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Background Laboratory monitoring is not recommended when subcutaneous unfractionated heparin (SQ-UFH) is administered at prophylactic doses. However, aPTT prolongation and associated hemorrhage has been reported in the neurocritically ill. At our institution, Neuroscience Intensive Care Unit (Neuro-ICU) patients with prolonged aPTT are further evaluated with a follow up aPTT and anti-factor Xa. Purpose The purpose of this study was to describe concordance between aPTT and anti-factor Xa in neurocritically ill patients receiving prophylactic SQ-UFH with evidence of aPTT prolongation. Methods A retrospective chart review of adult patients admitted to the Neuro-ICU from June 2017 to June 2019 was performed. Patients were included if they received SQ-UFH with aPTT levels and at least one anti-factor Xa level drawn within one hour of each other. Concordance between paired aPTT and anti-factor Xa was evaluated using Cohen’s weighted kappa. Results Forty two patients with 56 paired aPTT and anti-factor Xa levels were included. The most prescribed SQ-UFH regimen was 5000 units every 8 hours (60.7%) and anti-factor Xa levels were drawn a median (IQR) of 5.7 (3.1-10.7) hours after the SQ-UFH dose. Only 16 (28.6%) pairs were in concordance. The analysis showed a weighted kappa of .09; 95% CI [−.05 to .22] indicating poor agreement. Conclusions In neurocritically ill patients receiving prophylactic SQ-UFH with aPTT prolongation, there was poor concordance between aPTT and anti-factor Xa. This suggests that aPTT prolongation may not be solely driven by heparin activity and further evaluation of mechanistic drivers for coagulopathy in this population is necessary.

Background and Purpose— Perihematomal edema (PHE) is a promising surrogate marker of secondary brain injury in patients with spontaneous intracerebral hemorrhage, but it can be challenging to accurately and rapidly quantify. The aims of this study are to derive and internally validate a fully automated segmentation algorithm for volumetric analysis of PHE. Methods— Inpatient computed tomography scans of 400 consecutive adults with spontaneous, supratentorial intracerebral hemorrhage enrolled in the Intracerebral Hemorrhage Outcomes Project (2009–2018) were separated into training (n=360) and test (n=40) datasets. A fully automated segmentation algorithm was derived from manual segmentations in the training dataset using convolutional neural networks, and its performance was compared with that of manual and semiautomated segmentation methods in the test dataset. Results— The mean volumetric dice similarity coefficients for the fully automated segmentation algorithm were 0.838±0.294 and 0.843±0.293 with manual and semiautomated segmentation methods as reference standards, respectively. PHE volumes derived from the fully automated versus manual (r=0.959; P P P P P Conclusions— The fully automated segmentation algorithm accurately quantified PHE volumes from computed tomography scans of supratentorial intracerebral hemorrhage patients with high fidelity and greater efficiency compared with manual and semiautomated segmentation methods. External validation of fully automated segmentation for assessment of PHE is warranted.

Background and Purpose— Hematoma volume measurements influence prognosis and treatment decisions in patients with spontaneous intracerebral hemorrhage (ICH). The aims of this study are to derive and validate a fully automated segmentation algorithm for ICH volumetric analysis using deep learning methods. Methods— In-patient computed tomography scans of 300 consecutive adults (age ≥18 years) with spontaneous, supratentorial ICH who were enrolled in the ICHOP (Intracerebral Hemorrhage Outcomes Project; 2009–2018) were separated into training (n=260) and test (n=40) datasets. A fully automated segmentation algorithm was derived using convolutional neural networks, and it was trained on manual segmentations from the training dataset. The algorithm’s performance was assessed against manual and semiautomated segmentation methods in the test dataset. Results— The mean volumetric Dice similarity coefficients for the fully automated segmentation algorithm when tested against manual and semiautomated segmentation methods were 0.894±0.264 and 0.905±0.254, respectively. ICH volumes derived from fully automated versus manual ( R 2 =0.981; P R 2 =0.978; P R 2 =0.990; P P P Conclusions— The fully automated segmentation algorithm quantified hematoma volumes from computed tomography scans of supratentorial ICH patients with similar accuracy and substantially greater efficiency compared with manual and semiautomated segmentation methods. External validation of the fully automated segmentation algorithm is warranted.

