Suboptimal Cerebral Perfusion is Associated with Ischemia After Intracerebral Hemorrhage.

BACKGROUND: Remote ischemic lesions on diffusion-weighted imaging (DWI) occur in one third of patients with intracerebral hemorrhage (ICH) and are associated with worse outcomes. The etiology is unclear and not solely due to blood pressure reduction. We hypothesized that impaired cerebrovascular autoregulation and hypoperfusion below individualized lower limits of autoregulation are associated with the presence of DWI lesions. METHODS: This was a retrospective, single-center study of all primary ICH with intraparenchymal pressure monitoring within 10 days from onset and subsequent magnetic resonance imaging. Pressure reactivity index was calculated as the correlation coefficient between mean arterial pressure and intracranial pressure. Optimal cerebral perfusion pressure (CPPopt) is the cerebral perfusion pressure (CPP) with the lowest corresponding pressure reactivity index. The difference between CPP and CPPopt, time spent below the lower limit of autoregulation (LLA), and time spent above the upper limit of autoregulation (ULA) were calculated by using mean hourly physiologic data. Univariate associations between physiologic parameters and DWI lesions were analyzed by using binary logistic regression. RESULTS: A total of 505 h of artifact-free data from seven patients without DWI lesions and 479 h from six patients with DWI lesions were analyzed. Patients with DWI lesions had higher intracranial pressure (17.50 vs. 10.92 mm Hg; odds ratio 1.14, confidence interval 1.01-1.29) but no difference in mean arterial pressure or CPP compared with patients without DWI lesions. The presence of DWI lesions was significantly associated with a greater percentage of time spent below the LLA (49.85% vs. 14.70%, odds ratio 5.77, confidence interval 1.88-17.75). No significant association was demonstrated between CPPopt, the difference between CPP and CPPopt, ULA, LLA, or time spent above the ULA between groups. CONCLUSIONS: Blood pressure reduction below the LLA is associated with ischemia after acute ICH. Individualized, autoregulation-informed targets for blood pressure reduction may provide a novel paradigm in acute management of ICH and require further study.

A generalizable physiological model for detection of Delayed Cerebral Ischemia using Federated Learning.

Delayed cerebral ischemia (DCI) is a complication seen in patients with subarachnoid hemorrhage stroke. It is a major predictor of poor outcomes and is detected late. Machine learning models are shown to be useful for early detection, however training such models suffers from small sample sizes due to rarity of the condition. Here we propose a Federated Learning approach to train a DCI classifier across three institutions to overcome challenges of sharing data across hospitals. We developed a framework for federated feature selection and built a federated ensemble classifier. We compared the performance of FL model to that obtained by training separate models at each site. FL significantly improved performance at only two sites. We found that this was due to feature distribution differences across sites. FL improves performance in sites with similar feature distributions, however, FL can worsen performance in sites with heterogeneous distributions. The results highlight both the benefit of FL and the need to assess dataset distribution similarity before conducting FL.

Quantification of hematoma and perihematomal edema volumes in intracerebral hemorrhage study: Design considerations in an artificial intelligence validation (QUANTUM) study.

BACKGROUND: Hematoma and perihematomal edema volumes are important radiographic markers in spontaneous intracerebral hemorrhage. Accurate, reliable, and efficient quantification of these volumes will be paramount to their utility as measures of treatment effect in future clinical studies. Both manual and semi-automated quantification methods of hematoma and perihematomal edema volumetry are time-consuming and susceptible to inter-rater variability. Efforts are now underway to develop a fully automated algorithm that can replace them. A (QUANTUM) study to establish inter-quantification method measurement equivalency, which deviates from the traditional use of measures of agreement and a comparison hypothesis testing paradigm to indirectly infer quantification method measurement equivalence, is described in this article. The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study aims to determine whether a fully automated quantification method and a semi-automated quantification method for quantification of hematoma and perihematomal edema volumes are equivalent to the hematoma and perihematomal edema volumes of the manual quantification method. METHODS/DESIGN: Hematoma and perihematomal edema volumes of supratentorial intracerebral hemorrhage on 252 computed tomography scans will be prospectively quantified in random order by six raters using the fully automated, semi-automated, and manual quantification methods. Primary outcome measures for hematoma and perihematomal edema volumes will be quantified via computed tomography scan on admission (<24 h from symptom onset) and on day 3 (72 ± 12 h from symptom onset), respectively. Equivalence hypothesis testing will be conducted to determine if the hematoma and perihematomal edema volume measurements of the fully automated and semi-automated quantification methods are within 7.5% of the hematoma and perihematomal edema volume measurements of the manual quantification reference method. DISCUSSION: By allowing direct equivalence hypothesis testing, the Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study offers advantages over radiology validation studies which utilize measures of agreement to indirectly infer measurement equivalence and studies which mistakenly try to infer measurement equivalence based on the failure of a comparison two-sided null hypothesis test to reach the significance level for rejection. The equivalence hypothesis testing paradigm applied to artificial intelligence application validation is relatively uncharted and warrants further investigation. The challenges encountered in the design of this study may influence future studies seeking to translate artificial intelligence medical technology into clinical practice.

