Small Nerve Research Articles

Anatomical study of the medial calcaneal nerve using high-resolution ultrasound.

To determine whether high-resolution ultrasound (US) can identify the course and relations of the medial calcaneal nerve (MCN). This investigation was initially undertaken in eight cadaveric specimens and followed by a high-resolution US study in 20 healthy adult volunteers (40 nerves) by two musculoskeletal radiologists in consensus. The location and course of the MCN as well as its relationship to adjacent anatomical structures were evaluated. The MCN was consistently identified by US along its entire course. The mean cross-sectional area of the nerve was 1 mm2 (range 0.5-2). The level at which the MCN branched from the tibial nerve was variable, located a mean of 7mm (range - 7-60) proximal to the tip of the medial malleolus. At the level of the medial retromalleolar fossa, the MCN was located inside the proximal tarsal tunnel a mean of 8mm (range 0-16) posterior to the medial malleolus. More distally, the nerve was depicted in the subcutaneous tissue at the surface of the abductor hallucis fascia with a mean direct distance to the fascia of 1.5mm (range 0.4-2.8). High-resolution US can identify the MCN at the level of the medial retromalleolar fossa, as well as more distally in the subcutaneous tissue at the surface of the abductor hallucis fascia. In the setting of heel pain, precise sonographic mapping of the MCN course may enable the radiologist to make diagnosis of nerve compression or neuroma, and perform selective US-guided treatments. In the setting of heel pain, sonography is an attractive tool for diagnosing compression neuropathy or neuroma of the medial calcaneal nerve, and enables the radiologist to perform selective image-guided treatments such as diagnostic blocks and injections. • The MCN is a small cutaneous nerve which rises from the tibial nerve in the medial retromalleolar fossa to the medial side of the heel. • The MCN can be depicted by high-resolution ultrasound along its entire course. • In the setting of heel pain, precise sonographic mapping of the MCN course may enable the radiologist to make diagnosis of neuroma or nerve entrapment, and perform selective ultrasound-guided treatments such as steroid injection or tarsal tunnel release.

Concordance between the Stockholm Workshop Scale and the International Consensus Criteria for grading the severity of neurosensory manifestations in hand-arm vibration syndrome in a Swedish clinical setting

ObjectivesOccupational exposure to vibration using hand-held tools may cause hand-arm vibration syndrome (HAVS). Correct diagnosis and grading of severity are crucial in protecting the individual’s health and for workers’ compensation...

Gadolinium contrast agents: dermal deposits and potential effects on epidermal small nerve fibers

Small fiber neuropathy (SFN) affects unmyelinated and thinly myelinated nerve fibers causing neuropathic pain with distal distribution and autonomic symptoms. In idiopathic SFN (iSFN), 30% of the cases, the underlying aetiology remains unknown. Gadolinium (Gd)-based contrast agents (GBCA) are widely used in magnetic resonance imaging (MRI). However, side-effects including musculoskeletal disorders and burning skin sensations were reported. We investigated if dermal Gd deposits are more prevalent in iSFN patients exposed to GBCAs, and if dermal nerve fiber density and clinical parameters are likewise affected. 28 patients (19 females) with confirmed or no GBCA exposure were recruited in three German neuromuscular centers. ISFN was confirmed by clinical, neurophysiological, laboratory and genetic investigations. Six volunteers (two females) served as controls. Distal leg skin biopsies were obtained according to European recommendations. In these samples Gd was quantified by elemental bioimaging and intraepidermal nerve fibers (IENF) density via immunofluorescence analysis. Pain phenotyping was performed in all patients, quantitative sensory testing (QST) only in a subset (15 patients; 54%). All patients reported neuropathic pain, described as burning (n = 17), jabbing (n = 16) and hot (n = 11) and five QST scores were significantly altered. Compared to an equal distribution significantly more patients reported GBCA exposures (82%), while 18% confirmed no exposures. Compared to unexposed patients/controls significantly increased Gd deposits and lower z-scores of the IENF density were confirmed in exposed patients. QST scores and pain characteristics were not affected. This study suggests that GBCA exposure might alter IENF density in iSFN patients. Our results pave the road for further studies investigating the possible role of GBCA in small fiber damage, but more investigations and larger samples are needed to draw firm conclusions.

Cadaveric Study for Safe Elevation of a Profunda Artery Perforator Flap: Anatomy of the Perforators and Obturator Nerves.

