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.

Predictors and outcomes of first pass efficacy in posterior circulation strokes: Insights from STAR collaboration.

Background: First-pass efficacy (FPE) has been established as an important predictor of favorable functional outcomes after endovascular thrombectomy (ET) in anterior circulation strokes. In this retrospective cohort study, we investigate predictors and clinical outcomes of FPE in posterior circulation strokes (pcAIS). Methods: The Stroke Thrombectomy and Aneurysm Registry database was used to identify pcAIS patients who achieved FPE. Their baseline characteristics and outcomes were compared with the non-FPE group. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0-3. Univariate (UVA) and multivariate (MVA) analyses were done to evaluate predictors of FPE. Safety outcomes included distal emboli, vessel rupture, symptomatic intracranial hemorrhage, and mortality. Results: Of 359 patients, 179 (50%) achieved FPE. Clot burden, occlusion site, and ET technique-related variables were similar between the two groups except for shorter procedure time with FPE. The primary outcome was significantly better with FPE (56.4% vs. 32.8%, p < 0.001). Complications were similar except for a higher rate of distal emboli in non-FPE group (11.1% vs. 3.2%, p = 0.032). Atrial fibrillation (Afib) had increased odds (aOR: 2.06, 95% CI; 1.24, 3.4, p = 0.005) and prior ischemic stroke had decreased odds (aOR: 0.524, 95% CI; 0.28, 0.97, p = 0.04) of FPE. Afib was the only independent predictor of FPE on MVA (1.94, 95% CI; 1.1, 3.43, p = 0.022). Conclusions: Higher rate of FPE in Afib-related pcAIS could possibly be explained by the differences in clot composition and degree of in-situ atherosclerotic disease burden. Future studies are warranted to explore the relationship of clot composition with ET outcomes.

External validation of TICI-ASPECTS-glucose score as a predictive model for symptomatic intracranial hemorrhage following mechanical thrombectomy.

INTRODUCTION: The indication for mechanical thrombectomy for acute ischemic stroke (AIS) secondary to large vessel occlusion has substantially increased in the past few years, but predictors of symptomatic intracranial hemorrhage (sICH) remain largely unstudied. A recent study assessing these predictors, led to the development of the TICI-ASPECTS-glucose (TAG) score, an internally validated model to predict sICH following thrombectomy. METHODS: To externally validate this scoring system and identify other potential risk factors for hemorrhagic conversion following endovascular therapy for AIS, 420 consecutive patients treated with mechanical thrombectomy from 2014-2017 were retrospectively reviewed. Data were collected pertaining to admission factors, procedural metrics, and functional outcomes. The components comprising the TAG score consist of modified thrombolysis in cerebral infarction (mTICI) score (mTICI 0-2a=2 points; 2b-3=0 points), Alberta stroke program early CT (ASPECTS) score (<6=4 points, 6-7=2 points, ≥8=0 points), and glucose (≥150 mg/dL=1 point, <150 mg/dL=0 points). Statistical analyses including univariate analysis, logistic regression analysis, and area under the receiver-operating curve (AUROC) were performed to validate the predictive capability of the model. RESULTS: The patients with sICH presented with lower ASPECTS (8.13±1.55 v 9.16±1.24, p < 0.001), but no significant correlation with mTICI scores and admission glucose was observed. Decreasing ASPECTS correlated with increased risk of sICH (OR 1.57, 95% CI 1.25-1.96, p < 0.001), and increasing TAG score was associated with increased sICH (OR 1.46, 95% CI 1.11-1.94, p < 0.01). AUROC of the model was 0.633. Stratifying patients into low (TAG 0-2), intermediate,3,4 and high5-7 risk groups identified similar results to the original study with sICH risks of 5.2%, 10.5%, and 33.3%, respectively. CONCLUSION: The TICI-ASPECTS-glucose (TAG) score adequately predicts sICH following mechanical thrombectomy, and appropriately stratifies individual patient risk. Further inclusion of additional predictors of sICH would likely yield a more robust model.

An Immunologic Storm: A Case of Encephalitis and Thrombotic Thrombocytopenic Purpura With Underlying Likely Sjogren's Syndrome Induced by a COVID-19 Immune Response.

