Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.

Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.

Predicting long-term outcomes in patients with classical trigeminal neuralgia following microvascular decompression with an MRI-based radiomics nomogram: a multicentre study.

OBJECTIVES: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). MATERIALS AND METHODS: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. RESULTS: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. K‒M survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). CONCLUSION: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. CLINICAL RELEVANCE STATEMENT: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. KEY POINTS: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments.

Proximal trigeminal nerve atrophy is associated with favourable outcomes and persistent facial numbness following percutaneous balloon compression for primary trigeminal neuralgia.

OBJECTIVE: Whether nerve atrophy can affect the prognosis of primary trigeminal neuralgia (PTN) patients undergoing percutaneous balloon compression (PBC) remains unclear. This study aimed to determine the association between nerve characteristics observed on preoperative magnetic resonance imaging (MRI) and PBC outcomes. METHODS: Between January 2019 and December 2022, a cohort of 58 patients with unilateral PTN treated with PBC were analysed retrospectively and included in this study. The relationship between MRI findings, including the proximal and distal nerve cross-sectional areas (CSAs), and favourable pain outcomes (BNI Grades I-III) was analysed through Kaplan‒Meier analysis. RESULTS: After a mean follow-up period of 23.8 ± 13.0 months (range, 6-50 months), 48 (82.8%) patients with PTN were pain free with or without medication. A smaller proximal CSA ratio (proximal CSA of the affected nerve/proximal CSA of the unaffected nerve) was significantly associated with favourable outcomes. The Kaplan-Meier survival analysis showed that patients with proximal nerve atrophy (proximal CSA ratio ≤ 87% after receiver operating characteristic curve analysis) had a higher estimated 4-year probability of maintaining a favourable outcome than those without nerve atrophy (94.4% vs. 30.8%, p = 0.005). In addition, patients with proximal nerve atrophy were more likely to suffer from postoperative persistent facial numbness. CONCLUSIONS: Proximal nerve atrophy is correlated with both favourable outcomes and persistent facial numbness following PBC. Prospective studies are required to determine the optimal duration and pressure of balloon compression in relation to the proximal CSA ratio to achieve better pain outcomes and less facial numbness.

Combined surgical and endovascular treatment for spinal arteriovenous fistula associated with Parkes Weber syndrome.

BACKGROUND: Parkes Weber syndrome (PWS) is a rare and congenital vascular malformation manifesting as hemihypertrophy of the extremities, cutaneous hemangiomas, varicose veins, and arteriovenous fistula of the affected limbs. The incidence rate of spinal arteriovenous fistula (AVF) associated with PWS is extremely rare. CASE PRESENTATION: We reported a case of an adolescent girl with PWS who presented with a rupture spinal perimedullary AVF at the level of T12-L1. She was successfully treated with emergent surgical decompression and subsequent endovascular embolization. The clinical features and treatment of spinal AVF associated with PWS were discussed and a brief literature review was presented. CONCLUSION: Based on this case report, we suggested that the management of spinal AVF in PWS should also be individualized and be tailored according to the condition and expectation of the patients as well as the angioarchitecture of the vascular malformation.

The Relationship Between Basilar Invagination and Chiari Malformation Type I: A Narrative Review.

Basilar invagination (BI) and Chiari malformation type I CM-I) are the most common adult craniovertebral junction malformations, and they are frequently associated with each other and present synchronously. The relationship between BI and CM-I has remained incompletely understood, and the choice of surgical strategy has remained controversial. This brief review focuses on the different aspects of BI and CM-I, and further discusses the relationship between these two concomitant pathologies on the basis of the concepts proposed over the last three decades.

Stable Rat Model of Mechanical Allodynia in Diabetic Peripheral Neuropathy: The Role of Nerve Compression.

