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Background: Digital neurovascular bundle defects are often encountered during crush or avulsion injuries and require complex reconstruction. Use of an arterialized nerve graft (neurovascular graft) serving both as an interpositional arterial conduit and as a nerve graft could be a reconstructive option in these cases. In this anatomical study, the authors aimed to describe a neurovascular graft of the posterior interosseous nerve and a branch of the anterior interosseous artery for neurovascular bundle reconstruction of the fingers., Methods: Eighteen forearms were injected with red latex in order to collect the anatomical characteristics of the posterior interosseous nerve and the artery running near it., Results: In all cases, the posterior interosseous nerve was followed by a branch of the anterior interosseous artery: the distal dorsal branch of the anterior interosseous nerve. The origin of this artery was proximal to the radiocarpal joint, at an average of 56.5 ± 11.1 mm. The proximal and distal diameters of the branch of the anterior interosseous artery were 1.6 ± 0.2 and 1.1 ± 0.2 mm, respectively. The proximal and distal diameters of the posterior interosseous nerve were 1.2 ± 0.3 mm and 1.1 ± 0.3 mm, respectively., Conclusions: These results show that a potential free neurovascular graft using the posterior interosseous nerve as nerve graft and the anterior interosseous artery as an arterial bypass to reconstruct both the nerve and arterial tree of the finger could be a useful approach. The authors speculate that this graft could be used to reconstruct the neurovascular bundle of amputated or devascularized digits., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Peripheral nerves are provided with a blood-nerve barrier which prevents the invasion of harmful substances and pathogens, and also regulates metabolic and ionic homeostasis within nerve fascicles. The barrier functions are attributed to both the concentric layer of flattened cells in the perineurium and blood vessels running in the endoneurium. The perineurial cells develop continuous tight junctions as a diffusion barrier. In order to take up a predominant nutrient, glucose, the perineurium as well as endoneurial capillaries expresses GLUT1, a glucose transporter. An axon-Schwann cell complex within peripheral nerves utilizes glucose as a major energy source via the GLUT1, as does the brain. Under conditions of a reduced utilization of glucose, only the perineurial cells can transfer other nutrients, namely monocarboxylates such as ketone bodies and lactate via MCT1. Thus, MCT1 colocalizes with GLUT1 in the perineurium but not in endoneurial capillaries. To identify the cellular origins of the nerve sheath, marker proteins such as glial specific S100 protein, GLUT1, endoneurial CD34, and EMA (epithelial membrane antigen) are useful. Immunohistochemical findings for these markers are reviewed in this paper, focusing on the perineurium and endoneurium and their derivatives, Pacinian and Meissner corpuscles. Growing evidence throws light on the critical involvement of the nerve sheaths in the development, maintenance, and diseases of peripheral nerves.

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood-nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models.

The quantitative analysis of blood vessel networks is an important component in many animal models of disease. We describe a nondestructive technique for blood vessel imaging that visualizes in situ vasculature in harvested tissues. The method allows for further analysis of the same tissues with histology and other methods that can be performed on fixed tissue. Consequently, it can easily be incorporated upstream to analysis methods to augment these with a three-dimensional reconstruction of the vascular network in the tissues to be analyzed. The method combines iodine-enhanced micro-computed tomography with a deep learning algorithm to segment vasculature within tissues. The procedure is relatively simple and can provide insight into complex changes in the vascular structure in the tissues.

Objective: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs)., Methods: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients., Results: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( p < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( p < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels ( p < 0.01) and epineurial vessels occluded by intraluminal eosinophils ( p < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group ( p < 0.01)., Conclusions: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients., (© 2020 American Academy of Neurology.)

Olfaction is critical for survival in neonatal mammals. However, little is known about the neural substrate for this ability as few studies of synaptic development in several olfactory processing regions have been reported. Odor information detected in the nasal cavity is first processed by the olfactory bulb and then sent via the lateral olfactory tract to a series of olfactory cortical areas. The first of these, the anterior olfactory nucleus pars principalis (AONpP), is a simple, two layered cortex with an outer plexiform and inner cell zone (Layers 1 and 2, respectively). Five sets of studies examined age-related changes in the AONpP. First, immunocytochemistry for glutamatergic (VGlut1 and VGlut2) and GABAergic (VGAT) synapses demonstrated that overall synaptic patterns remained uniform with age. The second set quantified synaptic development with electron microscopy and found different developmental patterns between Layers 1 and 2. As many of the interhemispheric connections in the olfactory system arise from AONpP, the third set examined the development of crossed projections using anterograde tracers and electron microscopy to explore the maturation of this pathway. A fourth study examined ontogenetic changes in immunostaining for the proteoglycans aggrecan and brevican, markers of mesh-like extracellular structures known as perineuronal nets whose maturation is associated with the end of early critical periods of synaptogenesis. A final study found no age-related changes in the density of vasculature in the peduncle from P5 to P30. This work is among the first to examine early postnatal changes in this initial cortical region of the olfactory system., (© 2019 Wiley Periodicals, Inc.)