This cadaveric study aimed to describe the anatomy of the profunda artery perforators (PAPs). In total, nine free cadavers with 18 upper thighs were dissected, 12 of which were from female cadavers, and 6 were from male cadavers. The average age of the cadavers was 84.7 ± 4.2 years. Dissection was performed to evaluate the anatomic position and characteristics of the femoral PAPs. The perforator distance from the gluteal sulcus, number of perforators, perforating muscles, diameter of the perforators, origin of the perforators, and number of nerves passing above and below the perforators were determined. The average number of perforators that penetrate the adductor magnus muscle was 2.5. The average distance from the origin of the perforators to the gluteal sulcus was 71.72 ± 28.23 mm. The average numbers of the obturator nerves passing above and below the perforator in the adductor magnus muscle were 1.3 (range, 0-4) and 0.7 (range, 0-2), respectively. The results provide a detailed anatomic basis for the PAP flap. The perforators of a PAP flap may be included in a flap with a transverse design. Sacrificing the small obturator nerves during dissection may not lead to significant donor site morbidity.

Corneal Confocal Microscopy Demonstrates No Evidence of Small Nerve Fiber Pathology in Obese Children and Adolescents (P2-9.008)

<h3>Objective:</h3> To assess for evidence of small nerve fiber pathology in obese children and adolescents using corneal confocal microscopy (CCM). <h3>Background:</h3> The global prevalence of obesity among children and adolescents has increased dramatically over the past few decades, and childhood obesity has become a significant public health concern. Studies have shown an increased prevalence of neuropathic symptoms in obese children indicating small nerve fiber pathology. We have previously used corneal confocal microscopy (CCM), a rapid, non-invasive ophthalmic technique, to show corneal nerve fiber loss in adults with painful diabetic neuropathy, adults with obesity and children with type 1 diabetes. <h3>Design/Methods:</h3> Twenty obese children and adolescents (age 14.0 ± 2.51 years, BMI 37.27 ± 7.14 kg/m²) and 20 healthy controls (age 12.83 ± 1.91 years, BMI 22.27 ± 5.47 kg/m²) underwent vibration perception threshold (VPT) assessment and CCM to quantify corneal nerve fiber density (CNFD) (no./mm²), corneal nerve branch density (CNBD) (no./mm²) and corneal nerve fiber length (CNFL) (mm/mm²). Obese children also underwent body composition analysis using TANITA to assess body fat percentage. <h3>Results:</h3> Obese children had a normal VPT (3.20 ± 0.95 vs. controls). There was a non-significant trend for a lower CNFD (19.01 ± 5.2 vs. 21.91 ± 4.6; P=0.06), but no difference in CNBD (33.02 (26.13–42.04) vs. 35.04 (29.46–5134); P=0.25) or CNFL (14.5 ± 2.6 vs. 14.4 ± 2.1; P=0.89) in obese children compared to healthy controls. There was no correlation between CNFD (P=0.643), CNBD (P=0.950) and CNFL (P=0.598) with body fat percentage. <h3>Conclusions:</h3> There is no evidence of abnormal vibration perception or small nerve fiber damage in obese children and adolescents. <b>Disclosure:</b> Ms. Wahbeh has nothing to disclose. Hoda Gad has nothing to disclose. Mrs. Elgassim has nothing to disclose. The institution of Ioannis Petropoulos has received research support from GBS CIDP Foundation International . Georgios Ponirakis has nothing to disclose. Prof. Hussain has nothing to disclose. Prof. Malik has nothing to disclose.

Spinal Nerve Sheath Myxoma

Nerve sheath myxoma (NSM) is a rare myxoid form of schwannoma, which is a benign tumor that usually grows in the same place. They usually arise from small cutaneous nerves in the head, neck, and extremities, but exceptionally, they have also been reported to develop in the spinal canal. Here we describe a case of spinal NSM. The patient was a 4-month-old male who presented with incomplete tetra paresis. Spine magnetic resonance imaging showed a well-demarcated small intradural extramedullary mass at the T10-L1 level. The tumor has typical histological features of myxoid type NSM with myxoid lobules that are separated by fibrous septa or bands of more compact cellular area. Nerve sheath myxomas should be included in the differential diagnosis of spinal canal tumors. Ultrastructural observation of tumor cefis with perineurial, fibroblast-like, and Schwann differentiation suggests an origin from nerve sheath precursor cefis.

Distension evoked mucosal secretion in human and porcine colon in vitro.

