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Macrophages are present in all mammalian tissues and coexist with various cell types in order to respond to different environmental cues. However, the role of these cells has been underestimated in the context of peripheral nerve damage. More importantly, macrophages display divergent characteristics, associated with their origin, and in response to the modulatory effects of their microenvironment. Interestingly, the advent of new techniques such as fate mapping and single-cell transcriptomics and their synergistic use has helped characterize in detail the origin and fate of tissue-resident macrophages in the peripheral nervous system (PNS). Furthermore, these techniques have allowed a better understanding of their functions from simple homeostatic supervisors to chief regulators in peripheral neuropathies. In this review, we summarize the latest knowledge about macrophage ontogeny, function and tissue identity, with a particular focus on PNS-associated cells, as well as their interaction with reactive oxygen species under physiological and pathological conditions. We then revisit the process of Wallerian degeneration, describing the events accompanying axon degeneration, Schwann cell activation and most importantly, macrophage recruitment to the site of injury. Finally, we review these processes in light of internal and external insults to peripheral nerves leading to peripheral neuropathies, the involvement of macrophages and the potential benefit of the targeting of specific macrophages for the alleviation of functional defects in the PNS. Graphical Abstract

Purpose We compared oncologic outcomes of laparoscopic surgery following self-expandable metallic stent (SEMS) insertion with one-stage emergency surgical treatment of obstructive left-sided colon and rectal cancers. Methods From April 1996 to October 2007, 95 consecutive patients with left-sided obstructive colorectal cancers were included: 25 underwent preoperative stenting and elective laparoscopic surgery (SLAP) and 70 underwent emergency open surgery with intraoperative colon lavage (OLAV). Long-term oncologic outcomes were analyzed on an intention-to-treat basis. Results There were no significant differences in baseline characteristics of patients between groups. Perineural invasion of the primary tumor was more frequent with SLAP (76 vs. 51.4 %, p  = 0.033). The median follow-up was 51 months (range, 4–139 months). There were no significant differences between groups in 5-year overall survival rates (SLAP vs. OLAV, 67.2 vs. 61.6 %, p  = 0.385). Five-year disease-free survival rates were also similar between groups (SLAP vs. OLAV, 61.2 vs. 60.0 %, p  = 0.932). Conclusions Laparoscopic surgery after SEMS was feasible and safe for patients with obstructive left-sided colorectal cancer, and oncologic outcomes were comparable to emergency open surgery with intraoperative colon lavage. These results support the continued use of SLAP in this setting. Further large-scale study is needed to investigate any clinical impact attached to the higher rates of perineural invasion observed in SLAP.

Background: It is important that the peripheral nerve (PN) pathologies are identified early as most patients are young, and delay in treatment can have lasting implications. Magnetic resonance imaging (MRI) is routinely used in formulating an appropriate management plan. Objectives: This study was aimed at assessing usefulness and efficacy of MRI in diagnosing PN pathologies by comparing the preoperative MRI findings with the intraoperative findings, thereby helping in prognostication and treatment planning. Methods and Material: It was a double-blind prospective, nonrandomized study of diagnostic efficacy that was conducted on 95 surgically treated patients with PN pathologies in the Department of Neurosurgery. The radiologist conducted a preoperative MRI evaluation, while one of the coauthors from the operating team had no access to the preoperative MRI scan findings. The senior operating neurosurgeon evaluated intraoperative findings, keeping the radiologist blind. The data were then compared to determine concordance and discordance between the two findings. Cohen's Kappa test was used for agreement. Diagnostic analysis was performed using Medcalc software (version 22). A P value less than 0.05 was considered significant. Results: We found that the overall sensitivity of MRI for diagnosing PN problems was 97.52%, with a specificity of 91.95%, a positive predictive value of 89.39%, and a negative predictive value of 98.16%. The overall accuracy was found to be 94.24%, with Cohen's kappa value of 0.88, showing a strong level of agreement. Conclusions: MRI is an effective tool that helps in accurately diagnosing a plethora of PN problems with significant intraoperative correlation, ultimately helping in patient care and management.

Introduction Perineural invasion is a unique characteristic of pancreatic adenocarcinoma biology and is present in the majority of resected pathologic specimens. The purpose of this study was to understand the relationships between preoperative pain and perineural invasion in patients with pancreatic adenocarcinoma. Methods Fifty-two chemotherapy naive patients undergoing resection for pancreatic adenocarcinoma from 2012 to 2014 completed a previously validated Brief Pain Inventory survey for preoperative clinical pain scoring. Preoperative pain was correlated with multiple clinicopathologic features. Results Preoperative pain was not associated with pathologic cancer stage, lymph node status, lymph node positivity ratio, resection margin status, or tumor location within the pancreas. In the subgroup of pancreatic head cancers, pain interference with affect was associated with the absence of perineural invasion ( p  = 0.02). Patients with stage I cancer had higher pain interference scores than those with stage II cancer ( p  = 0.02). Conclusions Preoperative pain does not predict the presence of perineural invasion or other pathologic prognostic factors in patients with resectable pancreatic adenocarcinoma. Higher pain scores in pancreatic head cancers correlated with absence of perineural invasion and early cancer stage. The effects of preoperative pain on quality and interference of daily life deserve further investigation in larger prospective studies involving patients with pancreatic cancer.

