Small Fiber Neuropathy Research Articles

Biopsychosocial rehabilitation therapy in small fiber neuropathy: research protocol to study the effect of rehabilitation treatment

BackgroundSmall fiber neuropathy (SFN) is a chronic neuropathic pain condition that can lead to a decreased quality of life (QOL) and disability. Current pain treatment is mainly symptomatic, consisting of analgesics, with often disappointing results. There is a need for new, more effective treatment modality. Treatment based on a biopsychosocial approach on SFN-related pain may be a promising alternative. A rehabilitation treatment study protocol is presented with the following main objective: to test the effect of a tailored interdisciplinary rehabilitation treatment targeting both cognitive and psychological factors related to pain, in decreasing disability, and improving QOL in SFN.MethodsSingle-case experimental design. Ten participants with SFN will be included. Every patient will be offered a personalized program based on one of three rehabilitation treatment modules (graded activity, exposure in vivo or acceptance and commitment therapy) depending on the most prominent factor maintaining disability. Treatment will be provided for at least 8 weeks with 2 sessions a week.Discussion/conclusionThis is the first study investigating personalized rehabilitation treatment in patients with idiopathic SFN. The findings are expected to result in an effective treatment for SFN with an increase in QOL and a decrease in disability.Clinical trial registrationClinicalTrials.gov, identifier NCT05798949.

Assessing corneal dendritic cells in glucose dysregulation small-fibre neuropathy.

Small-fibre neuropathy (SFN) is associated with glucose dysregulation, including impaired glucose tolerance (IGT) and type 2 diabetes (T2D). Corneal confocal microscopy (CCM) offers a non-invasive tool to assess corneal nerve damage and dendritic cell density (DCD). In this study, we investigated corneal DCD in patients with SFN and glucose dysregulation, defined as IGT or T2D. We enrolled 38 patients with SFN + glucose dysregulation, 51 with SFN + non-glucose dysregulation and 20 healthy controls. All participants underwent neurological examination, neurophysiology and CCM. Individuals with SFN and glucose dysregulation had higher DCD compared with healthy controls (p = .01), and mature DCD was higher in IGT SFN patients than in T2D patients. Higher DCD in IGT compared with controls and patients with established T2D may suggest that DCD is a biomarker of early neuropathy.

Small fiber neuropathy associated with COVID-19 infection and vaccination: A prospective case-control study.

Small fiber neuropathy (SFN) after both COVID-19 infection or vaccination has been reported in sporadic cases, but a detailed description and comparison are missing. We aimed to screen a large cohort of patients complaining of pain and autonomic symptoms after COVID-19 natural infection or vaccination to ascertain the presence of SFN and its correlation with autoimmune diseases. We prospectively recruited for this case-control study 66 patients: 33 developing sensory and autonomic symptoms after a natural COVID-19 infection (P-COVID) and 33 after a mRNA vaccination against COVID-19 (P-VAC). We also used 33 matched healthy controls (HC) collected before 2019 when the COVID-19 virus appeared. Patients underwent neurological examination and clinical scales, an extensive serum screening, and skin biopsy to detect small nerve fiber involvement. Clinical scales showed higher scores for autonomic symptoms in P-COVID patients than in P-VAC patients, but the other scales did not differ. P-COVID and P-VAC patients showed a significant decrease in somatic small nerve fibers compared with HC, whereas autonomic innervation did not differ. SFN was more frequent in P-COVID patients (94%) than in P-VAC patients (79%). Epidermal innervation was correlated with clinical scales for pain and autonomic dysfunctions. Autoimmune abnormalities were frequent in both groups but importantly they were not correlated with SFN. Somatic SFN was frequently found in both P-COVID and P-VAC patients, with a higher incidence in the former group. Spared skin autonomic innervation was spared in both groups although a subtle autonomic involvement in P-COVID patients was suggested by a high COMPASS-31 scale score. SFN was not correlated with autoimmune dysfunctions, although autoimmune diseases were frequent in both groups.

