A systems-biology approach connects aging mechanisms with Alzheimer's disease pathogenesis.

Age is the strongest risk factor for developing Alzheimer's disease, the most common neurodegenerative disorder. However, the mechanisms connecting advancing age to neurodegeneration in Alzheimer's disease are incompletely understood. We conducted an unbiased, genome-scale, forward genetic screen for age-associated neurodegeneration in Drosophila to identify the underlying biological processes required for maintenance of aging neurons. To connect genetic screen hits to Alzheimer's disease pathways, we measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease. We further identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons. Through multi-omic, multi-species network integration of these data, we identified relationships between screen hits and tau-mediated neurotoxicity. Furthermore, we computationally and experimentally identified relationships between screen hits and DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to attenuate the effects of age on neurodegeneration and Alzheimer's disease.

Neuroinvasive West Nile Virus Infection in Immunosuppressed and Immunocompetent Adults.

Importance: West Nile virus (WNV) is the leading cause of human arboviral disease in the US, peaking during summer. The incidence of WNV, including its neuroinvasive form (NWNV), is increasing, largely due to the expanding distribution of its vector, the Culex mosquito, and climatic changes causing heavy monsoon rains. However, the distinct characteristics and outcomes of NWNV in individuals who are immunosuppressed (IS) and individuals who are not IS remain underexplored. Objective: To describe and compare clinical and radiographic features, treatment responses, and outcomes of NWNV infection in individuals who are IS and those who are not IS. Design, Setting, and Participants: This retrospective cohort study used data from the Mayo Clinic Hospital system collected from July 2006 to December 2021. Participants were adult patients (age ≥18 years) with established diagnosis of NWNV infection. Data were analyzed from May 12, 2020, to July 20, 2023. Exposure: Immunosuppresion. Main Outcomes and Measures: Outcomes of interest were clinical and radiographic features and 90-day mortality among patients with and without IS. Results: Of 115 participants with NWNV infection (mean [SD] age, 64 [16] years; 75 [66%] male) enrolled, 72 (63%) were not IS and 43 (37%) were IS. Neurologic manifestations were meningoencephalitis (98 patients [85%]), encephalitis (10 patients [9%]), and myeloradiculitis (7 patients [6%]). Patients without IS, compared with those with IS, more frequently reported headache (45 patients [63%] vs 18 patients [42%]) and myalgias (32 patients [44%] vs 9 patients [21%]). In contrast, patients with IS, compared with those without, had higher rates of altered mental status (33 patients [77%] vs 41 patients [57%]) and myoclonus (8 patients [19%] vs 8 patients [4%]). Magnetic resonance imaging revealed more frequent thalamic T2 fluid-attenuated inversion recovery hyperintensities in individuals with IS than those without (4 patients [11%] vs 0 patients). Individuals with IS had more severe disease requiring higher rates of intensive care unit admission (26 patients [61%] vs 24 patients [33%]) and mechanical ventilation (24 patients [56%] vs 22 patients [31%]). The 90-day all-cause mortality rate was higher in the patients with IS compared with patients without IS (12 patients [28%] vs 5 patients [7%]), and this difference in mortality persisted after adjusting for Glasgow Coma Scale score (adjusted hazard ratio, 2.22; 95% CI, 1.07-4.27; P = .03). Individuals with IS were more likely to receive intravenous immunoglobulin than individuals without IS (12 individuals [17%] vs 24 individuals [56%]), but its use was not associated with survival (hazard ratio, 1.24; 95% CI, 0.50-3.09; P = .64). Conclusions and Relevance: In this cohort study of individuals with NWNV infection, individuals with IS had a higher risk of disease complications and poor outcomes than individuals without IS, highlighting the need for innovative and effective therapies to improve outcomes in this high-risk population.

Integrating Systemic Therapies into the Multimodality Therapy of Patients with Craniopharyngioma.

OPINION STATEMENT: The integration of targeted therapy into the multimodal management of craniopharyngiomas represents a significant advancement in the field of neuro-oncology. Historically, the management of these tumors has been challenging due to their proximity to vital brain structures, necessitating a delicate balance between tumor control and the preservation of neurological function. Traditional treatment modalities, such as surgical resection and radiation, while effective, carry their own set of risks, including potential damage to surrounding healthy tissues and the potential for long-term side effects. Recent insights into the molecular biology of craniopharyngiomas, particularly the discovery of the BRAF V600E mutation in nearly all papillary craniopharyngiomas, have paved the way for a targeted systemic treatment approach. However, advances have been limited for adamantinomatous craniopharyngiomas. The success of BRAF/MEK inhibitors in clinical trials underscores the potential of these targeted therapies not only to control tumor growth but also to reduce the need for more invasive treatments, potentially minimizing treatment-related complications. However, the introduction of these novel therapies also brings forth new challenges, such as determining the optimal timing, sequencing, and duration of targeted treatments. Furthermore, there are open questions regarding which specific BRAF/MEK inhibitors to use, the potential need for combination therapy, and the strategies for managing intolerable adverse events. Finally, ensuring equitable access to these therapies, especially in healthcare systems with limited resources, is crucial to prevent widening healthcare disparities. In conclusion, targeted therapy with BRAF/MEK inhibitors holds great promise for improving outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. However, additional research is needed to address the questions that remain about its optimal use and integration into comprehensive treatment plans.

