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Background: Postural tachycardia syndrome (POTS) is a heterogenous disorder of the autonomic nervous system that is commonly associated with small fiber neuropathy, Ehlers-Danlos Syndrome and autoimmune disorders, but association with rare conditions may also occur., Methods: Reported here are clinical features, diagnostic tests and treatment outcomes of 6 unique patients who presented with POTS and were subsequently diagnosed with Fabry disease, McArdle disease, Complex V mitochondrial disease, carcinoid tumor, Hodgkin's lymphoma and chemotherapy-induced neuropathy., Results: All patients (age range 15-57 years, 3 females, 3 males) presented with orthostatic intolerance of at least 6 months duration, and all patients had co-morbid small fiber neuropathy. Five patients presented with symptoms of POTS months to years before the underlying or associated medical condition was discovered, and three out of six patients experienced either complete resolution or significant improvement of POTS after treatment of the underlying or associated medical condition., Conclusion: In rare cases, POTS can present as a possible manifestation of genetic, neoplastic or neurotoxic disorders. Unusual clinical features that fall outside of the typical spectrum of dysautonomia can point toward the presence of another disorder and help guide further diagnostic investigation.

Small fiber neuropathy (SFN) is being recognized with increasing frequency in neuromuscular practice due to improved diagnostic techniques. Although there are some common etiologies, up to one-third of cases are considered idiopathic. In recent years, several disorders have unexpectedly been reported in association with SFN, on clinical grounds and complementary investigations, including quantitative sensory testing, intraepidermal nerve fiber density and confocal corneal microscopy. Knowledge of these disorders is important in clinical practice as increased awareness enables prompt diagnosis of SFN in these settings and early optimal therapeutic management of affected patients. Furthermore, these new developments may lead to a better understanding of the pathophysiologic mechanisms underlying SFN in these different disorders as well as, in some cases, an expanded spectrum of affected organs and systems. This article reviews these reported associations, their possible pathophysiologic bases, and the potential resulting management implications., (© 2020 Wiley Periodicals, Inc.)

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.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major, dose-limiting side effect of treatment with neurotoxic cancer treatments which can result in long-term impairment. Deficits often reflect a large fiber polyneuropathy, however small fiber involvement resulting in neuropathic pain and autonomic dysfunction can occur. Quantification of both CIPN and small fiber neuropathy (SFN) remains a challenge. Accordingly, the prevalence and pathophysiology of small fiber neuropathy amongst cancer survivors remains poorly understood. This review will provide an overview of the clinical features of SFN associated with neurotoxic cancer treatments as well as a summary of current assessment tools for evaluating small fiber function, and their use in patients treated with neurotoxic chemotherapies. The continued development and utilization of novel measures quantifying small fiber involvement will help elucidate the pathophysiology underlying symptoms of CIPN and assist in informing treatment approaches. Accurately identifying subgroups of patients with neuropathic symptoms which may respond to existing pain medication may reduce the impact of CIPN and improve long-term quality of life as well as provide better categorization of patients for future clinical trials of neuroprotective and treatment strategies for CIPN. PERSPECTIVE: This review provides a critical analysis of SFN associated with neurotoxic cancer treatments and the assessment tools for evaluating small fiber dysfunction in cancer patients. Quantification of small fiber involvement in CIPN will assist in identifying subgroups of patients with neuropathic symptoms which may respond to existing pain medications., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Neurogenic inflammation is an onset characteristic of small fiber neuropathy (SFN), which is attributed to neuropathic manifestations. Tumor necrosis factor-α (TNFα) is a cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1), and targeting TNFα/TNFR1 signaling is a direction toward treating inflammatory diseases and injury-induced neuropathy. However, the relationships between TNFα/TNFR1 signaling and Ret signaling, which mediates pain hypersensitivity, remains elusive. This study used resiniferatoxin (RTX), an ultrapotent analog of capsaicin, to generate a mouse model of SFN, leading to marked hindpaw edema (p = 0.013) and parallel the release of TNFα (p = 0.014), which was associated with the upregulation of Ret(+) neurons (p = 0.0043) and partial depletion of TNFR1 caused by colocalization with TRPV1 depleted by RTX. Pharmacological intervention of TNFα with etanercept (Enbrel ® , Wyeth), a clinical application of TNFα blockers, relieved neurogenic inflammation and caused a reduction in hindpaw thickness (p = 0.03) and TNFα releases (p = 0.01), which were determined to be associated with the normalization of mechanical allodynia (p = 0.22). The extraction of either TNFR1(+) or Ret(+) neurons from total of TNFR1(+):Ret(+) neurons indicated that TNFR1(-)/Ret(+) neurons correlated with the mechanical threshold in an antiparallel fashion (r = -0.84, p < 0.0001) but had no relationship with thermal latencies. This study confirmed that TNFα rather than TNFα mediated neuropathic manifestation through the Ret receptor, specifically mechanical allodynia in RTX neuropathy., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