It was suggested that intestinal mucosal secretion is enhanced during muscle relaxation and contraction. Mechanisms of mechanically induced secretion have been studied in rodent species. We used voltage clamp Ussing technique to investigate, in human and porcine colonic tissue, secretion evoked by serosal (Pser) or mucosal (Pmuc) pressure application (2-60 mmHg) to induce distension into the mucosal or serosal compartment, respectively. In both species, Pser or Pmuc caused secretion due to Cl- and, in human colon, also HCO3- fluxes. In the human colon, responses were larger in proximal than distal regions. In porcine colon, Pmuc evoked larger responses than Pser whereas the opposite was the case in human colon. In both species, piroxicam revealed a strong prostaglandin (PG) dependent component. Pser and Pmuc induced secretion was tetrodotoxin (TTX) sensitive in porcine colon. In human colon, a TTX sensitive component was only revealed after piroxicam. However, synaptic blockade by ω-conotoxin GVIA reduced the response to mechanical stimuli. Secretion was induced by tensile rather than compressive forces as preventing distension by a filter inhibited the secretion. In conclusion, in both species, distension induced secretion was predominantly mediated by PGs and a rather small nerve dependent response involving mechanosensitive somata and synapses.

Abstract 1326: Perineural invasion and bone metastases in prostate cancer - is there a link

Abstract Bone metastases are the most common secondary lesions in prostate cancer (PCa) patients. Typically, initial bone metastases develop in the lower part of the spine and pelvis. While this metastatic pattern is not consistent with the random nature of the arterial osseous dissemination, previous reports suggested the role of the retrograde venous spread in this phenomenon. However, clinical data also indicate a positive association between the degree of perineural invasion (PNI) and bone metastases in PCa patients. Yet, the mechanism linking these two means of dissemination remains unknown. To identify the processes involved in the initial PCa dissemination we used the PC3-ML cell line, which was previously shown to trigger bone metastases, in the orthotopic xenograft model. To this end, the cells were injected into the prostates of male SCID/Bg mice and tumor development and progression was followed by magnetic resonance imaging (MRI) and histopathology. MRI indicated local invasion of the primary tumor, which later resulted in the formation of multiple secondary lesions along the lower spine. However, histopathological analysis revealed that these lesions were initiated in the soft tissues surrounding the vertebral column, while the subsequent invasion of the vertebra was the secondary event. The staining for neuronal markers, neurofilament (NF), tyrosine hydroxylase (TH) and neuropeptide Y (NPY), revealed that PCa cells created multicellular clusters spreading longitudinally along the small nerve fibers, particularly in the paraspinal muscle compartment. The staining for the endothelial cell marker, CD31, detected small vessels present within PCa clusters. However, no evident encapsulation of the PCa cells within blood vessels consistent with the retrograde venous spread was observed. Altogether, these results suggest PNI as the main route of the initial local dissemination of the PCa cells toward the bone, which then triggers bone invasion and subsequent hematogenous spread to distant bones. Further mechanistic studies are required to confirm this hypothesis. Citation Format: Dawid Sigorski, Susana Galli, Sung Hyeok Hong, Ewa Iżycka-Świeszewska, Joanna B. Kitlinska. Perineural invasion and bone metastases in prostate cancer - is there a link [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1326.

Corneal confocal microscopy identifies corneal nerve loss and increased Langerhans cells in presymptomatic carriers and patients with hereditary transthyretin amyloidosis

BackgroundHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo.MethodsThis cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed.ResultsCorneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density.ConclusionsCCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.

Fibromyalgia syndrome and the eye-Implications in corneal ultrastructure on confocal microscopy.

