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BioRxiv : the Preprint Server For... Sep 2023Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured...
UNLABELLED
Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or via collateral sprouting of neighboring uninjured afferents into the denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received relatively less attention. In this study, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hind paw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following an initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated the denervated epidermis, Interestingly, GFRα2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by trend towards regression. Presumptive sympathetic nerve fibers also sprouted into the denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so less efficiently. Conversely, rapidly adapting Aβ fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing collateral sprouting up to 8 weeks after nerve injury. Optogenetics and behavioral assays further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury.
SIGNIFICANCE STATEMENT
Following nerve injury, whereas one mechanism for tissue reinnervation is regeneration of injured neurons, another, less well studied mechanism is collateral sprouting of nearby uninjured neurons. In this study, we examined collateral sprouting in denervated mouse skin and showed that it involves some, but not all neuronal subtypes. Despite such heterogeneity, a significant degree of restoration of punctate mechanical sensitivity is achieved. These findings highlight the diversity of collateral sprouting among peripheral neuron subtypes and reveal important differences between pre- and post-denervation skin that might be appealing targets for therapeutic correction to enhance functional recovery from denervation and prevent unwanted sensory phenomena such as pain or numbness.
PubMed: 37745384
DOI: 10.1101/2023.09.12.557420 -
Modern Pathology : An Official Journal... Mar 2020Lipomatosis of nerve is a rare malformation characterized by a fibrolipomatous proliferation within peripheral nerve. Lipomatosis of nerve most frequently involves the...
Lipomatosis of nerve is a rare malformation characterized by a fibrolipomatous proliferation within peripheral nerve. Lipomatosis of nerve most frequently involves the median nerve, and manifests clinically as a compressive neuropathy. However, 30-60% of cases are associated with tissue overgrowth within the affected nerve's territory (e.g., macrodactyly for lipomatosis of nerve in the distal median nerve). Somatic activating PIK3CA mutations have been identified in peripheral nerve from patients with lipomatosis of nerve with type I macrodactyly, which is now classified as a PIK3CA-related overgrowth spectrum disorder. However, the PIK3CA mutation status of histologically confirmed lipomatosis of nerve, including cases involving proximal nerves, and cases without territory overgrowth, has not been determined. Fourteen histologically confirmed cases of lipomatosis of nerve involving the median (N = 6), brachial plexus (N = 1), ulnar (N = 3), plantar (N = 2), sciatic and superficial peroneal nerves (N = 1 each) were included. Ten cases had nerve territory overgrowth, ranging from macrodactyly to hemihypertrophy; and four cases had no territory overgrowth. Exome sequencing revealed "hotspot" activating PIK3CA missense mutations in 6/7 cases. Droplet digital polymerase chain reaction for the five most common PIK3CA mutations (p.H1047R, p.H1047L, p.E545K, p.E542K, and p.C420R) confirmed the exome results and identified an additional six cases with mutations (12/14 total). PIK3CA mutations were found in 8/10 cases with territory overgrowth (N = 7 p.H1047R and N = 1 p.E545K), including two proximal nerve cases with extremity overgrowth, and 4/4 cases without territory overgrowth (p.H1047R and p.H1047L, N = 2 each). The variant allele frequency of PIK3CA mutations (6-32%) did not correlate with the overgrowth phenotype. Three intraneural lipomas had no detected PIK3CA mutations. As PIK3CA mutations are frequent events in lipomatosis of nerve, irrespective of anatomic site or territory overgrowth, we propose that all phenotypic variants of this entity be classified within the PIK3CA-related overgrowth spectrum and termed "PIK3CA-related lipomatosis of nerve".
Topics: Adult; Cell Proliferation; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Infant, Newborn; Lipomatosis; Male; Mutation; Peripheral Nerves; Peripheral Nervous System Diseases; Phenotype; Polymerase Chain Reaction; Terminology as Topic; Exome Sequencing
PubMed: 31481664
DOI: 10.1038/s41379-019-0354-1 -
BMC Veterinary Research Jul 2020Long-acting local anaesthetics (e.g. bupivacaine hydrochloride) or sustained-release formulations of bupivacaine (e.g. liposomal bupivacaine) may be neurotoxic when...
BACKGROUND
Long-acting local anaesthetics (e.g. bupivacaine hydrochloride) or sustained-release formulations of bupivacaine (e.g. liposomal bupivacaine) may be neurotoxic when applied in the setting of diabetic neuropathy. The aim of the study was to assess neurotoxicity of bupivacaine and liposome bupivacaine in streptozotocin (STZ) - induced diabetic mice after sciatic nerve block. We used the reduction in fibre density and decreased myelination assessed by G-ratio (defined as axon diameter divided by large fibre diameter) as indicators of local anaesthetic neurotoxicity.
