Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation.

Association of timing and agent for venous thromboembolism prophylaxis in patients with severe traumatic brain injury on venous thromboembolism events, mortality, neurosurgical intervention, and discharge disposition.

BACKGROUND: Trauma patients are at increased risk for venous thromboembolism events (VTEs). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI). METHODS: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (Abbreviated Injury Scale head score of 3, 4, or 5). Data were collected at 35 Level 1 and 2 trauma centers from January 1, 2017, to June 1, 2022. Patients were placed into analysis cohorts: no VTEP, low-molecular-weight heparin (LMWH) ≤48 hours, LMWH >48 hours, heparin ≤48 hours, and heparin >48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTEs, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage. RESULTS: Of 12,879 patients, 32% had no VTEP, 36% had LMWH, and 32% had heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH ≤48 hours (4.1%). Venous thromboembolism event rates were lower with use of LMWH (1.6% vs. 4.5%; odds ratio, 2.98; 95% confidence interval, 1.40-6.34; p = 0.005) without increasing mortality or neurosurgical interventions. Venous thromboembolism event rates were lower with early prophylaxis (2.0% vs. 3.5%; odds ratio, 1.76; 95% confidence interval, 1.15-2.71; p = 0.01) without increasing mortality ( p = 1.0). Early VTEP was associated with more nonfatal intracranial operations ( p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition ( p = 0.7, p = 0.1, p = 0.5). CONCLUSION: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP ≤48 hours decreased VTE incidence and increased nonfatal neurosurgical interventions without affecting mortality. Low-molecular-weight heparin is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Functional Electrical Stimulation and Brain-Machine Interfaces for Simultaneous Control of Wrist and Finger Flexion.

Brain-machine interface (BMI) controlled functional electrical stimulation (FES) is a promising treatment to restore hand movements to people with cervical spinal cord injury. Recent intracortical BMIs have shown unprecedented successes in decoding user intentions, however the hand movements restored by FES have largely been limited to predetermined grasps. Restoring dexterous hand movements will require continuous control of many biomechanically linked degrees-of-freedom in the hand, such as wrist and finger flexion, that would form the basis of those movements. Here we investigate the ability to restore simultaneous wrist and finger flexion, which would enable grasping with a controlled hand posture and assist in manipulating objects once grasped. We demonstrate that intramuscular FES can enable monkeys with temporarily paralyzed hands to move their fingers and wrist across a functional range of motion, spanning an average 88.6 degrees at the metacarpophalangeal joint flexion and 71.3 degrees of wrist flexion, and intramuscular FES can control both joints simultaneously in a real-time task. Additionally, we demonstrate a monkey using an intracortical BMI to control the wrist and finger flexion in a virtual hand, both before and after the hand is temporarily paralyzed, even achieving success rates and acquisition times equivalent to able-bodied control with BMI control after temporary paralysis in two sessions. Together, this outlines a method using an artificial brain-to-body interface that could restore continuous wrist and finger movements after spinal cord injury.

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that Sarm1 is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve, Sarm1 is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. In Sarm1-/- mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of Sarm1-/- distal nerve tissue was demonstrated by grafting of Sarm1-/- nerve into WT recipients. SC lineage tracing in injured WT and Sarm1-/- mice revealed morphological differences. In the Sarm1-/- distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed. Ex vivo, p75NTR and c-Jun upregulation in Sarm1-/- nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that Sarm1 is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.

Patients with progression of spinal metastases who present to the clinic have better outcomes compared to those who present to the emergency department.

BACKGROUND: As cancer therapies have improved, spinal metastases are increasingly common. Resulting complications have a significant impact on patient's quality of life. Optimal methods of surveillance and avoidance of neurologic deficits are understudied. This study compares the clinical course of patients who initially presented to the emergency department (ED) versus a multidisciplinary spine oncology clinic and who underwent stereotactic body radiation therapy (SBRT) secondary to progression/presentation of metastatic spine disease. METHODS: We performed a retrospective analysis of a prospectively maintained database of adult oncologic patients who underwent spinal SBRT at a single hospital from 2010 to 2021. Descriptive statistics and survival analyses were performed. RESULTS: We identified 498 spinal radiographic treatment sites in 390 patients. Of these patients, 118 (30.3%) presented to the ED. Patients presenting to the ED compared to the clinic had significantly more severe spinal compression (52.5% vs. 11.7%; p < 0.0001), severe pain (28.8% vs. 10.3%; p < 0.0001), weakness (24.5% vs. 4.5%; p < 0.0001), and difficulty walking (24.5% vs. 4.5%; p < 0.0001). Patients who presented to the ED compared to the clinic were significantly more likely to have surgical intervention followed by SBRT (55.4% vs. 15.3%; p < 0.0001) compared to SBRT alone. Patients who presented to the ED compared to the clinic had a significantly quicker interval to distant spine progression (5.1 ± 6.5 vs. 9.1 ± 10.2 months; p = 0.004), systemic progression (5.1 ± 7.2 vs. 9.2 ± 10.7 months; p < 0.0001), and worse overall survival (9.3 ± 10.0 vs. 14.3 ± 13.7 months; p = 0.002). CONCLUSION: The establishment of multidisciplinary spine oncology clinics is an opportunity to potentially allow for earlier, more data-driven treatment of their spinal metastatic disease.

