Venous congestion as a central mechanism of radiculopathies.

Compression of roots/nerves can disrupt some of their functions, but does not necessarily cause pain. This is illustrated by the frequency of nearly asymptomatic spinal stenosis or disc herniations. In fact, pain of radiculopathies (and nerve entrapments) may mostly be the consequence of intraneural oedema induced by microscopical venous stasis around roots/spinal ganglia (or nerves) not or poorly shown by imaging. This narrative review first lists arguments for a role of congestion of vasa-nervorum in the pathophysiology of radiculopathies, including those induced by disc herniation and spinal stenosis, but also other sources of overpressures in spinal venous plexuses (pregnancy, vena cava atresia and thrombosis, portal hypertension, epidural varices, arterio-venous fistula, vertebral hemangioma or hemangioblastoma). It also details sources of venous congestion around nerves outside the spine, from pelvis (May-Thurner syndrome, Nut-cracker syndrome) to buttocks (superior and inferior gluteal veins), and even thighs and legs. A better recognition of a preeminent role of venous congestion in radiculopathies, plexopathies, and nerve entrapments, should have major consequences: (i) discard the dogma that compression is mandatory to induce root/nerve suffering, since root/nerve adherences in two locations can impair blood flow in vasa-nervorum through root/nerve stretching; (ii) implementation of sensitive techniques to visualise impingement of blood flow around or within roots and nerves; (iii) better prevention of roots/nerves adherence, or arachnoiditis induced by extravascular fibrin deposition secondary to venous stasis.; (iv) optimizing treatments dampening clot formation and/or extravascular fibrin leakage in the intradural/peridural spaces, or around roots/nerves, like guided injection of tissue plasminogen activator.

Vasa nervorum of epicardial nerves and valves of small veins investigated in porcine heart by two types of vascular injections.

The morphology of the vascular supply of peripheral branches of cardiac nerves has not been systematically described until now. The aim of this study was to describe the architectonics of the vasa nervorum of epicardial nerves in porcine hearts by using two injection techniques. Twenty-three hearts from young healthy pigs were used. In 10 hearts India ink solution was injected into the origin of the anterior interventricular branch. In another 10 hearts India ink solution was injected retrogradely through the coronary sinus. The hearts were then analyzed using a magnifying glass and light microscopy. The arterial injection showed the entirety of the rich venous components of the vasa nervorum, which often consisted of paired veins accompanying the epicardial nerves. The thickness of the nerves ranged from 50 to 815 µm. The vasa nervorum drained into larger subepicardial veins. In seven of the hearts prepared with venous injections the vasa nervorum of epicardial nerves were visualized in the same detail as in the arterial preparations and India ink solution filled the right ventricle via the smallest cardiac veins. The histological analysis of these seven hearts showed complete dehiscence and functional insufficiency of small and larger veins valves. In the other three hearts prepared with venous injections the valves were competent, which prevented retrograde filling of larger and smaller veins. The results obtained expand the current knowledge on epicardial nerves vasa nervorum and provide anatomical evidence behind the mechanism of retrograde application of cardioplegic solutions in cardiac surgery.

Morphological and hemodynamic changes of sciatic nerves and their vasa nervorum during circular compression and relaxation.

The main aim of this study was to evaluate the biomechanical and hemodynamic responses of vasa nervorum under transverse circular compression. In situ compress-and-hold experiments were performed on the sciatic nerves of healthy and diabetic rats, and the blood flow within the vasa nervorum was observed using Doppler-optical coherence tomography. A new technique was developed to obtain the time-course of the cross sectional area and the morphology of the vasa nervorum from the tomographic images. A quasi-linear viscoelastic model was used to investigate the overall biomechanical properties of the nerves, and a two-dimensional three-layered finite element model was constructed to analyze the distribution of stress and the morphological changes during the compression-relaxation process. The results showed that the lumenal area of vasa nervorum was reduced in the compression stage, especially for the diabetic nerves. The reduction was greater than 70% when the reduction of the nerve diameter was only 10%. The quasi-linear viscoelastic model showed that normal nerves were more elastic but less viscous than the diabetic nerves. The finite element analyses demonstrated that perineurium could sustain more stress than other layers, while epineurium served as a cushion to protect vasa nervora. In addition, there were regions within epineurium with less stress, so that vasa nervora in these saddle regions were less deformed. The vasa nervorum in diabetic rats was more prone to compression and reduction of blood flow than that of the normal rats. The histological studies supported the simulation results.

A technique for safe deep facial tissue dissection: Indocyanine green-assisted intraoperative real-time visualization of the vasa nervorum of facial nerve with a near-infrared camera.

