Epidermal Nerve Fiber Density Research Articles

Identifying and Evaluating Biological Markers of Postherpetic Neuralgia: A Comprehensive Review.

Postherpetic neuralgia (PHN) manifests as persistent chronic pain that emerges after a herpes zoster outbreak and greatly diminishes quality of life. Unfortunately, its treatment efficacy has remained elusive, with many therapeutic efforts yielding less than satisfactory results. The research to discern risk factors predicting the onset, trajectory, and prognosis of PHN has been extensive. However, these risk factors often present as nonspecific and diverse, indicating the need for more reliable, measurable, and objective detection methods. The exploration of potential biological markers, including hematological indices, pathological insights, and supportive tests, is increasing. This review highlights potential biomarkers that are instrumental for the diagnosis, management, and prognosis of PHN while also delving deeper into its genesis. Drawing from prior research, aspects such as immune responsiveness, neuronal injury, genetic makeup, cellular metabolism, and pain signal modulation have emerged as prospective biomarkers. The immune spectrum spans various cell subtypes, with an emphasis on T cells, interferons, interleukins, and other related cytokines. Studies on nerve injury are directed toward pain-related proteins and the density and health of epidermal nerve fibers. On the genetic and metabolic fronts, the focus lies in the detection of predisposition genes, atypical protein manifestations, and energy-processing dynamics, with a keen interest in vitamin metabolism. Tools such as functional magnetic resonance imaging, electromyography, and infrared imaging have come to the forefront in the pain signaling domain. This review compiles the evidence, potential clinical implications, and challenges associated with these promising biomarkers, paving the way for innovative strategies for predicting, diagnosing, and addressing PHN.

A study of PGP 9.5 immunohistochemical labeling on formalin-fixed paraffin embedded tissues for epidermal nerve fiber density testing

ABSTRACT There have been several methods established for immunohistochemical labeling of the PGP 9.5 antigen in human tissue for the assessment of epidermal nerve fiber density, none of which uses neutral-buffered formalin as the preferred fixative for paraffin-embedded tissue. The literature maintains that formalin-fixed paraffin embedded tissues are unable to be used for this purpose and that other fixatives must be used due to the cross-linkages caused by formalin fixation. This study was undertaken to develop a standardized method for the use of formalin-fixed paraffin embedded tissues for immunohistochemical labeling and assessment of epidermal nerve fiber density. Formalin-fixed paraffin embedded tissues from the punch biopsies of patients suspected to have small fiber neuropathy were prepared for immunohistochemical labeling using heat-induced epitope retrieval for one hour at 92°C. The tissues were then stained with a polyclonal rabbit anti-human PGP 9.5 primary antibody. The resulting stains were then evaluated by a licensed pathologist who counted the number of epidermal nerve fibers stained and recorded the epidermal length in millimeters. Human foreskin was used as the tissue control in these studies. Satisfactory immunohistochemical labeling of epidermal nerve fibers was achieved from formalin-fixed paraffin embedded tissues through the use of heat-induced epitope retrieval. The authors of this paper have concluded that formalin-fixed paraffin embedded tissues may be used to achieve satisfactory immunohistochemical labeling for the assessment of epidermal nerve fiber density.

Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies.

To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.

Reliable Method for Estimating Nerve Fiber Density in Epidermis Using Routine Histopathologic Tissue Preparation: A Promising Diagnostic Tool for Small Fiber Neuropathy.