Spectrum of hereditary transthyretin amyloidosis due to T60A(p.Thr80Ala) variant in an Irish Amyloidosis Network

BackgroundVariant transthyretin amyloidosis (ATTRv) is a hereditary multisystem disorder with clinical spectrum ranging from predominant cardiomyopathy to polyneuropathy. In the Irish population, the T60A mutation has been previously recognised as...

Small fiber neuropathy review

Small fiber neuropathy review

Orthostatic intolerance with tachycardia (postural tachycardia syndrome) and without (hypocapnic cerebral hypoperfusion) represent a spectrum of the same disorder.

Spectrum of chronic orthostatic intolerance without orthostatic hypotension includes postural tachycardia syndrome (POTS), with orthostatic tachycardia and hypocapnic cerebral hypoperfusion (HYCH), without orthostatic tachycardia. This study compared autonomic, cerebrovascular, and neuropathic features of POTS and HYCH. This retrospective study evaluated patients with orthostatic intolerance referred for autonomic testing. Analyzed data included surveys (Survey of Autonomic Symptoms, Compass-31, Neuropathy Total Symptom Score-6, Central Sensitization Inventory) and autonomic tests (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in the middle cerebral artery), respiratory (capnography), neuropathic (skin biopsies for assessment of small fiber neuropathy) and invasive cardiopulmonary exercise testing (iCPET). A total of 127 HYCH, 125 POTS, and 42 healthy controls were analyzed. Compared HYCH to POTS patients, there was no difference in the duration of symptoms, the prevalence of younger women, comorbidities, sensory and autonomic complaints, central sensitization syndrome, supine/standing norepinephrine levels, inflammatory markers and medical therapy except for gastrointestinal medication. Autonomic testing showed widespread but similar abnormalities in POTS and HYCH that included: reduced orthostatic CBFv and end-tidal CO2, preload failure (assessed in 16/19 POTS/HYCH), mild autonomic failure, and frequent small fiber neuropathy. HYCH and POTS are syndromes of orthostatic intolerance with cerebral hypoperfusion associated with reduced orthostatic cerebral blood flow, hypocapnia, mild autonomic failure and small fiber neuropathy of a similar degree and distribution; except for tachycardia in POTS. Similarities in peripheral domain abnormalities that affect heart rate suggest that orthostatic tachycardia in POTS is driven by the central nervous system overcompensation of orthostatic challenge. These findings provide additional evidence that HYCH and POTS represent a spectrum of the same disorder. Reduced orthostatic cerebral blood flow is a key unifying feature of HYCH and POTS.

Assessment of small fiber neuropathy and distal sensory neuropathy in female patients with fibromyalgia.

We investigated sudomotor dysfunction, small fiber neuropathy (SFN), and their clinical significance in female fibromyalgia patients. Fibromyalgia patients and healthy controls (HCs) were recruited. Clinical and laboratory data were measured. Electrochemical skin conductance (ESC) values of hands and feet were assessed by SUDOSCAN. Additionally, several other methods were employed, including nerve conduction study (NCS), electromyography (EMG), and questionnaires. Spearman correlation coefficient was calculated to identify factors associated with ESC values of SUDOSCAN. Twenty-two female fibromyalgia patients and 22 female HCs were recruited. The fibromyalgia group had lower EQ5D and higher Toronto Clinical Neuropathy scores than the HC group. Most of the EMG/NCS findings of motor and proximal sensory nerves were comparable between the fibromyalgia and HC groups, whereas sensory nerve action potential amplitudes of distal sensory nerves were significantly lower in the fibromyalgia group. Mean ESC values of hands and feet were significantly lower in the fibromyalgia group than in the HC group (57.6 ± 16.2 vs. 68.8 ± 10.3 μS, p = 0.010 for hands, 64.9 ± 11.5 vs. 72.0 ± 8.2 μS, p = 0.025 for feet, respectively). Moderate to severe SFN was more common in the fibromyalgia group (68.2%) than in the HC group (68.2 vs. 50%, p = 0.019). Fibromyalgia disease duration was significantly correlated with the ESC values of hands/feet, and tricyclic antidepressant (TCA) responders had higher ESC values than non-responders. SFN was commonly detected in fibromyalgia patients who had normal EMG/NCS findings and was more severe in fibromyalgia patients with longer disease duration. SUDOSCAN may predict response to TCA therapy.

