Analysis of the discontinuation and nonpublication of neurooncological randomized clinical trials.

Background: Premature discontinuation and nonpublication of clinical trials contribute to research waste and compromise our ability to improve patient outcomes. However, the extent to which these problems exist in neurooncological randomized clinical trials (RCTs) is not known. This study aimed to evaluate the prevalence of discontinuation and nonpublication of neurooncological RCTs, identify contributing factors, and assess trial characteristics associated with each. Methods: We performed a retrospective, cross-sectional study of neurooncological RCTs registered in Clinicaltrials.gov before March 7, 2023. Data were collected from Clinicaltrials.gov and associated publications were located. We attempted to contact authors for all trials without associated publications or an identified reason for discontinuation. Results: Of 139 included RCTs, 57 (41%) were discontinued. The most common reason for discontinuation identified was slow enrollment or accrual (23%), though 30 trials (53%) were discontinued for unknown reasons. Trials funded by sources other than industry or the National Institutes of Health were more likely to be discontinued (odds ratio 4.2, 95% confidence interval 1.3-13.8). In total, 67 of the 139 (48%) RCTs were unpublished, including 50 of the 57 (88%) discontinued studies and 17 of the 82 (21%) completed studies. Conclusions: In our study, discontinuation of neurooncological clinical trials was common and often occurred for unknown reasons. Trials were also frequently unpublished, particularly those that were discontinued. Addressing these findings may provide an opportunity to reduce research waste and improve outcomes for patients with neurological cancers.

Middle meningeal artery embolization following surgical evacuation of symptomatic chronic subdural hematoma improves outcomes, interim results of a prospective randomized trial.

BACKGROUND: Outcomes after surgical treatment of chronic subdural hematoma (cSDH) remain undesirable in a significant proportion of patients. We aimed to show the role of middle meningeal artery (MMA) embolization and to demonstrate its benefits. METHODS: Thirty-five patients with symptomatic cSDH were enrolled in a prospective randomized trial following evacuation surgery. Participants were randomized to embolization or control group (expectant management following surgical evacuation without embolization). Patients were followed throughout their hospitalization and outpatient follow-ups. The main goals of this planned interim analysis were to assess neurological outcome and resource utilization. RESULTS: The groups were comparable in terms of sex, age and follow-up retention rates. Side(s) of intervention(s) and hematoma size were similar. There was no statistical difference in neurological examination improvement at discharge, but at follow-up, we observed a decline in neurologic exam in the control group (p = 0.03). Control group participants required more re-interventions (p = 0.02) and were followed in clinic and during related readmissions for longer (p = 0.02). The number of imaging studies obtained in relation to the disease management was higher in the control group (p = 0.01). CONCLUSIONS: Our results suggest a beneficial role for the addition of MMA embolization to surgical intervention in the treatment of symptomatic chronic subdural hematoma. Neurological outcomes were significantly better in the embolization group. This contributed to less need for follow-up, re-interventions, and imaging studies.

Single episode of moderate to severe traumatic brain injury leads to chronic neurological deficits and Alzheimer's-like pathological dementia.

Traumatic brain injury (TBI) is one of the foremost causes of disability and mortality globally. While the scientific and medical emphasis is to save lives and avoid disability during acute period of injury, a severe health problem can manifest years after injury. For instance, TBI increases the risk of cognitive impairment in the elderly. Remote TBI history was reported to be a cause of the accelerated clinical trajectory of Alzheimer's disease-related dementia (ADRD) resulting in earlier onset of cognitive impairment and increased AD-associated pathological markers like greater amyloid deposition and cortical thinning. It is not well understood whether a single TBI event may increase the risk of dementia. Moreover, the cellular signaling pathways remain elusive for the chronic effects of TBI on cognition. We have hypothesized that a single TBI induces sustained neuroinflammation and disrupts cellular communication in a way that results later in ADRD pathology. To test this, we induced TBI in young adult CD1 mice and assessed the behavioral outcomes after 11 months followed by pathological, histological, transcriptomic, and MRI assessment. On MRI scans, these mice showed significant loss of tissue, reduced CBF, and higher white matter injury compared to sham mice. We found these brains showed progressive atrophy, markers of ADRD, sustained astrogliosis, loss of neuronal plasticity, and growth factors even after 1-year post-TBI. Because of progressive neurodegeneration, these mice had motor deficits, showed cognitive impairments, and wandered randomly in open field. We, therefore, conclude that progressive pathology after adulthood TBI leads to neurodegenerative conditions such as ADRD and impairs neuronal functions.

Industry payments to academic neurosurgeons in 2021: an open payments cross-sectional analysis.