Topical vancomycin to reduce surgical-site infections in neurosurgery: Study protocol for a multi-center, randomized controlled trial.

Surgical-site infections (SSIs) account for 20% of all healthcare-associated infections, are the most common nosocomial infection among surgical patients, and are a focus of quality improvement initiatives. Despite implementation of many quality care measures (e.g. prophylactic antibiotics), SSIs remain a significant cause of morbidity, mortality, and economic burden, particularly in the field of neurosurgery. Topical vancomycin is increasingly utilized in instrumented spinal and cardiothoracic procedures, where it has been shown to reduce the risk of SSIs. However, a randomized controlled trial assessing its efficacy in the general neurosurgical population has yet to be done. The principle aim of "Topical Vancomycin for Neurosurgery Wound Prophylaxis" (NCT02284126) is to determine whether prophylactic, topical vancomycin reduces the risk of SSIs in the adult neurosurgical population. This prospective, multicenter, patient-blinded, randomized controlled trial will enroll patients to receive the standard of care plus topical vancomycin, or the standard of care alone. The primary endpoint of this study is a SSI by postoperative day (POD) 30. Patients must be over 18years of age. Patients are excluded for renal insufficiency, vancomycin allergy, and some ineligible procedures. Univariate analysis and logistic regression will determine the effect of topical vancomycin on SSIs at 30days. A randomized controlled trial is needed to determine the efficacy of this treatment. Results of this trial are expected to directly influence the standard of care and prevention of SSIs in neurosurgical patients.

Bedside quantitative electroencephalography improves assessment of consciousness in comatose subarachnoid hemorrhage patients.

OBJECTIVE: Accurate behavioral assessments of consciousness carry tremendous significance in guiding management, but are extremely challenging in acutely brain-injured patients. We evaluated whether electroencephalography (EEG) and multimodality monitoring parameters may facilitate assessment of consciousness in patients with subarachnoid hemorrhage. METHODS: A retrospective analysis was performed of 83 consecutively treated adults with subarachnoid hemorrhage. All patients were initially comatose and had invasive brain monitoring placed. Behavioral assessments were performed during daily interruption of sedation and categorized into 3 groups based on their best examination as (1) comatose, (2) arousable (eye opening or attending toward a stimulus), and (3) aware (command following). EEG features included spectral power and complexity measures. Comparisons were made using bootstrapping methods and partial least squares regression. RESULTS: We identified 389 artifact-free EEG clips following behavioral assessments. Increasing central gamma, posterior alpha, and diffuse theta-delta oscillations differentiated patients who were arousable from those in coma. Command following was characterized by a further increase in central gamma and posterior alpha, as well as an increase in alpha permutation entropy. These EEG features together with basic neurological examinations (eg, pupillary light reflex) contributed heavily to a linear model predicting behavioral state, whereas brain physiology measures (eg, brain oxygenation), structural injury, and clinical course added less. INTERPRETATION: EEG measures of behavioral states provide distinctive signatures that complement behavioral assessments of patients with subarachnoid hemorrhage shortly after the injury. Our data support the hypothesis that impaired connectivity of cortex with both central thalamus and basal forebrain underlies decreasing levels of consciousness. Ann Neurol 2016;80:541-553.