RESULTS
Diabetic mice had higher plasma levels of glucose (P < 0.001) and significant differences in the tail flick and plantar test thermal latencies compared to healthy controls (P < 0.001). In both diabetic and nondiabetic mice, sciatic nerve block with 0.25% bupivacaine HCl resulted in a significantly greater G-ratio and an axon diameter compared to nerves treated with 1.3% liposome bupivacaine or saline (0.9% sodium chloride) (P < 0.01). Moreover, sciatic nerve block with 0.25% bupivacaine HCl resulted in lower fibre density and higher large fibre and axon diameters compared to the control (untreated) sciatic nerves in both STZ-induced diabetic (P < 0.05) and nondiabetic mice (P < 0.01). No evidence of acute or chronic inflammation was observed in any of the treatment groups.
CONCLUSIONS
In our exploratory study the sciatic nerve block with bupivacaine HCl (7 mg/kg), but not liposome bupivacaine (35 mg/kg) or saline, resulted in histomorphometric indices of neurotoxicity. Histologic findings were similar in diabetic and healthy control mice.
Topics: Anesthetics, Local; Animals; Bupivacaine; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Female; Injections; Liposomes; Mice, Inbred C57BL; Mice, Mutant Strains; Nerve Block; Sciatic Nerve
PubMed: 32680505
DOI: 10.1186/s12917-020-02459-4 -
Annals of Anatomy = Anatomischer... Feb 2023Various mouse and rat models of neuropathic pain after nerve injury exist. Whilst some models involve a proximal nerve lesion or ligation of the sciatic trifurcation in...
INTRODUCTION
Various mouse and rat models of neuropathic pain after nerve injury exist. Whilst some models involve a proximal nerve lesion or ligation of the sciatic trifurcation in mice and rats, others consists of a transection or ligation of distal nerves at the tibial bifurcation in mice or rats. The level of nerve cut directly affects the magnitude of hypersensitivity, and anatomical differences between mice and rats might therefore impact the development of hypersensitivity after distal tibial nerve transection as well.
METHODS
The bifurcation of the distal tibial nerve into the medial and lateral plantar nerve (MPN and LPN), and the presence of anatomical differences in sural and tibial nerve distribution between mice and rat was evaluated. Sural mechanical sensitivity after transection of the MPN or whole tibial nerve was assessed using von Frey test until 8 weeks after surgery in 48 rats and 16 mice.
RESULTS
The bifurcation of the tibial nerve into the MPN and LPN is situated proximal to the ankle in both mice and rats. The sural nerve joins the LPN in mice, but not in rats. A proximal communicating branch is present between the LPN and MPN in rats, but not in mice. MPN transection in mice caused hypersensitivity of the hindpaw innervated by the sural nerve, but not in rats. In rats, sural hypersensitivity only developed when both MPN and LPN were cut.
CONCLUSION
Inter-species variation in nerve anatomy should be taken in consideration when performing surgery to induce plantar hypersensitivity in rodents.
Topics: Rats; Animals; Tibial Nerve; Sural Nerve; Foot; Neurosurgical Procedures; Sciatic Nerve
PubMed: 36436721
DOI: 10.1016/j.aanat.2022.152038 -
Journal of Clinical Neurophysiology :... Jul 2021Comprehensive evaluation of the upstream sensory processing in diabetic symmetrical polyneuropathy (DSPN) is sparse. The authors investigated the spinal nociceptive... (Comparative Study)
Comparative Study
PURPOSE
Comprehensive evaluation of the upstream sensory processing in diabetic symmetrical polyneuropathy (DSPN) is sparse. The authors investigated the spinal nociceptive withdrawal reflex and the related elicited somatosensory evoked cortical potentials. They hypothesized that DSPN induces alterations in spinal and supraspinal sensory-motor processing compared with age- and gender-matched healthy controls.
METHODS
In this study, 48 patients with type 1 diabetes and DSPN were compared with 21 healthy controls. Perception and reflex thresholds were determined and subjects received electrical stimulations on the plantar site of the foot at three stimulation intensities to evoke a nociceptive withdrawal reflex. Electromyogram and EEG were recorded for analysis.