Fibromyalgia is a chronic systemic disorder associated with varied manifestations ranging from fatigue, sleep disturbances, headaches, muscular pain, cognitive issues, or even without symptoms. It is also known to be associated with chronic neuropathic pain.[1,2] Ocular features described include severe pain, necrotizing scleritis, and changes in optic disc perfusion.[3] Small fiber neuropathy and dysautonomia symptoms correlate with corneal denervation more commonly in women with fibromyalgia. These nerve plexus features were found to be associated with neuropathic pain and fibromyalgia in previous studies.[4] These patients have a higher incidence of dry eye disease as compared to the normal population.[5,6] Approximately 50% of patients with fibromyalgia have damage to small unmyelinated nerve fibers around the body.[7] Small fiber polyneuropathy may cause symptoms sometimes identified as fibromyalgia.[8] A skin punch biopsy is a sensitive and specific test that demonstrates the reduction in nerve fiber density associated with small fiber neuropathy. In vivo confocal microscopy (IVCM) is a noninvasive tool that can demonstrate nerve-related changes in the cornea and hence serve as an adjunct to skin biopsy for diagnosis and evaluation of the disease.[9] This photoessay highlights the nerve-related changes and the presence of microneuromas in the cornea and the use of IVCM in aiding in the diagnosis and management of these patients. Case Reports Three patients previously diagnosed with fibromyalgia presented with ocular pain and mild mixed dry eye. IVCM showed decreased corneal nerve fiber branching density with microneuromas in the cornea [Fig. 1]. They were on systemic therapy for chronic pain and their ocular condition was managed with topical anti-inflammatory and lubricating eye drops. These patients can be at a risk for postoperative dry eye and wound-healing complications and should be evaluated in detail preoperatively to avoid this.Figure 1: (a, b, and c) show microneuromas in the subbasal nerve plexus on IVCM of all three patients with fibromyalgia and dry eye. Figure d shows reduced nerve density, e shows altered nerve morphology and f shows the image used for the calculation of nerve density using the CCMetrics softwareFinancial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Ultrasound-guided treatment of meralgia paresthetica: case report

Meralgia paresthetica (MP) or so-called as lateral femoral cutaneous nerve (LFCN) entrapment is a mononeuropathy characterized by a localized area of paresthesia, dysesthesia, tingling, burning, and numbness on the anterolateral aspect of the thigh, between the inguinal ligament and the knee without associated loss of reflexes and motor weakness. The incidence of MP increases with obesity and diabetes. Ultrasound-guided has been demonstrated useful for visualization of peripheral nerves, in particular very small nerves such as the LFCN. Hereby, we reported a case of 63-year-old man diagnosed with MP. The patient complained of numbness, and no pain when pinched in his anterolateral aspect of the left thigh since 3 weeks ago. On physical examination, his body mass index (BMI) was 27 (overweight) with normal vital signs. Neurological examination revealed normal motoric function and refleks; but decreased sensation to pinprick in the left anterolateral thigh in the LFCN distribution. No abnormal findings on plain radiographs of the pelvis and lumbar spine. Ultrasound-guided injection was performed in this patient.

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

Specific features of the morphology of the spinal nodes of homeothermal vertebrate animals in the comparative and anatomical series

Scientific studies that reflect the evolutionary morphology of the nervous system, namely the spinal nodes of homoeothermic vertebrates, allow us to identify specific patterns, trends, and criteria that relate to the structural organization of the organ at the population and cellular levels of their organization. The evolutionary direction of research into the macro- and microstructure of spinal cord nodes provides an opportunity to investigate the patterns of formation of optimal relationships of their structural components: nerve and glial cells, capillaries concerning the level of development of the organism, and their motor activity. The article contains the results of the morphometric characteristics of the spinal nodes of warm-blooded vertebrates in a comparative aspect: class Aves – Birds (Gallus gallus, forma domestica L., 1758 – domestic chicken); class Mammalia – Mammals (Oryctolagus cuniculus L., 1758 – European krill, Canis lupus familiaris L., 1758 – domestic dog, Sus scrofa, forma domestica L., 1758 – domestic pig, Bos taurus taurus L., 1758 – domestic bull). When performing this work, complex research methods were used: anatomical, neurohistological, morphometric, and statistical. The morphological study of the structural components of the organs of the nervous system was studied on histological sections by the method of light microscopy following the requirements of the international principles of the “European Convention for the Protection of Vertebrate Animals Used in Experiments and for Other Scientific Purposes” (Strasbourg, 1986), a decision of the First National Congress on Bioethics (Kyiv, 2001), Law of Ukraine No. 692 “On the Protection of Animals from Cruel Treatment” (3447-IV) dated February 21, 2006. For histological examination, the newly selected material was immediately fixed in a 10% aqueous neutral formalin solution, with a fixation period of 30 days, followed by step-by-step embedding in paraffin. Using a sled microtome, histological sections with a thickness of 6–10 μm were obtained. The general histological structure and microstructural changes in histological preparations were studied under a light microscope MC (Micros Austria) at magnifications from 70 to 600 times. Photomicrographs of histological preparations were carried out using a CAM V200 video camera mounted in a Micros MC microscope. The work aims to conduct a complex morpho-functional study of spinal nodes in a comparative anatomical series of representatives of higher vertebrates. It was investigated that in phylogenesis, a particular structural and morphofunctional rearrangement of the central and peripheral nervous system organs, namely the spinal nodes, takes place. They differ in shape and size. It was established that the neurocytic organization of the spinal cord nodes of all species of animals studied is characterized by the presence of large, medium, and small nerve cells. Adaptation to various living conditions of animals was formed based on morphometric indicators (the volume of neurocytes and their nuclei), their morphological structures, the density of nerve cells per 0.1 mm2, the number of glial cells per 0.1 mm2, an indicator of nuclear-cytoplasmic ratio, degree of polymorphism chromatophilia. Nissl staining of histopreparations of spinal nodes of homoothermic animals showed that the neuroplasm of nerve cells contains well-defined depths of basophilic substance, compared with lower animals, as evidence of a higher degree of development in nerve cells of the protein-synthesizing apparatus. According to the method of impregnation of spinal cord nodes with silver nitrate in all studied animals, a different intensity of coloring of nerve cells is revealed: dark, light-dark, light, which is related to the peculiarities of species and age neuromorphology, the morphofunctional state of the nervous system and the type of higher nervous activity. The obtained morpho-functional features of the organs of the nervous system are essential not only for evolutionary and comparative morphology but also for developing issues of physiology, pathology, and treatment of peripheral nervous system diseases.