OBJECTIVE: Intracranial pressure waveform morphology reflects compliance, which can be decreased by ventriculitis. We investigated whether morphologic analysis of intracranial pressure dynamics predicts the onset of ventriculitis. METHODS: Ventriculitis was defined as culture or Gram-stain positive cerebrospinal fluid warranting treatment. We developed a pipeline to automatically isolate segments of intracranial pressure waveforms from extraventricular catheters, extract dominant pulses, and obtain morphologically similar groupings. We utilized a previously validated clinician-supervised active learning paradigm to identify meta-clusters of triphasic, single-peak, and artifactual peaks. Meta-cluster distributions were concatenated with temperature and routine blood laboratory values to create feature vectors. A L2-regularized logistic regression classifier was trained to distinguish patients with ventriculitis from matched controls and the discriminative performance using area under receiver operating characteristic curve with bootstrapping cross-validation was reported. RESULTS: Fifty-eight patients were included for analysis. Twenty-seven patients with ventriculitis from two centers were identified. Thirty-one patients with catheters but without ventriculitis were selected as matched controls based on age, gender, and primary diagnosis. There were 1590 hours of segmented data including 396,130 dominant pulses in ventriculitis patients and 557,435 pulses in patients without ventriculitis. There were significant differences in meta-cluster distribution comparing before culture-positivity vs during culture-positivity (p

Carotid stenosis involves narrowing of the lumen in the carotid artery potentially leading to a stroke, which is the third leading cause of death in the United States. Several recent investigations have found that plaque structure and composition may represent a more direct biomarker of plaque rupture risk compared with the degree of stenosis. In this study, pulse wave imaging was applied in 111 (n = 11, N = 13 plaques) patients diagnosed with moderate (50%) to severe (80%) carotid artery stenosis to investigate the feasibility of characterizing plaque properties based on the pulse wave-induced arterial wall dynamics captured by pulse wave imaging. Five (n = 5 patients, N = 20 measurements) healthy volunteers were also imaged as a control group. Both conventional and high-frame-rate plane wave radiofrequency imaging sequences were used to generate piecewise maps of the pulse wave velocity (PWV) at a single depth along stenotic carotid segments, as well as intra-plaque PWV mapping at multiple depths. Intra-plaque cumulative displacement and strain maps were also calculated for each plaque region. The Bramwell-Hill equation was used to estimate the compliance of the plaque regions based on the PWV and diameter. Qualitatively, wave convergence, elevated PWV and decreased cumulative displacement around and/or within regions of atherosclerotic plaque were observed and may serve as biomarkers for plaque characterization. Intra-plaque mapping revealed the potential to capture wave reflections between calcified inclusions and differentiate stable (i.e., calcified) from vulnerable (i.e., lipid) plaque components based on the intra-plaque PWV and cumulative strain. Quantitatively, one-way analysis of variance indicated that the pulse wave-induced cumulative strain was significantly lower (p0.01) in the moderately and severely calcified plaques compared with the normal controls. As expected, compliance was also significantly lower in the severely calcified plaques regions compared with the normal controls (p0.01). The results from this pilot study indicated the potential of pulse wave imaging coupled with strain imaging to differentiate plaques of varying stiffness, location and composition. Such findings may serve as valuable information to compensate for the limitations of currently used methods for the assessment of stroke risk.

BACKGROUND/PURPOSE: Blood type has become an increasingly recognized risk factor for coagulopathy. We explored the association between blood type and hematoma expansion (HE) after intracerebral hemorrhage (ICH). METHODS: Spontaneous ICH patients prospectively enrolled in an ongoing ICH cohort study at Columbia University Irving Medical Center from 2009 to 2016 were evaluated. Primary ICH patients with admission blood type testing were evaluated for HE differences, defined as > 33% relative HE. The association of blood type with radiographic HE outcomes was assessed using multivariable logistic regression models. The association of blood type and poor clinical outcomes using modified Rankin Scale (mRS 4–6) was additionally explored. RESULTS: Of 272 ICH patients with blood type data and neuroimaging available to determine HE, there were 146 (54%) type-O, 82 (30%) type-A, 34 (13%) type-B, and 10 (3%) type-AB patients. No significant baseline demographic, clinical, or radiographic differences were noted between blood types. Type-B blood was associated with more HE compared to other blood types (OR 2.82; 95% CI 1.23–6.45) after adjusting for known covariates of HE (anticoagulant use, time to admission computed tomography scan, and baseline hematoma volume). No associations with blood type and poor 3 month mRS were identified, but these analyses were limited secondary to our smaller cohort. CONCLUSIONS: There may be differences in HE after ICH in patients with different blood types. Further work is required to replicate these findings and identify the pathophysiologic mechanisms behind coagulopathy between blood types after ICH.