RESULTS
Patients with DSPN had higher perception (P < 0.001) and reflex (P = 0.012) thresholds. Fewer patients completed the recording session compared with healthy controls (34/48 vs. 21/21; P = 0.004). Diabetic symmetrical polyneuropathy reduced the odds ratio of a successful elicited nociceptive withdrawal reflex (odds ratio = 0.045; P = 0.014). Diabetic symmetrical polyneuropathy changed the evoked potentials (F = 2.86; P = 0.025), and post hoc test revealed reduction of amplitude (-3.72 mV; P = 0.021) and prolonged latencies (15.1 ms; P = 0.013) of the N1 peak.
CONCLUSIONS
The study revealed that patients with type 1 diabetes and DSPN have significantly changed spinal and supraspinal processing of the somatosensory input. This implies that DSPN induces widespread differences in the central nervous system processing of afferent A-δ and A-β fiber input. These differences in processing may potentially lead to identification of subgroups with different stages of small fiber neuropathy and ultimately differentiated treatments.
Topics: Adult; Aged; Diabetes Mellitus; Diabetic Neuropathies; Electric Stimulation; Electromyography; Evoked Potentials, Somatosensory; Female; Humans; Male; Middle Aged; Nociception; Reflex; Spinal Nerves
PubMed: 32501945
DOI: 10.1097/WNP.0000000000000691 -
Folia Morphologica 2021The aim of this study was to compare the histological structure (cross-sectional area [CSA] and number of nerve fascicles) of the distal part of the tibial nerve (TN)...
BACKGROUND
The aim of this study was to compare the histological structure (cross-sectional area [CSA] and number of nerve fascicles) of the distal part of the tibial nerve (TN) and its terminal branches (medial plantar nerve [MPN], lateral plantar nerve [LPN]) in the fresh and fresh-frozen cadavers using computer assisted image analysis.
MATERIALS AND METHODS
The TNs with terminal branches (MPN and LPN) were dissected from the fresh and fresh-frozen cadavers. Each nerve was harvested 5 mm proximally and respectively 5 mm distally from the TN bifurcation, marked, dehydrated, embedded in paraffin, sectioned at 2 μm slices and stained with haematoxylin and eosin. Then the specimens were photographed and analysed using Olympus cellSens software.
RESULTS
The fresh cadavers' group comprised 60 feet (mean age 68.1 ± 15.2 years). The mean CSA and the number of nerve fascicles were respectively 15.25 ± 4.6 mm2, 30.35 ± 8.45 for the TN, 8.76 ± 1.93 mm2, 20.75 ± 7.04 for the MPN and 6.54 ± 2.02 mm2, 13.40 ± 5.22 for the LPN. The fresh-frozen cadavers' group comprised 21 feet (mean age 75.1 ± 9.0 years). The mean CSA and the number of nerve fascicles were respectively 13.71 ± 5.66 mm2, 28.57 ± 8.00 for the TN, 7.55 ± 3.25 mm2, 18.00 ± 6.72 for the MPN and 4.29 ± 1.93 mm2, 11.33 ± 1.93 for the LPN. Only LPNs showed statistical differences in the CSA and the number of nerve fascicles between examined groups (p = 0.000, p = 0.037, respectively). A positive correlation was found between donors age and tibial nerve CSA in the fresh cadavers group (r = 0.44, p = 0.000). A statistical difference was found between the MPN and LPN both in the CSA and the number of nerve fascicles (p < 0.001, p < 0.001, respectively).
CONCLUSIONS
The CSA and the number of nerve fascicles of the tibial and medial plantar nerves were similar in the fresh and fresh-frozen cadavers whilst different in the LPN. The TN showed increasing CSA with the advanced age in the fresh cadavers. The MPN had larger CSA and more nerve fascicles than the LPN.
Topics: Aged; Cadaver; Foot; Humans; Image Processing, Computer-Assisted; Tibial Nerve
PubMed: 32789845
DOI: 10.5603/FM.a2020.0088 -
Regional Anesthesia and Pain Medicine Sep 2023Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and...
BACKGROUND
Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient populations but has shortcomings limiting use. These limitations include its invasiveness, potential for local anesthetic systemic toxicity, risk of infection with an indwelling catheter, and relatively short duration of blockade compared with the period of pain after major injuries. Focused ultrasound is capable of inhibiting the peripheral nervous system and has potential as a pain management tool. However, investigations of its effect on peripheral nerve nociceptive fibers in animal models of acute pain are lacking. In an in vivo acute pain model, we investigated focused ultrasound's effects on behavior and peripheral nerve structure.
