Prevalence of Electrographic Seizures in Hospitalized Patients With Altered Mental Status With No Significant Seizure Risk Factors Who Underwent Continuous EEG Monitoring: A Retrospective Study.

OBJECTIVES: The objective of this study is to evaluate the prevalence of electrographic seizures in hospitalized patients with altered mental status and no significant risk factors for seizures. METHODS: We retrospectively reviewed over a six-year period (2013-2019) the medical records of all adults admitted at Ohio State University Wexner Medical Center (OSUWMC), who underwent continuous electroencephalography (cEEG) monitoring for > 48 hours. Our primary objective was to identify the prevalence of electrographic seizures in patients with altered mental status and no significant acute or remote risk factors for seizures. RESULTS: A total of 1966 patients were screened for the study, 1892 were excluded (96.2%) and 74 patients met inclusion criteria. Electrographic seizures were identified in seven of 74 patients (9.45%). We found a significant correlation between electrographic seizures and a history of hepatic cirrhosis, n= 4 (57%), (p=0.035), acute chronic hepatic failure during admission, 71% (n=5), (p=0.027), and hyperammonemia (p =0.009). CONCLUSION: In this retrospective study of patients with altered mental status and no significant acute or remote risk factors for seizures who underwent cEEG monitoring for > 48 hours, electrographic seizures were identified in 9.45%. Electrographic seizures were associated with hepatic dysfunction and hyperammonemia. Based on our results, cEEG monitoring should be considered in patients with altered mental status and hepatic dysfunction even in the absence of other seizure risk factors.

Cognitive Motor Dissociation: Gap Analysis and Future Directions.

BACKGROUND: Patients with disorders of consciousness who are behaviorally unresponsive may demonstrate volitional brain responses to motor imagery or motor commands detectable on functional magnetic resonance imaging or electroencephalography. This state of cognitive motor dissociation (CMD) may have prognostic significance. METHODS: The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of monthly online meetings between September 2021 and April 2023 to examine the science of CMD and identify key knowledge gaps and unmet needs. RESULTS: The group identified major knowledge gaps in CMD research: (1) lack of information about patient experiences and caregiver accounts of CMD, (2) limited epidemiological data on CMD, (3) uncertainty about underlying mechanisms of CMD, (4) methodological variability that limits testing of CMD as a biomarker for prognostication and treatment trials, (5) educational gaps for health care personnel about the incidence and potential prognostic relevance of CMD, and (6) challenges related to identification of patients with CMD who may be able to communicate using brain-computer interfaces. CONCLUSIONS: To improve the management of patients with disorders of consciousness, research efforts should address these mechanistic, epidemiological, bioengineering, and educational gaps to enable large-scale implementation of CMD assessment in clinical practice.

Cerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms.

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.

Collateral status, hyperglycemia, and functional outcome after acute ischemic stroke.

BACKGROUND: Mixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial. METHODS: In this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05. RESULTS: Among the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0). CONCLUSIONS: In a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke. TRIAL REGISTRATION: ClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

Characterizing CD38 Expression and Enzymatic Activity in the Brain of Spontaneously Hypertensive Stroke-Prone Rats.

Background: CD38 is a transmembrane glycoprotein that catabolizes nicotinamide adenine dinucleotide (NAD+) and is the main source for the age-dependent decrease in NAD+ levels. Increased CD38 enzymatic activity has been implicated in several neurological diseases. However, its role in the pathogenesis of cerebral small vessel disease (CSVD) remains unknown. We aimed to characterize CD38 expression and enzymatic activity in the brain of spontaneously hypertensive stroke-prone rats (SHRSP), a genetic model for hypertension and human CSVD, in comparison to age-matched normotensive Wistar Kyoto rats (WKY). Materials and Methods: Age-matched male 7- and 24-week-old WKY and SHRSP were studied. CD38 enzymatic activity was determined in the brain homogenate. Immunohistochemistry and Western Blotting (WB) were used to characterize CD38 expression and localize it in the different cell types within the brain. In addition, expression of nitric oxide synthase (NOS) isoforms and the levels of nitric oxide (NO), superoxide, nicotinamide dinucleotide (phosphate) NAD(P)H were measured the brain of in WKY and SHRSP. Results: CD38 expression and enzymatic activity were increased in SHRSP brains compared to age matched WKY starting at 7 weeks of age. CD38 expression was localized to the endothelial cells, astrocytes, and microglia. We also identified increased CD38 expression using WB with age in SHRSP and WKY. CD38 enzymatic activity was also increased in 24-week SHRSP compared to 7-week SHRSP. In association, we identified evidence of oxidative stress, reduced NO level, reduced NAD(P)H level and endothelial NOS expression in SHRSP compared to age matched WKY. NAD(P)H also decreased with age in WKY and SHRSP. Additionally, activation of astrocytes and microglia were present in SHRSP compared to WKY. Conclusions: CD38 is overexpressed, and its enzymatic activity is increased in SHRSP, a genetic model for marked hypertension and human CSVD. Our results suggest a potential role for CD38 enzymatic activation in the pathogenesis of CSVD and points to the need for future mechanistic and pharmacological studies.

Association of Vascular Properties With the Brain White Matter Hyperintensity in Middle-Aged Population.

Background The periventricular white matter is more sensitive to the systemic hemodynamic alterations than the deep white matter because of differences in its vascular structure and systemic circulation relationship. We hypothesize that periventricular white matter hyperintensity (PVWMH) volume shows greater association than deep white matter hyperintensity (DWMH) volume with vascular properties (VPs) reflecting arterial stiffness and cardiovascular remodeling, indicators of the systemic circulation. Methods and Results A total of 426 participants (age, 59.0±6.1 years; 57.5% women; and 39.7% Black race) in the Genetic Study of Atherosclerosis Risk who were aged ≥50 years and had brain magnetic resonance imaging were studied. VPs included pulse pressure, hypertensive response to exercise, diastolic brachial artery diameter, diastolic common carotid artery diameter, common carotid artery distensibility coefficient, and left ventricular function. The relative associations of VPs with PVWMH and DWMH as multiple measures within the same individual were determined using multilevel linear models. We also determined if age modified the differences in VPs associations with PVWMH and DWMH. Our findings indicated that, within the same subject, PVWMH volume had greater association than DWMH volume with pulse pressure (P=0.002), hypertensive response to exercise (P=0.04), diastolic brachial artery diameter (P=0.012), and diastolic common carotid artery diameter (P=0.04), independent of age and cardiovascular risk factors. The differences of PVWMH versus DWMH associations with VPs did not differ at any age threshold. Conclusions We show, for the first time, that PVWMH has greater association than DWMH, independent of age, with vascular measurements of arterial stiffness and cardiovascular remodeling suggesting that changes in the systemic circulation affect the PVWMH and DWMH differently.

Modeling the effect of cerebral capillary blood flow on neuronal firing.

Adequate cerebral blood flow has long been recognized as essential for the maintenance of the neuronal function while interruption of cerebral blood flow for durations as short as minutes can result in permanent brain damage. A primary goal of this work is to determine how a neuron's ability to respond to synaptic input depends on parameters that control cerebral blood flow. A complex mathematical model is constructed that integrates detailed biophysical models of neuronal action potentials, mitochondrial ATP production and cerebral capillary blood flow. The model also provides insights of the role of astrocytes in maintaining neuronal responses, as well as the impact of elevated cytosolic calcium, due to increased synaptic activity, on mitochondrial ATP production. Both dynamical systems analysis and numerical simulations are used to determine how the maximum frequency at which the neurons can respond to synaptic input depends on capillary blow flow, as well as the ability of astrocytes to buffer extracellular potassium and cytosolic calcium handling. Results are presented for both the cases of homogenous and heterogeneous capillary networks. These results demonstrate, through this interconnected model, that heterogeneity of the capillary flow results in a decrease in the ability of neurons to respond to synaptic stimulation and that intact glial function provides a further protective role for the neurons.

Evaluation of energy intake compared with indirect calorimetry requirements in critically ill patients with acute brain injury.

BACKGROUND: Nutrition support in critically ill patients with acute brain injury is vitally important because of known hypermetabolism. We aimed to describe energy and protein intake within the first 72 h in a broad neurocritical care population and compare energy intake with the indirect calorimetry (IC) resting energy expenditure (REE) target. METHODS: IC data, daily energy, and protein intake were collected through chart review over the first 7 days of hospital admission. We evaluated the type and amount of tube-feed product received, volume of propofol (1.1 kcal/ml) and clevidipine (2 kcal/ml), and amount of supplemental protein received. RESULTS: Ninety-one patients were included, with the majority presenting with either intracerebral hemorrhage (35.2%) or acute ischemic stroke (26.4%). The median day of admission on which IC was completed and enteral nutrition was initiated was day 3 (2-5) and day 1 (1-2), respectively. The difference in kilocalories received compared with IC REE target within the first 72 h was significantly different (2831 kcal [1663-4072] vs 4275 kcal [3450-5811]; Z = -6.469; P < .001). The median kilocalories received as tube feeds during the first 72 h was 88% (55%-99%), and the mean protein received in the first 72 h was 0.7 ± 0.5 g/kg/day. CONCLUSION: In this population, patients had lower energy intake compared with their energy needs determined by IC during the first 72 h of admission but attained 7-day goals. Future studies should investigate barriers to improve energy delivery in this patient population.

Characterizing the Neuroimaging and Histopathological Correlates of Cerebral Small Vessel Disease in Spontaneously Hypertensive Stroke-Prone Rats.

Introduction: Spontaneously hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD). To decipher and understand the underlying disease dynamics, assessment of the temporal progression of CSVD histopathological and neuroimaging correlates is essential. Materials and Methods: Eighty age-matched male SHRSP and control Wistar Kyoto rats (WKY) were randomly divided into four groups that were aged until 7, 16, 24 and 32 weeks. Sensorimotor testing was performed weekly. Brain MRI was acquired at each study time point followed by histological analyses of the brain. Results: Compared to WKY controls, the SHRSP showed significantly higher prevalence of small subcortical hyperintensities on T2w imaging that progressed in size and frequency with aging. Volumetric analysis revealed smaller intracranial and white matter volumes on brain MRI in SHRSP compared to age-matched WKY. Diffusion tensor imaging (DTI) showed significantly higher mean diffusivity in the corpus callosum and external capsule in WKY compared to SHRSP. The SHRSP displayed signs of motor restlessness compared to WKY represented by hyperactivity in sensorimotor testing at the beginning of the experiment which decreased with age. Distinct pathological hallmarks of CSVD, such as enlarged perivascular spaces, microbleeds/red blood cell extravasation, hemosiderin deposits, and lipohyalinosis/vascular wall thickening progressively accumulated with age in SHRSP. Conclusions: Four stages of CSVD severity in SHRSP are described at the study time points. In addition, we find that quantitative analyses of brain MRI enable identification of in vivo markers of CSVD that can serve as endpoints for interventional testing in therapeutic studies.

Brain Atlas Guided Attention U-Net for White Matter Hyperintensity Segmentation.

White Matter Hyperintensities (WMH) are the most common manifestation of cerebral small vessel disease (cSVD) on the brain MRI. Accurate WMH segmentation algorithms are important to determine cSVD burden and its clinical con-sequences. Most of existing WMH segmentation algorithms require both fluid attenuated inversion recovery (FLAIR) images and T1-weighted images as inputs. However, T1-weighted images are typically not part of standard clinical scans which are acquired for patients with acute stroke. In this paper, we propose a novel brain atlas guided attention U-Net (BAGAU-Net) that leverages only FLAIR images with a spatially-registered white matter (WM) brain atlas to yield competitive WMH segmentation performance. Specifically, we designed a dual-path segmentation model with two novel connecting mechanisms, namely multi-input attention module (MAM) and attention fusion module (AFM) to fuse the information from two paths for accurate results. Experiments on two publicly available datasets show the effectiveness of the proposed BAGAU-Net. With only FLAIR images and WM brain atlas, BAGAU-Net outperforms the state-of-the-art method with T1-weighted images, paving the way for effective development of WMH segmentation. Availability: https://github.com/Ericzhang1/BAGAU-Net.

Mathematical modeling of cerebral capillary blood flow heterogeneity and its effect on brain tissue oxygen levels.

Maintaining cerebral blood flow is critical for adequate neuronal function. Previous computational models of brain capillary networks have predicted that heterogeneous cerebral capillary flow patterns result in lower brain tissue partial oxygen pressures PO2). However, these previous models have often considered simple capillary networks in terms of their geometric properties. In this current work, we developed and analyzed computational models of brain capillary networks to determine how perturbations of network properties impact tissue oxygen levels. The models include variabilities in both their geometric (segment lengths and diameters) and three-dimensional, topological structure. Two classes of capillary network models are considered. The first consists of equations for the oxygen partial pressure, PO2, in both a capillary network and the surrounding tissue. In order to gain insight into the behavior of this detailed model, we also consider a reduced model for changes in PO2 in just the capillary network. The main result is that for a general class of networks, random perturbations of either segment diameters or conductances will always, on average, decrease the average tissue oxygen levels. This result is supported through both simulations of the models and mathematical analysis. Our results promise to expand our understanding of cerebral capillary blood flow and its impact on the brain function in health and disease.

Indirect Calorimetry Measurements Compared With Guideline Weight-Based Energy Calculations in Critically Ill Stroke Patients.

BACKGROUND: Perturbations in resting energy expenditure (REE) among critically ill stroke patients are ill defined, and guidelines recommend weight-based dosing when indirect calorimetry (IC) is not feasible to estimate daily energy requirements. We aimed to determine whether guideline-recommended weight-based dosing provides adequate energy requirements compared with guidelines recommended IC target. METHODS: IC data was collected on stroke patients admitted to a neurocritical care unit. We compared low-weight-based dosing (25 kcal/kg) and high (30 kcal/kg) with the IC REE target. Subsequently, we analyzed the effect of stroke subtype on the differences among these measurements. RESULTS: Seventy-two metabolic studies were performed (45.1% intracerebral hemorrhage [ICH], 18.3% aneurysmal subarachnoid hemorrhage [aSAH], and 36.6% acute ischemic stroke [AIS]). Energy needs, estimated using low-weight-based group, were significantly lower than IC REE target (1496 kcal/day [IQR, 1224-1850] vs 1770 kcal/day [IQR, 1400-2150]; P = .003). High weight-based group energy measurements were similar to IC REE target (1806 kcal/day [IQR, 1530-2236] vs 1770 kcal/day; P = .343). Subgroup analysis showed that low-weight-based calculations were significantly lower than those of IC in ICH and aSAH, but they were similar in AIS (P ≤ .001, .016, and .078, respectively). Linear regression analysis showed that weight, height, and hemorrhagic stroke subtype were associated with IC (P ≤ .001, .024, and .051, respectively). CONCLUSION: Important differences between weight-based estimation of energy needs and guideline-recommended IC estimation exist for critically ill stroke patients. Low-weight-based calculations of REE underestimate energy needs in ICH and aSAH patients.

White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease.

INTRODUCTION: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. METHODS: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. RESULTS: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (ß = -0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: ß = -0.03, p = 0.003, C20: ß = -0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (ß = -0.0103, p = 0.027). CONCLUSIONS: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.

Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke.

Stroke research has traditionally focused on the cerebral processes following ischemic brain injury, where oxygen and glucose deprivation incite prolonged activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, reactive oxygen species proliferation, and ultimately neuronal death. A recent growing body of evidence, however, points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, peripheral immunodepression in conjunction with hyperstimulation of autonomic and neuroendocrine pathways and motor pathway impairment result in dysfunction of the respiratory, urinary, cardiovascular, gastrointestinal, musculoskeletal, and endocrine systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke. Using a pathophysiology-based approach, this current review discusses the pathophysiological mechanisms following ischemic brain insult that result in end organ dysfunction. By characterizing stroke as a systemic disease, future research must consider bidirectional interactions between the brain and peripheral organs to inform treatment paradigms and develop effective, comprehensive therapeutics for acute ischemic stroke.

Postcardiac arrest neurological prognostication with quantitative regional cerebral densitometry.

PURPOSE: To quantitatively assess the severity of anoxic-ischemic brain injury early after cardiac arrest (CA) using a novel automated method applied to head computed tomography (HCT). METHODS: Adult patients who were comatose and underwent HCT < 24 h after arrest were included in a retrospective analysis. Principal endpoint was unfavorable outcome (UO) defined as Cerebral Performance Category (CPC) of 3-5 at hospital discharge. We developed an automated processing algorithm for HCT images to be registered, atlas-segmented in 181 regions, and region-specific radiologic densities determined in Hounsfield Units. This approach was compared with an established manual method evaluating grey-white matter ratios (GWR). We tested univariable and multivariable prognostic models which integrated clinical and HCT features including densities in lobes and in nodes of cerebral networks linked to CA recovery. RESULTS: Ninety-one patients were enrolled among whom 66 (73%) had an UO. HCTs were interpreted as normal or without acute abnormality by a neuroradiologist in 77 cases (85%). Compared to the favorable outcome group, UO patients had significantly lower densities in all lobes and in nodes of cerebral networks. A model combining clinical variables with the automated method applied to cerebral network nodes had the highest prognostic performance although not significantly different than the combined clinical-GWR method (AUC [95% CI] 0.94 [0.86-1.00] and 0.92 [0.83-1.00] respectively). CONCLUSION: In comatose survivors of CA, automated quantitative analysis of HCT revealed very early multifocal changes in brain tissue density which are mostly overlooked on conventional neuroradiologic interpretation and are associated with neurological outcome.

Utilization of Hospice Care in Patients With Acute Ischemic Stroke.

BACKGROUND:: A significant percentage of terminally ill patients are discharged to hospice care following a devastating stroke. OBJECTIVE:: We sought to determine the factors associated with hospital discharge to hospice care in a large cohort of patients with stroke. METHODS:: Using the institutional Get With The Guidelines-Stroke database, all consecutive patients with acute ischemic stroke (AIS) who were alive at discharge, from January 2009 until July 2015, were analyzed. Univariate and multivariable statistical analyses were performed to determine the factors associated with discharge to hospice care. RESULTS:: Of 2446 patients with AIS, 3.4% died and were excluded of remaining 2363 patients, and 4.2% were discharged to hospice care. Univariate analysis identified patients who were discharged to hospice care to be older, caucasian, Medicare or private insurance, have atrial fibrillation, heart failure and less often had diabetes mellitus or smoked. Altered mentation at presentation and urinary tract infection were more common in patients discharged to hospice. On multivariable analysis, patients transferred to hospice care were older (odds ratio [OR]: 1.04, 95% confidence interval [CI]: 1.01-1.07; P < .001), had a high National Institute of Health Stroke Scale (NIHSS; OR: 1.15, 95% CI: 1.10-1.20; P < .001), and altered mental status at presentation (OR: 2.42, 95% CI: 1.29-4.55; P < .001). CONCLUSION:: In our study, elderly patients with high NIHSS and altered mental status were identified as factors associated with transition to hospice care following AIS. Prospective studies on the optimal timing of initiation of these consults are needed.