The neurochemical effects of adenosine signaling in small-fiber neuropathy leading to neuropathic pain are yet to be explored in a direct manner. This study examined this system at the level of ligand (through the ectonucleotidase activity of prostatic acid phosphatase [PAP]) and adenosine A1 receptors (A1Rs) in resiniferatoxin (RTX) neuropathy, a peripheral neurodegenerative disorder that specifically affects nociceptive nerves expressing transient receptor potential vanilloid type 1 (TRPV1). We conducted immunohistochemistry on dorsal root ganglion (DRG) neurons, high-performance liquid chromatography for functional assays, and pharmacological interventions to alter PAP and A1Rs in mice with RTX neuropathy. In DRG of RTX neuropathy, PAP(+) neurons were reduced compared with vehicle-treated mice (P = 0.002). Functionally, PAP ectonucleotidase activity was consequently reduced (ie, the content of adenosine in DRG, P = 0.012). PAP(+) neuronal density was correlated with the degree of mechanical allodynia, which was reversed by intrathecal (i.t.) lumbar puncture injection of recombinant PAP with a dose-dependent effect. Furthermore, A1Rs were downregulated (P = 0.002), and this downregulation was colocalized with the TRPV1 receptor (31.0% ± 2.8%). Mechanical allodynia was attenuated in a dose-dependent response by i.t. injection of the A1R ligand, adenosine; however, no analgesia was evident when an exogenous adenosine was blocked by A1R antagonist. This study demonstrated dual mechanisms of neuropathic pain in TRPV1-induced neuropathy, involving a reduced adenosine system at both the ligand (adenosine) and receptor (A1Rs) levels.

Patients with diabetes mellitus (DM) or those experiencing the neurotoxic effects of chemotherapeutic agents may develop sensation disorders due to degeneration and injury of small-diameter sensory neurons, referred to as small fiber neuropathy. Present animal models of small fiber neuropathy affect both large- and small-diameter sensory fibers and thus create a neuropathology too complex to properly assess the effects of injured small-diameter sensory fibers. Therefore, it is necessary to develop an experimental model of pure small fiber neuropathy to adequately examine these issues. This protocol describes an experimental model of small fiber neuropathy specifically affecting small-diameter sensory nerves with resiniferatoxin (RTX), an ultrapotent agonist of transient receptor potential vanilloid type 1 (TRPV1), through a single dose of intraperitoneal injection, referred to as RTX neuropathy. This RTX neuropathy showed pathological manifestations and behavioral abnormalities that mimic the clinical characteristics of patients with small fiber neuropathy, including intraepidermal nerve fiber (IENF) degeneration, specifically injury in small-diameter neurons, and induction of thermal hypoalgesia and mechanical allodynia. This protocol tested three doses of RTX (200, 50, and 10 µg/kg, respectively) and concluded that a critical dose of RTX (50 µg/kg) is required for the development of typical small fiber neuropathy manifestations, and prepared a modified immunostaining procedure to investigate IENF degeneration and neuronal soma injury. The modified procedure is fast, systematic, and economic. Behavioral evaluation of neuropathic pain is critical to reveal the function of small-diameter sensory nerves. The evaluation of mechanical thresholds in experimental rodents is particularly challenging and this protocol describes a customized metal mesh that is suitable for this type of assessment in rodents. In summary, RTX neuropathy is a new and easily established experimental model to evaluate the molecular significance and intervention underlying neuropathic pain for the development of therapeutic agents.

Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy. Mice with RTX neuropathy exhibited thermal hypoalgesia and mechanical allodynia, reduced skin innervation, and altered DRG expression profiles with decreased TrkA(+) neurons and increased Ret(+) neurons. RTX neuropathy induced the expression of activating transcription factor 3 (ATF3), and ATF3(+) neurons were colocalized with Ret but not with TrkA (P<0.001). As a neuroprotectant, 4-Methylcatechol (4MC) promoted skin reinnervation partially with correlated reversal of the neuropathic behaviors and altered neurochemical expression. Gambogic amide, a selective TrkA agonist, normalized thermal hypoalgesia, and GW441756, a TrkA kinase inhibitor, induced thermal hypoalgesia, which was already reversed by 4MC. Mechanical allodynia was reversed by a Ret kinase inhibitor, AST487, which induced thermal hyperalgesia in naïve mice. The activation of Ret signaling by XIB4035 induced mechanical allodynia and thermal hypoalgesia in RTX neuropathy mice in which the neuropathic behaviors were previously normalized by 4MC. Distinct neurotrophic factor receptors, TrkA and Ret, accounted for negative and positive neuropathic behaviors in RTX-induced small fiber neuropathy, respectively: TrkA for thermal hypoalgesia and Ret for mechanical allodynia and thermal hypoalgesia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sensory defects associated with small-fiber neuropathy (SFN) can lead to profound disabilities. The relationship between the sensory nervous system and modulation of the renin-angiotensin system (RAS) has been described and focused on pain and neurodegeneration in several animal models. We have recently developed an experimental model of functional sensory neuropathy showing thermal hypoalgesia and neuropeptide depletion without nerve fiber degeneration. Here, we aimed to determine whether the modulation of angiotensin II (Ang II) activity could prevent sensory neuropathy induced by RTX. Control and RTX mice received ramipril, an Ang II converting enzyme (ACE) inhibitor, (0.5 mg/kg/day) or candesartan, an Ang II type 1 receptor (AT1R) blocker (0.5 mg/kg/day), one day before vehicle or RTX administration, and each day for the next seven days. Ramipril did not have a beneficial effect in RTX mice, whereas candesartan prevented thermal hypoalgesia and reduced neuropeptide depletion in intraepidermal nerve fibers and dorsal root ganglion neurons. The preventive effect of candesartan was not observed in mice deficient for the Ang II type 2 receptor (AT2R) and was counteracted in wild type mice by EMA200, an AT2R antagonist (3 mg/kg/day). Thus, candesartan may promote AT2R activation by blocking AT1R and increasing Ang II production and enhance its mechanisms of neuroprotection in our RTX model. Our finding that candesartan prevents nociception deficits and neuropeptide depletion encourages the evaluation of its therapeutic potential in patients presenting SFN, particularly those who experience chemotherapy-induced SFN., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pyridoxine (vitamin B6) toxicity is a well-known cause of primary sensory, length-dependent, axonal polyneuropathy. Although sensory symptoms predominate, autonomic symptoms have also been reported in some cases. To date, there is no objective evidence of autonomic dysfunction reported in the literature. We present the case of a 41-year-old woman with 2 years of progressive burning pain, numbness, tingling, and weakness in a stocking-glove distribution who was found to have severe pyridoxine toxicity. Concurrent presence of large and small fiber nerve dysfunction was noted in the form of abnormal electromyography/nerve conduction study demonstrating a chronic sensory polyneuropathy and autonomic testing demonstrating abnormal responses to quantitative sweat testing and cardiovagal function testing. This case highlights the need for consideration of small fiber nerve damage by obtaining autonomic testing in cases of pyridoxine toxicity.

Background: Damage to the peripheral nervous system influences wound healing and, after a deep burn, imperfect cutaneous nerve regeneration occurs. A third-degree burn model was developed in rats combined with the use of resiniferatoxin (RTX), known to promote sensory neuropathy., Methods: Rats were injected intraperitoneally either with RTX or vehicle. A mechanical sensory assay and the hot plate thermal sensory test were performed. The structural integrity of the sciatic nerve was assessed using transmission electron microcopy. After RTX injection, third-degree thermal burns were performed. Wound closure was monitored and samples were collected for histological analysis, immunohistochemistry and immunoblotting for neuronal markers., Results: RTX promoted both mechanical and thermal hypoalgesia. This transient RTX-mediated sensory deficit occurred without damaging the integrity of nerve fibers and induced a significant depletion of neuropeptides in both neuronal bodies and intraepidermal nerve fibers. Although wound closure rates were similar in both groups, the kinetic of granulation tissue remodeling was delayed in the RTX group compared with control group. A significant reduction of the peripherin expression in the RTX group was observed indicating impaired axonal regrowth of small fibers within the wound., Conclusion: Our study confirms the important roles of innervation during skin healing and the defect of nerve regeneration after burn., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.