Practical yet reliable diagnostic tools for small-fiber neuropathy are needed. We aimed to establish a histopathologic protocol for estimating intraepidermal nerve fiber density (eIENFD) on formalin-fixed, paraffin-embedded tissue (FFPE), evaluate its reliability through intraobserver and interobserver analyses, and provide normative reference values for clinical use. Sixty-eight healthy participants underwent nerve conduction studies and quantitative sensory testing. Skin biopsies from the distal and proximal leg were taken and processed using routine immunohistochemistry (anti-PGP9.5 antibodies) on thin 5 µm sections. eIENFD was assessed with a modified counting protocol. Interobserver and intraobserver reliabilities were excellent (ICC=0.9). eIENFD was higher in females than males (fibers/mm, 14.3±4.4 vs. 11.6±5.8, P <0.05), decreased with age ( r s =-0.47, P <0.001), and was higher proximally than distally (15.0±5.5 vs. 13.0±5.3, P =0.002). Quantile regression equations for the fifth percentile of distal and proximal eIENFD were presented: 13.125-0.161×age (y)-0.932×sex (male=1; female=0) and 17.204-0.192×age (y)-3.313×sex (male=1; female=0), respectively. This study introduces a reliable and reproducible method for estimating epidermal nerve fiber density through immunostaining on 5-µm thin FFPE tissue samples. Normative data on eIENFD is provided. Regression equations help identify abnormal decreases in small nerve fiber density.

Ratio of Distal to Proximal Epidermal Nerve Fiber Density in Small Fiber Neuropathy (P1-11.006)

Ratio of Distal to Proximal Epidermal Nerve Fiber Density in Small Fiber Neuropathy (P1-11.006)

Characterizing Acute-Onset Small Fiber Neuropathy.

Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

Gastrointestinal manifestations seen in pediatric patients diagnosed with small fiber neuropathy.

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. 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. 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. 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.

Modifying quantitative sensory testing to investigate behavioral reactivity in a pediatric global developmental delay sample: Relation to peripheral innervation and chronic pain outcomes.

Early tactile and nociceptive (pain) mechanisms in children with global developmental delay at risk for intellectual and developmental disability are not well understood. Sixteen children with global developmental delay (mean age=5.1 years, SD=1.4; 50% male) completed a modified quantitative sensory testing (mQST) protocol, an epidermal (skin) punch biopsy procedure, and parent-endorsed measures of pain. Children with reported chronic pain had significantly greater epidermal nerve fiber density (ENFd) compared to children without chronic pain. Based on the mQST trials, ENFd values were associated with increased vocal reactivity overall and specifically during the light touch and cool thermal stimulus trials. The findings support the feasibility of an integrative biobehavioral approach to test nociceptive and tactile peripheral innervation and behavioral reactivity during a standardized sensory test in a high-risk sample for which there is often sensory dysfunction and adaptive behavior impairments.

Small fiber neuropathy and intractable scalp pruritus in dermatomyositis patients.

Scalp pruritus is a common symptom in Dermatomyositis (DM) patients. There are indications that small nerve fibers neuropathy could be involved in this symptom, however the etiology of scalp pruritus is not fully understood. To assess epidermal nerve fiber (ENF) density of dermatomyositis patients with scalp pruritus by biopsy by confocal microscopy and immunohistochemistry with subsequent imaging analysis. DM patients with severe scalp pruritus from the dermatology outpatient clinic were compared to healthy volunteers. Two 4-mm scalp skin biopsies were obtained above the right ear in the parietal region and below the occipital protuberance in the occipital region. Biopsy specimens were incubated with primary antibodies to protein gene product (PGP 9.5), calcitonin gene-related peptide (CGRP), substance P (SP) were used to visualize nerve fibers (ENF) and collagen IV was used to label the epidermal basement membrane. The number of ENFs per millimeter was counted and recorded as the mean of ± SD of counts in 16 images at two micrometer increments/sections, two from each of the samples. ENF densities were compared between groups and a multiple linear regression model was applied to associated factors with ENF density. Fifteen DM patients with severe scalp pruritus and 12 healthy volunteers were included in the study. The mean number of ENF/mm in occipital region of DM group was 16.0±13.9 while the control group in the same region was 99.8±33.1. In parietal region the number of ENF/mm of DM group was 18.0±20.7 while in control group was 50.4±17.4 (p<0.001). DM patients with pruritus could have some impairment of small nerve fiber density that could explain their recalcitrant scalp pruritus.