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease.

Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identify over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1526 and 3308 circRNAs are custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 29% of Parkinson's and 12% of Alzheimer's disease-associated genes produced validated circRNAs. circDNAJC6, which is transcribed from a juvenile-onset Parkinson's gene, is already dysregulated during prodromal, onset stages of common Parkinson's disease neuropathology. Globally, addiction-associated genes preferentially produce circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.

Cerebral enhancement in MOG antibody-associated disease.

INTRODUCTION: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS). METHODS: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed. RESULTS: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate. CONCLUSIONS: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS.

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease.

Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identified over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1,526 and 3,308 circRNAs were custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 88% of Parkinson's and 80% of Alzheimer's disease-associated genes produced circRNAs. circDNAJC6, produced from a juvenile-onset Parkinson's gene, was already dysregulated during prodromal, onset stages of common Parkinson's disease neuropathology. Globally, addiction-associated genes preferentially produced circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA- regulated synaptic specialization in neuropsychiatric diseases.

Hirayama Disease: A 15-Year-Old Male With Progressive Distal Right Upper Extremity Weakness.

INTRODUCTION: Hirayama disease is a rare neuromuscular disorder characterized by abnormal forward displacement of the cervical spinal cord, resulting in focal ischemic changes of anterior horn cells. CASE REPORT: A 15-year-old male presented with 6 months of progressive right upper extremity weakness. Electromyography/nerve conduction study indicated a chronic neurogenic process involving the C8-T1 myotome. Cervical spine magnetic resonance imaging in the neutral position demonstrated minor disk bulges without significant spinal canal narrowing. With flexion, there was a forward displacement of the dorsal dural sac and marked effacement of the subarachnoid spaces from vertebral levels C5 through C7. In addition, prominent flow voids were now seen in the dorsal epidural space consistent with engorged venous structures. CONCLUSION: The diagnosis of Hirayama disease requires a high index of suspicion, and imaging should include a series with the neck in a flexed position, as imaging in the neutral position is often unrevealing and the disorder can otherwise easily be missed.

Incidence of Status Migrainosus in Olmsted County, Minnesota, United States: Characterization and Predictors of Recurrence.

BACKGROUND AND OBJECTIVES: SM is recognized as a complication of migraine in which pain and/or associated symptoms are unremitting and debilitating for more than 72 hours. The epidemiology of SM in the general population is not known. The aim of this study is to determine the incidence, recurrence rate, and clinical associations of status migrainosus (SM) in care-seeking residents of Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project was used to identify the incident cases of SM according to the International Classification of Headache Disorders, Third Edition criteria and based on the first physician-encountered case in the record. The clinical characteristics of the incident cases were abstracted from the medical record. One-year recurrence-free survival was evaluated and compared between clinically relevant groups, including baseline demographics, migraine characteristics, and treatment exposures. RESULTS: Between January 1, 2012, and December 31, 2017, 237 incident cases of SM were identified. The median age was 35 (IQR 26-47) years, and 210 (88.6%) were female. A history of chronic migraine was recorded in 82/226 (36.3%) and a history of aura in 76/213 (35.7%). At the time of the incident case, medication reconciliation included a triptan or ergotamine in 127/233 (53.6%) and/or an opioid-containing analgesic in 43/233 (18.5%). The overall age- and sex-adjusted incidence rate was 26.60 per 100,000 [95% CI, 23.21-29.97], with a peak incidence between ages 40 and 49 years. The median (95% CI) attack duration was 5 (4.48-5.42) days. The most frequent triggers were stress (40/237, 16.9%) and too much or too little sleep (27/237, 11.4%). Recurrence occurred in 35/237 (14.8%) at a median of 58 (IQR 23-130) days following the initial attack. In our age- and sex-adjusted multivariable model, too much or too little sleep as a trigger was associated with 12-month risk of recurrence (adjusted OR 3.59 [95% CI 1.58-8.14], p = 0.0022). DISCUSSION: Our study provides a population-based estimate of SM incidence. We identified aberrant sleep patterns as a potentially modifiable risk factor for 1-year SM recurrence.

Aquaporin-4 IgG neuromyelitis optica spectrum disorder onset after Covid-19 vaccination: Systematic review.