Peripheral nerve regeneration remains a challenge in tissue engineering and regenerative medicine. However, the existing approaches have limited regenerative capability. 3D-printed nerve conduits with well-defined properties are potent tools to facilitate peripheral nerve regeneration after injuries. Meanwhile, the vascular networks within the constructs can promote the exchange of oxygen, neurotrophic factors, and removal of waste products, thereby providing an advantageous microenvironment for tissue regeneration. It will be an interesting approach to integrate 3D-printed nerve conduit with vascular networks for the guidance of regenerated nerves. We hypothesize that 3D-printed vascularized nerve conduit will be an effective platform to promote nerve regeneration and functional restoration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The crosstalk between vascularization and nerve regeneration in the peripheral nervous system has recently been suggested to play an important role in the treatment of peripheral nerve injury. Regenerative strategies via synergistic delivery of multiple biochemical cues have received growing attention, especially the combination of pro-angiogenic factors and neurotrophic factors. Here we developed a self-assembling peptide nanofiber hydrogel dual-functionalized with vascular endothelial growth factor (VEGF)- and brain-derived neurotrophic factor (BDNF)-mimetic peptide epitopes for peripheral nerve reconstruction. It could simultaneously present VEGF- and BDNF-mimetic peptide epitopes and provides a three-dimensional (3D) neurovascular microenvironment for endothelial cell and neural cell growth. In vitro cellular experiments showed that the functionalized peptide hydrogel scaffold effectively promoted the pro-myelination of Schwann cell, as well as the adhesion and proliferation of endothelial cell compared with scaffolds presenting VEGF- or BDNF-mimetic peptide epitope alone. When implanted in a rat model to bridge a critical-size sciatic nerve gap in vivo, the functionalized peptide hydrogel significantly improved the number of newly formed blood vessels, the density of regenerating axons, the morphometric analysis of the regenerated muscles and the electrophysiological findings, indicating the synergistic effect of the two bioactive motifs on peripheral nerve regeneration. Collectively, constructing an artificial neurovascular microenvironment in the lesion area by using the functionalized self-assembling peptide nanofiber hydrogel may have a great potential for promoting nerve tissue engineering and regeneration in other tissues.

Biofabricated nanostructured and microstructured scaffolds have exhibited great potential for nerve tissue regeneration and functional restoration, and prevascularization and biotransportation within 3D fascicle structures are critical. Unfortunately, an ideal internal fascicle and microvascular model of human peripheral nerves is lacking. In this study, we used microcomputed tomography (microCT) to acquire high-resolution images of the human sciatic nerve. We propose a novel deep-learning network technique, called ResNetH3D-Unet, to segment fascicles and microvascular structures. We reconstructed 3D intraneural fascicles and microvascular topography to quantify the fascicle volume ratio (FVR), microvascular volume ratio (MVR), microvascular to fascicle volume ratio (MFVR), fascicle surface area to volume ratio (FSAVR), and microvascular surface area to volume ratio (MSAVR) of human samples. The frequency distributions of the fascicle diameter, microvascular diameter, and fascicle-to-microvasculature distance were analyzed. The obtained microCT analysis and reconstruction provided high-resolution microstructures of human peripheral nerves. Our proposed ResNetH3D-Unet method for fascicle and microvasculature segmentation yielded a mean intersection over union (IOU) of 92.1% (approximately 5% higher than the U-net IOU). The 3D reconstructed model showed that the internal microvasculature runs longitudinally within the internal epineurium and connects to the external vasculature at some points. Analysis of the 3D data indicated a 48.2 ± 3% FVR, 23.7 ± 1.8% MVR, 4.9 ± 0.5% MFVR, 7.26 ± 2.58 mm -1 FSAVR, and 1.52 ± 0.52 mm -1 MSAVR. A fascicle diameter of 0.98 mm, microvascular diameter of 0.125 mm, and microvasculature-to-fascicle distance of 0.196 mm were most frequent. This study provides fundamental data and structural references for designing bionic scaffolding constructs with 3D microvascular and fascicle distributions., (© 2019 John Wiley & Sons, Ltd.)

Background: Entrapment neuropathies include a wide field of locations. In most cases, the microsurgical decompression is still the therapy of choice. However, the role of venous stasis and ischemia is still discussed controversially. Here the authors evaluated the visualization of microvessels and the microperfusion at peripheral nerves with a contact endoscope during the surgical decompression for the first time., Methods: Eight patients were subjected to endoscopic or endoscopically assisted peripheral nerve decompression. In 3 patients with nerve tumors, the tumor carrying nerve was inspected endoscopically proximal and distal to the tumor site before and after resection. Microcirculation was assessed by a contact endoscope, allowing a 150-fold magnification, at superficial areas proximal and distal to the compression site. The electronically stored records were analyzed retrospectively using image processing software. Vessel diameter, red blood cell velocity, and blood flow, before and after decompression, were extracted., Results: The contact endoscope was easy to handle intraoperatively without problems. All minimally invasive procedures were performed without complications. In the offline computer-assisted analysis, single arterioles and veins were visualized showing decreased red blood cell velocity prior to decompression. After surgical treatment, a statistically significant increase of blood flow was observed., Conclusions: Basically, the application of a contact endoscope for visualization of peripheral nerves' microcirculation is feasible. The observed effect of increased blood flow after decompression should be compared with the clinical outcome in a further prospective randomized study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2017 Wiley Periodicals, Inc.)

Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in diabetic neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells. Diabetic rats and high glucose-exposed N2A cells showed reduction in SIRT1 expression with consequent decline in mitochondrial biogenesis and autophagy. ILQ (10 & 20 mg/kg, po) administration to diabetic rats for 2 weeks and exposure to glucose-insulted N2A cells resulted in significant SIRT1 activation with concurrent increase in mitochondrial biogenesis and autophagy. ILQ administration also enhanced NAD + /NADH ratio in peripheral sciatic nerves which explains its possible SIRT1 modulatory effect. Functional and behavioural studies show beneficial effect of ILQ as it alleviated nerve conduction and nerve blood flow deficits in diabetic rats along with improvement in behavioural parameters (hyperalgesia and allodynia). ILQ treatment to N2A cells reduced high glucose-driven ROS production and mitochondrial membrane depolarization. Further, ILQ-mediated SIRT1 activation facilitated the Nrf2-directed antioxidant signalling. Overall, results from this study suggest that SIRT1 activation by ILQ mimic effects of calorie restriction, that is, PGC-1α-mediated mitochondrial biogenesis, FOXO3a mediated stress resistance and AMPK mediated autophagy effects to counteract the multiple manifestations in experimental DN., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Regression of myelinated peripheral nerve fibers in the lower extremities contributes to sarcopenia and balance dysfunction in normal aging. This subclinical regression of myelinated fibers (MFs) is heavily influenced by alterations in microvasculature, though the mechanism underlying these age-related degenerative phenomena remains unclear. The aim of the present study was to examine age-related regressions in myelinated distal peripheral nerve fibers as well as capillary architecture in rats using both morphological and histochemical methods., Results: MFs were categorized into tertiles of 'large', 'medium', and 'small' sizes based on the distribution of MF diameters. A two-way ANOVA was used to assess effects of fiber size (large/medium/small) and group (young/elderly) on myelin thickness, axon diameter, myelin perimeter, axon perimeter, and G-ratio (axon diameter/fiber diameter). Significant main effects were observed for both MF size and group with respect to all dimensions except for G-ratio. Values for fiber diameter (P < 0.01), myelin thickness (P < 0.01), axon diameter (P < 0.01), myelin perimeter (P < 0.01), and axon perimeter (P < 0.01) were significantly lower than those in the young group. Additionally, mean capillary diameter and number of microvascular branch points were significantly lower in the elderly group than in the young group., Conclusions: The present study demonstrated that spontaneous age-related regression predominantly occurs for all fiber sizes in the distal peripheral nerves and the capillary architecture. The results of the present study further suggest that both the distal MFs and capillaries in the peripheral nerve may simultaneously regress with aging.

The repair of large crushed or sectioned segments of peripheral nerves remains a challenge in regenerative medicine due to the complexity of the biological environment and the lack of proper biomaterials and architecture to foster reconstruction. Traditionally such reconstruction is only achieved by using fresh human tissue as a surrogate for the absence of the nerve. However, recent focus in the field has been on new polymer structures and specific biofunctionalization to achieve the goal of peripheral nerve regeneration by developing artificial nerve prostheses. This review presents various tested approaches as well their effectiveness for nerve regrowth and functional recovery., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

Background: Better postoperative results can be expected in nerve reconstruction when vascularized nerve grafts are used. Previous studies reported reconstruction with flaps including "vascularized" nerves; however, few have evaluated blood supply to these nerves. The aim of this study was to quantitatively assess blood perfusion to nerves included in anterolateral thigh (ALT) flaps by indocyanine green (ICG) fluorescence angiography., Patients and Methods: Participants comprised eight patients who underwent reconstructive surgery with nerve defects using free ALT flaps, including the vastus lateralis motor nerve and/or femoral cutaneous nerve. Intraoperative ICG fluorescent angiography was performed. Time after the drug injection and the intensity of fluorescence in these nerves were analyzed as time-intensity curves. Maximum intensity (Imax), time to Imax (Tmax), and time at the beginning of intensity elevation (Te) were measured at three points: Point C, the central portion of the flap-attached region of the nerve; Point P, 2 cm from the proximal flap-attached edge; and Point D, 2 cm from the distal edge., Results: Imax and Te at point C and Imax/Tmax-Te at point P were significantly different between these two nerves (p = 0.03125, p = 0.02895, p = 0.03125, respectively). Fluorescence in the vastus lateralis motor nerve was slightly quicker and stronger than that in the femoral cutaneous nerve, and also exhibited an axial pattern of fluorescence., Conclusion: Intraoperative ICG fluorescent angiography can be used to determine which nerve is better for nerve reconstruction. The indexes of Imax, Te, and Imax/Tmax-Te may be the suitable criteria for decision making regarding donor nerve selection., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The present study investigates the vascular anatomy of the vastus lateralis motor nerve (VLMN) to be used as a vascularized nerve graft in facial nerve reconstruction. We evaluated the maximum length of the nerve that can be included in the flap and its vascular pedicle. In addition, we discuss its adequacy for use in early reconstruction of the facial nerve both as ipsilateral facial nerve reconstruction and as cross-facial nerve graft., Methods: Five fresh cadavers were used in this study. In all specimens, the VLMN and its vascular pedicle were dissected, photodocumented and measured using calipers. In addition, two vascularized VLMN were injected with a radiopaque contrast and underwent CT angiography and three dimensional reconstructions were scanned to illustrate the vascular supply of the nerve using OsiriX Software., Results: The VLMN was divided into two divisions, an oblique proximal and a descending distal, in 70% of the dissections with a mean maximal length of 8.4 ± 4.5 cm for the oblique division and 15.03 ± 3.87 cm for the descending division. The length of the oblique division, when present, was shorter than the length of the descending branch in all specimens. The mean length of the pedicle was 2.93 ± 1.69 cm, and 3.27 ± 1.49 cm until crossing the oblique and the descending division of the nerve respectively. The mean caliber of the nerve was 2.4 ± 0.62 mm. Three-dimensional computed tomography angiography demonstrated perfusion throughout the entire VLMN by branches from the descending branch of the lateral femoral circumflex artery which ran parallel to the descending division of the VLMN. Additionally, we observed that technically it was possible to preserve the oblique branch of the VLMN., Conclusion: This study confirms that VLMN presents adequate anatomic features to be used as a vascularized nerve graft for facial nerve reconstruction in terms of length, pedicle, and caliber., (© 2014 Wiley Periodicals, Inc.)