Background: Perihematomal edema (PHE) is a promising marker of secondary injury in patients with spontaneous intracerebral hemorrhage (ICH). It can be challenging to accurately and rapidly quantify. The aims of this study are to derive and internally validate a fully automated segmentation algorithm for volumetric PHE analysis. Methods: Inpatient CT scans of 400 consecutive adults with spontaneous supratentorial ICH enrolled in the Intracerebral Hemorrhage Outcomes Project (2009-2018) were separated into training (n=360) and test (n=40) datasets. A fully automated algorithm was derived from manual segmentations in the training dataset using convolutional neural networks and its performance was compared to manual and semi-automated segmentation methods in the test dataset. Results: The mean volumetric Dice similarity coefficients for the fully automated algorithm were 0.838±0.294 and 0.843±0.293 with manual and semi-automated segmentations as reference standards, respectively. PHE volumes derived from fully automated vs. manual (R 2 =0.959;p2 =0.960;p2 =0.961; p Conclusions: The fully automated algorithm accurately quantified PHE from CT scans of supratentorial ICH patients with high fidelity and greater efficiency compared with manual and semi-automated segmentation methods.

Introduction: There is conflicting evidence of the risks and benefits of platelet transfusions after intracerebral hemorrhage (ICH). Current practice does not necessitate the transfusion of ABO matched platelets despite evidence that platelet recovery is suboptimal in patients receiving ABO incompatible platelet transfusions. Hypothesis: We hypothesize that ICH patients receiving compatible platelet transfusions after ICH have better platelet recovery and outcomes compared to those receiving incompatible platelets. Methods: We conducted single-center, prospective cohort study of consecutive ICH patients admitted to a tertiary-referral academic medical center between 2009 and 2016. Spontaneous ICH patients who received 1 platelet transfusion within 24 hours after presentation were analyzed. Subjects were excluded if they had more than 1 platelet transfusion or non-medication related coagulopathy. Linear regression was used to evaluate the association of incompatible platelet transfusions with absolute count increment ([ACI], a continuous measure of platelet change after transfusion), adjusting for time between CBCs. Additional logistic regression analysis was performed to explore associations of ABO incompatible platelet transfusions with clinical outcomes: discharge mortality, poor modified Rankin Scale (mRS 4-6) at discharge and 3 months, after adjusting for ICH score, sex, and race. Results: Of the 135 patients studied, 62% received ABO compatible platelets and 38% incompatible platelet transfusions after ICH. Patients who received incompatible platelets had lower ACI than those who received compatible platelets (median -1 vs 15; standardized Beta=0.181, p=0.042). There was an association between incompatible transfusions and increased odds of discharge mortality (adjusted OR 4.208 [95%CI 1.478-11.985]; p=0.007). Conclusions: The majority of patients received ABO incompatible platelet transfusions, and these patients had worse platelet count recovery, higher mortality, and worse neurologic outcomes at discharge compared to those that received ABO compatible transfusions. Our findings warrant investigation into the impact of ABO compatibility in platelet transfusions and clinical outcomes after ICH.

Disorder of consciousness (DOC) is common in patients with acute brain injury (ABI) and it weighs heavily in goals of care discussion.1 Dopaminergic agents to support recovery have shown encouraging results in chronic DOC following traumatic brain injury (TBI) and are currently the most promising candidates to also support recovery during the acute post injury phase.2 Amantadine is a neurohormonal modulator that increases the concentration of dopamine at the synaptic cleft. Behavioural assessments of consciousness alone are often operator dependent, time consuming to obtain and may miss patients with covert consciousness.3 Our hypothesis is that resting Electroencephalogram (EEG) features follow a predictable course preceding behavioural recovery in patients with acute non-hypoxic-ischaemic brain injury receiving amantadine and may serve as biomarkers for recovery of consciousness. We studied 44 patients with ABI that were not following commands and were on EEG monitoring before and after the start of amantadine. A full description of the methods is available in the online supplementary file. ### Supplementary data [jnnp-2019-322645supp001.pdf] ### Study cohort From a cohort of 44 patients, 30 (68%) recovered consciousness prior to hospital discharge (online supplementary tables S1, S2). ### Baseline predictors of recovery Age, focal versus diffuse brain injury and admission Glasgow Coma Score were not associated with recovery of command following. Presence of sleep structures in the EEG (spindles and K-complexes) prior to starting amantadine was independently associated with recovery of command following (online supplementary table S3). Average spectrogram plots for each EEG recording classified according to the ‘ABCD’ model representing thalamocortical integrity were generated (figure 1A, online supplementary figure).4 The percent of patients that recovered command following did not increase hierarchically with higher ‘ABCD’ levels (figure 1B). Power spectral density analysis …