The role of age in intracerebral hemorrhages.

We aimed to identify the role of age in intracerebral hemorrhage (ICH), as well as characterize the most commonly used age cut off points in the literature, with the hope of understanding and guiding treatment. Strokes are one of the leading causes of death in the USA, and ICH is the deadliest type. Age is a strong risk factor, but it also affects the body in numerous ways, including changes to the cardiovascular and central nervous systems that interplay with the multiple risk factors for ICH. Understanding the role of age in risk and outcomes of ICH can guide treatment and future clinical trials. A current review of the literature suggests that the age cut offs for increased rates of mortality and morbidity vary from 60-80 years of age, with the most common age cut offs being at 65 or 70 years of age. In addition to age as a determinant of ICH outcomes, age has its own effects on the maturing body in terms of changes in physiology, while also increasing the risk of multiple chronic health conditions and comorbidities, including hypertension, diabetes, and anticoagulant treatment for atrial fibrillation, all of which contribute to the pathology of ICH. The interaction of these chronic conditions, changes in physiology, age, and ICH is evident. However, the exact mechanism and extent of the impacts remains unclear. The ambiguity of these connections may be further obscured by individual patient preferences, and there are limitations in the literature which guides the current recommendations for aging patients.

A quantitative lateral flow assay to detect complement activation in blood.

Complement is a major effector arm of the innate immune system that responds rapidly to pathogens or altered self. The central protein of the system, C3, participates in an amplification loop that can lead to rapid complement deposition on a target and, if excessive, can result in host tissue damage. Currently, complement activation is routinely monitored by assessing total C3 levels, which is an indirect and relatively insensitive method. An alternative approach would be to measure downstream C3 activation products such as C3a and iC3b. However, in vitro activation can produce falsely elevated levels of these biomarkers. To circumvent this issue, a lateral flow immunoassay system was developed that measures iC3b in whole blood, plasma, and serum and avoids in vitro activation by minimizing sample handling. This assay system returns results within 15 min and specifically measures iC3b while having minimal cross-reactivity to other C3 split products. While evaluating the potential of this assay, it was observed that circulating iC3b levels can distinguish healthy individuals from those with complement activation-associated diseases. This tool is engineered to provide an improved method to assess complement activation at point of care and could facilitate studies to monitor disease progression in a variety of inflammatory conditions.

Pathological mechanisms underlying aneurysmal subarachnoid haemorrhage and vasospasm.

Aneurysmal subarachnoid haemorrhage is a cerebrovascular disease associated with an overall mortality as high as 50%. Delayed ischaemic neurologic deficits are a major contributor to this statistic, as well as the significant morbidity associated with the disease. Studies examining the pathophysiologic events causing these devastating changes in cerebral blood flow have identified several mechanisms which are thought to contribute to the development of delayed ischaemic neurological deficits, perhaps the most damaging of which are increased intracranial pressure and cerebral vasospasm. In addition, the presence of blood in the subarachnoid space can trigger a myriad of reactions resulting in increased capillary permeability, breakdown of the blood-brain barrier, and inflammation in surrounding neural tissue that adds to the devastating effects of haemorrhage. A detailed understanding of the post-haemorrhagic cellular and molecular changes that contribute to the development of cerebral ischaemia and vasospasm is imperative to the formulation of treatment and prevention options for subarachnoid haemorrhage patients. Despite a large body of research within this field, a complete understanding of rupture and vasospasm remains elusive. This study reviews the role of vasoactive substances, such as endothelin-1, as well as the histochemistry and molecular pathology of post-haemorrhage inflammation in the development of vasospasm and cerebral ischaemia.

Hemicraniectomy for malignant middle cerebral artery territory infarction: an updated review.

