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.

Kelp dissolved organic carbon release is seasonal and annually enhanced during senescence.

Macroalgae influence local and global biogeochemical cycles through their production of dissolved organic carbon (DOC). Yet, data remain scarce and annualized estimates are typically based on high growth periods without considering seasonal variability. Although the mechanisms of active exudation and passive leakage need clarifying, ecophysiological stress is known to enhance DOC release. Therefore, DOC leakage from seasonally senescent macroalgae may be overlooked. This study focuses on the annual kelp Saccharina japonica var. religiosa (class Phaeophyceae) from Oshoro Bay, Hokkaido, Japan. Three years (2020-2022) of seasonal data were collected and analyzed, with least squares mean DOC release rates established for kelp (n = 88) across 16 incubation experiments (t ≥ 4 d, DOC samples ≥1 · d-1) under different photosynthetically active radiation (PAR) treatments (200, 400, 1200, or 1500 µmol photons · m-2 · s-1). Differences in PAR, dry weight biomass (g DW), sea surface temperature, or salinity could not explain DOC release-rate variability, which was high between individual kelp. Instead, there were significant intra-annual differences, with mean DOC release rates (mg C · g-1 DW · d-1 ± standard error between n kelp) higher during the autumn "late decay" period (0.71 ± 0.10, n = 27) compared to the winter "early growth" period (0.14 ± 0.025, n = 10) and summer "early decay" period (0.25 ± 0.050, n = 24). This relationship between seasonal senescence and macroalgal DOC release is further evidence that long-term, place-based studies of DOC dynamics are essential and that global extrapolations are premature.

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.

Oxygen-Based Autoregulation Indices Associated with Clinical Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

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: Study participants with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10 s moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In study participants with subdural electrocorticography (ECoG) monitoring, SD was also scored. Associations between clinical outcomes using the modified Rankin scale and occurrence of either isolated or clustered SD were assessed. RESULTS: A total of 320 study participants were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors, such as modified Fisher scale score and World Federation of Neurosurgical Societies scale grade, 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 ~ 100 mm Hg. Multiple autoregulation indices were available for review based on moving correlations between mean arterial pressure (MAP) and various surrogates of cerebral blood flow (CBF). We calculated the pressure reactivity (PRx) using two different sources for intracranial pressure (ICP). We calculated the oxygen reactivity (ORx) using the partial pressure of brain tissue oxygen (PbtO2) from the Licox probe. We calculated the cerebral blood flow reactivity (CBFRx) using perfusion measurements from the Bowman perfusion probe. Finally, we calculated the cerebral oxygen saturation reactivity (OSRx) using regional cerebral oxygen saturation measured by near-infrared spectroscopy from the INVOS sensors. Only worse ORx and OSRx were associated with worse clinical outcomes. Both ORx and OSRx also were found to 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.

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.

Cerebral Autoregulation Correlation With Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia remains one of the principal therapeutic targets after aneurysmal subarachnoid hemorrhage. While large vessel vasospasm may contribute to ischemia, increasing evidence suggests that physiological impairment through disrupted impaired cerebral autoregulation (CA) and spreading depolarizations (SDs) also contribute to delayed cerebral ischemia and poor neurological outcome. This study seeks to explore the intermeasure correlation of different measures of CA, as well as correlation with SD and neurological outcome. METHODS: Simultaneous measurement of 7 continuous indices of CA was calculated in 19 subjects entered in a prospective study of SD in aneurysmal subarachnoid hemorrhage undergoing surgical aneurysm clipping. Intermeasure agreement was assessed, and the association of each index with modified Rankin Scale score at 90 days and occurrence of SD was assessed. RESULTS: There were 4102 hours of total monitoring time across the 19 subjects. In time-resolved assessment, no CA measures demonstrated significant correlation; however, most demonstrate significant correlation averaged over 1 hour. Pressure reactivity (PRx), oxygen reactivity, and oxygen saturation reactivity were significantly correlated with modified Rankin Scale score at 90 days. PRx and oxygen reactivity also were correlated with the occurrence of SD events. Across multiple CA measure reactivity indices, a threshold between 0.3 and 0.5 was most associated with intervals containing SD. CONCLUSIONS: Different continuous CA indices do not correlate well with each other on a highly time-resolved basis, so should not be viewed as interchangeable. PRx and oxygen reactivity are the most reliable indices in identifying risk of worse outcome in patients with aneurysmal subarachnoid hemorrhage undergoing surgical treatment. SD occurrence is correlated with impaired CA across multiple CA measurement techniques and may represent the pathological mechanism of delayed cerebral ischemia in patients with impaired CA. Optimization of CA in patients with aneurysmal subarachnoid hemorrhage may lead to decreased incidence of SD and improved neurological outcomes. Future studies are needed to evaluate these hypotheses and approaches.