In this study, the venous drainage patterns of white New Zealand rabbits' peripheral nerves were examined in an effort to provide an animal model for studies focusing on the venous drainage of the healing nerves. Extremities of rabbits sacrificed via intraarterial lead oxide-gelatin solution, and thus had their peripheral bloods pushed out of the arteries and into the veins were dissected for the venous drainage of radial, median, ulnar, femoral, sciatic, tibial and fibular nerves. The observations revealed that white New Zealand rabbit was a feasible model due to its consistent venous anatomy draining the major nerves and accessibility and workability of them. Of those dissected, the most suitable set of nerves suitable for such studies seem to be the Median nerve of the anterior extremity, and Sciatic nerve of the posterior extremity (Fig. 12, Ref. 16). Text in PDF www.elis.sk. Text in PDF www.elis.sk.

Purpose: The aim of this study was to establish dynamic contrast-enhanced perfusion in peripheral nerves for determination of blood-nerve permeability (K) and nerve blood volume (NBV) in peripheral neuropathies as compared with healthy controls., Methods: The study was approved by the institutional ethics committee, and written informed consent was obtained from all participants. Forty-three controls (24 women, 19 men; age, 48.7 ± 17.5 years) and 59 patients with peripheral neuropathy (28 women, 31 men; age, 52.7 ± 12.4 years) were examined by a standard protocol including a T1-weighted dynamic contrast-enhanced sequence (time of repetition/time of echo, 4.91/1.64; 10 slices; resolution 0.8 × 0.6 × 3.0 mm3). Time - signal intensity analysis was performed by normalizing to pre-bolus arrival and calculating the mean contrast uptake (MCU) for each patient. Further analyses were performed by customized software to calculate K trans and NBV. Statistical analysis included 2-sided Student's t tests of controls versus patients, receiver operating characteristic analysis, and subgroup analysis of patients according to etiologies of neuropathy., Results: Time-signal intensity analysis showed significantly increased contrast uptake in patients as compared with controls (MCU, 1.29 ± 0.15 vs 1.18 ± 0.08; P < 0.001). This was caused mainly by an increase in K trans (0.046 ± 0.025 vs 0.026 ± 0.016 min(-1); P < 0.001) and less by an increase in NBV (3.9 ± 2.6 vs 3.0 ± 1.9 mL/100 mL; P = 0.12). This trend was true for all etiologies except entrapment neuropathies. Excluding these, receiver operating characteristic analysis found an area under the curve of 0.78 (95% confidence interval, 0.69-0.89) for MCU and 0.77 (95% confidence interval, 0.65-0.90) for K to discriminate neuropathy from control., Conclusions: Dynamic contrast-enhanced perfusion is a feasible technique to assess K trans and NBV in peripheral nerves and may be used in future investigations on peripheral neuropathies.

Objective: Detection of nerve enlargement in polyneuropathies by sonography is a new research area. No systematic investigation has been done yet in chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore we investigated this in CIDP., Methods: Eleven patients with CIDP fulfilling the international criteria on CIDP underwent ultrasonographic examination of the median, ulnar, fibular and posterior tibial nerves and sometimes the brachial plexus bilaterally, using a standardized protocol. We assessed presence of nerve thickening and increased nerve vascularization., Results: In 7 of the 11 patients multiple nerve enlargements were detected: ulnar nerve 7, fibular nerve 5, posterior tibial nerve 4 and median nerve in 4 patients. The number of enlarged nerves was related with the MRC sum-score (p=0.03) and the total protein in the cerebrospinal fluid (CSF) at diagnosis (p=0.02). Increased vascularization was seen in 6 of the 11 patients: 4 in one nerve and in 2 in multiple nerves. The number of nerves with increased vascularization was associated with the number of enlarged nerves (p=0.01) and total protein in the CSF (p=0.006)., Conclusion: Multiple nerve enlargements occur in CIDP showing a relation with a lower MRC sum-score, increased nerve vascularization and a higher total protein of the CSF., Significance: Our findings of nerve enlargement and increased nerve vascularization may be tools to monitor disease activity in CIDP, but further studies are needed., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The international standard of nomenclature and classification in vasculitis, CHCC 1994,was revised as CHCC 2012. In the first part of this review article I briefly summarized the CHCC 2012 and pointed out the changes in this revision, especially on the disorders related to vasculitic neuropathy. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. In the second part, I mentioned the tips for the diagnosis and treatment of vasculitic neuropathy. Because most of the vasculitic neuropathy patients require rigorous, long-standing immunosuppressive therapy, the accurate diagnosis based on the pathological detection of vasculitic changes is mandatory. In this regard, the value of sural nerve biopsy is still not ignorable. In the treatment of vascultic neuropathy, there are no controlled treatment trials and clinical practice is guided by experience from case series and indirectly by analogy with systemic vasculitis. Although combined therapy using prednisolone and cyclophosphamide is usually recommended by experts, tailor-made treatment regimen based on the conditions of each patient would produce the best outcome in vasculitic neuropathy.

