Spreading Depolarization Induces a Transient Potentiation of Excitatory Synaptic Transmission.

Spreading depolarization (SD) is a slowly propagating wave of prolonged activation followed by a period of synaptic suppression. Some prior reports have shown potentiation of synaptic transmission after recovery from synaptic suppression and noted similarities with the phenomenon of long-term potentiation (LTP). Since SD is increasingly recognized as participating in diverse neurological disorders, it is of interest to determine whether SD indeed leads to a generalized and sustained long-term strengthening of synaptic connections. We performed a characterization of SD-induced potentiation, and tested whether distinctive features of SD, including adenosine accumulation and swelling, contribute to reports of SD-induced plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the hippocampal CA1 subregion of murine brain slices, and SD elicited using focal microinjection of KCl. A single SD was sufficient to induce a consistent potentiation of slope and amplitude of fEPSPs. Both AMPA- and NMDA-receptor mediated components were enhanced. Potentiation peaked ∼20 minutes after SD recovery and was sustained for ∼30 minutes. However, fEPSP amplitude and slope decayed over an extended 2-hour recording period and was estimated to reach baseline after ∼3 hours. Potentiation was saturated after a single SD and adenosine A1 receptor activation did not mask additional potentiation. Induction of LTP with theta-burst stimulation was not altered by prior induction of SD and molecular mediators known to block LTP induction did not block SD-induced potentiation. Together, these results indicate an intermediate duration potentiation that is distinct from hippocampal LTP and may have implications for circuit function for 1-2 hours following SD.

Oxygen-based autoregulation indices associated with clinical outcomes and spreading depolarization in aSAH.

Background: Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH), however there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Methods: Subjects with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10 second moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In subjects with subdural ECoG (electrocorticography) monitoring, SD was also scored. Associations between clinical outcomes using the mRS (modified Rankin Scale) and occurrence of either isolated or clustered SD was assessed. Results: 320 subjects were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors such as mFS and WFNS (World Federation of Neurosurgical Societies scale) were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern with a linear increase in probability below MAP of ∼100mmHg.Autoregulation indices were available for intracranial pressure (ICP) measurements (PRx), PbtO2 from Licox (ORx), perfusion from the Bowman perfusion probe (CBFRx), and cerebral oxygen saturation measured by near infrared spectroscopy (OSRx). Only worse ORx and OSRx were associated with worse clinical outcomes. ORx and OSRx also were found to both increase in the hour prior to SD for both sporadic and clustered SD. Conclusions: Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.

Cerebral autoregulation, spreading depolarization, and implications for targeted therapy in brain injury and ischemia.

Cerebral autoregulation is an intrinsic myogenic response of cerebral vasculature that allows for preservation of stable cerebral blood flow levels in response to changing systemic blood pressure. It is effective across a broad range of blood pressure levels through precapillary vasoconstriction and dilation. Autoregulation is difficult to directly measure and methods to indirectly ascertain cerebral autoregulation status inherently require certain assumptions. Patients with impaired cerebral autoregulation may be at risk of brain ischemia. One of the central mechanisms of ischemia in patients with metabolically compromised states is likely the triggering of spreading depolarization (SD) events and ultimately, terminal (or anoxic) depolarization. Cerebral autoregulation and SD are therefore linked when considering the risk of ischemia. In this scoping review, we will discuss the range of methods to measure cerebral autoregulation, their theoretical strengths and weaknesses, and the available clinical evidence to support their utility. We will then discuss the emerging link between impaired cerebral autoregulation and the occurrence of SD events. Such an approach offers the opportunity to better understand an individual patient's physiology and provide targeted treatments.

Continuous irrigation with thrombolytics for intraventricular hemorrhage: case-control study.