During deep tissue dissection in the face, it is sometimes difficult to distinguish the facial nerve from surrounding tissue, leading to a risk of facial nerve injury. To identify the facial nerve during such procedures, we used a fluorescence-assisted near-infrared camera. Indocyanine green (ICG)-assisted direct visualization was used intraoperatively in 13 cases. The procedures included excision of neurofibromas (n = 10) and lymphatic malformations (n = 3). Intravenously injected ICG was distributed systemically and filled the lumen of epineural vessels around the nerves (vasa nervorum) within 1 min. The nerve trajectories were directly visualized using a fluorescence-detecting near-infrared camera. The facial nerve was distinguishable from surrounding tissues such as retaining ligaments and, in all cases, was safely secured, preserving postoperative facial nerve function. Postoperative mean differences of left/right facial volume were significantly reduced compared with preoperative values. Patient satisfaction ranged from satisfied to very satisfied. Injuries to the facial nerve could be effectively avoided via direct intraoperative visualization of the vasa nervorum of nerve through intravenous ICG injection. A portable near-infrared camera enabled direct and real-time visualization of the vasa nervorum, facilitating injury prevention. This technique might help to reduce the risk of disastrous complication of facial palsy through a simple and efficient method.

Vitamin D as a Potential Agent for Ischemic Axonal Regeneration after Epineurial Devascularization of the Sciatic Nerve.

BACKGROUND: Although vitamin D has several noncalcemic functions particularly on nervous system, its neuroregenerative roles on ischemic peripheral nerve injury has not been reported. In this study, it was aimed to investigate the effect of vitamin D3 after epineurial devascularization of the sciatic nerve. METHODS: Forty adult female Wistar rats were randomly divided into four groups: Group 1 (Control), Group 2 (Sham-operated), Group 3 (Epineurial devascularization + vitamin D3 treatment), Group 4 (Epineurial devascularization + vehicle treatment). Recovery of the sciatic nerve was analyzed by functional (sciatic functional index, pinch test and biochemical analyses) and morphological (electron microscopic analysis and wet muscle weight analysis) methods. RESULTS: Comparison of the data revealed that vitamin D3 administration had a beneficial effect on regeneration after epineurial devascularization. CONCLUSION: We suggest that vitamin D3 is an effective agent in the prevention of ischemic peripheral nerve insults.

Vaso-nervorumitis: responsible for pain in Buerger's disease?

Buerger's disease (BD) is an episodic, inflammatory, and occlusive peripheral vascular disease with unknown etiology, which can lead to tissue or limb loss. BD patients usually present neurological symptoms from the early stages of the disease including numbness, cold sensation, and allodynia as the disease progresses. Pain in the late stages of BD is very severe, almost resistant to opioid pain killers, and sometimes compels the patient to pursue major amputation. Therefore, pain management in BD patients is one of the most important and, at the same time, challenging issues since its main etiology is not well understood. Recently, a 39-year-old male smoker with a diagnosis of BD underwent a below-knee amputation in his left leg. Oddly, we found that the vasa-nervorum of the sural nerve had the pathological changes usually observed in BD, including inflammation and proliferation of endothelial cells. Notably, the inflammation was limited to the vasa-nervorum and did not extend to the nerve fascicles. Our findings could provide a clue to taking the approach of managing pain in BD as if it were vasculitis neuropathy; and the inflammation of the vasa-nervorum individually might be responsible for the pain characteristic of BD. In addition, our findings could indicate that BD is a systemic vasculitis of microcirculation and, hence, a different treatment approach for BD might be needed in addition to antithrombotic and vasodilator.

Monomelic Ischemic Neuropathy of the Tibial and Peroneal Nerve After Onyx Embolization of Vasa Nervorum Supplying a Surgically Excluded Popliteal Artery Aneurysm.

Ischemic neuropathy is an exceedingly rare complication after peripheral artery embolization. We report a case of ischemic damage to the tibial and peroneal nerve after embolization of the vasa nervorum that served as feeding collaterals to a surgically excluded popliteal artery aneurysm.

Vasa nervorum angiogenesis in prostate cancer with perineural invasion.

BACKGROUND: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination in malignancies associated with highly enervated organs. However, the effect of cancer cells on vasa nervorum remains unknown. We studied this effect in locally advanced prostate cancer, a high-risk feature associated with approximately 20% of prostate cancer specific mortality. METHODS: We used immunohistochemistry for CD34, fibroblast growth factor-2 (FGF-2), FSHR, podoplanin, vascular endothelial growth factor (VEGF), and VEGFR-2 as well as histochemical methods to examine the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients. RESULTS: The percentage of the nerve area occupied by CD34-positive vasa nervorum endothelial cells in nerves with PNI was much higher than in nerves without PNI (7.3 ± 1.2 vs 1.9 ± 0.4; P < 0.001 and 5.8 ± 0.6 vs 1.23 ± 0.8; P < 0.001 in pT3a and pT3b prostate cancer specimens, respectively). In 19/85 of the patients the CD34-positive vasa nervorum microvessels have a thick basement membrane, similar to the vessels in diabetic microangiopathy. This subendothelial layer contains collagen fibers. Vasa nervorum endothelia and Schwann cells express FGF-2 (nuclear localization) and FSHR (plasma membrane and cytoplasmic staining). Prostate cancer cells invading nerves express VEGF, a critical cytokine in tumor angiogenesis. The vasa nervorum of prostatic nerves with PNI did not express detectable levels of VEGFR-2. No podoplanin-positive lymphatic vessels were seen in nerves. CONCLUSION: In locally advanced prostate cancer, PNI of cancer cells is associated with formation of new endoneurial capillaries and changes of vasa nervorum morphology.

Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy.

BACKGROUND/AIMS: High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFκB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. METHODS: We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFκB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. RESULTS: Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFκB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. CONCLUSIONS: Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury.

Microangiopathy-A Potential Contributing Factor to Idiopathic Polyneuropathy: A Mini Review.

Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive predominantly sensory axonal polyneuropathy. The prevalence of CIAP increases with age. The pathogenic cause of CIAP is unknown although there are several prevailing etiological hypotheses. In this mini review, we focus on the hypothesis of disturbed microcirculation in the vasa nervorum of peripheral nerves as a pathogenic cause of CIAP. There is an association between CIAP and metabolic risk factors. Furthermore, the phenotype of CIAP resembles diabetic neuropathy both clinically and electrophysiologically. In sural nerve biopsies from patients with diabetes mellitus, structural abnormalities indicating microangiopathy in the endoneurial microvessels are well documented. Similarly, sural microvessel abnormalities have been shown in patients with atherosclerotic non-diabetic peripheral vascular disease. However, the reported histopathological alterations of microvasculature in sural nerves of CIAP patients are inconsistent. Two studies report microangiopathic changes in CIAP sural nerves comparable with those found in patients with diabetic neuropathy. Conversely, another recent study showed no significant differences in the microangiopathic parameters in the endoneurial microvessels in the sural nerve biopsies from CIAP patients compared to controls without polyneuropathy. However, this CIAP patient group was younger compared to the patient groups in the other two studies. A general limitation with the published morphological studies are that different methods have been used in the assessment of microangiopathy, and there is also a risk of subjectivity in the results. Immunohistochemistry studies of sural nerves with verification of microangiopathy using specific biomarkers would be of great interest to develop.

Local blood flow in peripheral nerves and their ganglia: Resurrecting key ideas around its measurement and significance.

Over 3 decades ago, seminal work by Phillip Low and colleagues established exquisite physiology around the measurement of nerve blood flow (NBF). Although not widely explored recently, its connection to the clinic has awaited human methodology. While human studies have not achieved a convincing level of rigour, newer imaging technologies are offering early information. The peripheral nerve trunk has parallel blood flow compartments that include epineurial flow dominated by arteriovenous shunts and downstream endoneurial blood flow (EBF). NBF and EBF have lower values than central nervous system blood flow, lack autoregulation yet have sympathetic and peptidergic neurovascular control. Contrary to expectation, injury to nerves is often associated with rises in NBF rather than ischemia, a finding of biological interest corroborated by human studies. Despite its potential importance, quantitative human measurements of EBF and NBF are not yet available. However, with development, careful NBF analysis may present new insights into nerve disorders. Muscle Nerve 57: 884-895, 2018.

Facial palsy after embolization of dural arteriovenous fistula: A case report and literature review.

BACKGROUND: Dural arteriovenous fistulas (DAVF) are unusual intracranial vascular malformations consisting of anomalous connections between meningeal arteries and dural sinuses or the veins that pass through them. They have variable clinical presentation and prognosis, which depend on their location and venous hemodynamics. Treatment is based on the closure of the abnormal connections, which is usually conducted via arterial and/or transvenous endovascular techniques. CASE DESCRIPTION: We present a male patient who complained of headaches and left-sided pulsatile tinnitus due to DAVF from the external carotid artery branches draining directly into the ipsilateral sigmoid sinus. Embolization with Onyx® was successful, obtaining angiographic occlusion and symptom remission. However, on postoperative day 4, the patient presented with left facial palsy and spontaneous regression. CONCLUSION: Although embolization is an effective and safe procedure, complications may occur. Reflux of the embolic agent to the vasa nervorum of the cranial nerve may lead to ischemic neuropathy. Here, we reported a case of embolized DAVF presenting with a postoperative peripheral facial palsy where the two embolized pedicles were branches of the middle meningeal and occipital arteries involved in the vascularization of the extratemporal segment of the facial nerve. We discuss the etiopathogenic, anatomical, and pathophysiological aspects of this complication.