Introduction: Subacute symptomatic neurological decline is a significant and preventable contributor to patient morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). 3-Aminopropanal (3-AP) is a potent neurotoxin that is upregulated in the setting of cerebral ischemia. Targeted neutralization has achieved a neuroprotective effect in preclinical models. This phase II trial evaluated the efficacy of Tiopronin administration in reducing 3-AP levels in patients with aSAH. Methods: We designed a prospective, randomized, double-blind, placebo-controlled clinical trial that was conducted in three centers in the United States. 60 patients were enrolled and assigned to receive Tiopronin or placebo in a 1:1 ratio from enrolment until the earlier to occur of post-bleed day 14 or hospital discharge. Patients received a total of 3 grams daily, in 3 divided doses. The primary efficacy endpoint was the change in serum and/or cerebrospinal fluid (CSF) 3-AP from enrolment to study drug discontinuation. Results: Of the 60 enrolled patients, 29 (97%) in the treatment arm and 27 (93%) in the control arm received more than one dose of the study drug. A greater relative reduction in serum 3-AP level was observed in the treatment arm (adj Beta=-0.689, 95% C.I.=-2.730, -0.008; p=0.049). This was most apparent, but did not reach significance, in patients with grade IV-V aSAH (adj Beta=-0.808; 95% C.I.=-3.872, 0.167; p=0.067). No difference in the change in CSF level was observed (adj Beta=0.048, 95% C.I.=-2.334, 2.589; p=0.903). Pre-specified adverse events led to early cessation of treatment for four patients in the treatment arm, and two in the control arm. Conclusion: Tiopronin attenuated the accumulation of serum 3-AP, providing the first translational evidence for the use of 3-AP antagonists in aSAH. Further investigation to evaluate for a dose-response relationship in Tiopronin’s ability to cross the blood-brain barrier is recommended.

Background Carotid endarterectomy (CEA) is an effective treatment for the prevention of stroke in patients with carotid artery stenosis. We aimed to clarify the incidence and risk factors for early cognitive dysfunction (eCD) and early cognitive improvement (eCI), defined as change in cognitive performance ≤24 hours after surgery, using a battery of neuropsychometric tests. Methods In total, 585 patients undergoing CEA were tested with neuropsychometric tests before and after surgery; 155 patients undergoing “simple” spine surgery were the reference group. Patient performance for each test was evaluated by z scores. Cognitive change was defined as eCD (or eCI) if: 1) patients had a z score ≤–2 (or ≥2) in ≥2 cognitive domains or 2) patients had mean z scores across all domains ≤–1.5 (or ≥1.5). Associations between the categorical cognitive outcomes and variables of interest were modeled using the proportional odds model. Results Of the 585 subjects, 24% had eCD, 6% had eCI, and 70% had “no change.” Patients who had eCD were more likely to be statin naive (odds ratio [OR] 1.23 [1.03–1.48], P = 0.02) or women (OR 1.27 [1.06–1.53], P = 0.02). Those with eCI were less likely to have less formal education (OR 0.95 [0.90–1.00], P = 0.04) and less likely to have diabetes mellitus (OR 0.8 [0.65–0.99], P = 0.04). Conclusions Patients having CEA may develop eCD or eCI postoperatively. Medications likely to be associated with less eCD are statins and aspirin, which correlate most strongly in asymptomatic patients. In addition to confirming previous findings, we found that women were more likely than men to develop eCD. More sex-specific studies and analysis are needed to better explore these findings.

Purpose Accurate prediction of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) can be critical for planning interventions to prevent poor neurological outcome. This paper presents a model using convolution dictionary learning to extract features from physiological data available from bedside monitors. We develop and validate a prediction model for DCI after SAH, demonstrating improved precision over standard methods alone. Methods 488 consecutive SAH admissions from 2006 to 2014 to a tertiary care hospital were included. Models were trained on 80%, while 20% were set aside for validation testing. Modified Fisher Scale was considered the standard grading scale in clinical use; baseline features also analyzed included age, sex, Hunt-Hess, and Glasgow Coma Scales. An unsupervised approach using convolution dictionary learning was used to extract features from physiological time series (systolic blood pressure and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation). Classifiers (partial least squares and linear and kernel support vector machines) were trained on feature subsets of the derivation dataset. Models were applied to the validation dataset. Results The performances of the best classifiers on the validation dataset are reported by feature subset. Standard grading scale (mFS): AUC 0.54. Combined demographics and grading scales (baseline features): AUC 0.63. Kernel derived physiologic features: AUC 0.66. Combined baseline and physiologic features with redundant feature reduction: AUC 0.71 on derivation dataset and 0.78 on validation dataset. Conclusion Current DCI prediction tools rely on admission imaging and are advantageously simple to employ. However, using an agnostic and computationally inexpensive learning approach for high-frequency physiologic time series data, we demonstrated that we could incorporate individual physiologic data to achieve higher classification accuracy.