Intraventricular hemorrhage (IVH) is a complication of a spontaneous intracerebral hemorrhage. Standard treatment is with external ventricular drain (EVD). Intraventricular thrombolysis may improve mortality but does not improve functional outcomes. We present our initial experience with a novel irrigating EVD (IRRAflow) that automates continuous irrigation with thrombolysis.Single-center case-control study including patients with IVH treated with EVD compared to IRRAflow. We compared standard demographics, treatment, and outcome parameters between groups. We developed a brain phantom injected with a human clot and assessed clot clearance using EVD/IRRAflow approaches with CT imaging.Twenty-one patients were treated with standard EVD and 9 patients with IRRAflow. Demographics were similar between groups. Thirty-three percent of patients with EVD also had at least one dose of t-PA and 89% of patients with IRRAflow received irrigation with t-PA (p = 0.01). Mean drain days were 8.8 for EVD versus 4.1 for IRRAflow (p = 0.02). Days-to-clearance of ventricular outflow was 5.8 for EVD versus 2.5 for IRRAflow (p = 0.02). Overall clearance was not different. Thirty-seven percent of EVD patients achieved good outcome (mRS ≥ 3) at 90 days versus 86% of IRRAflow patients (p = 0.03). Assessing only t-PA, reduction in mean days-to-clearance (p = 0.0004) and ICU days (p = 0.04) was observed. In the benchtop model, the clot treated with IRRAflow and t-PA showed a significant reduction of volume compared to control.Irrigation with IRRAflow and t-PA is feasible and safe for patients with IVH. Improving clot clearance with IRRAflow may result in improved clinical outcomes and should be incorporated into randomized trials.

Synaptic Zn2+ contributes to deleterious consequences of spreading depolarizations.

Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+ release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+ chelator with rapid kinetics (ZX1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+ transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+ during SD. These results demonstrate a role for synaptic Zn2+ release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.

Synaptic Zn2+ contributes to deleterious consequences of spreading depolarizations.

Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+ release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+ chelator with rapid kinetics (ZX-1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX-1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+ transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+ during SD. These results demonstrate a role for synaptic Zn2+ release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.

HummingFlow: novel single twist-drill access for ventricular drainage, irrigation, monitoring, and automated local drug delivery in subarachnoid hemorrhage.

OBJECTIVE: The management of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH) remains one of the most important targets for neurocritical care. Advances in monitoring technology have facilitated a more thorough understanding of the pathophysiology and therapeutic approaches, but interventions are generally limited to either systemic therapies or passive CSF drainage. The authors present a novel approach that combines a multimodal monitoring bolt-based system with an irrigating ventricular drain capable of delivering intrathecal medications and describe their early experience in patients with aSAH. METHODS: The authors performed a retrospective review of cases treated with the combined Hummingbird multimodal bolt system and the IRRAflow irrigating ventriculostomy. RESULTS: Nine patients were treated with the combined multimodal bolt system with irrigating ventriculostomy approach. The median number of days to clearance of the third and fourth ventricles was 3 days in patients with obstructive intraventricular hemorrhage. Two patients received intrathecal alteplase for intraventricular hemorrhage clearance, and 2 patients received intrathecal nicardipine as rescue therapy for severe symptomatic angiographic vasospasm. CONCLUSIONS: Combined CSF drainage, irrigation, multimodality monitoring, and automated local drug delivery are feasible using a single twist-drill hole device. Further investigation of irrigation settings and treatment approaches in high-risk cases is warranted.

Ketamine improves neuronal recovery following spreading depolarization in peri-infarct tissues.

Spreading depolarization (SD) has emerged as an important contributor to the enlargement of acute brain injuries. We previously showed that the N-methyl-D-aspartate receptor antagonist ketamine was able to prevent deleterious consequences of SD in brain slices, under conditions of metabolic compromise. The current study aimed to extend these observations into an in vivo stroke model, to test whether gradients of metabolic capacity lead to differential accumulation of calcium (Ca2+ ) following SD. In addition, we tested whether ketamine protects vulnerable tissuewhile allowing SD to propagate through surrounding undamaged tissue. Focal lesions were generated using a distal middle cerebral artery occlusion in mice, and clusters of SD were generated at 20 min intervals with remote microinjection of potassium chloride. SDs invading peri-infarct regions had significantly different consequences, depending on the distance from the infarct core. Proximal to the lesion, Ca2+ transients were extended, as compared with responses in better-perfused tissue more remote from the lesion. Extracellular potential shifts were also longer and hyperemia responses were reduced in proximal regions following SDs. Consistent with in vitro studies, ketamine, at concentrations that did not abolish the propagation of SD, reduced the accumulation of intracellular Ca2+ in proximal regions following an SD wave. These findings suggest that deleterious consequences of SD can be targeted in vivo, without requiring outright block of SD initiation and propagation.

Dural venous sinus stenting technique for idiopathic intracranial hypertension in patients with tortuous venous anatomy.