Clinical autonomic nervous system laboratories in Europe: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies.

Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p= 0.021). This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin.

Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P = 0.014). Facial involvement was more common in seropositive patients (P = 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P = 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P = 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P = 0.052), and prior erroneous diagnosis (P = 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%. TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers. They are often misdiagnosed but may respond subjectively and objectively to IVIG.

Increased Epidermal Nerve Growth Factor without Small-Fiber Neuropathy in Dermatomyositis.

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.

The Armadillo as a Model for Leprosy Nerve Function Impairment: Preventative and Therapeutic Interventions.

Mycobacterium leprae infection of peripheral nerves and the subsequent nerve function impairment (NFI), especially in response to reactional episodes, are hallmarks of leprosy. Improved treatments for M. leprae-induced nerve injury are needed, as most if not all of the disability and stigma associated with leprosy arises from the direct or indirect effects of NFI. Nine-banded armadillos (Dasypus novemcinctus), like humans, exhibit the full clinical spectrum of leprosy and extensive involvement of the peripheral nerves. In this study, state-of-the-art technology was used to compare nerve function between uninfected and M. leprae-infected armadillos. Motor nerve conduction velocity (MNCV) and compound muscle action potential (cMAP), which measure changes in the rate of impulse conduction velocity and amplitude, revealed a progression of impairment that was directly correlated with the duration of M. leprae infection and enabled development of an objective nerve impairment scoring system. Ultrasonography accompanied by color Doppler imaging detected enlargement of the M. leprae-infected nerves and increased vascularity, possibly due to inflammation. Assessment of epidermal nerve fiber density (ENFD), which shows a length-dependent innervation in armadillos that is similar to humans, identified small fiber degeneration early after M. leprae infection. Staining for neuromuscular junction (NMJ) integrity, which is an indicator of signal transduction efficiency into skeletal muscle, discerned a markedly lower number and structural integrity of NMJ in M. leprae-infected armadillo footpads. These tools for assessing nerve injury were used to monitor the effects of intervention therapy. Two potential neuro-protective drugs, ethoxyquin (EQ) and 4-aminopyridine (4-AP), were tested for their ability to ameliorate peripheral nerve injury in M. leprae-infected armadillos. 4-AP treatment improved MNCV, cMAP, and EFND compared to untreated animals, while EQ had less effect. These results support the armadillo as a model for M. leprae-induced peripheral nerve injury that can provide insights toward the understanding of NFI progression and contribute to the preclinical investigation of the safety and efficacy of neuro-preventive and neuro-therapeutic interventions for leprosy.

Identification and quantification of nociceptive Schwann cells in mice with and without Streptozotocin-induced diabetes

Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to support peripheral axons in mouse skin by forming a mesh-like neural-glio networking structure in subepidermal area, but also contributing to transduction of mechanical sensation and neuropathic pain. Diabetic neuropathy (DPN) is one of the most common complication of diabetes, however, the mechanisms behind painful and painless DPN remain unclear. Using a mouse model of DPN, we want to investigate if there are quantitative differences in nociceptive SC density between the condition of hyperglycemia-induced sensory abnormalities and control condition and at which stage in the disease the damage occurs. Here, we developed a set of counting rules for nociceptive SCs based on immunofluorescent staining, and applied the method to quantify the density of nociceptive SCs in control mice (n = 10), mice with nociceptive hypersensitivity at early diabetic stage (n = 5), and mice with sensory hyposensitivity at late diabetic stage (n = 5) in the Streptozotocin (STZ) model of type 1 diabetes. Nociceptive SCs were identified as S100+/Sox10+/DAPI+ cells abutting to peripheral nerves, with the somas located within 25 µm depth in the subepidermal area and outside glands and large fiber bundles. Hypersensitive diabetic mice had decreased nociceptive SC density, despite having normal epidermal nerve fiber density, compared with age-matched control mice (P = 0.023). In contrast, there was a reduction in intraepidermal nerve fiber density but no difference in nociceptive SC density between hyposensitive diabetic mice and the age-matched control mice. This study provides a detailed description of how to identify and quantify nociceptive SC and demonstrates that nociceptive SC density declines before nerve fiber deterioration, which supports previous observations that nociceptive SCs are critical for maintenance of cutaneous sensory nerves.