OBJECTIVE: The Open Payments Program (OPP) was a database started in 2013 by the US government to report payments made by the medical device and pharmaceutical industry to physicians. Neurosurgery is a technologically advanced field that relies heavily on the latest innovations for complex treatment of its patient population. This study sought to explore the financial relationship between academic neurosurgeons and the industry. METHODS: OPP data were reviewed for the year 2021 of all faculty neurosurgeons affiliated with a neurosurgery residency program. Trends related to general payments, research payments, associated research funding, ownership and investment interest, name of the companies making payments, monetary amount of payments per company, and number of payments per company were analyzed. RESULTS: Industry payments to 1151 US academic neurosurgeons were reviewed. These neurosurgeons received $121.4 million in payments. Three hundred thirty-two companies made 18,466 payments. The average payment per neurosurgeon was approximately six-fold higher than that of all other physicians. Vascular and spine subspecialties received the highest payments. A higher proportion of research money was allocated to the Pacific division, while all other categories (including total amount) were higher in the Eastern US. Most financial contributions were made by a small number of companies. CONCLUSIONS: Neurosurgery has been rated by many as a field fueled by research, innovation, and technology. In 2021, academic neurosurgeons had a strong relationship with the medical device and pharmaceutical industry as reflected in the OPP data. While the true impact on patient care cannot be directly measured, the advancement of the field relies heavily on these collaborations.

Endoscopic endonasal obliteration of the frontal recess and anterior skull base.

BACKGROUND: Although endoscopic techniques have become more widespread in repair of frontal sinus (FS) defects, certain pathologies still require open approach (extensive trauma or tumors). Under certain circumstances even multiple complex open reconstructive procedures might fail to resolve persistent pneumocephalus or CSF leak and subsequently surgeons tend to escalate the invasiveness and employ even more complex and aggressive approaches. We present our experience treating persistent pneumocephalus or CSF leak after previously failed transcranial reconstruction utilizing an endoscopic endonasal approach (EEA). METHODS: We retrospectively reviewed a prospectively maintained database of all patients undergoing an EEA for repair of persistent pneumocephalus or CSF leak following FS cranialization between 2016 and 2020. RESULTS: Six patients who underwent cranialization of the FS with subsequent persistent pneumocephalus or CSF leak were identified; two patients suffered a traumatic fracture of the FS, remaining four patients had undergone previous cranial surgery. Clear violation of the FS was not recognized in one patient. All patients underwent cranialization of the FS either directly following initial craniotomy or during open repair of a FS fracture. Two patients underwent multiple transcranial surgeries including using vascularized free tissue transfer. Complete cessation of pneumocephalus/CSF leak was achieved in 83.3% (5/6) after the first and 100% (6/6) after two endoscopic procedures. No morbidity or mortality resulted from the endoscopic procedure. CONCLUSIONS: Skull base defects following a failed cranialization of FS are usually located in or in close proximity to the frontal recess. These defects can be safely and effectively repaired via an EEA.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

No change in network connectivity measurements between separate rsfMRI acquisition times.

The role of resting state functional MRI (rsfMRI) is increasing in the field of epilepsy surgery because it is possible to interpolate network connectivity patterns across the brain with a high degree of spatial resolution. Prior studies have shown that by rsfMRI with scalp electroencephalography (EEG), an epileptogenic network can be modeled and visualized with characteristic patterns of connectivity that are relevant to both seizure-related and neuropsychological outcomes after surgery. The aim of this study is to show that a 5-min acquisition time provides reproducible results related to the relevant connectivity metrics when compared to a separately acquired 5-min scan. Fourteen separate rsfMRI sessions from ten different patients were used for comparison, comprised of patients with temporal lobe epilepsy both pre- and post-operation. Results showed that there was no significant difference in any of the connectivity metrics when comparing both 5-min scans to each other. These data support the continued use of a 5-min scan for epileptogenic network modeling in future studies because the inter-scan variability is sufficiently low as not to alter the output metrics characterizing the network connectivity.

Revision and removal of vagus nerve stimulation systems: twenty-five years' experience.