Venous sinus stenting (VSS) for medically refractory idiopathic intracranial hypertension (IIH) is emerging as a safe and effective alternative to shunting. However, stent navigation past the jugular bulb with commonly used carotid stenting systems via femoral access in cases with tortuous venous anatomy can present a challenge, leading to procedural failure. We present a technical refinement using a cervical access and peripheral vascular stent with a more stable 0.035-in. delivery platform as an alternative to the traditional approach to simplify the procedure and overcome the technical difficulties in cases with tortuous venous anatomy. Our institutional database for patients who had IIH and undergone VSS using the peripheral vascular stent between 2013 and 2023 was retrospectively reviewed. Data on 36 patients (33 women, 3 men, mean age 32 years) was collected. VSS was technically successful in all patients (100%) without major complications or thrombosis. There was one case of minor neck cellulitis treated with oral antibiotics. Three patients underwent repeat stenting, and 2 patients had ventriculoperitoneal shunt placement after stenting due to persistent or recurrent symptoms. All patients (100%) had improvement or resolution of papilledema; however, six patients had evidence of optic atrophy and persistent vision loss. Headache was resolved or improved in 91% of patients. In the presence of tortuous venous anatomy, VSS using cervical access and a peripheral vascular stent with a more stable 0.035-in. delivery platform can be considered as a safe and effective alternative approach with shorter procedure time. This approach is particularly advantageous in situations where the procedure is prolonged or high dose of contrast has been administered due to the technical challenges associated with the traditional use of carotid systems via femoral access for stent delivery.

Improving Neurotrauma by Depolarization Inhibition With Combination Therapy: A Phase 2 Randomized Feasibility Trial.

BACKGROUND AND OBJECTIVES: Spreading depolarizations (SDs) are a pathological mechanism that mediates lesion development in cerebral gray matter. They occur in ∼60% of patients with severe traumatic brain injury (TBI), often in recurring and progressive patterns from days 0 to 10 after injury, and are associated with worse outcomes. However, there are no protocols or trials suggesting how SD monitoring might be incorporated into clinical management. The objective of this protocol is to determine the feasibility and efficacy of implementing a treatment protocol for intensive care of patients with severe TBI that is guided by electrocorticographic monitoring of SDs. METHODS: Patients who undergo surgery for severe TBI with placement of a subdural electrode strip will be eligible for enrollment. Those who exhibit SDs on electrocorticography during intensive care will be randomized 1:1 to either (1) standard care that is blinded to the further course of SDs or (2) a tiered intervention protocol based on efficacy to suppress further SDs. Interventions aim to block the triggering and propagation of SDs and include adjusted targets for management of blood pressure, CO 2 , temperature, and glucose, as well as ketamine pharmacotherapy up to 4 mg/kg/ hour. Interventions will be escalated and de-escalated depending on the course of SD pathology. EXPECTED OUTCOMES: We expect to demonstrate that electrocorticographic monitoring of SDs can be used as a real- time diagnostic in intensive care that leads to meaningful changes in patient management and a reduction in secondary injury, as compared with standard care, without increasing medical complications or adverse events. DISCUSSION: This trial holds potential for personalization of intensive care management by tailoring therapies based on monitoring and confirmation of the targeted neuronal mechanism of SD. Results are expected to validate the concept of this approach, inform refinement of the treatment protocol, and lead to larger-scale trials.

Repetitive Spreading Depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways.

Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, there is uncertainty surrounding the potential activation of beneficial pathways such as cell survival and plasticity. The present study used unbiased assessments of gene expression to evaluate that compensatory and repair mechanisms could be recruited following SD, regardless of the induction method, which prior to this work had not been assessed. We also tested assumptions of appropriate controls and the spatial extent of expression changes that are important for in vivo SD models. SD clusters were induced with either KCl focal application or optogenetic stimulation in healthy mice. Cortical RNA was extracted and sequenced to identify differentially expressed genes (DEGs). SDs using both induction methods significantly upregulated 16 genes (versus sham animals) that included the cell proliferation-related genes FOS, JUN, and DUSP6, the plasticity-related genes ARC and HOMER1, and the inflammation-related genes PTGS2, EGR2, and NR4A1. The contralateral hemisphere is commonly used as control tissue for DEG studies, but its activity could be modified by near-global disruption of activity in the adjacent brain. We found 21 upregulated genes when comparing SD-involved cortex versus tissue from the contralateral hemisphere of the same animals. Interestingly, there was almost complete overlap (21/16) with the DEGs identified using sham controls. Neuronal activity also differs in SD initiation zones, where sustained global depolarization is required to initiate propagating events. We found that gene expression varied as a function of the distance from the SD initiation site, with greater expression differences observed in regions further away. Functional and pathway enrichment analyses identified axonogenesis, branching, neuritogenesis, and dendritic growth as significantly enriched in overlapping DEGs. Increased expression of SD-induced genes was also associated with predicted inhibition of pathways associated with cell death, and apoptosis. These results identify novel biological pathways that could be involved in plasticity and/or circuit modification in brain tissue impacted by SD. These results also identify novel functional targets that could be tested to determine potential roles in recovery and survival of peri-infarct tissues.