Corneal Confocal Microscopy Identifies People with Type 1 Diabetes with More Rapid Corneal Nerve Fibre Loss and Progression of Neuropathy.

There is a need to accurately identify patients with diabetes at higher risk of developing and progressing diabetic peripheral neuropathy (DPN). Fifty subjects with Type 1 Diabetes Mellitus (T1DM) and sixteen age matched healthy controls underwent detailed neuropathy assessments including symptoms, signs, quantitative sensory testing (QST), nerve conduction studies (NCS), intra epidermal nerve fiber density (IENFD) and corneal confocal microscopy (CCM) at baseline and after 2 years of follow-up. Overall, people with type 1 diabetes mellitus showed no significant change in HbA1c, blood pressure, lipids or neuropathic symptoms, signs, QST, neurophysiology, IENFD and CCM over 2 years. However, a sub-group (n = 11, 22%) referred to as progressors, demonstrated rapid corneal nerve fiber loss (RCNFL) with a reduction in corneal nerve fiber density (CNFD) (p = 0.0006), branch density (CNBD) (p = 0.0002), fiber length (CNFL) (p = 0.0002) and sural (p = 0.04) and peroneal (p = 0.05) nerve conduction velocities, which was not related to a change in HbA1c or cardiovascular risk factors. The majority of people with T1DM and good risk factor control do not show worsening of neuropathy over 2 years. However, CCM identifies a sub-group of people with T1DM who show a more rapid decline in corneal nerve fibers and nerve conduction velocity.

Topical Janus kinase-signal transducers and activators of transcription inhibitor tofacitinib is effective in reducing nonatopic dermatitis chronic itch: A case series

To the Editor: Chronic and refractory pruritus is a highly common complaint among patients with dermatologic conditions and remains difficult to treat with current drug therapies. In particular, there is an unmet need for potent topical antipruritics. The Janus kinase (JAK) 1/3 inhibitor tofacitinib significantly decreases itch-associated interleukin 22, 23, and 31 levels and may rescue inhibitory itch mechanisms via increased peptidergic epidermal nerve fiber density, making it a good candidate for the treatment of chronic and refractory pruritus.

Laser evoked potentials in fibromyalgia with peripheral small fiber involvement

ObjectiveTo evaluate multichannel laser evoked potentials (LEPs) in patients with fibromyalgia (FM) and small fiber impairment. MethodsWe 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. ResultsWe 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. ConclusionsThe 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. SignificanceMultichannel LEPs are not the expression of small fiber impairment in FM. Rather, they reflect the complexity of the disease.

Association of painful human immunodeficiency virus distal sensory polyneuropathy with aberrant expectation of pain relief: functional magnetic resonance imaging evidence.

Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood, yet 40% of those with distal neuropathy (or 20% of all people with HIV) suffer from this debilitating condition. Central pain processing mechanisms are thought to contribute to the development of HIV neuropathic pain, yet studies investigating central mechanisms for HIV neuropathic pain are few. Considering the motivational nature of pain, we aimed to examine the degree to which expectation of pain onset and expectation of pain offset are altered in sixty-one male patients with HIV-related distal sensory polyneuropathy with (N = 30) and without (N = 31) chronic neuropathic pain. By contrasting painful (foot) and non-painful (hand) sites between those with and without neuropathic pain, we could identify unique neural structures that showed altered activation during expectation of pain offset or relief. Our results showed no evidence for peripheral mechanisms evidenced by lack of significant between group differences in thermo-sensation, subjective pain response or epidermal nerve fibre density. Likewise, we found no significant differences between groups in subjective or brain mechanisms underlying the expectation of pain onset. Conversely, we found significant interaction within right anterior insula during expectation of pain offset in our study in that individuals in the pain group compared to the no-pain group exhibited increased anterior insula activation on the painful compared to the non-painful site. Our findings are consistent with abnormal processing of expectation of pain offset or abnormal pain relief-related mechanisms potentially due to increased emotional distress regarding the experience of chronic endogenous pain.