Background: Cadaveric studies have revealed that cutaneous perforators are linked by either reduced-caliber "choke" arteries, or by vessels without change in caliber, the true anastomoses. These true anastomotic vessels are often found in parallel with the cutaneous nerves and accompanying veins, and are associated both experimentally and clinically with larger areas of flap survival. The Doppler probe and computed tomographic angiography are already used preoperatively to determine perforator locations but currently cannot reveal the type of anastomotic connections., Methods: Thermal images were taken in a previously described fashion and compared with both computed tomographic angiographic studies where available and with cadaveric angiographic studies previously performed by the authors' laboratory., Results: Perforators larger than 1 mm were accurately localized by thermography when compared with computed tomographic angiography. Perforator angiosome rewarming closely approximated a log-based line of best fit. Interperforator zones were variable in their rewarming and correlated with known anatomical patterns of true and choke anastomoses between perforator angiosomes., Conclusions: Thermography now offers a new modality with which to bridge the gap not only by identifying the perforator "hot spots" but also by the robustness of their interconnections. The pattern of these interconnections seen on thermographic imaging has in turn been found to match those seen in the authors' cadaveric studies.

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Painful diabetic polyneuropathy (PDPN) is generally considered a variant of diabetic polyneuropathy (DPN) but the identification of distinctive aspects that characterize painful compared with painless DPN has however been addressed in many studies, mainly with the purpose of better understanding the mechanisms of neuropathic pain in the scenario of peripheral nerve damage of DPN, of determining risk markers for pain development, and also of recognizing who might respond to treatments. This review is aimed at examining available literature dealing with the issue of similarities and differences between painful and painless DPN in an attempt to respond to the question of whether painful and painless DPN are the same disease or not and to address the conundrum of why some people develop the insensate variety of DPN whilst others experience distressing pain. Thus, from the perspective of comparing painful with painless forms of DPN, this review considers the clinical correlates of PDPN, its distinctive framework of symptoms, signs, and nerve functional and structural abnormalities, the question of large and small fiber involvement, the peripheral pain mechanisms, the central processing of pain and some new insights into the pathogenesis of pain in peripheral polyneuropathies and PDPN.

We investigated whether the use of vascularized peripheral nerve grafts on the optic nerve stump enhances axonal regeneration of retinal ganglion cells compared with isolated nonvascularized grafts. The rat median nerve was microsurgically sutured with its supplying artery and vein to the optic nerve stump. The number of retinal ganglion cells with regenerating axons was evaluated by retrograde labeling into the grafted peripheral nerve, and the myelination of the regenerating axon fibers was examined by electron microscopy. The number of retinal ganglion cells with regenerating axons was significantly higher in the vascularized graft than in the nonvascularized graft. The ratio of myelinated axon fibers was also increased in vascularized grafts. Thus, grafting with their supplying arteries and veins to an injured nerve stump represents a promising strategy to accelerate axonal regeneration from neurons of the central nervous system.

Aim: To cover the large tissue deficits associated with significant loss of function following surgery, a 3D gel-patch-like nerve-vascular reconstitution system was developed using the skeletal muscle-derived multipotent stem cell (Sk-MSC) sheet pellet., Materials & Methods: The Sk-MSC sheet pellet was prepared from GFP transgenic mice by the collagenase extraction and 7 days expansion cell culture, and transplanted into a severe muscle damage model with large disruptions to muscle fibers, blood vessels and peripheral nerves., Results: At 4 weeks after transplantation, engrafted cells contributed to nerve-vascular regeneration associated with cellular differentiation into Schwann cells, perineurial/endoneurial cells, vascular endothelial cells and pericytes. However, skeletal myogenic differentiation was scarcely observed. Paracrine effects regarding donor cells/tissues could also be expected, because of the active expression of neurogenic and vasculogenic factor mRNAs in the sheet pellet., Conclusion: These results indicate that the vigorous skeletal myogenic potential of Sk-MSCs was clearly reduced in the sheet pellet preparation and this method may be a useful adjuvant for nerve-vascular regeneration in various tissue engineering applications.

The vascular anatomy at the spinoglenoid and suprascapular notches appears to be more variable than previously thought. In patients presenting with signs of suprascapular nerve compression, vascular causes must be considered. Especially when considering percutaneous or arthroscopic treatment, awareness of these entities may help to guide treatment decisions, aid in identification of the anatomy, and prevent unwanted vascular insult., (Copyright 2013, SLACK Incorporated.)