BACKGROUND: Preclinical studies involving animal models are essential for understanding the underlying mechanisms of diabetic neuropathic pain. METHODS: Rats were divided into four groups: two controls and two experimental. Diabetes mellitus was induced by streptozotocin (STZ) injection in two experimental groups. The first group involved one sham operation. The second group involved one latex tube encircling the sciatic nerve. The vehicle-injection rats were used as two corresponding control groups: sham operation and encircled nerves. By the third week, STZ-injected rats with encircled nerves were further divided into three subgroups: one involving continuing observation and the other two involving decompression (removal of the latex tube) at different time points (third week and fifth week). Weight and blood glucose were monitored, and behavioral analysis, including paw withdrawal threshold (PWT) and latency, was performed every week during the experimental period (7 weeks). RESULTS: Hyperglycemia was induced in all STZ-injected rats. A significant increase in weight was observed in the control groups when compared with the experimental groups. By the third week, more STZ-injected rats with encircled nerves developed mechanical allodynia than those without (P < 0.05), while no significant difference was noted (P > 0.05) on the incidence of thermal hyperalgesia. Mechanical allodynia, but not thermal hyperalgesia, could be ameliorated by the removal of the latex tube at an early stage (third week). CONCLUSION: With the combined use of a latex tube and STZ injection, a stable rat model of painful diabetic peripheral neuropathy (DPN) manifesting both thermal hyperalgesia and mechanical allodynia has been established.

Dynamic Quantitative Assessment of Motor Axon Sprouting after Direct Facial-Hypoglossal End-To-Side Neurorrhaphy in Rats.

BACKGROUND: End-to-side (ETS) neurorrhaphy is a promising procedure for peripheral nerve repair, yet controversies regarding the efficacy of this repair in facial nerve anastomosis for facial paralysis still exist. MATERIALS AND METHODS: Thirty rats were divided into three groups: intact control group, direct facial-hypoglossal ETS neurorrhaphy, and end-to-end (ETE) neurorrhaphy. Nerve regeneration was assessed with vibrissae motor performance, electrophysiological tests, retrograde labeling, and histomorphological analysis at 4 and 8 months postoperatively. RESULTS: Both ETS and ETE neurorrhaphies resulted in axonal regeneration and functional recovery of the recipient nerve but did not reach the level of intact controls. Significantly higher numbers of myelinated axons and labeled neurons giving regenerating fibers were found in group ETE compared with group ETS at both time points, consistent with the functional and electrophysiological recovery. Group ETS showed significantly smaller fiber diameter and thinner myelin thickness than group ETE at 4 months, but the difference became nonsignificant at 8 months. ETS neurorrhaphy had a very slight effect on the donor nerve, as determined electrophysiologically and histomorphologically. Sparsely distributed double-labeled neurons and relatively large amounts of single-labeled neurons contributing to reinnervation were found through double retrograde neuronal labeling in group ETS. Further quantitative analysis of the percentage of double-labeled neurons showed a pronounced tendency to decline from 19.8% at 4 months to 6.0% at 8 months postoperatively. CONCLUSION: Successful reinnervation after ETS neurorrhaphy could be achieved through both collateral sprouting and terminal sprouting, with the latter seeming to be the principal origin of motor nerve sprouting.

Mechanical Allodynia Predicts Better Outcome of Surgical Decompression for Painful Diabetic Peripheral Neuropathy.

BACKGROUND: To determine the role of mechanical allodynia (MA) in predicting good surgical outcome for painful diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Data of 192 patients with painful DPN were collected in this study, with 148 surgical patients and 44 patients in the control group. Both groups were further divided into subgroups based on the presence of MA on admission. Clinical evaluations including the visual analog scale (VAS), the Hospital Anxiety and Depression Scale (HADS), nerve conduction velocity (NCV), and high-resolution ultrasonography (cross-sectional area, CSA) were performed preoperatively and postoperatively. RESULTS: The levels of VAS and HADS and the results of NCV and CSA were improved in the surgical group (p < 0.05). In the surgical subgroups, pain reduction, psychiatric amelioration, improvement in NCVs, and the restoration of the CSA were observed in patients with signs of MA (p < 0.05), whereas only pain reduction, psychiatric amelioration, and restoration of the CSA were noted in patients without signs of MA (p > 0.05). Furthermore, better pain reduction was achieved in patients with MA when compared with those without MA (p < 0.05). CONCLUSIONS: MA is proved to be a reliable predictor of good surgical outcome for painful DPN.

CD151 mediates netrin-1-induced angiogenesis through the Src-FAK-Paxillin pathway.