BACKGROUND: Epilepsy, a disease characterized by recurrent seizures, is a common chronic neurologic condition. Antiepileptic drugs (AED) are the mainstay of treatment for epilepsy. Vagus nerve stimulation (VNS) surgery is an adjuvant therapy for the treatment of drug refractory epilepsy (DRE). VNS revision and implant removal surgeries remain common. METHODS: Using a single neurosurgeon data registry for epilepsy surgery, we retrospectively analyzed a total of 824 VNS surgeries. Patients were referred to two Level IV Comprehensive Epilepsy centers (from 08/1997 to 08/2022) for evaluation. Patients were divided into four groups: new device placement, revision surgery, removal surgery, and battery replacement for end-of-life of the generator. The primary endpoint was to analyze the reasons that led patients to undergo revision and removal surgeries. The time period from the index surgery to the removal surgery was also calculated. RESULTS: The median age of patients undergoing any type of surgery was 34 years. The primary reason for revision surgeries was device malfunction, followed by patients' cosmetic dissatisfaction. There was no statistical sex-difference in revision surgeries. The median age and body mass index (BMI) of patients who underwent revision surgery were 38 years and 26, respectively. On the other hand, the primary reason for removal was lack of efficacy, followed again by cosmetic dissatisfaction. The survival analysis showed that 43% of VNS device remained in place for 5 years and 50% of the VNS devices were kept for 1533 days or 4.2 years. CONCLUSIONS: VNS therapy is safe and well-tolerated. VNS revision and removal surgeries occur in less than 5% of cases. More importantly, attention to detail and good surgical technique at the time of the index surgery can increase patient satisfaction, minimize the need for further surgeries, and improve acceptance of the VNS technology.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Altered endocannabinoid metabolism compromises the brain-CSF barrier and exacerbates chronic deficits after traumatic brain injury in mice.

Endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)], endogenously produced arachidonate-based lipids, are anti-inflammatory physiological ligands for two known cannabinoid receptors, CB1 and CB2, yet the molecular and cellular mechanisms underlying their effects after brain injury are poorly defined. In the present study, we hypothesize that traumatic brain injury (TBI)-induced loss of endocannabinoids exaggerates neurovascular injury, compromises brain-cerebrospinal fluid (CSF) barriers (BCB) and causes behavioral dysfunction. Preliminary analysis in human CSF and plasma indicates changes in endocannabinoid levels. This encouraged us to investigate the levels of endocannabinoid-metabolizing enzymes in a mouse model of controlled cortical impact (CCI). Reductions in endocannabinoid (2-AG and AEA) levels in plasma were supported by higher expression of their respective metabolizing enzymes, monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and cyclooxygenase 2 (Cox-2) in the post-TBI mouse brain. Following increased metabolism of endocannabinoids post-TBI, we observed increased expression of CB2, non-cannabinoid receptor Transient receptor potential vanilloid-1 (TRPV1), aquaporin 4 (AQP4), ionized calcium binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and acute reduction in cerebral blood flow (CBF). The BCB and pericontusional cortex showed altered endocannabinoid expressions and reduction in ventricular volume. Finally, loss of motor functions and induced anxiety behaviors were observed in these TBI mice. Taken together, our findings suggest endocannabinoids and their metabolizing enzymes play an important role in the brain and BCB integrity and highlight the need for more extensive studies on these mechanisms.

Protocol for behavioral and neural recording during stimulation of the macaque monkey nucleus basalis.

We present an experimental protocol to record neuronal activity during intermittent stimulation of nucleus basalis (NB), as macaque monkeys perform cognitive tasks. This protocol includes implantation of electrodes and generator devices to deliver electrical stimulation to NB using multiple approaches in monkeys. Direct stimulation of NB avoids peripheral cholinergic side effects, optimizes timing, and activates non-cholinergic projection neurons. We describe electrode preparation, surgery, and implantation for direct evaluation of how stimulation affects monkeys' behavior and neuronal activity. For complete details on the use and execution of this profile, please refer to Qi et al. (2021).

Rescuing mitochondria in traumatic brain injury and intracerebral hemorrhages - A potential therapeutic approach.

Mitochondria are dynamic organelles responsible for cellular energy production. Besides, regulating energy homeostasis, mitochondria are responsible for calcium homeostasis, signal transmission, and the fate of cellular survival in case of injury and pathologies. Accumulating reports have suggested multiple roles of mitochondria in neuropathologies, neurodegeneration, and immune activation under physiological and pathological conditions. Mitochondrial dysfunction, which occurs at the initial phase of brain injury, involves oxidative stress, inflammation, deficits in mitochondrial bioenergetics, biogenesis, transport, and autophagy. Thus, development of targeted therapeutics to protect mitochondria may improve functional outcomes following traumatic brain injury (TBI) and intracerebral hemorrhages (ICH). In this review, we summarize mitochondrial dysfunction related to TBI and ICH, including the mechanisms involved, and discuss therapeutic approaches with special emphasis on past and current clinical trials.

CSF Leak After COVID-19 Nasopharyngeal Swab: A Case Report.