Local Control in Patients with Metastatic Renal Cell Carcinoma to the Spine: The Experience of an Institution with a Multidisciplinary Spine Oncology Program.

BACKGROUND: The outcomes for patients with metastatic renal cell carcinoma (RCC) to the spine who underwent stereotactic body radiotherapy (SBRT) through a multidisciplinary spine oncology program are not well described. We sought to describe the clinical course and local control rates at 1 and 2 years for these patients. METHODS: A retrospective analysis of a prospectively maintained database of adult oncologic patients receiving SBRT to the spine through a multidisciplinary spine oncology program at a single institution from 2010 to 2021 was performed. Patients with a pathologic diagnosis of RCC were included. RESULTS: A total of 75 spinal sites were treated in 60 patients. Of the 60 patients, 75.0% were men, and the mean patient age was 59.2 ± 11.3 years. At 1 year after treatment, 6 of the 60 patients were lost to follow-up. Of the remaining 54 patients, 18 were censored by death and 7 treatment sites showed local recurrence, for 37 of 44 treatment sites with local control (87.8%). At 2 years, 1 additional local recurrence had developed, 15 patients were censored by death, and no additional patients had been lost to follow-up, resulting in 28 of 36 treatment sites with local control (83.2%). None of the patients who had undergone repeat SBRT had local recurrence at 1 or 2 years. For those with local recurrence, the average time from treatment to progression was 6.6 ± 6.5 months. CONCLUSIONS: In this cohort, one of the largest reported studies of spine SBRT for metastatic RCC, local control was high at 1 and 2 years. Our findings support the role of coordinated, algorithmic treatment for these patients.

Navigated retrodiaphragmatic/retroperitoneal approach for the treatment of symptomatic kyphoscoliosis: an operative video.

Retropleural, retrodiaphragmatic, and retroperitoneal approaches are utilized to access difficult thoracolumbar junction (T10-L2) pathology. The authors present a 58-year-old man with chronic low-back pain who failed years of conservative therapy. Preoperative radiographs demonstrated significant levoconvex scoliosis with coronal and sagittal imbalance. He underwent a retrodiaphragmatic/retroperitoneal approach for T12-L1, L1-2, L2-3, and L3-4 interbody release and fusion in conjunction with second-stage facet osteotomies, L4-5 TLIF, and T10-iliac posterior instrumented fusion. This video focuses on the retrodiaphragmatic approach assisted by 3D navigation. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2215.

Survival, fusion, and hardware failure after surgery for spinal metastatic disease.

OBJECTIVE: Decompression with instrumented fusion is commonly employed for spinal metastatic disease. Arthrodesis is typically sought despite limited knowledge of fusion outcomes, high procedural morbidity, and poor prognosis. This study aimed to describe survival, fusion, and hardware failure after decompression and fusion for spinal metastatic disease. METHODS: The authors retrospectively examined a prospectively collected, single-institution database of adult patients undergoing decompression and instrumented fusion for spinal metastases. Patients were followed clinically until death or loss to follow-up. Fusion was assessed using CT when performed for oncological surveillance at 6-month intervals through 24 months postoperatively. Estimated cumulative incidences for fusion and hardware failure accounted for the competing risk of death. Potential risk factors were analyzed with univariate Fine and Gray proportional subdistribution hazard models. RESULTS: One hundred sixty-four patients were identified. The mean age ± SD was 62.2 ± 10.8 years, 61.6% of patients were male, 98.8% received allograft and/or autograft, and 89.6% received postoperative radiotherapy. The Kaplan-Meier estimate of median survival was 11.0 months (IQR 3.5-37.8 months). The estimated cumulative incidences of any fusion and of complete fusion were 28.8% (95% CI 21.3%-36.7%) and 8.2% (95% CI 4.1%-13.9%). Of patients surviving 6 and 12 months, complete fusion was observed in 12.5% and 16.1%, respectively. The estimated cumulative incidence of hardware failure was 4.2% (95% CI 1.5-9.3%). Increasing age predicted hardware failure (HR 1.2, p = 0.003). CONCLUSIONS: Low rates of complete fusion and hardware failure were observed due to the high competing risk of death. Further prospective, case-control studies incorporating nonfusion instrumentation techniques may be warranted.