Crosstalk between the nervous and vascular systems is important during development and in response to injury, and the laminin-like axonal guidance protein netrin-1 has been studied for its involvement in angiogenesis and vascular remodelling. In this study, we examined the role of netrin-1 in angiogenesis and explored the underlying mechanisms. The effect of netrin-1 on brain tissues and endothelial cells was examined by immunohistochemistry and western blotting in a middle cerebral artery occlusion model and in human umbilical vein endothelial cells. Cell proliferation and cell cycle progression were assessed by the MTT assay and flow cytometry, and the Transwell and tube formation assays were used to examine endothelial cell motility and function. Netrin-1 up-regulated CD151 and VEGF concomitant with the activation of focal adhesion kinase (FAK), Src and Paxillin in vitro and in vivo and the induction of cell proliferation, migration and tube formation in vitro. Silencing of CD151 abolished the effects of netrin-1 on promoting cell migration and tube formation mediated by the activation of FAK/Src signalling. Netrin-1 promoted angiogenesis in vitro and in vivo by activating the FAK/Src/Paxillin signalling pathway through a mechanism dependent on the expression of the CD151 tetraspanin, suggesting the existence of a netrin-1/FAK/Src/CD151 signalling axis involved in the modulation of angiogenesis.

Management of Cerebral Radiation Necrosis: A Retrospective Study of 12 Patients.

BACKGROUND: Cerebral radiation necrosis (RN) is a severe complication of radiotherapy for cerebral pathologies. This study discusses the radiographic and pathological features of 12 patients with RN and investigates the management strategy. METHODS: Eleven patients with brain tumors, and one with cerebral cavernous angioma, treated by surgical resection or Gamma Knife alone before radiotherapy developed RN during follow-up. Surgical resection for the cerebral RN was performed in nine patients, and the other three patients received medical treatment. The clinical features, magnetic resonance imaging (MRI), surgical findings, and pathological sections are reviewed. RESULTS: The diagnosis of RN was confirmed by histological study in all the patients; those with surgical and medical treatment recovered. CONCLUSION: As a major complication of radiotherapy, from the clinical and neuroradiological points of view, RN may simulate tumor recurrence. Due to the increasing number of patients with RN who will need to be treated in future years, the definite diagnosis and appropriate treatment of RN remain critical.

Combination of Magnetic Resonance Imaging and Electrophysiological Studies in Lumbar Disc Herniation.

Objective We aimed to study the clinical value of magnetic resonance imaging (MRI) and electrophysiological studies in the diagnosis of lumbar disc herniation and in the evaluation of the therapeutic effect of discectomy. Methods In this study, 265 patients with LDH were treated with discectomy after assessment by the Japanese Orthopedic Association (JOA) score, MRI, and electrophysiological studies. All the patients were followed-up for 6 years. The effects of the operation were assessed by determining the angle between the nerve root canal and disc protrusion (AN value), the stenotic ratio of the spinal canal, the width of the lateral recess, motor conduction velocity (MCV), sensory conduction velocity (SCV), and nerve action potential (NAP) before and after operation. Results The AN value, stenotic ratio of the spinal canal, and the width of the lateral recess of protruding intervertebral discs showed significant differences from these values for the patients' unaffected intervertebral discs (P < 0.05). The MCV, SCV, and NAP of the affected limb showed significant differences from these values for the patients' unaffected limbs (P < 0.05). In all the patients the values for these indicators showed significant differences before and after operation (P < 0.05). Conclusion MRI and electrophysiological studies can be used in the diagnosis of lumbar disc herniation, and in the evaluation of the effect of surgery.

Use of High-Resolution Ultrasonography in Anterior Subcutaneous Transposition of the Ulnar Nerve for Cubital Tunnel Syndrome.

OBJECTIVES: Cubital tunnel syndrome (CTS) is the most common form of ulnar nerve entrapment. In this study, ultrasonography (US) was used not only for diagnosis but also for operation. US findings could be used to establish the diagnosis of CTS and could demonstrate the pathological anatomy in the cubital tunnel region to guide anterior subcutaneous transposition of the ulnar nerve. METHODS: Sixty-two patients with clinical and electrophysiological evidence of ulnar nerve entrapment were included. All patients received ultrasonographic examination and anterior subcutaneous transposition of the ulnar nerve. The maximal diameter of the ulnar nerve (MDU) was measured in longitudinal views and the range of the hypoechoic area around the nerve was observed. The cross-sectional area (CSA) was also measured on transverse scans. The actual MDU was measured during operation. RESULTS: The actual MDU was 6.4 ± 0.4 mm, measured during operation. The preoperative MDU was 3.1 ± 0.2 mm. The MDU values recorded in CTS patients were greater than those in normal subjects. The range of the hypoechoic area observed on longitudinal US scans was 2.9-5.6 mm (mean, 4.1 ± 0.4 mm). CONCLUSIONS: High-resolution US can be used not only in the diagnosis of CTS, also for providing effective preoperative evaluation for the anterior subcutaneous transposition of the ulnar nerve in CTS.