Introduction: There are rare cases of Sjogren's syndrome presenting with manifestations of encephalitis. There are also rare patients with Sjogren's presenting with acute thrombotic thrombocytopenic purpura (TTP). There are no cases of both occurring together as the only symptoms of the syndrome. During the COVID-19 pandemic, more cases of autoimmunity are being described given its robust immune response. It is important to keep a wide differential about these varying clinical presentations. Case Presentation: Our patient is a 19-year-old female with a history of menorrhagia, recent COVID-19 infection, and remote suicidal ideation. She presented with headaches, vomiting, and psychosis. Her labs found platelets of 12,000 and she was soon discovered to have TTP. She was found to have contrast enhancing lesions scattered in her left hemisphere on magnetic resonance imaging as well as seizures. Her workup was negative for infection, but labs revealed a positive antinuclear antibody, elevated anti-Ro antibody (anti-SSA) and anti-La antibody (anti-SSB), and elevated COVID-19 antibodies. She was treated with antiepileptics, pulse dose steroids for 5 days, plasmapheresis, and weekly rituximab for 4 weeks. She had significant clinical improvement. Conclusion: Sjogren's syndrome can have varying presentations including TTP with or without encephalitis as a presenting feature. Autoimmunity can also be triggered from COVID-19 infection.

Evaluation of the Safety of Rapid Administration of Undiluted High-Dose Intravenous Levetiracetam.

Background: Intravenous (IV) levetiracetam (LEV) is an antiseizure medication traditionally given as an intermittent infusion to mitigate potential adverse effects given its acidic formulation. The process of compounding may lead to delays in treating status epilepticus, which is why administration of undiluted doses is of interest. Prior studies have shown safety of IV doses from 1000 mg to 4500 mg; however, assessments of adverse side effects outside IV site reactions have not been studied. Methods: A retrospective analysis was completed with patients who received 1500 mg doses of undiluted IV LEV. We included patients ≥ 18 years old that received at least 1 dose of IV LEV 1500 mg from January 2018 to February 2021. Study end points included assessment of hemodynamic disturbance (bradycardia [HR less than 50 beats per minute] or hypotension [SBP less than 90 mmHg] within 1 hour or documented infusion reaction within 12 hours of LEV. Descriptive statistics were utilized. Results: A total 213 doses of 1500 mg of IV LEV were administered to 107 patients. Peripheral lines were used for 85.9% of doses. Approximately half of doses (57) were administered to patients on the general wards, with the remainder in the intensive care unit or emergency department. Two patients (1.9%) experienced bradycardia; however, 1 patient had pre-existing bradycardia. Three patients (3.8%) experienced hypotension; however, those patients were receiving vasopressors prior to the dose. There were no cases of infusion reaction. Conclusion: Undiluted, rapid administration of IV LEV 1500 mg was well tolerated and safe.

The landscape of disparities in obstetric neurocritical care and a path forward.

Health disparities in the obstetric population affect maternal morbidity and mortality. In the past years, there has been no significant improvement in disparities in care in the obstetric population. Patients who are pregnant are known to have a higher risk of pregnancy-associated neurologic conditions such as stroke and intracerebral hemorrhage. They can also experience concomitant neurocritical care disease states such as status epilepticus and traumatic brain injury. Studies exploring the disparities of care among pregnant patients who are neurotically ill are lacking. We aim to provide the landscape of disparities of care among the obstetric neurocritically-ill population and provide potential actionable opportunities to address these disparities in care.

Admission Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker of Outcomes in Large Vessel Occlusion Strokes.

Background and Purpose- The purpose of this study is to evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR) at admission with safety and efficacy outcomes in acute stroke patients with large vessel occlusion after mechanical thrombectomy. Methods- Consecutive large vessel occlusion patients treated with mechanical thrombectomy during a 4-year period were evaluated. Outcome measures included symptomatic intracranial hemorrhage, 3-month mortality, successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b/3), and 3-month functional independence (modified Rankin Scale scores of 0-2). Results- A total of 293 large vessel occlusion patients underwent mechanical thrombectomy (median admission NLR, 3.5; interquartile range [IQR], 1.7-6.8). In initial univariable analyses, higher median admission NLR values were documented in patients with symptomatic intracranial hemorrhage (8.5; IQR, 4.7-11.3) versus (3.9; IQR, 1.9-6.5); P<0.001 and individuals who were dead at 3-months (5.4; IQR, 2.8-9.6) versus (4.0; IQR, 1.8-6.4); P=0.004. Lower NLR values were recorded in patients with 3-month functional independence (3.7; IQR, 1.7-6.5) versus (4.3; IQR, 2.6-8.3); P=0.039. After adjustment for potential confounders, a 1-point increase in NLR was independently associated with higher odds of symptomatic intracranial hemorrhage (odds ratio, 1.11; 95% CI, 1.03-1.20; P=0.006) and 3-month mortality (odds ratio, 1.08; 95% CI, 1.01-1.16; P=0.014). Conclusions- Higher admission NLR is an independent predictor of symptomatic intracranial hemorrhage and 3-month mortality in large vessel occlusion patients treated with mechanical thrombectomy, and it may identify a target group for testing adjunctive anti-inflammatory therapies.