Three-dimensional (3D) printers are a developing technology penetrating a variety of markets, including the medical sector. Since its introduction to the medical field in the late 1980s, 3D printers have constructed a range of devices, such as dentures, hearing aids, and prosthetics. With the ultimate goals of decreasing healthcare costs and improving patient care and outcomes, neurosurgeons are utilizing this dynamic technology, as well. Digital Imaging and Communication in Medicine (DICOM) can be translated into Stereolithography (STL) files, which are then read and methodically built by 3D Printers. Vessels, tumors, and skulls are just a few of the anatomical structures created in a variety of materials, which enable surgeons to conduct research, educate surgeons in training, and improve pre-operative planning without risk to patients. Due to the infancy of the field and a wide range of technologies with varying advantages and disadvantages, there is currently no standard 3D printing process for patient care and medical research. In an effort to enable clinicians to optimize the use of additive manufacturing (AM) technologies, we outline the most suitable 3D printing models and computer-aided design (CAD) software for 3D printing in neurosurgery, their applications, and the limitations that need to be overcome if 3D printers are to become common practice in the neurosurgical field.

To analyze the impact of inflammation and negative nitrogen balance (NBAL) on nutritional status and outcomes after subarachnoid hemorrhage (SAH).This was a prospective observational study of SAH patients admitted between May 2008 and June 2012. Measurements of C-reactive protein (CRP), transthyretin (TTR), resting energy expenditure (REE), and NBAL (g/day) were performed over 4 preset time periods during the first 14 postbleed days (PBD) in addition to daily caloric intake. Factors associated with REE and NBAL were analyzed with multivariable linear regression. Hospital-acquired infections (HAI) were tracked daily for time-to-event analyses. Poor outcome at 3 months was defined as a modified Rankin Scale score ≥ 4 and assessed by multivariable logistic regression.There were 229 patients with an average age of 55 ± 15 years. Higher REE was associated with younger age (p = 0.02), male sex (p0.001), higher Hunt Hess grade (p = 0.001), and higher modified Fisher score (p = 0.01). Negative NBAL was associated with lower caloric intake (p0.001), higher body mass index (p0.001), aneurysm clipping (p = 0.03), and higher CRP:TTR ratio (p = 0.03). HAIs developed in 53 (23%) patients on mean PBD 8 ± 3. Older age (p = 0.002), higher Hunt Hess (p0.001), lower caloric intake (p = 0.001), and negative NBAL (p = 0.04) predicted time to first HAI. Poor outcome at 3 months was associated with higher Hunt Hess grade (p0.001), older age (p0.001), negative NBAL (p = 0.01), HAI (p = 0.03), higher CRP:TTR ratio (p = 0.04), higher body mass index (p = 0.03), and delayed cerebral ischemia (p = 0.04).Negative NBAL after SAH is influenced by inflammation and associated with an increased risk of HAI and poor outcome. Underfeeding and systemic inflammation are potential modifiable risk factors for negative NBAL and poor outcome after SAH.

In vivo rodent models of focal cerebral ischemia have been developed to investigate stroke therapy. Typically these models require rapid quantification of cerebral infarct volumes using vital stains with tetrazolium salts to delineate the extent of neuronal death. To avoid animal sacrifice, we sought a study with MR acquired volumetric rat data where surrogate of ground truth is obtained by repeated manual delineation by experts, and an automated hybrid segmentation is evaluated for accuracy. We propose a rating system for the expert delineations that captures intra- and inter-expert discrepancy. Our preliminary results show that surrogate ground truth derived from MR data is at least as good as the one derived from histologic stained slices. Hence animal sacrifice is not necessary to evaluate ischemic stroke automated segmentation in a rat model of temporary middle cerebral artery occlusion.

Background and Purpose: Very few cases of intracranial aneurysms (IAs) in twins have been reported. Previous work has suggested that vulnerability to IA formation is heritable. Twin studies provide an opportunity to evaluate the impact of genetics on IA characteristics, including IA location. We therefore sought to examine IA location concordance, multiplicity, and rupture status within affected twin-pairs. Methods: The Familial Intracranial Aneurysm study was a multicenter study whose goal was to identify genetic and other risk factors for formation and rupture of IAs. The study required at least three affected family members or an affected sibling pair for inclusion. Subjects with fusiform aneurysms, an IA associated with an AVM, or a family history of conditions known to predispose to IA formation, such as polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, or moyamoya syndrome were excluded. Twin-pairs were identified by birth date and were classified as monozygotic (MZ) or dizygotic (DZ) through DNA marker genotypes. In addition to zygosity, we evaluated twin-pairs by smoking status, major arterial territory of IAs, and rupture status. Location concordance was defined as the presence of an IA in the same arterial distribution (ICA, MCA, ACA, and vertebrobasilar), irrespective of laterality, in both members of a twin-pair. The Fisher exact test was used for comparisons between MZ and DZ twin-pairs. Results: A total of 16 affected twin-pairs were identified. Location concordance was observed in 8 of 11 MZ twin-pairs but in only 1 of 5 DZ twin-pairs (p = 0.08). Three MZ subjects had unknown IA locations and comprised the three instances of MZ discordance. Six of the 11 MZ twin-pairs and none of the 5 DZ twin-pairs had IAs in the ICA distribution (p = 0.03). Multiple IAs were observed in 11 of 22 MZ and 5 of 10 DZ twin-pairs. Thirteen (13) of the 32 subjects had an IA rupture, including 10 of 22 MZ twins. Conclusions: We found that arterial location concordance was greater in MZ than DZ twins, which suggests a genetic influence upon aneurysm location. The 16 twin-pairs in the present study are nearly the total of affected twin-pairs that have been reported in the literature to date. Further studies are needed to determine the impact of genetics in the formation and rupture of IAs.