AMPK induces regulatory innate lymphoid cells after traumatic brain injury.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.

Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

Atypical Intracranial Meningioma with Metastasis to C7 Vertebral Body: A Case Report.

BACKGROUND: Extracranial metastasis, mainly a feature of World Health Organization (WHO) grade III meningiomas, is only rarely reported in grade II meningiomas. CASE DESCRIPTION: We report a case of a 48-year-old man who was initially diagnosed in 2010 with an occipital convexity meningioma based on computed tomography scan/magnetic resonance imaging (MRI) and treated with surgical therapy and gamma knife. The first operation achieved a macroscopically complete resection. The tumor was histologically classified as an atypical meningioma. The patient had a recurrence in 2014 on the left tentorial leaflet as noted on postcontrast MRI. The patient was asymptomatic, without focal neurologic deficits. In 2016, the patient reported new-onset pain in the neck and left upper extremity. MRI indicated complete replacement of the C7 vertebral marrow, with a soft tissue component extending posteriorly into the epidural space that appeared to be flattening the thecal sac but without evidence of abnormal cord signal. Histopathology of resection confirmed atypical meningioma. CONCLUSIONS: This case represents a rare instance of intraosseous spine as the first site of metastasis of WHO grade II atypical meningioma and is the first reported case of extracranial metastasis of a meningioma to the C7 vertebral body.

A Retrospective Cohort Analysis of Hemorrhagic Arteriovenous Malformations Treated with Combined Endovascular Embolization and Gamma Knife Stereotactic Radiosurgery.

BACKGROUND: The management of brain arteriovenous malformations (AVMs) remains a controversial topic. Given the relatively low incidence, high heterogeneity, and high morbidity and mortality of these lesions, consensus on treatment strategies is an issue of concern to organized neurosurgery. The present retrospective analysis examined and quantified the outcomes of patients with an initial presentation of intracranial hemorrhage from a Spetzler-Martin grade III or IV AVM, later ruled out as surgical candidates. METHODS: A total of 16 patients (5 females; 11 males) had presented with symptomatic hemorrhage confirmed by non-contrast-enhanced computed tomography and were deemed to not be surgical candidates owing to AVM location and/or architecture. The patients underwent combined endovascular embolization and gamma knife stereotactic radiosurgery (SRS). The modified Rankin scale was used to measure the clinical outcomes, comparing the scores at presentation, gamma knife treatment, and the last known follow-up examination. A radiographic evaluation was used to determine the level of AVM nidus involution after the procedure. RESULTS: The present study identified 16 patients with ruptured high-grade AVMs of high surgical risk. All the patients had undergone immediate embolization with delayed SRS for treatment of the hemorrhage and nidus of the AVM. A statistically significant proportion of patients showed marked improvement in the modified Rankin scale scores. No subsequent repeat hemorrhage or any associated complications after embolization occurred in any patient. CONCLUSION: These findings warrant consideration of endovascular embolization with adjuvant SRS as a powerful treatment option for cases with high surgical morbidity due to AVM characteristics.

Clinically Silent Adrenocorticotropic Hormone-Positive Crooke Cell Adenoma: Case Report and Review of Literature.

BACKGROUND: Pituitary adenomas are one of the most common tumors of adulthood; however, subtypes such as Crooke cell adenoma are relatively rare. CASE DESCRIPTION: We present the case of a 55-year-old woman who presented with new-onset intermittent headache and dizziness. Clinical and laboratory investigations were not suggestive of corticotroph tumor. However, subsequent computed tomography and magnetic resonance imaging scans revealed the presence of a suprasellar pituitary adenoma displacing the optic chiasma superiorly, with hemorrhage and sellar expansion. The lesion was removed by transsphenoidal surgery and the biopsy confirmed the lesion to be a nonfunctioning pituitary macroadenoma. Further investigation revealed that the specimen demonstrated Crooke hyaline changes, with strong immunoreactivity for adrenocorticotropic hormone. However, initial workup and postoperative testing lacked evidence of Cushing disease. There was no sign of recurrence after 1-year follow-up. CONCLUSIONS: Clinically silent Crooke cell adenomas are rare occurrences, and as such we report this case with investigation of past cases.

Genetic Interactions Between the Meiosis-Specific Cohesin Components, STAG3, REC8, and RAD21L.