The nasopharyngeal swab has been used with increased frequency since the beginning of the COVID-19 pandemic. Little has been written in the literature regarding the complications arising from this procedure, as it is generally accepted as safe. In this report, we describe a case in which a young woman sustained a traumatic skull base injury during a nasopharyngeal swab for COVID-19. We then discuss the subsequent treatment and outcome. This case demonstrates the potential for significant complications arising from this widespread procedure and the necessity for awareness of these potential complications. Laryngoscope, 131:1927-1929, 2021.

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.

Concomitant central venous sinus thrombosis and subdural hematoma in acute promyelocytic leukemia: middle meningeal artery embolization enables safe anticoagulation. Illustrative case.

BACKGROUND: Acute promyelocytic leukemia (APL) has long been associated with coagulation disorders. The proposed mechanism is a combination of fibrinolysis, proteolysis, platelet dysfunction, thrombocytopenia, and possibly disseminated intravascular coagulation. Hemorrhagic complications are prominent. OBSERVATIONS: In this case, a 25-year-old female with newly diagnosed APL developed extensive cerebral venous thrombosis (CVT) and was initiated on a protocol with idarubicin and all-trans retinoic acid. The general recommendation for treating CVT is anticoagulation to stabilize the existing thrombus and prevent propagation. The patient was initiated on a heparin drip, but her clinical course was complicated by subdural hemorrhage (SDH) and epidural hemorrhage in the setting of thrombocytopenia. Anticoagulation was held, and her CVT propagated on follow-up imaging. To restart anticoagulation for CVT with a limited risk of SDH, the authors pursued middle meningeal artery (MMA) embolization. The patient was transitioned to apixaban and discharged to home. LESSONS: MMA embolization enables safe anticoagulation in patients with concomitant CVT and SDH. The authors report the complex clinical course and effective management of this rare clinical scenario.

Tethered brain: disentangling unintentional brain-mesh interfaces. Illustrative case.

BACKGROUND: Surgical meshes have found widespread use in neurosurgical practice. While commonly recognized risks of synthetic mesh include infection, exposure of mesh implants, and foreign body reaction, the risk of mesh tethering to neural structures is often overlooked. OBSERVATIONS: The authors presented the first case, to their knowledge, of the disentanglement of mesh interfaced to cortical tissue. The patient, a 68-year-old woman, presented with severe intractable seizure disorder and worsening left hand function and incoordination after meningioma resection and cranioplasty 9 years earlier. Magnetic resonance imaging (MRI) demonstrated interval progression of macrocystic encephalomalacia involving the right supplementary motor area, with fluid-attenuated inversion recovery signal extending posteriorly into the right primary motor cortex. Both computed tomography and MRI suggested potential tethering of the cortex to the overlying cranioplasty mesh. Because of the progressive nature of her condition, the decision was made to surgically remove the tethered mesh. LESSONS: De-tethering brain parenchyma from surgical mesh requires careful microdissection and judicious use of electrocautery to minimize further tissue damage and preserve neurological function. This inadvertent complication evinces the importance of using dural substitutes when unable to primarily repair the dura to prevent scarring and tethering of neural tissues to synthetic cranioplasty materials.

Anatomic Study Quantifying the Relationship Between the Arcuate Eminence and the Root of the Zygoma: Application to Skull Base Surgery.

OBJECTIVE: The aim of this study was to define the structural relationship between the arcuate eminence (AE) and a known fixed external bony landmark, the root of the zygoma (ZR), and to determine its reliability as a consistent guide for guiding surgical approaches. To our knowledge, this is the only anatomic study to quantify the relationship between the AE and ZR. METHODS: Twenty-one dry temporal bones were measured using digital calipers. The distance from the posterior aspect of the ZR to the midpoint of the AE was measured. Additionally, the anteroposterior distance between the ZR and AE and vertical distance between the 2 structures were measured. Student's t-test was used to compare the left and right sides. RESULTS: An AE was found in every specimen. The mean ZR to AE distance was 30.9 mm. On most sides (91%), the ZR was located more inferiorly than the AE with a mean distance of 3 mm between the 2 structures. The mean distance between the AE and ZR was 17 mm. On all sides, the AE was located posterior to the ZR. No significant differences were found between sides. No anatomic variations or pathologic conditions were noted in any of the specimens. CONCLUSIONS: The ZR is an easily identifiable and consistent bony landmark often used by skull base surgeons. In this investigation, we measured the anatomic relationships between the ZR and AE. Such data might assist in planning surgical trajectories and minimizing complications when skull base pathologies are approached.

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions.

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.