Small Fiber Neuropathy in Burning Mouth Syndrome: A Systematic Review.

Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder, characterized by persistent burning sensations and pain without clear pathological causes. Recent research suggests that small fiber neuropathy (SFN) may play a significant role in the neuropathic pain and sensory disturbances associated with BMS. Following PRISMA guidelines, this systematic review aims to evaluate and synthesize current evidence supporting SFN's involvement in BMS. The protocol is registered in PROSPERO (CRD42024555839). The results show eight studies reported reductions in nerve fiber density in tongue biopsies (ranging from 30% to 60%), along with morphological changes indicative of small fiber damage. Additionally, an increase in TRPV1-positive, NGF-positive, and P2X3-positive fibers, overexpression of Nav1.7, and slight underexpression of Nav1.9 mRNA were observed in BMS patients. Quantitative Sensory Testing in seven studies revealed sensory abnormalities such as reduced cool detection and cold pain thresholds. Blink reflex and corneal confocal microscopy also indicated peripheral and central small fiber damage, along with increased artemin mRNA expression. The evidence strongly supports SFN as a key factor in the pathophysiology of BMS, particularly due to reductions in nerve fiber density and altered sensory thresholds. However, variability across studies highlights the need for larger, standardized research to establish causal relationships and guide therapeutic strategies.

From Sudoscan to bedside: theory, modalities, and application of electrochemical skin conductance in medical diagnostics.

The human body has two main types of sweat glands: apocrine and eccrine. Eccrine glands are widely distributed across the skin, including areas with hair. While the eccrine glands on palms and soles help improve grip, those on the rest of the body primarily aid in thermoregulation. Sudomotor function, which controls sweating, is regulated by the sympathetic division of the autonomic nervous system through cholinergic and adrenergic pathways. The activation of eccrine glands involves intricate processes, including neurotransmitter binding, ion channel modulation, and voltage generation. Sudoscan technology utilizes electrochemical skin conductance (ESC) to non-invasively measure sudomotor function. This method, which has been standardized for accuracy, has established normative benchmarks and has proven reliable across diverse populations. Sudoscan's diagnostic performance is comparable to invasive methods such as intraepidermal nerve fiber density testing, making it a valuable tool for diagnosing small fiber neuropathy. Moreover, it has been shown to correlate with corneal nerve fiber length, providing insights into various neuropathic conditions. Compared to traditional sudomotor function tests, Sudoscan proves superior in terms of its accessibility, simplicity, and reliability, with the potential to replace or complement existing diagnostic methods. It is important to differentiate ESC, as measured by Sudoscan, from other skin conductance measures, such as galvanic skin response (GSR) or electrodermal activity (EDA). Although these methods share a common physiological principle, ESC is specifically designed for diagnosing sudomotor function, unlike GSR/EDA, which is typically used for continuous monitoring. Sudoscan's success has led to its integration into consumer health devices, such as the BodyScan from Withings, showcasing its versatility beyond clinical settings. Future research may explore ESC applications in diverse medical fields, leveraging real-world data from integrated consumer devices. Collaborative efforts between researchers and engineers promise to offer new insights into sudomotor function and its implications for broader health monitoring. This study provides a comprehensive overview of ESC, including topics such as eccrine gland physiology, sudomotor function, Sudoscan technology, normative benchmarks, diagnostic comparisons, and potential future applications.