Microvasculature associated with the sciatic nerve was examined using high-resolution micro-CT scanning in one group of rats and surgical exploration in another. The results indicate that blood supply to the sciatic nerve is an "open-ended" system in which the vessels run longitudinally within the epineurium and connect with external vasculature primarily at junction points. Although the range of vasculature found extended down to 4-5 μ, only a few isolated vessels of this size were found, with no capillary "mesh" as such, possibly because of the close proximity of the intrinsic vessel to nerve fibers within the epineurium. While the study did not include direct measurements of flow or nerve function, the "open-ended" pattern of vasculature found has important implications regarding the relationship between the two. Specifically, the nerve is less vulnerable to a severe or complete disruption in blood supply than it would be under a close-ended system such as that of the heart or brain, where a severe disruption can occur with the obstruction of only a single vessel. Indeed, the pattern of vasculature found, subject to further study of vasculature at the capillary level, suggests that flow within the intrinsic vessels may be in either direction, depending on circumstances, somewhat like flow within the circle of Willis in the cerebral circulation., (© 2012 Peripheral Nerve Society.)

Purpose/objectives: To evaluate the evidence for strength- and balance-training programs in patients at high risk for falls, discuss how results of existing studies might guide clinical practice, and discuss directions for additional research., Data Sources: A search of PubMed and CINAHL® databases was conducted in June 2011 using the terms strength, balance training, falls, elderly, and neuropathy. Only clinical trials conducted using specific strength- or balance-training exercises that included community-dwelling adults and examined falls, fall risk, balance, and/or strength as outcome measures were included in this review., Data Synthesis: One matched case-control study and two randomized, controlled studies evaluating strength and balance training in patients with diabetes-related peripheral neuropathy were identified. Eleven studies evaluating strength and balance programs in community-dwelling adults at high risk for falls were identified., Conclusions: The findings from the reviewed studies provide substantial evidence to support the use of strength and balance training for older adults at risk for falls, and detail early evidence to support strength and balance training for individuals with peripheral neuropathy., Implications for Nursing: The evidence demonstrates that strength and balance training is safe and effective at reducing falls and improving lower extremity strength and balance in adults aged 50 years and older at high risk for falls, including patients with diabetic peripheral neuropathy. Future studies should evaluate the effects of strength and balance training in patients with cancer, particularly individuals with chemotherapy-induced peripheral neuropathy.

Purpose: The mechanical impact of a neighboring vessel on a "punched" nerve segment is thought to be one possible cause of compression neuropathy but has not been proven definitively. We report on 9 subjects with unclear clinical mononeuropathies in whom we could clearly define peripheral nerve impairment by such vessels on real-time high-resolution ultrasound (HRUS)., Materials and Methods: Nine subjects with unclear mononeuropathy based on clinical neurological examination were referred to our department for HRUS assessment. The shape, inner and outer echotexture, size and diameter, and overall integrity of these nerves were assessed including an exact analysis of the surrounding soft tissues to search for potentially extraneural pathology. This included duplex imaging to identify even tiny atypical vascular structures., Results: In all patients duplex HRUS showed the pulsatile and "punching" character of the relevant vessels and the direct mechanical impact of these vessel. The involved nerve segments appeared enlarged with a hypoechoic change of echotexture including at least partial masking of their inner fascicular texture., Conclusion: Although rare, a "punching" vessel can be the cause of a compression neuropathy. Therefore, duplex HRUS must be included in every HRUS examination of patients with otherwise unclear mononeuropathy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To clarify the orientation, classification, and relationships of the greater superficial petrosal nerve (GSPN), and to provide a detailed description on the microsurgical anatomic features and some landmarks to its identification., Methods: A microsurgical anatomic dissection of the GSPN was studied in 40 specimens obtained from 20 adult cadaveric heads fixed in formalin. The course of the GSPN and its relationship to neighboring anatomic structures were observed., Results: The GSPN could be divided into four segments: intrapetrosal, suprapetrosal, of foramen lacerum, and of pterygoid canal. About 17.5% (7/40) of GSPNs had communication with the glossopharyngeal nerve (GN). According to communication between the GSPN, internal carotid plexus, and GN, the segment of the foramen lacerum could be divided into five types. The middle meningeal artery and internal maxillary artery were the major blood suppliers of the GSPN. The GSPN usually ran parallel with the lesser petrosal nerve, but sometimes they were at angle to each other., Conclusions: The relationships between the GSPN and its surrounding structures were studied. The vulnerability of the GSPN is attributed to diverse factors. We confirmed the communication branches between the GSPN and the GN. Our study is important to the understanding of the relationship of the GSPN with adjacent structures and will improve further information during skull base operations., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rationale and Objectives: Blood perfusion of peripheral nerves plays an important role in regeneration after nerve injury. Functional recovery after a peripheral nerve injury depends not only on the survival of the affected neurons but also on the recovered blood perfusion. Previous studies have shown that it is possible to quantitatively assess blood perfusion of tissue using contrast-enhanced ultrasound (CEUS). The aim of this study was to evaluate the usefulness of CEUS for the quantitative evaluation of blood perfusion of the sciatic nerves with crush injury., Materials and Methods: Crush injuries were created in the left sciatic nerve of 30 New Zealand white rabbits. CEUS of the bilateral sciatic nerves was performed in six experimental rabbits at 3 days, 1 week, 2 weeks, 4 weeks, and 8 weeks after injury. Pulse-inversion harmonic imaging was used for real-time CEUS. The other six rabbits were used as a control group. Serial laser Doppler measurements of blood flow and quantitative histologic evaluation were performed parallel to CEUS on all animals., Results: Quantitative analysis of CEUS showed that the perfusion index of the crushed sciatic nerves was increased at 3 days after injury, with a peak at 1 week after injury (P = .000). The area under the curve for the crushed sites was increased at 3 days after injury, with a peak at 2 weeks after injury (P = .000). The mean transit time and maximum intensity of the crushed site of the left sciatic nerves were not significantly changed during the 2 months after injury (P = .335 and P = .157 respectively). The perfusion indices measured by CEUS correlated well with those measured by laser Doppler (r = 0.791, P = .000). Marked Wallerian degeneration was found at the crushed site of sciatic nerves at 3 days after injury. The percentage of degenerated myelinated axons was increased during the first 2 weeks after injury and then decreased during the following period. Regenerated axons with small diameter and thin myelin sheaths were found at 2 weeks after injury and during the following period., Conclusions: CEUS may provide a new imaging method to quantitatively analyze blood perfusion of injured peripheral nerves., (Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.)