Background and Purpose— Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods— Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. Results— Genome-wide evidence of association was detected in the discovery sample on chromosome 9 ( CDKN2BAS ; rs10733376: P −11 ), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9 , was associated with IA (rs10230207; P =4.14×10 −8 ). This association replicated in the Dutch sample ( P =0.01) but failed to show association in the Finnish sample ( P =0.25). Meta-analysis results of the 3 cohorts reached statistical significant ( P =9.91×10 −10 ). Conclusions— We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9 ), suggesting a possible genetic link between this stroke subtype and IA.

The epidemiology and natural history of cerebral arteriovenous malformations (AVMs) remains incompletely elucidated. Several factors are responsible. With regard to the incidence and prevalence of AVMs, the results of prior studies have suffered because of the retrospective design, the use of nonspecific ICD-9 codes, and a focus on small genetically isolated populations. Recent data from the New York Islands AVM Hemorrhage Study, an ongoing, prospective, population-based survey determining the incidence of AVM-related hemorrhage and the associated rates of morbidity and mortality in a zip code–defined population of 10 million people, suggests that the AVM detection rate is 1.21/100,000 person-years (95% confidence interval [CI] 1.02–1.42) and the incidence of AVM-hemorrhage is 0.42/100,000 person-years (95% CI 0.32–0.55). Contemporaneous data from the Northern Manhattan Stroke Study, a prospective, longitudinal population-based study of nearly 150,000 patients in which the focus is to define the incidence of stroke, suggest the crude incidence for first-ever AVM-related hemorrhage to be 0.55/100,000 person-years (95% CI 0.11–1.61). Efforts are ongoing to study the natural history of both ruptured and unruptured AVMs in these datasets to examine the relevance of prior studies of patients selected for conservative follow up in Finland. In addition, data are being gathered to determine whether risk factors for future hemorrhage, which have previously been established in small case series, are valid when applied to whole populations. Together, these data should help inform therapeutic decisionmaking.

There is little information on the effect of pain on neuropsychological test performance. We have undertaken this study to explore which tests are affected by pain, the magnitude of these changes, and other confounders of neuropsychological performance in a population of patients having spine surgery. Twenty-four elderly English speaking Caucasian patients (age > 60 years) were enrolled pre-operatively in this Institutional Review Board approved study. Pain scores using an 11-point Numeric Pain Intensity scale and performance on a neuropsychological battery (Controlled Oral Word Association, Rey Complex Figure, Trails A and B) were assessed at two times, before and one day after surgery. Scores were calculated using the standard algorithms and change scores were calculated by subtracting the baseline from follow-up scores. After surgery, performance on the Rey Complex Figure (r = -0.577, p = 0.004) and Trails Part A (r = 0.527, p = 0.01) declined with increasing post-operative pain scores. Women reported higher pain scores post-operatively than men (p = 0.046), and performed worse than men for change in performance on Trails Part A (p = 0.027). These data suggest that pain can influence performance on certain cognitive tests, and that some gender differences in these effects may occur. Interpretation of performance measures should take into account possible effects of pain, although our understanding of pain effects and ability to predict them in individual people, currently are quite limited.

Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular tributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothesis, and to show that microvascular thrombosis occurs as an ongoing, dynamic process after the onset of stroke, we tested the effects of a potent antiplatelet agent given both before and after the onset of middle cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates in the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In concordance with these data, there is a nearly threefold increase in the ipsilateral accumulation of 111In-labeled platelets in mice subjected to stroke compared with mice not subjected to stroke. When a novel inhibitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administered immediately before MCA occlusion, platelet accumulation was reduced 48%, and fibrin accumulation was reduced by 47% by immunoblot densitometry. GPI 562 exhibited a dose-dependent reduction of cerebral infarct volumes measured by triphenyltetrazolium chloride staining, as well as improvement in postischemic cerebral blood flow, measured by laser doppler. GPI 562 caused a dose-dependent increase in tail vein bleeding time, but intracerebral hemorrhage (ICH) was not significantly increased at therapeutic doses; however, there was an increase in ICH at the highest doses tested. When given immediately after withdrawal of the MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%. These data support the hypothesis that in ischemic regions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage.