METHODS
Focused ultrasound was applied directly to the sciatic nerve of rats just prior to a hindpaw incision; three control groups (focused ultrasound sham only, hindpaw incision only, focused ultrasound sham+hindpaw incision) were also included. For all four groups (intervention and controls), behavioral testing (thermal and mechanical hyperalgesia, hindpaw extension and flexion) took place for 4 weeks. Structural changes to peripheral nerves of non-focused ultrasound controls and after focused ultrasound application were assessed on days 0 and 14 using light microscopy and transmission electron microscopy.
RESULTS
Compared with controls, after focused ultrasound application, animals had (1) increased mechanical nociceptive thresholds for 2 weeks; (2) sustained increase in thermal nociceptive thresholds for ≥4 weeks; (3) a decrease in hindpaw motor response for 0.5 weeks; and (4) a decrease in hindpaw plantar sensation for 2 weeks. At 14 days after focused ultrasound application, alterations to myelin sheaths and nerve fiber ultrastructure were observed both by light and electron microscopy.
DISCUSSION
Focused ultrasound, using a distinct parameter set, reversibly inhibits A-delta peripheral nerve nociceptive, motor, and non-nociceptive sensory fiber-mediated behaviors, has a prolonged effect on C nociceptive fiber-mediated behavior, and alters nerve structure. Focused ultrasound may have potential as a peripheral nerve blockade technique for acute pain management. However, further investigation is required to determine C fiber inhibition duration and the significance of nerve structural changes.
Topics: Rats; Animals; Anesthetics, Local; Acute Pain; Rats, Sprague-Dawley; Nerve Fibers; Hyperalgesia; Sciatic Nerve; Models, Animal
PubMed: 36822815
DOI: 10.1136/rapm-2022-104060 -
Academic Radiology Apr 2020The medial plantar proper digital nerve, also called Joplin's nerve, arises from the medial plantar nerve, courses along the medial hallux metatarsophalangeal joint, and...
Ultrasound-guided Therapeutic Injection and Cryoablation of the Medial Plantar Proper Digital Nerve (Joplin's Nerve): Sonographic Findings, Technique, and Clinical Outcomes.
RATIONALE AND OBJECTIVES
The medial plantar proper digital nerve, also called Joplin's nerve, arises from the medial plantar nerve, courses along the medial hallux metatarsophalangeal joint, and can be a source of neuropathic pain due to various etiologies, following acute injury including bunion surgery and repetitive microtrauma. We describe our clinical experience with diagnostic ultrasound assessment of Joplin's neuropathy and technique for ultrasound-guided therapeutic intervention including both injection and cryoablation over a 6-year period.
MATERIALS AND METHODS
Retrospective review of all diagnostic studies performed for Joplin's neuropathy and therapeutic Joplin's nerve ultrasound-guided injections and cryoablations between 2012 and 2018 was performed. Indications for therapeutic injection and cryoablation, were recorded. Studies were assessed for sonographic abnormalities related to the nerve and perineural soft tissues. Post-treatment outcomes including immediate pain scores, clinical follow-up, and periprocedural complications were documented.
RESULTS
Twenty-four ultrasound-guided procedures were performed, including 15 perineural injections and nine cryoablations. With respect to sonographic abnormalities, nerve thickening (33%) and perineural hypoechoic scar tissue (27%) were the most common findings. The mean pain severity score prior to the therapeutic injection was 6.4/10 (range 4-10) and 0.25/10 (range 0-2) following the procedure; mean follow-up was 26.2 months (range 3-63 months). All of the cryoablation patients experienced sustained pain relief with a mean length follow-up of 3.75 months (range 0.2-10 months).
CONCLUSION
Therapeutic injection of Joplin's nerve is a safe and easily performed procedure under ultrasound guidance, with high rates of immediate symptom improvement. For those experiencing a relapse or recurrent symptoms, cryoablation offers an effective secondary potential treatment option.
Topics: Cryosurgery; Humans; Retrospective Studies; Tibial Nerve; Treatment Outcome; Ultrasonography; Ultrasonography, Interventional
PubMed: 31279644
DOI: 10.1016/j.acra.2019.05.014 -
Multiple Sclerosis and Related Disorders Feb 2022Lower urinary tract symptoms (LUTSs) are common in patients with multiple sclerosis (MS). Percutaneous posterior tibial nerve stimulation (PTNS) is a minimally invasive... (Meta-Analysis)
Meta-Analysis Review
Percutaneous posterior tibial nerve stimulation (PTNS) for lower urinary tract symptoms (LUTSs) treatment in patients with multiple sclerosis (MS): A systematic review and meta-analysis.