Introduction: The placement of a vascularized nervous graft is an option for acute nervous injuries treatment, as this has demonstrated a longer viability., Objective: To carry out a macroscopic and microscopic analysis of the vascularity of the main lower limb nerves used as vascularized nervous grafts., Materials and Methods: It was followed out a descriptive, transversal and non-comparative study to analyse the saphenous, the sural, the deep peroneal and the superficial peroneal nerves vascularity. This study was performed in two stages: 1) an in situ vascularity study and 2) a morphometric study., Results: By the in situ study, it was demonstrated the following: the total length of the lower limb nerves used as graft, was in a decrease order: sural nerve (micro = 29.26 cm, +/- 4.05 cm), superficial peroneal nerve (micro = 28.61 cm, +/- 3.97 cm), deep peroneal nerve (micro = 26.64 cm, +/- 5.21 cm) and saphenous nerve (micro = 25.12 cm, +/- 4.42 cm). The morphometric study demonstrated that the dominant artery with the major diameter belongs to the saphenous nerve, with a diameter of 1.13 mm; then we have the superficial peroneal nerve with a 1.01 mm diameter, followed by the deep peroneal nerve with 0.91 mm, and finally the sural nerve with the smallest diameter, 0.85 mm., Conclusions: The saphenous nerve has the most appropriated morphological characteristics to be used as a vascularized graft; by the contrary the deep peroneal nerve represents the last option from all the nerves included in this study.

Treatment of the chronic painful nerve by pedicled or free tissue transfer is a complex surgical procedure, requiring specialized microsurgical training and technique. This procedure is indicated only in patients who have had repeated failure of simpler, conventional procedures. Patients with chronic painful peripheral nerves may be potentially salvaged by external neurolysis and circumferential wrapping of the involved segments of nerve with well-vascularized pedicled or free flaps of fascia, subcutaneous fatty tissue, omentum or muscle, or by the replacement of superficial hypersensitive cutaneous areas and nerves with the same tissues., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study was designed to determine if cigarette smoking adversely affects functional recovery following ischemia/reperfusion (I/R) injury in peripheral nerves. Forty Wistar rats were divided evenly among four groups. Animals in groups A and B were exposed to cigarette smoke via a controlled smoking chamber for 20 minutes daily. On study day 14, all animals underwent a controlled I/R injury to one sciatic nerve. Recovery was assessed with walking track assessments, malondialdehyde (MDA) assay, and histology. Walking track results on study day 21 did not differ significantly between the smoking and nonsmoking animals. However, by study day 28, the nonsmoking animals showed a greater degree of functional recovery (SFI = -18.0 and -22.8, respectively, P = 0.03). MDA concentration in the smoking group was significantly higher than the nonsmoking group at the 28 day time point (P = 0.04). Exposure to cigarette smoke was associated with a slower functional recovery following peripheral nerve I/R injury., (Copyright © 2010 Wiley-Liss, Inc.)

The blood-nerve barrier (BNB) defines the physiological space within which the axons, Schwann cells, and other associated cells of a peripheral nerve function. The BNB consists of the endoneurial microvessels within the nerve fascicle and the investing perineurium. The restricted permeability of these two barriers protects the endoneurial microenvironment from drastic concentration changes in the vascular and other extracellular spaces. It is postulated that endoneurial homeostatic mechanisms regulate the milieu intérieur of peripheral axons and associated Schwann cells. These mechanisms are discussed in relation to nerve development, Wallerian degeneration and nerve regeneration, and lead neuropathy. Finally, the putative factors responsible for the cellular and molecular control of BNB permeability are discussed. Given the dynamic nature of the regulation of the permeability of the perineurium and endoneurial capillaries, it is suggested that the term blood-nerve interface (BNI) better reflects the functional significance of these structures in the maintenance of homeostasis within the endoneurial microenvironment.

The blood-nerve barrier (BNB) is one of the functional barriers sheltering the nervous system from circulating blood. It is very important to understand the cellular properties of endothelial cells of endoneurial origin because these cells constitute the bulk of the BNB. This chapter describes a standard protocol for isolating the endothelial cells forming the BNB. In addition, methods for confirming some of the barrier properties of isolated endothelial cells are also described.