The Evolving Landscape of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) belongs to a heterogeneous group of disorders in which thinly myelinated Aδ and unmyelinated C-fibers are primarily affected, leading to neuropathic pain and autonomic symptoms. SFN can be associated with systemic conditions such as diabetes, autoimmune diseases, exposure to drugs and toxins, and infection, with the list of associated diseases continuing to expand. Variants in the SCN9A, SCN10A, and SCN11A genes encoding Nav 1.7, Nav 1.8, and Nav 1.9 sodium channel subunits, as well as in the TRPA1 gene, have been found in SFN patients, expanding the spectrum of underlying conditions and enhancing our understanding of pathophysiological mechanisms. There is also growing interest in immune-mediated forms that could help identify potentially treatable subgroups. According to international criteria, diagnosis is established through clinical examination, the assessment of intraepidermal nerve fiber density, and/or quantitative sensory testing. Autonomic functional tests allow for a better characterization of dysautonomia in SFN, which can be subclinical. Other tests can support the diagnosis. Currently, the management of SFN prioritizes treating the underlying condition, if identified, within a multidisciplinary approach that combines symptomatic pain therapy, lifestyle changes, and biopsychological interventions. Emerging insights from the molecular characterization of SFN channelopathies hold promise for improving diagnosis, potentially leading to the discovery of new drugs and refining trial designs in the future. This article reviews the clinical presentation, diagnostic workup, and advancing knowledge of associated conditions and interventional management of SFN.

Comparison of intraepidermal nerve fiber density and confocal corneal microscopy for neuropathy.

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

SMALL FIBER NEUROPATHY DIAGNOSIS IN PARKINSON'S DISEASE PATIENTS: A CASE SERIES

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Motor impairments, particularly in gait and balance, significantly reduce the quality of life in patients, increasing the risk of falls. Non-motor symptoms, including autonomic dysfunctions and peripheral neuropathy, are prevalent as the disease progresses. Peripheral neuropathy, present in 55% of PD patients, manifests with sensory loss, postural instability, and pain, further impairing motor function and increasing fall risk. This study aimed to adapt and test a simple method to identify small fiber neuropathy in PD patients, specifically using the Skin Wrinkling Test (SWT), and to correlate its findings with autonomic dysfunctions. Four PD patients were evaluated using questionnaires (Non-Motor Symptoms Questionnaire, COMPASS-31) and SWT. All patients showed alterations in the SWT, suggesting the presence of small fiber neuropathy, regardless of disease duration or comorbid conditions such as diabetes. Despite the small sample size, our findings support the SWT as a practical tool for assessing small fiber neuropathy in clinical practice. Further large-scale studies are needed to validate these results and their implications for diagnosing peripheral neuropathy in PD patients.

The Detection of Peripheral Neuropathy by Clinical Scales in Patients Diagnosed With Alcohol Use Disorder.

Introduction Peripheral neuropathy is a well-known manifestation of alcohol overconsumption, but neurophysiological confirmation of peripheral nerve damage is costly and sometimes involves invasive procedures. The aim of this study was to investigate the ability of commonly used clinical scales to detect the presence of neuropathy in patients with alcohol use disorder (AUD). Methods Data were collected retrospectively on 116 patients diagnosed with AUD and treated voluntarily in a detoxification special unit. Ninety-eight age and gender-matched healthy subjects without a diagnosis of AUD were used as the control group. The five tested clinical neuropathy scales were the Neuropathy Symptoms Score (NSS), the Neuropathy Disability Score, the Neuropathy Impairment Score (NIS), the Neuropathy Impairment Score of the Lower Limbs, and the modified Toronto Clinical Neuropathy Scale. Results The mean values of all tested clinical scales of the patients with AUD were significantly higher than the control group. All examined clinical scales were determined to be useful in discriminating between patients with neuropathy from patients without neuropathy. The strongest discrimination was seen with the NIS, including the best sensitivity and specificity for the range of scores obtained. All scales, except NSS, showed a stronger correlation with measures of large (LFN) than small fiber neuropathy (SFN). Conclusion Our study suggests that clinical scales could be used to detect peripheral neuropathy in patients with AUDwhen neurophysiological testing is not available. Moreover, we suggest that the NIS and the NSS scales would be most helpful in assessing LFN and SFN, respectively, in patients with AUD.