A decompressive hemicraniectomy is frequently performed for patients with malignant middle cerebral artery territory infarction (MMI) to reduce the intracranial hypertension, which may otherwise result in transtentorial herniation. However, certain clinically significant issues ­ diagnostic criteria, predictors of the MMI clinical course, benefit of surgery in certain populations, timing of surgery ­ are unresolved. In this article, we provide an updated review on the diagnosis and management of MMI. An extensive search of the PubMed, EMBASE, and Cochrane was conducted using varying combinations of the search terms, "hemicraniectomy," "decompressive craniectomy," "malignant middle cerebral artery territory infarction," "massive middle cerebral artery territory infarction," "massive ischemic stroke," "decompressive surgery," and "neurosurgery for ischemic stroke." Several large, randomized trials within the past decade have firmly established the benefit of decompressive hemicraniectomy (DHC) as a treatment of MMI. Further studies since then have not only better characterized the diagnosis and predictors of MMI, but have also shown that this benefit extends to patients with additional clinical and demographic characteristics. Future randomized studies should continue to evaluate the benefit of a DHC in other subgroups, and assess neurocognitive and psychosocial secondary outcomes.

Underlying effect of age on outcome differences in arteriovenous malformation-associated intracerebral hemorrhage.

Brain arteriovenous malformations (AVM) are the most common cause of intracerebral hemorrhage (ICH) in young adults. Although previous studies have found that the mortality and morbidity of ICH due to AVM (AVM-ICH) is lower than in spontaneous ICH, it is unclear whether the more favorable prognosis is directly related to the presence of the vascular malformation. We included 34 patients with AVM-ICH and 187 with spontaneous intracerebral hemorrhage (sICH) due to either hypertension or cerebral amyloid angiopathy. Patient data were obtained from the prospective Intracerebral Hemorrhage Outcomes Project, which enrolls ICH patients admitted to Columbia University Medical Center. Using ICH etiology (AVM-ICH or sICH) and previously verified predictors of ICH outcome, two multivariate analyses were performed with and without age to compare the odds of death at 3 months and the functional outcome. Although mortality in AVM-ICH group was lower than the sICH group (20.6% versus 43.3%, respectively), this value was only significant when age was excluded (p=0.017) and lost its significance when we controlled for age (p=0.157). There was an analogous loss of significance with functional outcome using the modified Rankin Scale. In conclusion, our data suggests that the previously observed lower case fatality rate and more favorable functional outcomes in the AVM-ICH group compared to the sICH group may largely be the result of age.

The quantified patient: a patient participatory culture.

The Quantified Self Movement, which aims to improve various aspects of life and health through recording and reviewing daily activities and biometrics, is a new and upcoming practice of self monitoring that holds much promise. Now, the most underutilized resource in ambulatory health care, the patient, can participate like never before, and the patient's Quantified Self can be directly monitored and remotely accessed by health care professionals.

The role of admission timing in the outcome of intracerebral hemorrhage patients at a specialized stroke center.

INTRODUCTION: Admission at 'off times' has been suggested to result in increased risk of poor outcome. The utilization of high volume centers may be a potential remedy to this variability in care. OBJECTIVE: To assess the ability of a high volume center to mitigate variability in care due to timing of admission in a post hoc analysis of an observational study. METHODS: The medical records of 200 hypertensive intracerebral hemorrhage (ICH) patients admitted to the Neurological Intensive Care Unit (NICU) from 12 January 2009 to 4 April 2013 were identified and examined for variable outcome based on admission timing using the modified Rankin Scale (mRS). Multiple logistic regression was used to assess predictors of poor outcome, correcting severity of admission. RESULTS: Seventy-five admissions were recorded to have occurred on the weekend. The 3-month follow-up mRS of surviving patients was 3·78 in weekend admissions and 3·63 in weekday admissions (P  =  0·62). One hundred and seven night admissions occurred. The average mRS at 3 months of surviving patients was 3·56 in night admissions and 3·84 in daytime admissions (P  =  0·36). Thirteen patients were admitted in July. The 3-month mRS of surviving patients was 3·71 for July admissions and 3·38 for non-July admissions (P  =  0·58). Only ICH score was found to be a predictor of outcome on multivariate analysis (P < 0·001). CONCLUSIONS: No significant difference in the outcome of patients was identified regardless of time of admission. High volume centers may be less prone to temporal variability in care, though the existence of temporal variability in care at low volume centers is controversial.

The role of vascular remodeling and inflammation in the pathogenesis of intracranial aneurysms.