Risk Factors and Management of Incisional Cerebrospinal Fluid Leakage After Craniotomy: A Retrospective International Multicenter Study.

BACKGROUND: Incisional cerebrospinal fluid (iCSF) leakage is a serious complication after intradural cranial surgery. OBJECTIVE: To determine the incidence and risk factors of iCSF leakage after craniotomy. Secondarily, the complications after iCSF leakage and the success rate of iCSF leakage treatment was studied. METHODS: All patients who underwent an intradural cranial surgery from 2017 to 2018 at 5 neurosurgical centers were retrospectively included. Data were retrieved from medical records with 2 months of follow-up. First, univariate regression analyses were performed. Subsequently, identified risk factors were evaluated in a multivariate regression analysis. RESULTS: In total 2310 consecutive patients were included. Total iCSF leakage rate was 7.1% (n = 165). Younger age, male, higher body mass index, smoking, infratentorial surgery, and use of a dural substitute were associated with increased iCSF leakage risk, and use of a sealant reduced that risk. The odds for developing a wound infection and/or meningitis were 15 times higher in patients with iCSF leakage compared with patients without leakage. Initial conservative iCSF leakage treatment failed in 48% of patients. In 80% of cases, external cerebrospinal fluid drainage ceased the iCSF leakage. A total of 32% of patients with iCSF leakage required wound revision surgery. CONCLUSION: iCSF leakage risk increases by younger age, higher body mass index, smoking, infratentorial craniotomy, and dural substitute use, whereas sealant use reduced the risk for iCSF leakage. The leak increases the risk of postoperative infections. When iCSF leakage occurs, immediate external cerebrospinal fluid drainage or wound revision should be considered.

Is the Human Touch Always Therapeutic? Patient Stimulation and Spreading Depolarization after Acute Neurological Injuries.

Touch and other types of patient stimulation are necessary in critical care and generally presumed to be beneficial. Recent pre-clinical studies as well as randomized trials assessing early mobilization have challenged the safety of such routine practices in patients with acute neurological injury such as stroke. We sought to determine whether patient stimulation could result in spreading depolarization (SD), a dramatic pathophysiological event that likely contributes to metabolic stress and ischemic expansion in such patients. Patients undergoing surgical intervention for severe acute neurological injuries (stroke, aneurysm rupture, or trauma) were prospectively consented and enrolled in an observational study monitoring SD with implanted subdural electrodes. Subjects also underwent simultaneous video recordings (from continuous EEG monitoring) to assess for physical touch and other forms of patient stimulation (such as suctioning and positioning). The association of patient stimulation with subsequent SD was assessed. Increased frequency of patient stimulation was associated with increased risk of SD (OR = 4.39 [95%CI = 1.71-11.24]). The overall risk of SD was also increased in the 60 min following patient stimulation compared to times with no stimulation (OR = 1.19 [95%CI = 1.13-1.26]), though not all subjects demonstrated this effect individually. Positioning of the subject was the subtype of stimulation with the strongest overall effect on SD (OR = 4.92 [95%CI = 3.74-6.47]). We conclude that in patients with some acute neurological injuries, touch and other patient stimulation can induce SD (PS-SD), potentially increasing the risk of metabolic and ischemic stress. PS-SD may represent an underlying mechanism for observed increased risk of early mobilization in such patients.

Repetitive spreading depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways.

Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, there is uncertainty surrounding the potential activation of beneficial pathways such as cell survival and plasticity. The present study used unbiased assessments of gene expression to evaluate that compensatory and repair mechanisms could be recruited following SD, regardless of the induction method, which prior to this work had not been assessed. We also tested assumptions of appropriate controls and the spatial extent of expression changes that are important for in vivo SD models. SD clusters were induced with either KCl focal application or optogenetic stimulation in healthy mice. Cortical RNA was extracted and sequenced to identify differentially expressed genes (DEGs). SDs using both induction methods significantly upregulated 16 genes (vs. sham animals) that included the cell proliferation-related genes FOS, JUN, and DUSP6, the plasticity-related genes ARC and HOMER1, and the inflammation-related genes PTGS2, EGR2, and NR4A1. The contralateral hemisphere is commonly used as control tissue for DEG studies, but its activity could be modified by near-global disruption of activity in the adjacent brain. We found 21 upregulated genes when comparing SD-involved cortex vs. tissue from the contralateral hemisphere of the same animals. Interestingly, there was almost complete overlap (21/16) with the DEGs identified using sham controls. Neuronal activity also differs in SD initiation zones, where sustained global depolarization is required to initiate propagating events. We found that gene expression varied as a function of the distance from the SD initiation site, with greater expression differences observed in regions further away. Functional and pathway enrichment analyses identified axonogenesis, branching, neuritogenesis, and dendritic growth as significantly enriched in overlapping DEGs. Increased expression of SD-induced genes was also associated with predicted inhibition of pathways associated with cell death, and apoptosis. These results identify novel biological pathways that could be involved in plasticity and/or circuit modification in brain tissue impacted by SD. These results also identify novel functional targets that could be tested to determine potential roles in the recovery and survival of peri-infarct tissues.

Continuous Tissue Plasminogen Activator Infusion Using a Minimally Invasive Irrigating Catheter for the Treatment of Intraparenchymal Hemorrhage Within the Basal Ganglia: Case Reports.

BACKGROUND AND IMPORTANCE: Intraparenchymal hemorrhage (IPH) is a debilitating and highly morbid type of stroke with limited effective treatment modalities. Minimally invasive evacuation with tissue plasminogen activator (rt-PA) has demonstrated promise for mortality/functional improvements with adequate clot volume reduction. In this study, we report 2 cases of continuous rt-PA infusion using a closed circuit, dual lumen catheter, and irrigation system (IRRAflow) for IPH treatment. CLINICAL PRESENTATION: A 55-year-old man was admitted for acute onset left hemiparesis; he was found to have right basal ganglia IPH. He was treated with continuous rt-PA irrigation using the IRRAflow device, at a rate of 30 mL/h for 119 hours, with a total volume reduction of 87.8 mL and post-treatment volume of 1.2 mL. At 3-month follow-up, he exhibited a modified Rankin score of 4 and improved hemiparesis. A 39-year-old woman was admitted for acute onset left facial droop, left hemianopsia, and left hemiparesis; she was diagnosed with a right basal ganglia IPH. She was treated with drainage and continuous rt-PA irrigation at 30 mL/h for 24 hours, with a total hematoma volume reduction of 41 mL and with a final post-treatment volume of 9.1 mL. At 3-month follow-up, she exhibited a modified Rankin score of 3 with some improvement in left hemiparesis. CONCLUSION: Continuous rt-PA infusion using a minimally invasive catheter with saline irrigation was feasible and resulted in successful volume reduction in 2 patients with IPH. This technique is similar to the Minimally Invasive Surgery Plus rt-PA for Intracerebral Hemorrhage Evacuation (MISTIE) approach but offers the potential advantages of less breaks in the sterile circuit, continuous intracranial pressure monitoring, and may provide more efficient clot lysis compared with intermittent bolusing.

Spreading Depolarization as a Therapeutic Target in Severe Ischemic Stroke: Physiological and Pharmacological Strategies.

BACKGROUND: Spreading depolarization (SD) occurs nearly ubiquitously in malignant hemispheric stroke (MHS) and is strongly implicated in edema progression and lesion expansion. Due to this high burden of SD after infarct, it is of great interest whether SD in MHS patients can be mitigated by physiologic or pharmacologic means and whether this intervention improves clinical outcomes. Here we describe the association between physiological variables and risk of SD in MHS patients who had undergone decompressive craniectomy and present an initial case of using ketamine to target SD in MHS. METHODS: We recorded SD using subdural electrodes and time-linked with continuous physiological recordings in five subjects. We assessed physiologic variables in time bins preceding SD compared to those with no SD. RESULTS: Using multivariable logistic regression, we found that increased ETCO2 (OR 0.772, 95% CI 0.655-0.910) and DBP (OR 0.958, 95% CI 0.941-0.991) were protective against SD, while elevated temperature (OR 2.048, 95% CI 1.442-2.909) and WBC (OR 1.113, 95% CI 1.081-1.922) were associated with increased risk of SD. In a subject with recurrent SD, ketamine at a dose of 2 mg/kg/h was found to completely inhibit SD. CONCLUSION: Fluctuations in physiological variables can be associated with risk of SD after MHS. Ketamine was also found to completely inhibit SD in one subject. These data suggest that use of physiological optimization strategies and/or pharmacologic therapy could inhibit SD in MHS patients, and thereby limit edema and infarct progression. Clinical trials using individualized approaches to target this novel mechanism are warranted.