Peripheral nerve injury is associated with spinal microgliosis which plays a pivotal role in the development of neuropathic pain behavior. Several agents of primary afferent origin causing the microglial reaction have been identified, but the type(s) of primary afferents that release these mediators are still unclear. In this study, specific labeling of C-fiber spinal afferents by lectin histochemistry and selective chemodenervation by capsaicin were applied to identify the type(s) of primary afferents involved in the microglial response. Comparative quantitative morphometric evaluation of the microglial reaction in central projection territories of intact and injured peripheral nerves in the superficial (laminae I and II) and deep (laminae III and IV) spinal dorsal horn revealed a significant, about three-fold increase in microglial density after transection of the sciatic or the saphenous nerve. Prior perineural treatment of these nerves with capsaicin, resulting in a selective defunctionalization of C-fiber afferent fibers failed to affect spinal microgliosis. Similarly, peripheral nerve injury-induced increase in microglial density was unaffected in rats treated neonatally with capsaicin known to result in a near-total loss of C-fiber dorsal root fibers. Perineural treatment with capsaicin per se did not evoke a significant increase in microglial density. These observations indicate that injury-induced spinal microgliosis may be attributed to phenotypic changes in injured myelinated primary afferent neurons, whereas the contribution of C-fiber primary sensory neurons to this neuroimmune response is negligible. Spinal myelinated primary afferents may play a hitherto unrecognized role in regulation of neuroimmune and perisynaptic microenvironments of the spinal dorsal horn.

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae , is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and (c) strategies to achieve early diagnosis and prevent neurologic impairment to reduce the large burden of disability among newly identified cases; and among those who endure long-term disability in spite of completing multidrug therapy.

Abstract Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.

Sufficient functional restoration of damaged peripheral nerves is a big clinical challenge. In this study, a nerve guide conduit (NGC) with selective permeability was prepared by rolling an asymmetrically porous polycaprolactone/Pluronic F127 membrane fabricated using a novel immersion precipitation method. Dual stimulation (nerve growth factor [NGF] as a biological stimulus and low-intensity pulse ultrasound [US] as a physical stimulus) was adapted to enhance nerve regeneration through an NGC. The animal study revealed that each stimulation (NGF or US) has a positive effect to promote the peripheral nerve regeneration through the NGC, however, the US-stimulated NGC group allowed more accelerated nerve regeneration compared with the NGF-stimulated group. The NGC group that received dual stimulation (NGF and US) showed more effective nerve regeneration behavior than the groups that received a single stimulation (NGF or US). The asymmetrically porous NGC with dual NGF and US stimulation may be a promising strategy for the clinical treatment of delayed and insufficient functional recovery of a peripheral nerve.

Objective: Neuropathy is a well-recognized feature in spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD), but the pattern of neuropathy is still a matter of debate. This study aimed to evaluate peripheral nerve involvement in MJD patients. Neurophysiological and clinical data were analyzed to distinguish neuronopathy from length-dependent distal axonopathy. Methods: In the present study we evaluated 26 patients with clinical and molecular-proven MJD and investigated their peripheral nerve involvement. Neurophysiological and clinical data were compared and correlated aiming to distinguish neuronopathy from distal axonopathy. Results: The neurophysiological evaluation showed that 42.3% of the patients had polyneuropathy. Among these patients, 81.8% presented neuronopathy. Conclusion: We concluded that neuronopathy is the most common form of peripheral nerve involvement in MJD patients.

Disruption of axonal integrity during injury to the peripheral nerve system (PNS) sets into motion a cascade of responses that includes inflammation, Schwann cell mobilization, and the degeneration of the nerve fibers distal to the injury site. Yet, the injured PNS differentiates itself from the injured central nervous system (CNS) in its remarkable capacity for self-recovery, which, depending upon the length and type of nerve injury, involves a series of molecular events in both the injured neuron and associated Schwann cells that leads to axon regeneration, remyelination repair, and functional restitution. Herein we discuss the essential function of the second messenger, cyclic adenosine monophosphate (cyclic AMP), in the PNS repair process, highlighting the important role the conditioning lesion paradigm has played in understanding the mechanism(s) by which cyclic AMP exerts its proregenerative action. Furthermore, we review the studies that have therapeutically targeted cyclic AMP to enhance endogenous nerve repair.