NaV1.8/NaV1.9 double deletion mildly affects acute pain responses in mice.

The 2 tetrodotoxin-resistant (TTXr) voltage-gated sodium channel subtypes NaV1.8 and NaV1.9 are important for peripheral pain signaling. As determinants of sensory neuron excitability, they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and the release of neurotransmitters from sensory neuron terminals. NaV1.8 and NaV1.9, which are encoded by SCN10A and SCN11A, respectively, are predominantly expressed in pain-sensitive (nociceptive) neurons localized in the dorsal root ganglia (DRG) along the spinal cord and in the trigeminal ganglia. Mutations in these genes cause various pain disorders in humans. Gain-of-function missense variants in SCN10A result in small fiber neuropathy, while distinct SCN11A mutations cause, i. a., congenital insensitivity to pain, episodic pain, painful neuropathy, and cold-induced pain. To determine the impact of loss-of-function of both channels, we generated NaV1.8/NaV1.9 double knockout (DKO) mice using clustered regularly interspaced short palindromic repeats/Cas-mediated gene editing to achieve simultaneous gene disruption. Successful knockout of both channels was verified by whole-cell recordings demonstrating the absence of NaV1.8- and NaV1.9-mediated Na+ currents in NaV1.8/NaV1.9 DKO DRG neurons. Global RNA sequencing identified significant deregulation of C-LTMR marker genes as well as of pain-modulating neuropeptides in NaV1.8/NaV1.9 DKO DRG neurons, which fits to the overall only moderately impaired acute pain behavior observed in DKO mice. Besides addressing the function of both sodium channels in pain perception, we further demonstrate that the null-background is a very valuable tool for investigations on the functional properties of individual human disease-causing variants in NaV1.8 or NaV1.9 in their native physiological environment.

Correlation Between Orofacial Pain and Sensory and Autonomic Neuropathies.

Orofacial Pain (OFP) affects 15% of the general population. OFP conditions can be myofascial, also known as temporomandibular disorders (TMDs) or neuropathic. The underlying pathophysiology in several chronic OFP conditions, is unknown. Small fiber neuropathy (SFN) is a disorder of thinly myelinated A-delta and non-myelinated C-fibers and can manifest as sensory and autonomic neuropathies. SFN has been demonstrated in some OFP conditions. Our study aims to assess the presence of OFP in patients with sensory and autonomic neuropathies and assess the correlation between OFP, skin biopsy and autonomic dysfunction. This is a retrospective study (2018-2020) of patients from the SFN registry, Massachusetts General Hospital, Boston, USA, for the presence of OFP. All patients were included. Primary outcome: Prevalence of OFP in patients with chronic neuropathies. Secondary outcomes: Correlation between OFP and skin biopsy, dysautonomia, headaches, chronic nociceptive pain, psychological conditions, and patient factors, such as mean age and BMI. Charts of 450 patients with sensory and autonomic neuropathies were reviewed. 22.67% (n=102) had OFP. The mean (range) age at biopsy in patients with OFP was 48.36 (20-81) years, female: male ratio 3.25:1. More OFP patients had negative skin biopsy results (p value<0.05) than those with sensory neuropathies. Patients with OFP had significantly higher prevalence of psychological conditions (p value 0.000), and higher BMI >30 (p value 0.025). Dysautonomia was significantly higher in patients with TMDs when compared to the ones without TMDs (p value 0.030). There was no significant difference in mean age, gender predilection, presence of headaches, peripheral neuropathies, and nociceptive pain between patients with and without OFP. OFP and sensory neuropathies can be overlapping conditions. Patients presenting with concomitant TMD and dysautonomia can be further tested for SFN. This can further help us understand a correlation if any, between idiopathic TMD/OFP conditions and SFN and further our understanding of the pathophysiology of these conditions.