Spreading depolarization occurs in repeating, recognizable, patient-specific patterns after human brain injury.

Background and Objective: Electrocorticographic (ECoG) measurement of spreading depolarization (SD) has led to significant advances in understanding of injury progression in neuro ICU patients.  However, SD can be difficult to recognize in ECoG regions with high artifact. Heuristics for ECoG analysis within these regions would be highly valuable.Methods: Patients requiring craniotomy following subarachnoid hemorrhage, malignant hemispheric stroke, or traumatic brain injury were enrolled in this study. ECoG leads were placed intraoperatively and scoring of SDs was completed twice; once using traditional criteria and again with the intention of finding SD patterns. Utilizing covariance structures, graphical overlay and various measures surrounding DC shift, SDs were evaluated for patterns.Results: SD patterns were consistently observed and were unique to each patient and lead placement. No more than five different patterns were noted for any given patient, and statistical analysis utilizing covariance structures revealed high intra-pattern consistency.Conclusion: This validation of internal patient specific patterns offers more insight into ECoG readings of high artifact regions. This, in addition to traditional SD scoring heuristics, offers another scoring tool for the neuro-ICU care of patient experiencing SD. Furthermore, description of neurologic disease by its SD patterns may offer a new direction for precision medicine.

Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials.

BACKGROUND: Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. METHODS: For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. RESULTS: In brain slice studies, memantine (10-300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. CONCLUSIONS: These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.

Effect of Locally Delivered Nimodipine Microparticles on Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Recurrent spreading depolarizations (SDs) occur in patients after aneurysmal subarachnoid hemorrhage (aSAH), resulting in metabolic stress to brain. These events are closely associated with delayed cerebral ischemia. Preclinical data suggest that the beneficial effect of nimodipine demonstrated in clinical trials may be related to inhibition of SD rather than limitation of large artery vasospasm. METHODS: Subjects enrolled in a phase 3 trial of intraventricularly delivered, sustained-release nimodipine (EG-1962) versus standard of care oral nimodipine (NEWTON 2) who required surgical clipping had subdural strip electrodes implanted for monitoring of SD. SD was then scored blinded to NEWTON 2 allocation. RESULTS: Five subjects underwent electrocorticography monitoring of SD. Three of five patients had SD. There were fewer SDs, a lower rate of SD, and shorter depression durations in subjects treated with EG-1962 compared to standard of care. Outcomes were worse in the standard of care group, though there were baseline imbalances. CONCLUSIONS: These results are consistent with a beneficial effect of locally delivered nimodipine (EG-1962) on SD after aSAH in more severely injured patients who are at risk of delayed cerebral ischemia related to SD. Larger studies are warranted to test this effect.

Spreading Depolarization After Chronic Subdural Hematoma Evacuation: Associated Clinical Risk Factors and Influence on Clinical Outcome.

BACKGROUND: Chronic subdural hematoma (cSDH) is a common neurosurgical condition responsible for excess morbidity, particularly in the geriatric population. Recovery after evacuation is complicated by fluctuating neurological deficits in a high proportion of patients. We previously demonstrated that spreading depolarizations (SDs) may be responsible for some of these events. In this study, we aim to determine candidate risk factors for probable SD and assess the influence of probable SD on outcome. METHODS: We used two cohorts who underwent surgery for cSDH. The first cohort (n = 40) had electrocorticographic monitoring to detect SD. In the second cohort (n = 345), we retrospectively identified subjects with suspected SD based on the presence of transient neurological symptoms not explained by structural etiology or ictal activity on electroencephalography. We extracted standard demographic and outcome variables for comparisons and modeling. RESULTS: Of 345 subjects, 80 (23%) were identified in the retrospective cohort as having probable SD. Potential risk factors included history of hypertension, worse clinical presentation on the Glasgow Coma Scale, and lower Hounsfield unit density and volume of the preoperative subdural hematoma. Probable SD was associated with multiple worse-outcome measures, including length of stay and clinical outcomes, but not increased mortality. On a multivariable analysis, probable SD was independently associated with worse outcome, determined by the Glasgow Outcome Scale score at the first clinic follow-up (odds ratio 1.793, 95% confidence interval 1.022-3.146) and longer hospital length of stay (odds ratio 7.952, 95% confidence interval 4.062-15.563). CONCLUSIONS: Unexplained neurological deficits after surgery for cSDH occur in nearly a quarter of patients and may be explained by SD. We identified several potential candidate risk factors. Patients with probable SD have worse outcomes, independent of other baseline risk factors. Further data with gold standard monitoring are needed to evaluate for possible predictors of SD to target therapies to a high-risk population.

Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

What Should a Clinician Do When Spreading Depolarizations are Observed in a Patient?