Neuromyelitis optica spectrum disorder (NMOSD) is rarely reported following Coronavirus disease 2019 (COVID-19) vaccination. We identified 16 cases of new onset NMOSD with positive aquaporin-4 IgG (AQP4-IgG) following COVID-19 vaccination. Transverse myelitis was the most common clinical presentation (75%). Most patients received high dose steroids for acute treatment and maintenance therapy was started in 12 patients (75%). Twelve patients (75%) had improvement of their symptoms at the time of discharge or follow-up. The included cases share similar epidemiology and natural course to non-vaccine related cases. Clinicians should be aware of possible post-vaccination NMOSD to help with earlier diagnosis and treatment.

Drug-related immune-mediated myelopathies.

Iatrogenic immune-mediated inflammatory disorders of the spinal cord are an uncommon but potentially severe complication of drug therapy for several human diseases. Particularly the introduction of novel biological agents in the treatment of systemic inflammatory disorders and cancer immunotherapy have led to a significant increase in immune-related adverse events of the central nervous system (CNS). The use of Tumor necrosis factor alpha (TNF-alpha) inhibitors in rheumatic and inflammatory bowel diseases has been associated with demyelinating and other inflammatory CNS conditions, including myelitis. The introduction of immune checkpoint inhibitors in the treatment of several human malignancies has led to an increase in drug-induced immune-related adverse events including in the CNS. Other drugs that have been associated with immune-mediated myelitis include tyrosine-kinase inhibitors and chimeric antigen receptor (CAR) T Cell therapy. A high degree of suspicion is necessary when diagnosing these conditions, as early diagnosis and treatment is crucial in preventing further neurological damage and disability. The treatment of drug-induced inflammatory myelitis typically involves administration of high-dose intravenous corticosteroids, however additional immunosuppressive agents may be required in severe or refractory cases. While most cases are monophasic and remit following discontinuation of the offending agent, chronic immunosuppressive therapy may be indicated in cases with a progressive or relapsing disease course or when a diagnosis of a specific underlying neuro-inflammatory disorder is made. Outcomes are generally favorable, however depend on the specific therapeutic agent used, the clinical presentation and patient factors. In this review we aim to describe the clinical characteristics, imaging findings and management for the most common forms of iatrogenic immune-mediated myelopathies.

In Patients With Melanoma Brain Metastases, Is Combination Immune Checkpoint Inhibition a Safe and Effective First-Line Treatment? A Critically Appraised Topic.

BACKGROUND: Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis. OBJECTIVE: The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. RESULTS: A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12 wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B. CONCLUSIONS: Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.

Relevant pharmacologic interactions in the concurrent management of brain tumor-related epilepsy and venous thromboembolism: a systematic review.

INTRODUCTION: Co-administration of direct oral anticoagulants (DOACs) with antiepileptic drugs (AEDs) is increasingly common in brain tumor patients. We therefore performed a systematic review of the current evidence for potential drug interactions between DOACs and AEDs in this patient population. METHODS: We conducted a systematic review of the literature via PubMed according to PRISMA guidelines (last accessed December 15, 2021). Included were clinical studies and case reports, written in English language and published between 2010 and 2021, that investigated concurrent clinical use of AEDs with DOACs for any indication. Non-English articles, articles not related to our research question, review articles and commentaries were excluded. Full-text articles were evaluated for possible confounding factors and results were summarized using a data table highlighting the key characteristics of each article. RESULTS: We identified a total of 122 unique articles, of which 27 were deemed relevant to our research question. Of these, 8 articles were clinical studies (n = 295,415 patients) and 19 were case reports (n = 25 patients). Only 3 clinical studies and 2 case reports reported interactions between AEDs and DOACs in patients with active cancer and none reported interactions in patients with brain tumors. CONCLUSION: We have identified low (class IV) level evidence of potential drug interactions between DOACs and AEDs. Even though there is no current report of interactions in brain tumor patients, neuro-oncology providers should be aware of the emerging evidence regarding drug interactions between DOACs and AEDs and take this into consideration when concurrently prescribing these to patients.

Association of Optimism with Cardiovascular Events and All-Cause Mortality: Systematic Review and Meta-Analysis.