Blood pressure levels post mechanical thrombectomy and outcomes in non-recanalized large vessel occlusion patients.

OBJECTIVE: Permissive hypertension may benefit patients with non-recanalized large vessel occlusion (nrLVO) post mechanical thrombectomy (MT) by maintaining brain perfusion. Data evaluating the impact of post-MT blood pressure (BP) levels on outcomes in nrLVO patients are scarce. We investigated the association of the post-MT BP course with safety and efficacy outcomes in nrLVO. METHODS: Hourly systolic BP (SBP) and diastolic BP (DBP) values were prospectively recorded for 24 hours following MT in consecutive nrLVO patients. Maximum, minimum, and mean BP levels were documented. Three-month functional independence (FI) was defined as modified Rankin Scale (mRS) scores of 0-2. RESULTS: A total of 88 nrLVO patients were evaluated post MT. Patients with FI had lower maximum SBP (160±19 mmHg vs 179±23 mmHg; P=0.001) and higher minimum SBP levels (119±12 mmHg vs 108±25 mmHg; P=0.008). Maximum SBP (183±20 mmHg vs 169±23 mmHg; P=0.008) and DBP levels (105±20 mmHg vs 89±18 mmHg; P=0.001) were higher in patients who died at 3 months while minimum SBP values were lower (102±28 mmHg vs 115±16 mmHg; P=0.007). On multivariable analyses, both maximum SBP (OR per 10 mmHg increase: 0.55, 95% CI 0.39 to 0.79; P=0.001) and minimum SBP (OR per 10 mmHg increase: 1.64, 95% CI 1.04 to 2.60; P=0.033) levels were independently associated with the odds of FI. Maximum DBP (OR per 10 mmHg increase: 1.61; 95% CI 1.10 to 2.36; P=0.014) and minimum SBP (OR per 10 mmHg increase: 0.65, 95% CI 0.47 to 0.90; P=0.009) values were independent predictors of 3-month mortality. CONCLUSIONS: Our study demonstrates that wide BP excursions from the mean during the first 24 hours post MT are associated with worse outcomes in patients with nrLVO.

Impact of Beta-Blockers on Nonhead Injured Trauma Patients.

Catecholamine surge after traumatic injury may lead to dysautonomia with increased morbidity. Small retrospective studies have shown potential benefit of beta-blockers (BB) in trauma patients with and without traumatic brain injury (TBI). This study evaluates a large multiply injured cohort without TBI that received BB. Patients were identified from the trauma registry from January 1, 2003 to December 31, 2011. Patients who received >1 dose of BB were compared to controls. Patients with TBI, length of stay (LOS) < 2 days, and prehospital BB were excluded. Outcomes were mortality, intensive care unit (ICU) LOS, and LOS. Stepwise multivariable regression was used to identify variables significantly associated with mortality. During the study period, 19,151 eligible patients were admitted. The mean age was 39 years. Most were male (74%) and most sustained blunt mechanism (75%). A total of 1854 (11%) patients received BB. BB patients had longer LOS (16 vs 6 days), ICU LOS (7 vs 1 days), and higher mortality (2.8 vs 0.5%) (all P < 0.001). Multivariable regression demonstrated no benefit to BB after adjusting for potential confounding characteristics [odds ratio (OR) 0.952; confidence interval (CI) 0.620-1.461]. In conclusion, in this largest study to date, patients receiving BB were older, more severely injured, and had a higher mortality. Unlike TBI patients, multivariable regression showed no benefit from BB in this population.