The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in the September of 2018 devoted a section to address the question, "What should a clinician do when spreading depolarizations are observed in a patient?" Discussants represented a wide range of expertise, including neurologists, neurointensivists, neuroradiologists, neurosurgeons, and pre-clinical neuroscientists, to provide both clinical and basic pathophysiology perspectives. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was formally collated, reviewed, and incorporated into the final document which was subsequently approved by all authors.

Which Spreading Depolarizations Are Deleterious To Brain Tissue?

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.

Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

OBJECTIVE: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. METHODS: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate-Comfort Care order followed by terminal extubation. RESULTS: Withdrawal of life-sustaining therapies produced a decline in brain tissue partial pressure of oxygen (pti O2 ) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed "nonspreading depression," developed during the steep falling phase of pti O2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7-14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6-6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. INTERPRETATION: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295-310.

Synthesis and bioluminescence of thioluciferin.

The firefly luciferin analog thioluciferin (S-luc) was synthesised as a key element of bioluminescent reporters for oxidation state and thiol/disulfide equilibria. It shows blue-shifts in absorption and fluorescence compared to luciferin, and is a modest luciferase substrate. These features are attributed to a π-system that is less conjugated than luciferin.

Melanotic neuroectodermal tumor of infancy: A rare pediatric head and neck lesion.

Melanotic neuroectodermal tumors of infancy are rare tumors arising from the neural crest and typically present during the first 12 months of life. The majority involve the facial bones, although melanotic neuroectodermal tumors of infancy of the skull and extremities have been observed with less frequency, as in the present case. This entity may initially be presented to the dermatologist as a scalp mass and should be considered in the differential diagnosis of infants with rapidly growing head and neck lesions.

Microsurgical Vascular Manipulation in Aneurysm Surgery and Delayed Ischemic Injury.

BACKGROUND: The role of aggressive surgical manipulation with clot evacuation, arachnoid dissection, and papaverine-guided adventitial dissection of large vessels during ruptured aneurysm surgery in reducing vasospasm is controversial. Here we describe a single-institution experience in aneurysm surgery outcomes with and without aggressive surgery. METHODS: We performed retrospective analysis of all patients >18 years of age with subarachnoid hemorrhage (SAH) from anterior circulation aneurysms between 2008 and 2013 at the University of New Mexico Hospital. Vasospasm was characterized on days 3 through 14 after SAH based on: (1) angiography, (2) vasospasm requiring angiographic intervention, (3) development of delayed ischemic neurologic deficit (DIND), and (4) radiological appearance of new strokes. RESULTS: Of 159 patients, 114 (71.6%) had "aggressive" and 45 (28.3%) had standard microsurgery. More than 60% of patients presented with a Hunt and Hess score of ≥3 and a Fisher grade (FG) of 4. Compared with standard surgery, there was a statistically significant decrease in the incidence of DIND in patients undergoing aggressive surgery (18.4% vs 37.8%, p=0.01). Moreover, there was a reduction in the number of new strokes by 30% in the aggressive surgery group with moderate or higher degrees of vasospasm (46.0% vs 76.5%, p=0.06). In the same group with FG 4 SAH, however, this difference was more than 50% (30% vs 64.7%, p=0.02). CONCLUSIONS: We conclude that aggressive surgical manipulation during aneurysm surgery results in lower incidence of DIND and new strokes. This effect is most pronounced in patients with FG 4 SAH.

Prolapse of the Pipeline embolization device in aneurysms: incidence, management, and outcomes.

OBJECTIVE The Pipeline embolization device (PED) is frequently used in the treatment of anterior circulation aneurysms, especially around the carotid siphon, with generally excellent results. However, the PED has its own unique technical challenges, including the occurrence of device foreshortening or migration leading to prolapse into the aneurysm. The authors sought to determine the incidence of this phenomenon, the rescue strategies, and outcomes. METHODS Four institutional databases of neuroendovascular procedures were reviewed for cases of intracranial aneurysms treated with PEDs. Patient and aneurysm data as well as angiographic imaging were reviewed for all cases involving device prolapse into the aneurysm. RESULTS A total of 413 intracranial aneurysms were treated with PEDs during the study period, by 5 neurointerventionalists. Large and giant aneurysms (≥ 2 cm) accounted for 32 of these aneurysms. Among these 32 PEDs, prolapse into the aneurysm occurred in 3 patients, with 1 of these PEDs successfully rescued and the other 2 left in situ. No patients suffered any severe complications. The 2 patients in whom the PEDs were left in situ remained on antiplatelet therapy. CONCLUSIONS The PED may foreshorten or migrate during or after deployment, leading to prolapse into the aneurysm. This phenomenon appears to be associated with large and giant aneurysms, vessel tortuosity, short landing zones, and use of balloon angioplasty. Future study and follow-up is needed to further evaluate this phenomenon, but some of the observations and techniques described in this paper may help to prevent or salvage prolapsed devices.