Symptomatic Trigeminal Neuralgia Caused by Cerebellopontine Angle Tumors.

To investigate the characteristics of symptomatic trigeminal neuralgia (TN) caused by tumors and the relationship between anatomicosurgical findings and tumor type, the authors undertook a retrospective review of 35 patients with symptomatic TN between 2006 and 2015. The tumors included 16 meningiomas, 14 epidermoids, 4 vestibular schwannomas, and 1 hemangioblastoma. The studies show that patients with tumor-induced TN were significantly younger than those idiopathic TN (P <0.05). Meningioma-induced TN tended to have responsible vessels, while epidermoid tumor seemed to cause TN by wrapping or compressing the nerve. Additional vascular compression was observed in 15 (42.9%) of these 35 patients. All patients except one showed immediate pain relief following total or subtotal tumor removal with microvascular decompression (if required). Two patients with epidermoid-induced TN experienced symptom relapses caused by tumor regrowth, and one with meningioma-induced TN experienced pain recurrence caused by adhesive arachnoid. The key for operative success is to examine the entire nerve root for possible vascular compression after total or subtotal tumor resection.

Trochlear Nerve Schwannoma With Repeated Intratumoral Hemorrhage.

Trochlear nerve schwannoma is extremely rare, with only 35 pathologically confirmed patients being reported in the literature. Here, the authors report a patient of trochlear nerve schwannoma in the prepontine cistern manifesting as facial pain and double vision and presenting the image characteristics of repeated intratumoral hemorrhage, which has never been reported in the literature. Total tumor along with a portion of the trochlear nerve was removed by using a retrosigmoid approach. Facial pain disappeared after operation, and the diplopia remained. Follow-up studies have shown no tumor recurrence for 2 years and the simultaneous alleviation of diplopia. Information regarding the clinical presentation, radiological features and surgical outcomes of trochlear nerve schwannoma are discussed and reviewed in the paper.

Narrow Foramen Ovale and Rotundum: A Role in the Etiology of Trigeminal Neuralgia.

Primary trigeminal neuralgia (TN) may occasionally occur in absence of neurovascular compression. A mechanism other than nerovascular compression may play a role in TN. High-resolution computed tomographies (CTs) of 21 consecutive TN patients without vascular compression during surgery and 30 healthy volunteers were retrospectively performed. Measuring parameters (length, width, and aspect ratio) were obtained in the axial plane for foramen ovale, and in the reconstructed coronal plane for foramen rotundum on both sides in each subject. The right-sided foramen ovale is slightly narrower than the left-sided, but no difference was observed between the sides. No correlation was found between the foramen size and the gender in both groups. The affected side with a narrower ovale foramen (>0.5 mm) and a significantly greater aspect ratio compared with the unaffected side may contribute to TN. Meanwhile, no significant correlation, but more likely a tendency, was found between the right and left sides in size of foramen rotundum (P = 0.09). This study has speculatively suggested that a narrow skull foramen may be etiologically important in a small percentage of TN patients. If recurrent or residual TN was encountered in cases of TN without vascular compression during surgery, high-resolution CT may help to evaluate the anatomical morphology of skull foramen in great detail.

The Role of Percutaneous Radiofrequency Thermocoagulation for Persistent or Recurrent Trigeminal Neuralgia After Surgery.