Acute Sensory Neuropathy with Small and Large Nerve Fibre Involvement After Vaccination for Influenza Virus: a Rare Sensory Guillain–Barre variant? A Case Report

Acute Sensory Neuropathy with Small and Large Nerve Fibre Involvement After Vaccination for Influenza Virus: a Rare Sensory Guillain–Barre variant? A Case Report

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hind paw skin and glial cells in the spinal dorsal horn were examined via immunohistochemistry and immunofluorescence. Results: Oral cilostazol ameliorated the symptoms of mechanical allodynia but not thermal analgesia in DM rats. Significant reductions in PGP9.5-, P2X3-, CGRP, and TRPV-1-labeled penetrating nerve fibers in the epidermal layer indicated denervation of sensory nerves in the hind paw epidermis of DM rats. Denervation significantly improved in groups that received Cilo30 and Cilo100 in a dose-dependent manner. Cilostazol administration also suppressed microglial hyperactivation and increased astrocyte expressions in spinal dorsal horns. Conclusions: Oral cilostazol ameliorated hyperglycemia-induced peripheral small nerve fiber damage in the periphery of diabetic rats and effectively mitigated diabetic neuropathic pain via a central sensitization mechanism. Our findings present cilostazol not only as an effective option for managing symptoms of neuropathy but also for deterring the development of diabetic neuropathy in the early phase of type I diabetes.

Diagnostic value of diffusion-weighted MRI using apparent diffusion coefficient (ADC) in evaluation of median nerve in carpal tunnel syndrome

BackgroundThe diagnosis of carpal tunnel syndrome is based on a combination of clinical history, clinical examination and frequent use of electrodiagnostics as nerve conduction study and electromyography which often do not provide the spatial and anatomical localizing information, especially with small nerves of the extremities. Conventional magnetic resonance imaging can reveal morphological changes in carpal tunnel syndrome patients.AimThe purpose of our study was to assess the efficacy of diffusion magnetic resonance imaging as a functional imaging in evaluation of median nerve in carpal tunnel syndrome.Patients and methodsThis prospective study included a group of 33 patients with carpal tunnel syndrome diagnosed by both clinical examination and electromyography; 40 writs were examined. A control group of 20 subjects of matched age group were also included. All the participants were subjected to conventional and diffusion magnetic resonance imaging studies.ResultsMedian nerve apparent diffusion coefficient values of patients are lower than those of controls. The sensitivity and diagnostic accuracy of diffusion conventional magnetic resonance imaging were 95% and 97.5%, respectively, versus 25% and 62.5% of conventional magnetic resonance imaging. A cut-off apparent diffusion coefficient value ≤ 0.99 obtained at distal radio-ulnar joint level and > 1.07 at pisiform level as well as apparent diffusion coefficient ratio at a cut-off ≤ 0.2 was significantly valid for diagnosing carpal tunnel syndrome.ConclusionsDiffusion magnetic resonance imaging provides functional evaluation of median nerve in patients with carpal tunnel syndrome.

