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.

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.

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.

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.