Imaging of the Vasa Nervorum Using Contrast-Enhanced Ultrasound.

INTRODUCTION: We describe the use of intravenous contrast-enhanced ultrasonography to study vasa nervorum using contrast-enhanced ultrasound. METHODS: We imaged the median, femoral, or sciatic nerves in 4 patients in longitudinal plane using high-resolution ultrasound after intravenous bolus of activated Perflutren lipid microspheres. The images were acquired as photopic images (in brown color) in real time using 2-dimensional B-Flow mode scan within a selected region of interest. RESULTS: The vasa nervorum was seen as focal ovoid enhancement along either the superior and inferior aspects of the nerve most pronounced during arterial phase (peak enhancement) in all 4 patients. The fluctuating intensity of enchancement during cardiac cycle confirmed the arterial origin of enhacement. Punctate, linear, or diffuse enhancement was also seen along the trunk of the nerve. CONCLUSIONS: We were able to identify the vasa nervorum along the outer aspect of the studied nerves using contrast-enhanced ultrasound.

Regenerative capacity and histomorphometric changes in rat sciatic nerve following experimental neurotmesis / Capacidad regenerativa y cambios histomorfométricos en el nervio ciático de ratas luego de una neurotmesis experimental

Through a wide range of cellular and molecular events, the peripheral nervous system is endowed with great regenerative capacity, responding immediately to injuries that occur along the length of the nerve. The aim of this study was to histomorphometrically assess the degree of maturity of the nervous tissue and possible microscopic changes in newly formed nerve segments 60 days after experimental neurotmesis of the sciatic nerve in rats. Control Group (CG) and an Injury Group (IG) were used. IG underwent neurotmesis of the sciatic nerve of the right foot, with immediate surgical repair using the tubulization technique. 60 days following experimental surgery, animals from both groups had their sciatic nerves collected for histomorphometric analysis. Statistical analysis was performed, using the Student t-test for independent samples, expressed as mean ± standard deviation, with 5% significance. In the event of injury, peripheral nerve tissue is mobilized in an intrinsic self-healing process. 60 days following of nerve regeneration in neurotmesis injury, the peripheral nerve presents a segment joining the newly formed neural stump. The new stump has a number of regenerated axons compatible with an intact nerve, but which still show great immaturity in the axonal structural layers of the nerve.

Mediante diversos procesos celulares y moleculares, el sistema nervioso periférico tiene una gran capacidad regenerativa, respondiendo inmediatamente a las lesiones ocurridas a lo largo de su extensión. El objetivo de este estudio fue evaluar histomorfométricamente el grado de madurez del tejido nervioso y los posibles cambios microscópicos en los segmentos nerviosos recién formados 60 días después de la neurotmesis experimental en el nervio ciático de ratas. Se utilizaron 9 ratas (Wistar) separadas en grupo control (GC, n= 4) y Grupo lesión (GL, n= 5). A los 60 días de vida, el grupo GL fue sometido a neurotmesis del nervio ciático de la miembro posterior derecho, con inmediata corección quirúrgica con la técnica de tubolización. Completados 60 días luego de la cirugía experimental, los animales de ambos grupos fueron anestesiados y sus nervios ciáticos seccionados para el análisis histomorfométrico. Se realizó un análisis estadístico utilizando la prueba t de Student para muestras independientes, expresado como media ± desviación estándar, con un 5% de significancia. A los 60 días de la lesión por neurotmesis, el nervio ciático del GL presentó alteraciones histomorfométricas significativas para las variables: número de vasa nevorum, densidad de fibras mielínicas, diámetro axonal y de fibras mielínicas, espesor de la vaina de mielina y razón G, con similitud solamente para los números absolutos de fibras mielínicas regeneradas. El nervio periférico durante su proceso regenerativo, pasa por grandes alteraciones estructurales, siguiendo una secuencia coordinada de acciones, que dependiendo de las condiciones del microambiente donde ocurre esta regeneración, podrá ser clave para el nivel de regenerecion nerviosa periférica.

Evidence of bidirectional flow in the sciatic vasa nervorum.

The purpose of this study was to determine whether bidirectional flow exists in the sciatic vasa nervorum. Images obtained using high-frequency color Doppler ultrasound in duplex imaging mode (Vevo 2100) were studied retroactively. In Fig. 1 (left panel; rat 1), the color Doppler signal and flow-velocity waveforms are indicative of pulsatile flow traveling towards (B) and away (C) from the probe. In the right panel (Fig. 1; rat 2), there appears to be three distinct vessels, reflective of non-pulsatile negative flow (D), and pulsatile positive (E) and negative (F) flows. These data confirm the presence of bidirectional arterial flow in the sciatic vasa nervorum. Investigating bidirectional flow in the intact whole nerve may be helpful in elucidating novel features of nerve blood flow control in healthy and diseased states.