Abstract There is currently a stark therapeutic void in the treatment of evolving stroke. Although P-selectin is rapidly expressed by hypoxic endothelial cells in vitro, the functional significance of P-selectin expression in stroke remains unexplored. In order to identify the pathophysiological consequences of P-selectin expression and to identify P-selectin blockade as a potential new approach for the treatment of stroke, experiments were performed using a murine model of focal cerebral ischemia and reperfusion. Early P-selectin expression in the postischemic cerebral cortex was demonstrated by the specific accumulation of radiolabeled anti-murine P-selectin IgG, with the increased P-selectin expression localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the functional significance of increased P-selectin expression in stroke, neutrophil accumulation in the ischemic cortex of mice expressing the P-selectin gene (PS +/+) was demonstrated to be significantly greater than that in homozygous P-selectin–null mice (PS −/−). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measured by laser Doppler) in the PS −/− mice. In addition, PS −/− mice demonstrated smaller infarct volumes (5-fold reduction, P P

Objective: Rebleeding of an aneurysm is a leading cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Whereas numerous studies have demonstrated the risk factors associated with rebleeding, few data on complications of rebleeding, including its effect on the development of delayed cerebral ischemia (DCI), are available. Methods: A nested case-control study was performed on patients with rebleeding and control subjects matched for modified Fisher scale, Hunt-Hess grade, age, and sex previously entered into a prospective database. Rebleeding was defined as new hemorrhage apparent on repeat CT with or without new symptoms. Incidence and time course of DCI and hospital complications were compared. A secondary analysis of DCI and hospital complications was also performed on subjects surviving to postbleed day 7. Results: We identified 120 patients with rebleeding and 359 control subjects from 1996 to 2011. The rebleeding rate was 8.6%. In both the primary and secondary analyses, there was no difference in the incidence of DCI or its time course (29% vs 27%, p = 0.6; 7 ± 5 vs 7 ± 6 days, p = 0.9 for primary analysis; 39% vs 31%, p = 0.1, 7 ± 5 vs 7 ± 6 days, p = 0.6 for the secondary analysis). In a multivariate logistic regression model, rebleeding was associated with the complications of hyponatremia, respiratory failure, and hydrocephalus. Patients with rebleeding had higher rates of mortality, brain death, and poor outcomes. Conclusions: Rebleeding after SAH is associated with multiple medical and neurologic complications, resulting in higher morbidity and mortality, but is not associated with change of incidence or timing of DCI.

This study intends to develop a physiologic thumbprint for nonconvulsive seizures (NCSz) after acute brain injury. Abnormal electrographic brain activity including NCSz is common after acute brain injury and is associated with poor outcome. Mechanisms underlying this phenomenon are poorly understood but in animals periods of inadequate perfusion during seizures have been documented. In the present study we hope to gain better understanding of the relationship between abnormal electrographic patterns and brain homeostasis in patients with subarachnoid hemorrhage (SAH).

TNF-alpha is an inflammatory cytokine that plays a central role in promoting the cascade of events leading to an inflammatory response. Recent studies have suggested that TNF-alpha may play a key role in the formation and rupture of cerebral aneurysms, and that the underlying cerebral inflammatory response is a major determinate of outcome following subrarachnoid hemorrhage (SAH).We studied 14 comatose SAH patients who underwent multimodality neuromonitoring with intracranial pressure (ICP) and cerebral microdialysis as part of their clinical care. Continuous physiological variables were time-locked every 8h and recorded at the same point that brain interstitial fluid TNF-alpha was measured in brain microdialysis samples. Significant associations were determined using generalized estimation equations.Each patient had a mean of 9 brain tissue TNF-alpha measurements obtained over an average of 72h of monitoring. TNF-alpha levels rose progressively over time. Predictors of elevated brain interstitial TNF-alpha included higher brain interstitial fluid glucose levels (beta=0.066, p0.02), intraventricular hemorrhage (beta=0.085, p0.021), and aneurysm size6mm (beta=0.14, p0.001). There was no relationship between TNF-alpha levels and the burden of cisternal SAH; concurrent measurements of serum glucose, or lactate-pyruvate ratio.Brain interstitial TNF-alpha levels are elevated after SAH, and are associated with large aneurysm size, the burden of intraventricular blood, and elevation brain interstitial glucose levels.

Response: We appreciate the comments of Dr Silva and colleagues clarifying that etomidate should be used as rapid induction for intubation rather than as a long-term sedative. We also concur …

Response: We appreciate the comments by Dr Morikawa concerning the role of craniotomy in patients with intracerebral hemorrhage. Dr Morikawa is correct in saying that the STICH trial provided the best and most robust data, and the highest level of evidence, for recommendations …

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.