Cohesin is an essential structural component of chromosomes that ensures accurate chromosome segregation during mitosis and meiosis. Previous studies have shown that there are cohesin complexes specific to meiosis, required to mediate homologous chromosome pairing, synapsis, recombination, and segregation. Meiosis-specific cohesin complexes consist of two structural maintenance of chromosomes proteins (SMC1α/SMC1ß and SMC3), an α-kleisin protein (RAD21, RAD21L, or REC8), and a stromal antigen protein (STAG1, 2, or 3). STAG3 is exclusively expressed during meiosis, and is the predominant STAG protein component of cohesin complexes in primary spermatocytes from mouse, interacting directly with each α-kleisin subunit. REC8 and RAD21L are also meiosis-specific cohesin components. Stag3 mutant spermatocytes arrest in early prophase ("zygotene-like" stage), displaying failed homolog synapsis and persistent DNA damage, as a result of unstable loading of cohesin onto the chromosome axes. Interestingly, Rec8, Rad21L double mutants resulted in an earlier "leptotene-like" arrest, accompanied by complete absence of STAG3 loading. To assess genetic interactions between STAG3 and α-kleisin subunits RAD21L and REC8, our lab generated Stag3, Rad21L, and Stag3, Rec8 double knockout mice, and compared them to the Rec8, Rad21L double mutant. These double mutants are phenotypically distinct from one another, and more severe than each single knockout mutant with regards to chromosome axis formation, cohesin loading, and sister chromatid cohesion. The Stag3, Rad21L, and Stag3, Rec8 double mutants both progress further into prophase I than the Rec8, Rad21L double mutant. Our genetic analysis demonstrates that cohesins containing STAG3 and REC8 are the main complex required for centromeric cohesion, and RAD21L cohesins are required for normal clustering of pericentromeric heterochromatin. Furthermore, the STAG3/REC8 and STAG3/RAD21L cohesins are the primary cohesins required for axis formation.

Does CT wand guidance improve shunt placement in patients with hydrocephalus?

OBJECT: To evaluate the effectiveness of stereotactic navigation in enhancing the accuracy of ventricular shunt placement in patients with hydrocephalus. METHODS: A retrospective cohort study at a single institution by a single surgeon was performed. Consecutive patients who underwent implantation of a ventricular shunt for the management of hydrocephalus between July 2001 and December 2011 were included in the study, totaling 535 patients. Patients were classified as either having optimal or sub-optimal placement of the shunt into the ventricle. Multiple logistic regression analysis was used. RESULTS: Overall, 93.8% of patients were found to have optimal shunt placement. On multivariate analysis, navigation use was not significantly associated with improved accuracy of shunt placement (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.19-1.54; p = 0.25). Pseudotumor cerebri diagnosis was significantly associated with increased odds of sub-optimal shunt placement (OR = 6.41; 95% CI = 1.90-21.59; p=0.003). CONCLUSIONS: CT guided navigation did not significantly improve the accuracy of ventricular shunt placement in adults with hydrocephalus for an experienced surgeon. Further studies are required to assess the utility of CT guided navigation for less experienced surgeons and patients with small or dysmorphic ventricles.

Risk factors for failed transverse sinus stenting in pseudotumor cerebri patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH) when no underlying etiology is found, is a clinical syndrome characterized by elevated intracranial pressure (ICP) (>25 cm H2O), which may lead to headaches and visual symptoms. In patients with IIH who are found to have transverse sinus stenosis, placement of a venous stent across the stenosis has been shown to lower ICP and to resolve the symptoms in several case series, with generally favorable results. In this study, we examine common risk factors associated with failure of transvenous stenting for IIH. If venous sinus stenting fails, CSF diversion should be considered as the next line of treatment. METHODS: We retrospectively reviewed the records of eighteen patients diagnosed with IIH who underwent venous sinus stenting for transverse sinus stenosis with a mean pressure gradient (MPG) of at least 4 mmHg. Fifteen of these patients did not need further treatment. We compared their pre- and post-treatment, neurological and neuro-ophthalmological evaluations to the three patients who went on to have a shunt placement as a second line treatment. RESULTS: Shunting after stent placement patients (n=3) had a mean age of 30 years and a mean body mass index of 36.6 kg/m(2), whereas the group that underwent stent placement alone (n=15) had a mean age of 40.7 years and a mean body mass index of 33.3 kg/m(2). In the shunting after stent placement group, the mean opening pressure on the most recent lumbar puncture obtained prior to any intervention was 50 cm of H2O, whereas the group that underwent stent placement alone had an opening CSF pressure of 37 cm of H2O which was statistically significant (p<0.05). There were no other significant differences in pre- or post-intervention factors between the two groups. CONCLUSION: In patients with IIH and documented evidence of venous sinus stenosis with a pressure gradient, venous sinus stenting should be the primary treatment of choice; however, some patients may be refractory to stenting and still require permanent CSF diversion, which can be complicated in these chronically anticoagulated patients. Patients with persistent papilledema post-stenting and highly elevated opening pressure pre-stenting should be followed closely as they are at greatest risk of requiring a shunt and failing stenting.