567P A prospective observational study on the effect of intravenous immunoglobulin on small fiber neuropathy after SARS-CoV-2 infection or vaccination

567P A prospective observational study on the effect of intravenous immunoglobulin on small fiber neuropathy after SARS-CoV-2 infection or vaccination

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy.

Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

Correlates and Predictors of Symptom Severity Over Time in People Under Investigation for Postural Orthostatic Tachycardia Syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a poorly understood chronic disorder characterized by an unexplained excessive increase in heartbeat upon standing. The aim of this study was to investigate psychosocial and physiological correlates and predictors of symptom severity over time in patients presenting with POTS-like symptoms. Longitudinal cohort study of patients under investigation for POTS ( n = 149). Patients completed questionnaires at 1 month preclinic appointment and 6 months later. Diagnosis, blood pressure (BP), and heart rate (HR) measures were collected from medical records. Data were analyzed using hierarchical linear multiple regression. Orthostatic and small fiber neuropathy (SFN) symptoms remained stable over time and were significantly correlated with distress, cardiac anxiety, threatening views of the illness, and cognitive-behavioral responses to symptoms, but not with emotional reactivity or social support. Baseline psychosocial factors collectively explained 48% ( F = 5.37, p < .001) of the variance in orthostatic symptoms, and 35% ( F = 3.49, p < .001) of the variance of SFN symptoms at baseline, but a nonsignificant amount of variance in symptoms at 6 months when controlling for baseline symptoms. Hemodynamic measures explained a significant 4% ( F = 3.37, p = .026) of variance of orthostatic symptoms at 6 months. Symptom burden in patients with suspected POTS remained high over 6 months. Psychosocial factors explained a large amount of the variance in symptoms at baseline. As symptoms did not change/improve over time, baseline symptoms accounted for most of the variance in symptoms at 6 months. An integrated approach addressing psychosocial factors alongside medical treatments may promote adjustment to the condition and lessen symptom burden for this group.

Nociplastic Pain: A Critical Paradigm for Multidisciplinary Recognition and Management.

Our understanding of chronic pain has evolved significantly, shifting from a focus on peripheral damage to recognizing the central mechanisms underlying pain perception. This perspective article explores the concept of nociplastic pain, a term introduced by the International Association for the Study of Pain (IASP) in 2017, which describes pain arising from altered pain modulation within the central nervous system, without clear evidence of tissue damage or inflammation. The historical progression from fibrositis to fibromyalgia, and now to nociplastic pain, underscores the complexity of chronic pain syndromes and the need for a multidisciplinary approach to management. Nociplastic pain is characterized by central sensitization, leading to heightened pain sensitivity and often accompanied by comorbidities such as fatigue, sleep disturbances, and cognitive difficulties. Advances in neuroimaging have revealed altered connectivity within key brain networks, such as the default mode and salience networks, in patients with nociplastic pain, providing insights into the neural underpinnings of this condition. The article also addresses controversies surrounding the role of small fiber neuropathy and autonomic dysfunction in nociplastic pain, highlighting the ongoing debates in the field. The practical importance of recognizing nociplastic pain across various medical disciplines-including primary care, orthopedics, neurology, psychiatry, and rheumatology-is emphasized, with recommendations for integrating this knowledge into clinical practice. Emerging therapies, such as neurofeedback, hyperbaric oxygen therapy, and neuromodulation, offer new avenues for treatment, particularly for patients who do not respond to conventional approaches. The article calls for continued research into the mechanisms of nociplastic pain, the development of reliable diagnostic tools, and the exploration of novel therapeutic strategies to improve patient outcomes. The recognition and management of nociplastic pain are crucial for advancing the care of patients with chronic pain, necessitating interdisciplinary collaboration and a patient-centered approach.

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.