BACKGROUND
Lower urinary tract symptoms (LUTSs) are common in patients with multiple sclerosis (MS). Percutaneous posterior tibial nerve stimulation (PTNS) is a minimally invasive treatment which is considered to be effective for patients who suffer from LUTS symptoms. In previous studies, the endpoints of treatment reported differently. So, we designed this systematic review and meta-analysis to estimate pooled efficacy of PTNS based on different assessment methods.
METHODS
We systematically searched PubMed, Scopus, EMBASE, Web of Science, and google scholar. We also searched the gray literature including references of the included studies, and conference abstracts which were published up to May 2021. The search strategy included the MeSH and text words as (((Tibial Nerves) OR Posterior Tibial Nerve) OR (Posterior Tibial Nerves) OR (Medial Plantar Nerves) OR (Medial Plantar Nerve) OR (tibial Nerve Stimulation) OR (Trans-Cutaneous Tibial Nerve Stimulation) OR (Percutaneous Tibial Nerve Stimulation) OR (Cutaneous Tibial Nerve Stimulation) AND ((Multiple Sclerosis OR Sclerosis, Multiple) OR Sclerosis, Disseminated) OR Disseminated Sclerosis) OR MS (Multiple Sclerosis)) OR Multiple Sclerosis, Acute Fulminating).Two independent researchers independently evaluated the articles.
RESULTS
We found 2430 articles by literature search, after deleting duplicates 2027 remained. Eight articles remained for meta-analysis The pooled SMD of post voiding residual (PVR) (post-treatment - pre-treatment) was -0.75 (95%CI:-0.93, -0.56)(I=0, p = 0.67). The pooled SMD of voiding volume (post-treatment - pre-treatment) was 1.21 (95% CI:0.94-1.49) (I:0%, p = 0.4). The pooled SMD of nocturia (post-treatment - pre-treatment) was -1.10 (95% CI:-1.33, -0.87) (I:86.4%, p<0.001). The pooled SMD of leakage per day (post-treatment - pre-treatment) was -0.69 (95% CI:-0.93, -0.45) (I:84.3%, p<0.001). The pooled frequency of responders was 66%(95% CI:59%-73%)(I:0).
CONCLUSION
The results of this systematic review and meta-analysis show that PTNS in effective in treating LUTS in patients with MS.
Topics: Disease Progression; Humans; Lower Urinary Tract Symptoms; Multiple Sclerosis; Tibial Nerve; Transcutaneous Electric Nerve Stimulation; Treatment Outcome
PubMed: 35216773
DOI: 10.1016/j.msard.2021.103392 -
Plastic and Reconstructive Surgery.... Aug 2023Reconstructing a mangled limb is complex and requires expertise in both bone and soft-tissue reconstruction, particularly when there is significant muscle loss....
Reconstructing a mangled limb is complex and requires expertise in both bone and soft-tissue reconstruction, particularly when there is significant muscle loss. Typically, multistage surgery is necessary, starting with soft-tissue coverage, followed by bone grafting and tendon transfers. Sometimes, microsurgical techniques such as vascularized bone grafts and free functional muscle transfers are necessary, especially when there is a bone defect of over 6 cm; the soft-tissue environment is infected, scarred, or poorly vascularized; or there are extensive musculotendinous injuries. We treated a 34-year-old man who had a crushed left forearm resulting in an 18 × 8 cm open wound, 5-cm radius and 7-cm ulna bone defects, loss of the extensor pollicis longus and brevis muscles, and extensive injuries to the other musculotendinous structures of the forearm. To accomplish a one-stage reconstruction, we used a chimeric fibula osteomyocutaneous flap that included a 20 × 10 cm skin flap, peroneus brevis muscle with its motor nerve, and two segments of fibula. The proximal and distal fibula segments were used for ulnar and radial bone reconstruction, respectively, preserving forearm supination and pronation. The peroneus brevis tendon was sutured to the extensor pollicis longus tendon, and its motor nerve was coaptated with the posterior interosseous nerve to restore thumb extension. The skin flap provided complete coverage of all exposed bone and tendon structures. At the 12-month follow-up, the patient regained full extension of the thumb, and there were no difficulties with forearm supination and pronation or with foot eversion and plantar flexion at the donor leg.
PubMed: 37577248
DOI: 10.1097/GOX.0000000000005182