Therapeutic strategy is controversial and not yet uniform for patients with trigeminal neuralgia (TN) and persistent or recurrent facial pain after microvascular decompression, percutaneous radiofrequency thermocoagulation (PRT), or Gamma Knife surgery. The outcomes and risks of PRT for these patients are not clearly understood. The authors performed a retrospective study of 84 patients with persistent or recurrent TN after surgery who then underwent PRT between 2007 and 2013. Data were obtained with chart review and telephone interviews. The mean follow-up duration was 44.2 months. The immediate pain relief after PRT was 98%. The survival rates of pain free without medications at 1, 2, and 3 years after PRT were 85%, 68%, and 54%, respectively, with a nearly 80% rate for effective pain control (pain free, or pain controlled with medications) during the study period. The previous surgical method for TN did not have a significant effect on pain-free rates (P >0.05). Ninety-five percent of patients benefited from multiple PRT procedures and were satisfied with their pain relief. Fourteen of 17 patients who required retreatment selected additional PRT, resulting in 8 patients (57%) in excellent outcome and 12 (86%) in effective pain control. Two patients had failed all conventional invasive treatments. All patients experienced numbness of varying degrees, with 2 reporting severe and bothersome numbness. The complication rate was 15%, including 6 patients with masseter weakness, 2 patients with impaired taste acuity, 4 patients with absent or decreased corneal reflex, 1 patient with oculomotor paralysis. Percutaneous radiofrequency thermocoagulation is a safe and efficacious therapeutic method for patients with persistent or recurrent TN after surgery. Percutaneous radiofrequency thermocoagulation can serve as an alternative treatment option for these patients.

Facial-Hypoglossal End-To-Side Neurorrhaphy: Exploration of the Source of Axonal Sprouting.

Background The clinical application of end-to-side (ETS) neurorrhaphy is under debate partly due to a lack of consensus on the source of axonal sprouting. Methods In this study, 24 rats were divided into three groups: sham operation, facial-hypoglossal ETS neurorrhaphy, and end-to-end (ETE) neurorrhaphy. Electrophysiological tests were employed to detect the evoked compound muscle action potentials (CMAPs) in different situations, and the latencies and maximal amplitudes of the CMAPs recorded were compared. Fluorescence retrograde tracing studies, hematoxylin and eosin (HE) staining, and immunohistochemical staining of growth-associated protein 43 (GAP-43) were performed. The number and the diameter of myelinated axons proximal and distal to the coaptation sites were measured. Results Twelve weeks after the surgeries, reinnervation of whisker pad muscles by hypoglossal nerves in both the ETS and ETE groups were confirmed via electrophysiological study. The maximal amplitudes of the CMAPs recorded in different situations and the quantification of myelinated axons supported the coexistence spontaneous collateral sprouting and regenerative sprouting of axons. Double-labeled neurons were found within the hypoglossal nuclear areas in the ETS neurorrhaphy group and HE staining illustrated the axons crossed the coaptation site into the facial acceptor nerve. Although immunohistochemical staining of GAP-43 revealed different timeframes between ETS and ETE neurorrhaphy groups, no significant difference on latency or diameters of the myelinated axons distal to the coaptation sites was noted between ETE and ETS groups. Conclusion Both spontaneous collateral sprouting and regenerative sprouting of axons coexisted following ETS neurorrhaphy, which represents an alternative approach to peripheral nerve reconstruction.

Clinical Characteristics and Treatment of Trigeminal Neuralgia Following Herpes Zoster.

OBJECTIVE: The aim of this study was to illustrate the clinical characteristics and treatment of trigeminal neuralgia following herpes zoster. METHODS: From August 1, 2011 to August 1, 2013, 23 consecutive patients with trigeminal neuralgia following herpes zoster underwent microvascular decompression (MVD) at our cranial nerve disease center. All patients underwent preoperative MRI evaluation, intraoperative observation, and clinical effect evaluation. Clinical data were collected and analyzed in our center. RESULTS: V2 division was the most commonly affected branch. Unlike pretrigeminal neuralgia (PTN), trigger zone was only found in a small part of patients (21.7%). Unlike PTN, the adhesions and compressions between trigeminal nerve and offending vessels were usually not serious; trigeminal nerve usually is atrophic; superior cerebellar artery was the most common offending vessels (65.2%). Of 23 patients, 19 experienced pain relief (82.6%), 1 patient suffered from hearing loss, and another one suffered from cerebrospinal fluid leak; no severe complications were found. During follow-up period, no recurrence was found (3 lost). CONCLUSIONS: For patients who suffered from trigeminal neuralgia following herpes zoster, trigger zone was only found in a small part of patients. The trigeminal nerve usually is atrophic; microvascular decompression was equally applied to these patients if vessel compression was confirmed.