Rationale and Objectives: The blood perfusion of peripheral nerves plays an important role in regeneration after nerve injury. Previous studies have shown that it is possible to quantitatively assess the blood perfusion of the tissue using contrast-enhanced ultrasound (CEUS). The aim of this study was to evaluate the feasibility of CEUS for quantitative assessment of the blood perfusion of the sciatic nerve in normal New Zealand white rabbits and to compare these parameters to those of surrounding skeletal muscle and the main artery in the thigh., Materials and Methods: CEUS of the bilateral sciatic nerves was performed in 12 normal New Zealand white rabbits after a bolus injection of SonoVue (0.13 mL/kg). Pulse-inversion harmonic imaging was used for real-time CEUS. The blood perfusion of the left sciatic nerve was compared to that of its surrounding muscle, the arterial branch in the thigh, and the contralateral side., Results: The supplying arteries in the sciatic nerve could be demonstrated during the early phase of CEUS, followed by the homogeneous enhancement of the whole nerve. The area under the curve and the perfusion index of the sciatic nerve were higher than those of the surrounding muscle and lower than those of the arterial branch in the thigh (both P values = .000). The maximum intensity of the sciatic nerve was similar to that of skeletal muscle and lower than that of the arterial branch. The time to peak was not significantly different among the sciatic nerve, skeletal muscle, and arterial branch (P = .551). There were no differences in area under the curve, mean transit time, perfusion index, maximum intensity, and time to peak between the left and right sciatic nerves (P > .05)., Conclusions: CEUS may be a feasible method for the quantitative assessment of blood perfusion of the peripheral nerves., (Copyright © 2010 AUR. Published by Elsevier Inc. All rights reserved.)

Salmon has described first the vascularisation of the posterior cutaneous nerve in 1936. Since, few articles have described the collaterals of the artery accompanying the posterior cutaneous nerve. The authors conducted an anatomical study on 20 cadaveric dissections with injection in order to define the collaterals of the artery. The findings reveal an artery nourished proximally by fasciocutaneous branches of the profunda perforating arteries and distally by branches from popliteal and genicular arteries. Their association is variable., (2009 Elsevier Masson SAS. All rights reserved.)

Aim: Interleukin-6 (IL-6), a member of the neuropoietic cytokine family, participates in neural development and has neurotrophic activity. Recent research has also indicated actions to improve vasa nervorum function in diabetes. Both these facets are potentially relevant for treatment of diabetic neuropathy. The aim of this study was to determine whether IL-6 treatment corrected changes in neurovascular function in streptozotocin-induced diabetic rats., Methods: After 1 month of diabetes, rats were given IL-6 for 1 month. The rats were subjected to sensory testing and measurements of nerve conduction velocities and nerve blood flow by hydrogen clearance microelectrode polarography. Further groups were used to study responses of the isolated gastric fundus and renal artery. Results were statistically analysed using ANOVA and post hoc tests., Results: Diabetic rats showed mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia. The former was unaffected by IL-6 treatment, whereas the latter two measures were corrected. Immunohistochemical staining of dorsal root ganglia for IL-6 did not reveal any changes with diabetes or treatment. The results showed that 22 and 17.4% slowing of sciatic motor and saphenous sensory nerve conduction velocities, respectively, with diabetes were improved by IL-6. Sciatic endoneurial perfusion was halved by diabetes and corrected by IL-6. A 40.6% diabetic deficit in maximal non-adrenergic, non-cholinergic relaxation of gastric fundus to nerve stimulation was unaffected by IL-6. Renal artery endothelium-dependent relaxation was halved by diabetes, the endothelium-derived hyperpolarizing factor (EDHF) component being severely attenuated. IL-6 did not affect nitric oxide-mediated vasorelaxation, but markedly improved EDHF responses., Conclusions: IL-6 improved aspects of small and large nerve fibre and vascular endothelium dysfunction in diabetic rats. The functional benefits related to increased nerve blood flow via an EDHF mechanism, and IL-6 could have therapeutic potential in diabetic neuropathy and vasculopathy, which should be further evaluated.

Should the palmar digital artery be repaired in the pedicular section of the finger? This repair is discussed in the case of a unilateral pedicular lesion on a vascularised finger, and often neglected in current surgical practice. The problem is knowing the role of a permeable artery in sensory recovery and cold intolerance. The author presents a retrospective study on palmar digital nerve reinnervation after section with or without palmar digital artery section. Artery permeability was studied by doppler ultrasonography. Forty nerves in 35 patients were studied after at least 3 years had passed. Twenty-five nerves were associated with a permeable artery, 15 with a non permeable artery. The functional result was evaluated with the Weber test (S2PD) and by the presence or absence of cold intolerance. This work demonstrates the statistically significant role of the palmar digital artery in sensitive recovery quality and cold intolerance appearance. Its permeability ensures a better sensitive result with an 8.84 mm S2PD versus 13.47 mm with a non permeable artery. The benefit of the systematic repair of palmar digital artery is thus demonstrated for the first time. This repair is all the more justified if local conditions are unfavorable, in particular in contuse wounds with associated lesions (tendinous or bone)., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)