An In Vitro Study of Magnetic Field Interference with an Electronic Shunt Programmer.

BACKGROUND: Programmable shunts play a valuable role in the treatment of hydrocephalus. However, the use of magnets in programming these valves has caused obstacles in today's magnetized world. Previous studies have reported problems with magnetic toys and electronics unintentionally reprogramming shunt valves. This study investigated how an Apple Watch can interfere with the Codman CERTAS Plus electronic programmer. METHODS: In this in vitro study, we tested the magnetic field emitted by Apple Watch Series 3, 4, 5, and 6 using an electromagnetic field tester at distances of 0-50 mm. We conducted 20 trials of shunt programming and shunt setting reading with and without each watch. RESULTS: All 4 watches generated significant magnetic fields. Maximum magnetic fields were Series 3, 165.73 millitesla (mT); Series 4, 144.91 mT; Series 5, 131.09 mT; and Series 6, 130.68 mT. All 4 watches interfered with the programmer's ability to correctly read and program the valve setting. CONCLUSIONS: The Codman CERTAS Plus electronic programmer detects the magnetic field emitted from an Apple Watch and mistakes it for the valve, rendering programming difficult. These smartwatches and similar electronic devices should be kept away from the programmer and not worn by health care providers to avoid inappropriate readings and setting changes.

Evaluate the safety and efficacy of dura sealant patch in reducing cerebrospinal fluid leakage following elective cranial surgery (ENCASE II): study protocol for a randomized, two-arm, multicenter trial.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is a frequent and challenging complication in neurosurgery, especially in the posterior fossa, with a prevalence of 8%. It is associated with substantial morbidity and increased healthcare costs. A novel dural sealant patch (LIQOSEAL) was developed for watertight dural closure. The objective of this study is to clinically assess the safety and effectiveness of LIQOSEAL as a means of reducing intra- as well as postoperative CSF leakage in patients undergoing elective posterior fossa intradural surgery with a dural closure procedure compared to the best currently available dural sealants. METHODS: We will conduct a two-arm, randomized controlled, multicenter study with a 90-day follow-up. A total of 228 patients will be enrolled in 19 sites, of which 114 will receive LIQOSEAL and 114 an FDA-approved PEG sealant. The composite primary endpoint is defined as intraoperative CSF leakage at PEEP 20 cm H2O, percutaneous CSF leakage within 90 days of, wound infection within 90 days of or pseudomeningocele of more than 20cc on MRI or requiring intervention. We hypothesize that the primary endpoint will not be reached by more than 10 patients (9%) in the investigational arm, which will demonstrate non-inferiority of LIQOSEAL compared to control. DISCUSSION: This trial will evaluate whether LIQOSEAL is non-inferior to control as a means of reducing CSF leakage and safety TRIAL REGISTRATION: ClinicalTrials.gov NCT04086550 . Registered on 11 September 2019.

Brain Tsunamis in Human High-Grade Glioma: Preliminary Observations.

Gliomas make up nearly 40% of all central nervous system tumors, with over 50% of those being high-grade gliomas. Emerging data suggests that electrophysiologic events in the peri-tumoral region may play a role in the behavior and progression of high-grade gliomas. While seizures in the peri-tumoral zone are well described, much larger and slowly propagating waves of spreading depolarization (SD) may potentially have roles in both non-epileptic transient neurologic deficits and tumor progression. SD has only recently been observed in pre-clinical glioma models and it is not known whether these events occur clinically. We present a case of SD occurring in a human high-grade glioma using gold-standard subdural DC ECoG recordings. This finding could have meaningful implications for both clinical symptomatology and potentially for disease progression in these patients. Our observations and hypotheses are based on analogy with a large body of evidence in stroke and acute neurological injury that have recently established SD as cause of transient neurological deficits as well as a fundamental mechanism of ischemic expansion. Whether SD could represent a mechanistic target in this process to limit such progression is a high priority for further clinical investigations.