Diagnostic Accuracy of Perception Threshold Tracking in the Detection of Small Fiber Damage in Type 1 Diabetes.

An objective assessment of small nerve fibers is key to the early detection of diabetic peripheral neuropathy (DPN). This study investigates the diagnostic accuracy of a novel perception threshold tracking technique in detecting small nerve fiber damage. Participants with type 1 diabetes (T1DM) without DPN (n = 20), with DPN (n = 20), with painful DPN (n = 20) and 20 healthy controls (HCs) underwent perception threshold tracking on the foot and corneal confocal microscopy. Diagnostic accuracy of perception threshold tracking compared to corneal confocal microscopy was analyzed using logistic regression. The rheobase, corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) (all P < .001) differed between groups. The diagnostic accuracy of perception threshold tracking (rheobase) was excellent for identifying small nerve fiber damage, especially for CNFL with a sensitivity of 94%, specificity 94%, positive predictive value 97%, and negative predictive value 89%. There was a significant correlation between rheobase with CNFD, CNBD, CNFL, and Michigan Neuropathy Screening Instrument (all P < .001). Perception threshold tracking had a very high diagnostic agreement with corneal confocal microscopy for detecting small nerve fiber loss and may have clinical utility for assessing small nerve fiber damage and hence early DPN. NCT04078516.

Corneal nerve loss and increased Langerhans cells are associated with disease severity in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multisystem autoimmune disorder characterized by articular and extra-articular manifestations. Neuropathy is a poorly studied manifestation of RA. The aim of this study was to utilize the rapid non-invasive ophthalmic imaging technique of corneal confocal microscopy to identify whether there is evidence of small nerve fibre injury and immune cell activation in patients with RA. Fifty consecutive patients with RA and 35 healthy control participants were enrolled in this single-centre, cross-sectional study conducted at a university hospital. Disease activity was assessed with the 28-Joint Disease Activity Score and erythrocyte sedimentation rate (DAS28-ESR). Central corneal sensitivity was measured with a Cochet-Bonnet contact corneal esthesiometer. A laser scanning in vivo corneal confocal microscope was used to quantify corneal nerve fibre density (CNFD), nerve branch density (CNBD), nerve fibre length (CNFL), and Langerhans cell (LC) density. Corneal sensitivity (P = 0.01), CNFD (P = 0.02), CNBD (P < 0.001), and CNFL (P < 0.001) were lower, and mature (P = 0.001) and immature LC densities (P = 0.011) were higher in patients with RA compared to control subjects. CNFD (P = 0.016) and CNFL (P = 0.028) were significantly lower in patients with moderate to high (DAS28-ESR > 3.2) compared to mild (DAS28-ESR ≤ 3.2) disease activity. Furthermore, the DAS28-ESR score correlated with CNFD (r = -0.425; P = 0.002), CNBD (ρ = -0.362; P = 0.010), CNFL (r = -0.464; P = 0.001), total LC density (ρ = 0.362; P = 0.010) and immature LC density (ρ = 0.343; P = 0.015). This study demonstrates reduced corneal sensitivity, corneal nerve fibre loss and increased LCs which were associated with the severity of disease activity in patients with RA.

Age-related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment.

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti-aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes.

4D-Printed Soft and Stretchable Self-Folding Cuff Electrodes for Small-Nerve Interfacing.

Peripheral nerve interfacing (PNI) has a high clinical potential for treating various diseases, such as obesity or diabetes. However, currently existing electrodes present challenges to the interfacing procedure, which limit their clinical application, in particular, when targeting small peripheral nerves (<200µm). To improve the electrode handling and implantation, a nerve interface that can fold itself to a cuff around a small nerve, triggered by the body moisture during insertion, is fabricated. This folding is achieved by printing a bilayer of a flexible polyurethane printing resin and a highly swelling sodium acrylate hydrogel using photopolymerization. When immersed in an aqueous liquid, the hydrogel swells and folds the electrode softly around the nerve. Furthermore, the electrodes are robust, can be stretched (>20%), and bent to facilitate the implantation due to the use of soft and stretchable printing resins as substrates and a microcracked gold film as conductive layer. The straightforward implantation and extraction of the electrode as well as stimulation and recording capabilities on a small peripheral nerve in vivo are demonstrated. It is believed that such simple and robust to use self-folding electrodes will pave the way for bringing PNI to a broader clinical application.