Rupture of intracranial aneurysms is the most common cause of nontraumatic subarachnoid hemorrhage, but the intricate neuroinflammatory processes which contribute to aneurysm pathophysiology are not well-understood. Mounting evidence has implicated the complement cascade in the progression of aneurysms from their formation to rupture. In this article, we identify and review studies that have sought to determine the role of the complement system in the aneurysm pathogenesis. The studies were generally conducted by immunhistological analyses on aneurysm tissue collected intraoperatively, and multiple components of the complement cascade and its modulators were identified in specific regions of the aneurysm wall. The results of the studies suggest that the complement cascade is locally upregulated and disinhibited in the perianeurysmal environment, and that it contributes to chronic as well as acute immunological damage to the aneurysm wall. In the future, understanding the mechanisms at work in complement-mediated damage is necessary to leading the development of novel therapies.

Background: Between 9% and 23% of patients undergoing otherwise uncomplicated carotid endarterectomy (CEA) develop subtle cognitive decline 1 month postoperatively. The APOE -e4 allele has been associated with worse outcome following stroke. Objective: To investigate the ability of APOE -e4 to predict post-CEA neurocognitive dysfunction. Methods: Seventy-five patients with CEA undergoing elective CEA were prospectively recruited in this nested cohort study and demographic variables were recorded. Patients were evaluated before and 1 month after surgery with a standard battery of five neuropsychological tests. APOE genotyping was performed by restriction fragment length polymorphism analysis in all patients. Neuropsychological deficits were identified by comparing changes (before to 1 month post-operation) in individual performance on the test battery. Logistic regression was performed for APOE -e4 and previously identified risk factors. Results: Twelve of 75 (16%) CEA patients possessed the APOE -e4 allele. Eight of 75 (11%) patients experienced neurocognitive dysfunction on postoperative day 30. One month post-CEA, APOE -e4–positive patients were more likely to be cognitively injured (42%) than APOE -e4–negative patients (5%) ( p = 0.002). In multivariate analysis, the presence of the APOE -e4 allele increased the risk of neurocognitive dysfunction at 1 month 62-fold (62.28, 3.15 to 1229, p = 0.007). Diabetes (51.42, 1.94 to 1363, p = 0.02), and obesity (24.43, 1.41 to 422.9, p = 0.03) also predisposed to injury. Conclusion: The APOE -e4 allele is a robust independent predictor of neurocognitive decline 1 month following CEA.

When shunts are selectively used during carotid endarterectomy, the adequacy of collateral cerebral blood flow (CBF) after the carotid artery is clamped is determined by monitors based on different physiologic measurements. In this series of three patients, we used electroencephalography (EEG) to measure neuronal electrical activity and transcranial Doppler ultrasonography (TCD) to measure CBF velocity. In each of our cases, the EEG was unchanged from preclamp values, while TCD CBF velocity was dramatically reduced. All three patients had transient neuropsychometric or neurologic changes after surgery, which resolved.

Background and Purpose — The cause and clinical significance of residual dysplastic vessels after surgery for brain arteriovenous malformations (AVM) are unclear. We studied predictors and frequency of residual dysplastic vessels on cerebral angiography after AVM surgery. Methods — The 240 prospectively enrolled surgical patients from the New York AVM Databank underwent 269 AVM-related surgical procedures. Reported postoperative brain angiographic findings were classified post hoc as showing (1) persistent dysplastic vessels, (2) a residual AVM, (3) focal hyperemia in the surgical bed, (4) other changes, or (5) a normal angiogram. Univariate and multivariate models were applied to test for an association between residual dysplastic vessels and patient age, sex, preoperative AVM size, anatomic AVM location, number of embolization procedures before surgery, and the time interval between AVM surgery and the postoperative angiogram. Results — Of the 224 documented postoperative angiograms, 78 (35%) showed dysplastic vessels, 24 (11%) had evidence for a residual AVM, 16 (7%) showed focal hyperemia, 6 (2%) revealed other findings, and 100 (45%) were normal. The number of cases showing angiographic evidence for dysplastic vessels was significantly associated with increasing size of the AVM (in millimeter increments; P =0.0001); the mean diameter of AVMs in patients showing dysplastic vessels after surgery was significantly larger (41 mm, SD ±14) than in those without residual dysplastic vessels (27 mm, SD ±13; P Conclusions — The findings suggest that persistent dysplastic vessels may be found in approximately one third of angiograms after AVM surgery. Preoperative AVM size was found to be an independent predictor for the occurrence of dysplastic vessels on the postoperative angiogram.

BACKGROUND: Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized. METHODS: Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin-/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade. RESULTS: Bone marrow demonstrated a significant increase in Lin-/Sca1+ cell counts at 24 hrs (272 ± 60%; P

Active smokers comprise 35–55% of patients admitted with acute spontaneous subarachnoid hemorrhage (SAH). Transdermal nicotine replacement is sometimes prescribed to these patients to prevent a withdrawal syndrome, but the safety of exogenous nicotine during the acute period after SAH is unknown.