Small fiber neuropathy: Swiss cohort characterization.

Introduction/AimThere is currently insufficient clinical and epidemiological data concerning small fiber neuropathy (SFN). This research analyzes data from medical records to determine epidemiology, demographics, clinical characteristics and etiology of SFN.MethodsThis is a retrospective, observational study of sequential patients diagnosed with definite SFN (typical clinical features, normal nerve conduction studies, abnormal epidermal nerve fiber density) from the end of November 2016 to the middle of July 2019 at the Cantonal Hospital Lucerne, central Switzerland.ResultsA total of 84 patients (64.3% female) with a mean age of 54.7 y were analyzed. Symptoms had been present in patients for an average of 4.8 y when entering the study. A length dependent clinical pattern was seen in 79.8%. All patients had sensory discomfort. Etiology could not be determined in 35.7% of patients, who were diagnosed with idiopathic SFN; 34.5% of patients had an apparently autoimmune SFN, followed by14.3% of patients with metabolic causes. The estimated incidence was at least 4.4 cases/100.000 inhabitants/y. The minimum prevalence was 131.5 cases/100.000 inhabitants.DiscussionThis study indicates significant incidence and prevalence rates of SFN in Switzerland. SFN can vary greatly in its symptoms and severity. Extensive work‐up resulted in two thirds of the patients being assigned an etiological association. The largest group of patients could not be etiologically defined, underlining the importance of further research on etiologic identification. We expect increased awareness of the developing field of SFN.

Effect of Experimental Gestational Diabetes Mellitus on Mechanical Sensitivity, Capsaicin-Induced Pain Behaviors and Hind Paw Glabrous Skin Innervation of Male and Female Mouse Offspring.

PurposeGestational diabetes mellitus (GDM) induces cardiovascular and metabolic disturbances in offspring. However, the effects of GDM in pain processing in offspring and whether male and female offspring are equally affected is not well known. Thus, we determined: i) whether GDM in mice affects offspring hindpaw mechanical sensitivity, capsaicin-induced spontaneous pain-like behaviors, and epidermal nerve fiber density (ENFD); and ii) whether there is sexual dimorphism in these parameters in offspring from GDM dams.MethodsGDM was induced in pregnant ICR mice via i.p. streptozotocin (STZ). Then, glucose levels from dams and offspring were determined. Male and female offspring 2–3 months of age were evaluated for: a) baseline mechanical sensitivity of the hind paw by using von Frey filaments; b) number of flinches and time spent guarding induced by intraplantar capsaicin (0.1%); and c) density of PGP-9.5 and CGRP axons in the epidermis from the hind paw glabrous skin.ResultsPrepartum levels of glucose in STZ-treated dams were significantly increased compared to vehicle-treated dams; however, GDM or vehicle offspring displayed normal and similar blood glucose levels. Male and female GDM offspring showed significantly greater mechanical sensitivity and capsaicin-induced pain behaviors compared to vehicle offspring. Male GDM offspring displayed a slightly more intense nociceptive phenotype in the capsaicin test. PGP-9.5 and CGRP ENFD in hind paw glabrous skin were greater in male and female GDM offspring versus their controls. Sexual dimorphism was generally not observed in GDM offspring in most of the studied parameters.ConclusionThese results suggest GDM induced greater pain-like behaviors in adult offspring regardless of sex along with an increased ENFD of PGP-9.5 and CGRP in the hind paw glabrous skin. We show that GDM peripheral neuropathy differs from diabetic peripheral neuropathy acquired in adulthood and set the foundation to further study this in human babies exposed to GDM.