhibitor (-)-epicatechin gallate (20 mg/kg/day) for 4 weeks, after an initial 28 weeks of hyperglycaemia. Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and loss of intraepidermal nerve fibres. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fibre dysfunction without alleviation of hyperglycaemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fibre density were found with FeTMPS treatment only. Peroxynitrite injury and protein nitration are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts for treatment of diabetic peripheral neuropathy.

Response to Comment on Breiner et al. Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients? Diabetes Care 2014;37:1418–1424

We read with interest the comments of Vas et al. (1) regarding our article (2), which used noninvasive tests of small-fiber structure and function to demonstrate the presence of small-fiber dysfunction prior to large-fiber change in patients with type 1 diabetes. We would like to respond to the following points. Vas et al. (1) raised concerns regarding low laser Doppler imaging of heat-evoked flare (LDIflare) sensitivity for detection of polyneuropathy. In our study, LDIflare was measured using the moorLDI2 instrument (Moor Instruments Ltd., Axminster, U.K.), according to published techniques (3). In a previous study, we have shown …

Assessment of diabetic neuropathy using a point-of-care nerve conduction device shows significant associations with the LDIFLARE method and clinical neuropathy scoring.

Accurate assessment of diabetes polyneuropathy (DPN) is important in the prevention of foot ulcerations and amputations. Simple screening methods including the 10 g monofilament and the 128-Hz tuning fork are not sensitive enough nor intended for detection of early neuropathy, while more confirmatory tests such as nerve conduction studies are not universally available. We evaluated a rapid, low-cost, point-of-care nerve conduction device (POCD; NC-stat®|DPNCheck™) for the assessment of DPN and compared it with the LDIFLARE technique-an established method for early detection of small fibre dysfunction. A total of 162 patients with diabetes (DM) and 80 healthy controls (HC) were recruited. Based on the 10-point Neuropathy Disability Score (NDS), DPN was categorized into none (<2), mild (3-5) moderate (6-7), and severe (8-10). The LDIFLARE was performed in all patients according to previously described methodology. The associations between POCD outcomes and the LDIFLARE within the NDS categories were evaluated using regression analysis. In HC and DM, SNCV measured with the POCD correlated significantly with the LDIFLARE technique (r < 0.90 and r = 0.78, respectively) as did SNAP (r = 0.88 and r = 0.73, respectively); in addition, significance was found in all categories of DPN (r = 0.64 to 0.84; p= ≤ 0.03). ROC curves within each category of DPN showed that the POCD was sensitive in the assessment of DPN. We report highly significant linear relationships between the POCD with both comparators-the LDIFLARE technique and clinical neuropathy scores. Thus, the NC-stat|DPNCheck™ system appears to be an excellent adjunctive diagnostic tool for diagnosing DPN in the clinical setting.

Trigeminal laser-evoked potentials: a neurophysiological tool to detect post-surgical outcome in trigeminovascular contact neuralgia.

The aim of this study was to explore the nociceptive system of patients affected by trigeminal neuralgia (TN) secondary to documented vascular contact who underwent microvascular decompression. For that purpose, we used the classical trigeminal reflexes and the trigeminal laser-evoked potentials (tLEPs) before and after surgery, in order to verify any possible change after decompression and determine if there was any correlation between the neurophysiological parameters and the clinical outcome. Eleven patients affected by TN caused by trigeminovascular contact and 10 age-matched controls underwent conventional trigeminal reflexes (bilateral Blink Reflex/BR and Masseter Inhibitory Reflex stimulating infraorbital and mental nerves/MIR V2 and V3) and tLEPs. Patients repeated neurophysiological tests one week after surgery. Short-latency BR and MIR were normal in all patients before surgery and there was no statistical difference before and after surgery. Conversely, in patients before surgery, tLEPs' amplitudes were significantly lower in the affected than in the healthy side (p = 0.017 for V2 and 0.037 for V3 branches). After surgery, on the affected side, tLEP amplitude increased and the pre/post-operative difference was significant (p = 0.017 for V2 and 0.028 for V3 divisions). Nine patients referred satisfactory pain relief and the favourable clinical outcome correlated with the neurophysiological recovery. This study demonstrates that TN caused by trigeminovascular compression may be related to Aδ fibres impairment, and tLEPs are more sensitive than conventional trigeminal reflexes to reveal small fibre dysfunction and to monitor the post-surgical outcome in these patients.

Small fiber dysfunction in patients with Wilson's disease

Patients with Wilson's disease (WD) may develop a wide variety of neuropsychiatric symptoms, but there are few reports of autonomic dysfunction. Here, we described evidence of small fiber and/or autonomic dysfunction in 4 patients with WD and levodopa-responsive parkinsonism. We reviewed the charts of 4 patients with WD who underwent evaluation for the presence of neuromuscular dysfunction and water-induced skin wrinkling test (SWT). Two men and 2 women (33±3.5 years) with WD were evaluated. They all had parkinsonism at some point during their disease course. Parkinsonism on patient 4 almost completely subsided with treatment of WD. Two patients had significant sensory and 2 significant autonomic complaints, including syncopal spells. NCS/EMG was normal in all but SWT was abnormal in half of them (mean 4-digit wrinkling of 0.25 and 1). A subset of patients with WD exhibit evidence of abnormal skin wrinkling test (small fiber neuropathy).

Pain and small fiber function in charcot–marie–tooth disease type 1A

Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively. We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds. Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively. Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers.