Analysis of brain edema in RHAPSODY.

BACKGROUND: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema. AIMS: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers. METHODS: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment. RESULTS: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm. CONCLUSIONS: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.

Neurological Complications Associated with Hereditary Bleeding Disorders.

PURPOSE OF REVIEW: Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. RECENT FINDINGS: ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke.

PURPOSE OF REVIEW: This review aims to provide an overview of neuroinflammation in ischemic and hemorrhagic stroke, including recent findings on the mechanisms and cellular players involved in the inflammatory response to brain injury. RECENT FINDINGS: Neuroinflammation is a crucial process following acute ischemic stroke (AIS) and hemorrhagic stroke (HS). In AIS, neuroinflammation is initiated within minutes of the ischemia onset and continues for several days. In HS, neuroinflammation is initiated by blood byproducts in the subarachnoid space and/or brain parenchyma. In both cases, neuroinflammation is characterized by the activation of resident immune cells, such as microglia and astrocytes, and infiltration of peripheral immune cells, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species. These inflammatory mediators contribute to blood-brain barrier disruption, neuronal damage, and cerebral edema, promoting neuronal apoptosis and impairing neuroplasticity, ultimately exacerbating the neurologic deficit. However, neuroinflammation can also have beneficial effects by clearing cellular debris and promoting tissue repair. The role of neuroinflammation in AIS and ICH is complex and multifaceted, and further research is necessary to develop effective therapies that target this process. Intracerebral hemorrhage (ICH) will be the HS subtype addressed in this review. Neuroinflammation is a significant contributor to brain tissue damage following AIS and HS. Understanding the mechanisms and cellular players involved in neuroinflammation is essential for developing effective therapies to reduce secondary injury and improve stroke outcomes. Recent findings have provided new insights into the pathophysiology of neuroinflammation, highlighting the potential for targeting specific cytokines, chemokines, and glial cells as therapeutic strategies.

Contemporary Antiplatelet and Anticoagulant Therapies for Secondary Stroke Prevention: A Narrative Review of Current Literature and Guidelines.

PURPOSE OF REVIEW: Stroke is a leading cause of death and disability worldwide. The annual incidence of new or recurrent stroke is approximately 795,000 cases per year in the United States, of which 87% are ischemic in nature. In addition to the management of modifiable high-risk factors to reduce the risk of recurrent stroke, antithrombotic agents (antiplatelets and anticoagulants) play an important role in secondary stroke prevention. This review will discuss the published literature on the use of antiplatelets and anticoagulants in secondary prevention of acute ischemic stroke and transient ischemic attack (TIA), including their pharmacology, efficacy, and adverse effects. We will also highlight the role of dual antiplatelet therapy (DAPT) in secondary stroke prevention, along with supporting literature. RECENT FINDINGS: Single antiplatelet therapy (SAPT) with aspirin or clopidogrel reduces the risk of recurrent ischemic stroke in patients with non-cardioembolic ischemic stroke or TIA. However, as shown in recent trials, short-term DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute non-cardioembolic stroke or high-risk TIA. Although short-term DAPT is highly effective in preventing recurrent stroke, a more prolonged course can increase bleeding risks without additional benefit. DAPT for 90 days, followed by aspirin monotherapy for patients with large vessel intracranial atherosclerotic disease, is suitable for secondary stroke prevention. However, patients need to be monitored for both minor (e.g., bruising) and major (e.g., intracranial) bleeding complications. Conversely, oral warfarin and newer direct oral anticoagulant (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban are the agents of choice for secondary stroke prevention in patients with non-valvular cardioembolic strokes. DOACs may be preferred over warfarin due to decreased bleeding risks, including ICH, lack of need for international normalized ratio monitoring, no dietary restrictions, and limited drug-drug interactions. The choice between different antiplatelets and anticoagulants for prevention of ischemic stroke depends on the underlying stroke mechanism, cytochrome P450 2C19 polymorphisms, bleeding risk profile, compliance, drug tolerance, and drug resistance. Physicians must carefully weigh each patient's relative benefits and bleeding risks before initiating an antiplatelet/anticoagulant treatment regimen. Further studies are warranted to study the optimal duration of DAPT in symptomatic intracranial atherosclerosis since the benefit is most pronounced in the short term while the bleeding risk remains high during the extended duration of therapy.

Pathophysiology of Early Brain Injury and Its Association with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Review of Current Literature.

Background: Delayed cerebral ischemia (DCI) is a common and serious complication of aneurysmal subarachnoid hemorrhage (aSAH). Though many clinical trials have looked at therapies for DCI and vasospasm in aSAH, along with reducing rebleeding risks, none have led to improving outcomes in this patient population. We present an up-to-date review of the pathophysiology of DCI and its association with early brain injury (EBI). Recent Findings: Recent studies have demonstrated that EBI, as opposed to delayed brain injury, is the main contributor to downstream pathophysiological mechanisms that play a role in the development of DCI. New predictive models, including advanced monitoring and neuroimaging techniques, can help detect EBI and improve the clinical management of aSAH patients. Summary: EBI, the severity of subarachnoid hemorrhage, and physiological/imaging markers can serve as indicators for potential early therapeutics in aSAH. The microcellular milieu and hemodynamic pathomechanisms should remain a focus of researchers and clinicians. With the advancement in understanding the pathophysiology of DCI, we are hopeful that we will make strides toward better outcomes for this unique patient population.

Risk factors for development of cerebral edema following cardiac arrest.

BACKGROUND: Cerebral edema following cardiac arrest is a well-known complication of resuscitation and portends a poor outcome. We identified predictors of post-cardiac arrest cerebral edema and tested the association of cerebral edema with discharge outcome. METHODS: We performed a retrospective chart review including patients admitted at a single center between January 2015-March 2020 following resuscitation from in-hospital and out-of-hospital cardiac arrest who had head computed tomography imaging. Our primary outcome was moderate-to-severe cerebral edema, which we defined as loss of grey-white differentiation with effacement of the basal and ambient cisterns and radiographic evidence of uncal herniation. We used logistic regression to test associations of demographic information, clinical predictors and comorbidities with moderate-severe cerebral edema. RESULTS: We identified 727 patients who met the inclusion criteria, of whom 102 had moderate-to-severe cerebral edema. We identified six independent predictors of moderate-to-severe cerebral edema: younger age, prolonged arrest duration, pulseless electrical activity/asystole as initial rhythm, unwitnessed cardiac arrest, hyperglycemia on admission, and lower Glasgow coma score on presentation. Of patients with moderate-to-severe cerebral edema, 2% survived to discharge, 56% had withdrawal of life-sustaining therapies and 42% progressed to death by neurological criteria. CONCLUSIONS: Our study identified several risk factors associated with the development of cerebral edema following cardiac arrest. Further studies are needed to determine the benefits of early interventions in these high-risk patients.

Collaborative Integration of Palliative Care in Critically Ill Stroke Patients in the Neurocritical Care Unit: A Single Center Pilot Study.

INTRODUCTION: Patients admitted to the Neurocritical Care Unit (NCCU) with moderate-to-severe acute strokes, along with their surrogate decision makers, have the potential for unrecognized or unmet emotional and psychological needs. Our primary objective was to determine if early integration of palliative care consultations within this cohort was feasible and would impact understanding, decision-making and emotional support to patients and their surrogate decision makers. Our secondary objective was to evaluate the long-term impact of early palliative care assessment on the development of post-traumatic stress disorder (PTSD). METHODS: This was a single center prospective pilot study. Patients with moderate-to-severe ischemic and hemorrhagic strokes were randomized into two arms. The control arm received standard intensive care and the intervention arm received an additional early palliative care consultation within 72 hours of hospitalization. Study assessments with the participants were obtained on day 1-3, and day 5-7 of care with comparisons of total scores on the Questionnaire on Communication (QOC), Decisional Conflict Scale (DCS), and Hospital Anxiety and Depression Scale (HADS). Furthermore, comparisons of HADS and PTSD DSM-5 (PCL- 5) scores were completed at 3 months. Linear mixed effects models were conducted to examine the association between intervention and participant's scores. RESULTS: A total of 22 participants were enrolled between February 2019 and April 2020. Statistically significant improvement in scores was seen in the total HADS score (p=0.043) and PCL5 score (p=0.033) at 3 months following intervention. CONCLUSION: Collaboration between the intensive care and palliative care team with early palliative assessment may be beneficial in lowering anxiety, depression and PTSD symptoms in critically ill stroke patients and their caregivers. Further research is needed to validate these findings.

Cardiovascular Predictors of Intracerebral Hematoma Expansion.

BACKGROUND: There is limited evidence on the effect and relevance of cardiovascular parameters on the cerebrovascular system when an intracerebral hemorrhage (ICH) occurs. While recent studies evaluating this relationship are conflicting, one evaluating the effect of systolic cardiac function on clinical outcomes in ICH patients, found low cardiac ejection fractions to be associated with poor clinical outcomes. Our primary objective was to study such correlations and identify various cardiovascular disease states that may be associated with hematoma expansion. METHODS: This is an IRB-approved single-center retrospective study utilizing our institutional "Get with the Guidelines"-Stroke registry between 2013 and 2017. Patients included were older than 18 years of age, admitted with an acute ICH, and had an echocardiogram during their hospitalization. Univariate and multivariate logistical regression analyses were used to identify cardiovascular predictors of hematoma expansion. RESULTS: Two-hundred forty-nine patients were identified from our GWTG-S registry that met initial inclusion criteria. Of these patients, a history of peripheral arterial disease (PAD) (p = 0.015), presence of aortic stenosis (AS) on the echocardiogram (p = 0.025), and a positive spot sign on the CT-angiogram (CTA) of the head (p < 0.001) were found to be independently associated with ICH expansion. Both a history of hypertension and elevated blood pressure on presentation were not significant predictors. Additionally, patients with a history of congestive heart failure had decreased odds of hematoma expansion (p = 0.027). CONCLUSION: This exploratory study highlights potential novel cardiac predictors of hematoma expansion, including PAD and AS, which warrant further study. Larger prospective studies are needed to further investigate such associations to ultimately optimize cardio-cerebral health.

Perfusion Imaging Predicts Favorable Outcomes after Basilar Artery Thrombectomy.

OBJECTIVE: Perfusion imaging identifies anterior circulation stroke patients who respond favorably to endovascular thrombectomy (ET), but its role in basilar artery occlusion (BAO) is unknown. We hypothesized that BAO patients with limited regions of severe hypoperfusion (time to reach maximum concentration in seconds [Tmax] > 10) would have a favorable response to ET compared to patients with more extensive regions involved. METHODS: We performed a multicenter retrospective cohort study of BAO patients with perfusion imaging prior to ET. We prespecified a Critical Area Perfusion Score (CAPS; 0-6 points), which quantified severe hypoperfusion (Tmax > 10) in cerebellum (1 point/hemisphere), pons (2 points), and midbrain and/or thalamus (2 points). Patients were dichotomized into favorable (CAPS ≤ 3) and unfavorable (CAPS > 3) groups. The primary outcome was a favorable functional outcome 90 days after ET (modified Rankin Scale = 0-3). RESULTS: One hundred three patients were included. CAPS ≤ 3 patients (87%) had a lower median National Institutes of Health Stroke Scale score (NIHSS; 12.5, interquartile range [IQR] = 7-22) compared to CAPS > 3 patients (13%; 23, IQR = 19-36; p = 0.01). Reperfusion was achieved in 84% of all patients, with no difference between CAPS groups (p = 0.42). Sixty-four percent of reperfused CAPS ≤ 3 patients had a favorable outcome compared to 8% of nonreperfused CAPS ≤ 3 patients (odds ratio [OR] = 21.0, 95% confidence interval [CI] = 2.6-170; p < 0.001). No CAPS > 3 patients had a favorable outcome, regardless of reperfusion. In a multivariate regression analysis, CAPS ≤ 3 was a robust independent predictor of favorable outcome after adjustment for reperfusion, age, and pre-ET NIHSS (OR = 39.25, 95% CI = 1.34->999, p = 0.04). INTERPRETATION: BAO patients with limited regions of severe hypoperfusion had a favorable response to reperfusion following ET. However, patients with more extensive regions of hypoperfusion in critical brain regions did not benefit from endovascular reperfusion. ANN NEUROL 2022;91:23-32.

Role of Non-Perfusion Factors in Mildly Symptomatic Large Vessel Occlusion Stroke.

INTRODUCTION: Uncertainty regarding reperfusion of mildly-symptomatic (minor) large vessel occlusion (LVO)-strokes exists. Recently, benefits from reperfusion were suggested. However, there is still no strong data to support this. Furthermore, a proportion of those patients don't improve even after non-hemorrhagic reperfusion. Our study evaluated whether or not non-perfusion factors account for such persistent deconditioning. METHODS: Patients with identified minor LVO-strokes (NIHSS ≤ 8) from our stroke alert registry between January-2016 and May-2018 were included. Variables/ predictors of outcome were tested using univariate/multivariate logistic and linear regression analyses. Three month-modified ranking scale (mRS) was used to differentiate between favorable (mRS = 0-2) and unfavorable outcomes (mRS = 3-6). RESULTS: Eighty-one patients were included. Significant differences between the two outcome groups regarding admission-NIHSS and discharge-NIHSS existed (OR = 0.47, 0.49 / p = 0.0005, <0.0001 respectively).The two groups had matching perfusion measures. In the poor outcome group, discharge-NIHSS was unchanged from the admission-NIHSS while in the good outcome group, discharge-NIHSS significantly improved. CONCLUSION: Admission and discharge NIHSS are independent predictors of outcome in patients with minor-LVO strokes. Unchanged discharge-NIHSS predicts worse outcomes while improved discharge-NIHSS predicts good outcomes. Unchanged NIHSS in the poor outcome group was independent of the perfusion parameters. In literature, complement activation and pro-inflammatory responses to ischemia might account for the progression of stroke symptoms in major-strokes. Our study concludes similar phenomena might be present in minor-strokes. Therefore, discharge-NIHSS may be useful as a clinical marker for future therapies.

Clinician's Perception of Practice Changes for Stroke During the COVID-19 Pandemic.

BACKGROUND: Approach to acute cerebrovascular disease management has evolved in the past few months to accommodate the rising needs of the 2019 novel coronavirus (COVID-19) pandemic. In this study, we investigated the changes in practices and policies related to stroke care through an online survey. METHODS: A 12 question, cross-sectional survey targeting practitioners involved in acute stroke care in the US was distributed electronically through national society surveys, social media and personal communication. RESULTS: Respondants from 39 states completed 206 surveys with the majority (82.5%) from comprehensive stroke centers. Approximately half stated some change in transport practices with 14 (7%) reporting significant reduction in transfers. Common strategies to limit healthcare provider exposure included using personal protective equipment (PPE) for all patients (127; 63.5%) as well as limiting the number of practitioners in the room (129; 64.5%). Most respondents (81%) noted an overall decrease in stroke volume. Many (34%) felt that the outcome or care of acute stroke patients had been impacted by COVID-19. This was associated with a change in hospital transport guidelines (OR 1.325, P = 0.047, 95% CI: 1.004-1.748), change in eligibility criteria for IV-tPA or mechanical thrombectomy (MT) (OR 3.146, P = 0.052, 95% CI: 0.988-10.017), and modified admission practices for post IV-tPA or MT patients (OR 2.141, P = 0.023, 95% CI: 1.110-4.132). CONCLUSION: Our study highlights a change in practices and polices related to acute stroke management in response to COVID-19 which are variable among institutions. There is also a reported reduction in stroke volume across hospitals. Amongst these changes, updates in hospital transport guidelines and practices related to IV-tPA and MT may affect the perceived care and outcome of acute stroke patients.

Posterior Reversible Encephalopathy Syndrome: Clinical Features and Outcome.

Background: Posterior reversible encephalopathy syndrome (PRES) is an acute neurotoxic syndrome that is characterized by a spectrum neurological and radiological feature from various risk factors. Common neurological symptoms includes headache, impairment in level of consciousness, seizures, visual disturbances, and focal neurological deficits. Common triggering factors include blood pressure fluctuations, renal failure, eclampsia, exposure to immunosuppressive or cytotoxic agents and autoimmune disorders. The classic radiographic findings include bilateral subcortical vasogenic edema predominantly affecting the parieto-occipital regions but atypical features include involvement of other regions, cortical involvement, restricted diffusion, hemorrhage, contrast enhancement. This review is aimed to summarize the updated knowledge on the typical and atypical clinical and imaging features, prognostic markers and identify gaps in literature for future research. Methods: Systematic literature review using PUBMED search from 1990 to 2019 was performed using terms PRES was performed. Results: While clinical and radiographic reversibility is common, long-standing morbidity and mortality can occur in severe forms. In patients with malignant forms of PRES, aggressive care has markedly reduced mortality and improved functional outcomes. Although seizures were common, epilepsy is rare. Various factors that have been associated with poor outcome include altered sensorium, hypertensive etiology, hyperglycemia, longer time to control the causative factor, elevated C reactive protein, coagulopathy, extensive cerebral edema, and hemorrhage on imaging. Conclusion: Large prospective studies that accurately predict factors that are associated with poor outcomes, determine the pathophysiology, and targeted therapy are required.

Intraosseous Administration of Hypertonic Saline in Acute Brain-Injured Patients: A Prospective Case Series and Literature Review.

BACKGROUND: Central venous catheters are often used to administer hypertonic saline (HTS) but might be associated with serious complications. Intraosseous (IO) access is an alternative method of medication and fluid delivery which is not associated with life-threatening complications and can be inserted faster than CVCs. METHODS: A prospective case series was conducted on critically ill neurological patients that did not have central venous access, and for whom 3% HTS was indicated. Nonverbal indicators of pain were measured using the critical care pain observation tool. The pain score and serum sodium levels were collected at baseline, at 2, 6, 12, 18, and 24 hours after administration of 3% HTS using IO access. The area surrounding the IO insertion site was monitored for needle placement, extravasation, and tissue damage. RESULTS: Five patients were enrolled. Three had an IO placed in the proximal humerus and 2 in the proximal tibia. Most patients did not have nonverbal indicators of pain during insertion and initial bolus. Serum sodium levels increased appropriately, as determined by the care providers. There were no cases of device dislodgement, extravasation, infection, soft tissue injury, or other local complications. CONCLUSIONS: In this prospective case series, IO administration of 3% HTS was feasible, well-tolerated on the basis of nonverbal indicators of pain in the majority of patients and resulted in an appropriate rise in serum sodium levels. IO fills a niche among vascular access options for HTS, in emergent neurological situations when central venous access is not readily available or peripheral intravenous access is difficult to obtain.

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.

Positive clinical signs in neurological diseases - An observational study.

Many patients with organic neurological disease have symptoms and signs that are unexplained by their disease condition. We attempted to explore the prevalence of positive clinical signs in patients with various organic neurological diseases. We performed a prospective uncontrolled observational study on the presence of 7 positive signs in adults with various organic neurological diseases that were admitted to our tertiary care hospital. This observation was performed during their neurological examination in those who provided consent, could comprehend and lacked terminal illness or profound weakness that limited their ability to perform these tasks. We dichotomized them into two groups based on the presence of these signs. Out of 190 patients that were evaluated between 2014 and 2015, 37 patients had at least one positive sign. On univariate analysis: young age, female gender, prior anxiety, history of childhood abuse, identification of sensory deficits on examination and lack of imaging correlation with clinical localization were identified as risk factors for these positive signs. On multivariate analysis, anxiety (OR 2.88, 95% CI 1.11-7.49, p = 0.03) and presence of sensory deficits on examination (OR 5.81, 95% CI 2.36-14.32, p ≤ 0.001) were associated with these positive signs. Positive signs are common in patients with organic neurological diseases that have anxiety or sensory deficits and may imply a component of functional overlay. Large studies are required to understand its pathophysiology and impact on future outcomes.

Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.

OBJECTIVE: Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 µg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 µg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 µg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

Can Admission BNP Level Predict Outcome After Intravenous Thrombolysis in Acute Ischemic Stroke?

OBJECTIVE: Our study aimed to determine the prognostic value of elevated Brain Natriuretic Peptide (BNP) among patients who received intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). BACKGROUND: The elevation in BNP level is correlated with infarct size, poststroke mortality, and CHADS2 score. Currently, there is a lack of validated biomarker to predict the outcome in patients with acute ischemic stroke, and there is a complex interaction amongst multiple variables. DESIGN/METHODS: A retrospective review of medical records of patients admitted to our institution with acute ischemic stroke was performed. The patients who received intravenous thrombolysis were selected for analysis and divided into 2 groups based on the level of BNP. We compared the baseline demographics, past medical history, stroke etiology, discharge disposition, and 3-month mRS between both groups. Multivariate logistic regression analysis was performed to identify the predictors of poor outcome following intravenous thrombolysis in acute ischemic stroke. RESULTS: A total of 90 patients were recruited in the study; 53 patients were found to have an elevated BNP (high BNP was defined as >100 pg/mL) level, whereas 37 had low BNP levels. Our study showed that patients with elevated BNP were more likely to have an elevation in admission and discharge NIHSS, serum creatinine, left atrial size, and blood glucose (P<0.05). Atrial fibrillation and cardioembolic strokes were seen most often in the population with elevated BNP (P<0.05). The patients with elevated BNP were less likely to be discharged home, and 3-month mRS was found to be higher, but these were not significant. On multivariate analysis, elevated BNP was not found to be an independent factor for poor outcome. CONCLUSIONS: Elevated BNP level was not found to be an independent marker of poor outcome in AIS patients following IVT.

The intraventricular-spot sign: prevalence, significance, and relation to hematoma expansion and outcomes.

BACKGROUND: The presence of the spot sign on computed tomography angiogram (CTA) is considered a sign of active bleeding, and studies have shown it can predict hematoma expansion in intraparenchymal hemorrhage (IPH). The spot sign in intraventricular hemorrhage (IVH) has not been explored yet. The purpose of this study is to estimate the prevalence of the intraventricular-spot sign, and its prediction of hematoma expansion and clinical outcomes. METHODS: We retrieved data of hemorrhagic stroke patients seen at our medical center from January 2013 to January 2018. A total of 321 subjects were filtered for the prevalence analysis (PA). We further excluded 114 subjects without a follow-up CT-head for the hematoma expansion analysis (HEA). Patients were grouped based on the location of hemorrhage into three groups: isolated IPH with the spot sign always in IPH (i-IPH), isolated IVH with the spot sign always in IVH (i-IVH), and combined IPH and IVH which would be further sub-grouped according to the location of the spot sign: in IPH only (IPH+/IVH) and in IVH only (IPH/IVH+). The prevalence, demographics, and incidence of hematoma expansion were compared between the groups using Pearson's chi-square test and Student's t test. RESULTS: The prevalence of the spot sign was 8, 20, 17, 5% in (i-IPH), (i-IVH), (IPH+/IVH), and (IPH/IVH+) groups, respectively. The rate of hematoma expansion were (42 vs. 13%), (33 vs. 31%), (80 vs. 22%), and (25 vs. 22%) in spot sign positive vs. negative subjects in each group, respectively (p values = 0.023, = 1, <0.001, and = 1). CONCLUSION: We studied the prediction of spot sign on hematoma expansion and clinical outcomes in the different subtypes of ICH. Our study showed that spot sign is a good predictor in IPH but not IVH. Despite the rarity of IVH; the prevalence of spot sign was higher in IVH than IPH. This might be due to anatomical and physiological variations.