While the mechanisms triggering pathogenesis of intracranial aneurysms have not been fully elucidated, different mechanisms have been proposed ranging from hemodynamic mechanisms to genetic predispositions. One mechanism that has been thoroughly explored is the physiological and pathological vascular remodeling that occurs in conjunction with inflammatory reactions resulting in the initiation and progression of these lesions. Both hemodynamic stimuli and vascular inflammation can trigger a series of biochemical reactions resulting in vascular smooth muscle cell apoptosis and migration causing thinned, dilated areas of the cerebral vasculature. In addition, an imbalance between extracellular matrix remodeling proteins, such as matrix metalloproteinases and their inhibitors, can result in accelerated degradation of the internal elastic lamina and the adventitial layers, further weakening the vessel. While these processes occur under normal physiological conditions, situations that alter their balance such as inflammation caused by cigarette smoking or cocaine usage or hypoxia induced under chronic hypertensive conditions can alter the delicate balance of these reactions potentiating pathological remodeling and aneurysm development. The present study represents a thorough literature review of the vascular remodeling and inflammatory components to aneurysmal pathogenesis.

Reduced middle cerebral artery velocity during cross-clamp predicts cognitive dysfunction after carotid endarterectomy.

Transcranial Doppler (TCD) is a useful monitor that can be utilized during carotid endarterectomy (CEA). Cognitive dysfunction is a subtler and more common form of neurologic injury than stroke. We aimed to determine whether reduced middle cerebral artery (MCA) mean velocity (MV) predicts cognitive dysfunction and if so, whether a threshold of increased risk of cognitive dysfunction can be identified. One hundred twenty-four CEA patients were included in this observational study and neuropsychometrically evaluated preoperatively and 24 hours postoperatively. MCA-MV was measured by TCD and percentage of baseline during cross-clamp was calculated (MV(cross-clamp)/MV(baseline)). Patients with cognitive dysfunction had significantly lower MV during cross-clamp than those without cognitive dysfunction (33.1 ± 13.7 cm/s versus 39.6 ± 16.0 cm/s, p=0.02). In the final multivariate model, each percent reduction in MV was significantly associated with greater risk of cognitive dysfunction (odds ratio [OR]: 0.05 [95% confidence interval {CI} 0.01-0.23], p < 0.001) while statin use was associated with lower risk (OR: 0.33 [95% CI 0.12-0.92], p = 0.03). Using receiver operator characteristic curve analysis, the Youden index identified 72% of baseline MV during cross-clamp as the cutoff of maximum discrimination. Significantly more patients with MV < 72% of baseline during cross-clamp exhibited cognitive dysfunction than patients with MV ≥ 72% of baseline (74.1% versus 27.1%, p < 0.001). Reduced MCA-MV during cross-clamp is a predictor of cognitive dysfunction exhibited 24 hours after CEA. MCA-MV reduced to <72% of baseline, or a ≥28% reduction from baseline, is the threshold most strongly associated with increased risk of cognitive dysfunction. These observations should be considered by all clinicians that utilize intraoperative monitoring for CEA.

Apolipoprotein E-ε4 polymorphism and cognitive dysfunction after carotid endarterectomy.

Approximately 25% of patients undergoing carotid endarterectomy (CEA) exhibit cognitive dysfunction (CD) 1 day and 1 month after CEA. The apolipoprotein E (apoE)-ε4 polymorphism has been previously identified as a robust independent risk factor for CD 1 month after CEA. We aimed to determine whether the apoE-ε4 polymorphism is also an independent risk factor for CD as early as 1 day after CEA and to confirm the previous findings at 1 month. Patients undergoing elective CEA (n=411) were enrolled with written informed consent in this follow-up observational study. CD was evaluated via an extensive neuropsychometric battery. apoE-ε4 carriers exhibited significantly more CD 1 day (30.1% versus 17.9%, p=0.01) and 1 month (25.7% versus 9.8%, p=0.001) after CEA compared to non-carriers. Multivariate regression models were generated to determine independent predictors of CD. At 1 day, apoE-ε4 was significantly associated with higher risk of CD (odds ratio [OR]: 2.24 [95% confidence interval 1.29-3.84], p=0.004), while statin use was significantly associated with lower risk (OR: 0.40 [0.24-0.67], p<0.001). At 1 month, apoE-ε4 was significantly associated with higher risk of CD (OR: 3.14 [1.53-6.38], p=0.002), while symptomatic status was significantly associated with lower risk (OR: 0.45 [0.20-0.94], p=0.03). The apoE-ε4 polymorphism is an independent risk factor for CD as early as 1 day after CEA and is confirmed to be an independent risk factor for CD at 1 month as well.

Epidemiological trends in the neurological intensive care unit from 2000 to 2008.

Intensive care units (ICU) specializing in the treatment of patients with neurological diseases (Neuro-ICU) have become increasingly common. However, there are few data on the longitudinal demographics of this patient population. Identifying admission trends may provide targets for improving resource utilization. We performed a retrospective analysis of admission logs for primary diagnosis, age, sex, and length of stay, for all patients admitted to the Neuro-ICU at Columbia University Medical Center (CUMC) between 2000 and 2008. From 2000 to 2008, inclusive, the total number of Neuro-ICU admissions increased by 49.9%. Overall mean patient age (54.6 ± 17.4 to 56.2 ± 18.0 years, p=0.041) and gender (55.9-50.3% female, p=0.005) changed significantly, while median length of stay (2 days) did not. When comparing the time period prior to construction of a larger Neuro-ICU (2000-2004) to that after completion (2005-2008), patient age (56.0 ± 17.6 compared to 56.9 ± 17.5 years, p=0.012) and median length of stay (1 compared to 2 days, p<0.001) both significantly increased. Construction of a newer, larger Neuro-ICU at CUMC led to a substantial increase in admissions and changes in diagnoses from 2000 to 2008. Advances in neurocritical care, neurosurgical practices, and the local and global expansion and utilization of ICU resources likely led to differences in lengths of stay.

Convection enhanced drug delivery of BDNF through a microcannula in a rodent model to strengthen connectivity of a peripheral motor nerve bridge model to bypass spinal cord injury.

Models employing peripheral nerve to bypass spinal cord injury (SCI), although highly promising, may benefit from improved nerve regeneration and motor bridge connectivity. Recent studies have demonstrated that neuronal growth factor-induced enhancement of endogenous neurorestoration may improve neuronal connectivity after severe neurologic injury, particularly if delivered intraparenchymally with zero-order kinetics. We sought to investigate the effect of convection-enhanced delivery of brain-derived neurotrophic factor (BDNF), a neuronal growth factor, on the connectivity of a peripheral motor-nerve bridge in a rodent model using electrophysiology and immunohistochemistry (IHC). Spinal cords of 29 female rats were hemisected at the L1 level. Ipsilateral T13 peripheral nerves were dissected from their muscular targets distally, while maintaining their connections with the spinal cord, and inserted caudal to the injury site to establish the nerve bridge. A microcannula attached to a six-week mini-osmotic pump was used to deliver either BDNF (n=12), saline (n=14), or fluorescein dye (n=3) directly into the spinal cord parenchyma between the site of nerve insertion and hemisection to a depth of 2mm into the area of the lateral motor pool. After four weeks, gastrocnemius muscle activation was assessed electromyographically in five animals from each group. Spinal cords were harvested and analyzed with IHC for cannula-associated injury, and nerve regeneration. Strength of motor bridge connection was illustrated by electrophysiology data. Intraspinal BDNF levels were measured using enzyme-linked immunosorbent assay. IHC revealed increased intraparenchymal BDNF concentration at the nerve bridge insertion site with evidence of minimal trauma from cannulation. BDNF infusion resulted in stronger connections between bridge nerves and spinal motor axons. Bridge nerve electrical stimulation in BDNF-treated rats evoked hind leg electromyogram responses of shorter latency and larger amplitudes than saline-infused controls. Thus, direct convection-assisted delivery provides reliable administration of potent growth factors directly into the spinal cord parenchyma. Delivery of BDNF at the peripheral nerve bridge site results in enhanced connectivity of the peripheral motor bridge in a rodent model of SCI.