BACKGROUND: The effect of psychological health on cardiovascular disease is an underappreciated yet important area of study. Understanding the relationship between these two entities may allow for more comprehensive care of those with cardiovascular disease. The primary objective of this meta-analysis is to evaluate the relationship between optimism and risk of developing adverse events such as all-cause mortality or fatal and non-fatal cardiovascular disease in community-based populations. METHOD: A systematic search of electronic databases was conducted from inception through November 2021 for prospective studies evaluating optimism and adverse outcomes. Two reviewers independently selected prospective cohort studies that evaluated optimism and either all-cause mortality or cardiovascular disease and reported hazard ratios of these outcomes between optimistic and non-optimistic groups. Studies that reported odds ratio or other risk assessments were excluded. Pooled hazard ratios were calculated in random-effects meta-analyses. RESULTS: Pooled analysis of six studies (n = 181,709) showed a pooled hazard ratio of 0.87 (95% confidence interval [CI], 0.82-0.92) for all-cause mortality among those with more optimistic mindset. Analysis of seven studies (n = 201,210) showed a pooled hazard ratio of 0.59 (95% CI, 0.37-0.93) for cardiovascular disease and pooled hazard ratio of 0.57 (95% CI, 0.07-4.56) for stroke. CONCLUSIONS: In this pooled meta-analysis, optimism was associated with a reduced risk of all-cause mortality and of cardiovascular disease. These results suggest an important relationship between psychological health and cardiovascular disease that may serve as an area for intervention by clinicians.

A Stroke Alert With Unexpected Outcome.

INTRODUCTION: Observational studies have suggested that intravenous (IV) thrombolysis may be unfavorable in patients with high-grade gliomas. However, current literature on thrombolysis outcomes in patients with primary brain tumors is largely limited to case reports and may be influenced by publication bias. CASE REPORT: A 69-year-old male presented with acute left hemiplegia, left hemisensory loss, neglect, dysarthria and right gaze preference (National Institutes of Health Stroke Scale 22). An emergent noncontrast head computerized tomography showed hypoattenuation in the right parietal lobe of unclear chronicity and IV thrombolysis with tissue plasminogen activator was administered within the 4.5 hour window. Following IV thrombolysis, a computerized tomography angiogram of the head and neck revealed no large vessel occlusion. However, a marginally enhancing, and centrally nonenhancing mass within the right parietal lobe associated with vasogenic edema was elucidated. Subsequently, the patient developed abnormal left hemibody tonic-clonic motor activity, left gaze preference and left-beating nystagmus concerning for focal motor status epilepticus. An emergent electroencephalogram, following administration of IV levetiracetam, showed right hemispheric electrographic seizures and right hemispheric periodic lateralized epileptiform discharges. Brain magnetic resonance imaging with gadolinium revealed 2.5 cm ring-enhancing mass in the right parietal lobe. The patient underwent right sided craniotomy with resection of the mass and pathology revealed Glioblastoma. CONCLUSION: We report a case of thrombolysis administered in a patient with high-grade glioma with no apparent complications.

Reversible Cerebral Vasoconstriction Syndrome in the Setting of COVID-19 and Pleomorphic Sarcoma: A Case Report.

INTRODUCTION: Reversible cerebral vasonstriction syndrome (RCVS) is an increasingly recognized clinical and radiologic syndrome. However, it has been rarely reported in the setting of the novel coronavirus disease-2019 (COVID-19) infection or sarcomatous tumors. RCVS might be the initial manifestations of COVID-19 infection or noncatecholamine producing masses including sarcoma. CASE REPORT: A 44-year-old male who developed COVID-19-related symptoms followed by rapid onset of severe headaches in the setting of persistently elevated blood pressure (BP). Brain imaging showed multifocal arterial narrowing in the anterior and posterior circulation consistent with RCVS. Serial imaging demonstrated resolution of the arterial narrowing after BP control was achieved with improvement in the patient's headaches. Further investigation for secondary causes of the patient's elevated BP revealed a right renal mass, and the patient underwent right nephrectomy, and the biopsy results confirmed the diagnosis of pleomorphic sarcoma. CONCLUSION: Our case suggests a possible association between severe acute respiratory syndrome coronavirus 2 with development of RCVS, but further studies are needed to validate this observation, establish a causal relationship and define a pathophysiological mechanism. Considering tumors other than catecholamine-producing masses as a potential risk factor for developing RCVS might lead to earlier detection and treatment of any underlying malignancy in patients whom the main and sole presentation could be RCVS.

Is Autologous Stem Cell Transplantation a Safe and Effective Alternative to Whole Brain Radiation as Consolidation Therapy in Patients With Primary Central Nervous System Lymphoma?: A Critically Appraised Topic.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. RESULTS: A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. CONCLUSIONS: In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

Does General Anesthesia Compared With Conscious Sedation Result in Better Outcomes in Acute Stroke Patients Undergoing Endovascular Therapy?

BACKGROUND: There is considerable controversy surrounding the optimal use of sedation in patients with acute ischemic stroke undergoing mechanical thrombectomy. Several retrospective studies have favored conscious sedation (CS) over general anesthesia (GA) in terms of functional outcomes and mortality. Recent data from randomized controlled trials has challenged this view. OBJECTIVE: The aim was to critically assess current evidence regarding the use of CS versus GA in mechanical thrombectomy for acute ischemic stroke. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular neurology, vascular neurosurgery, and interventional neuroradiology. RESULTS: A randomized controlled trial was selected for critical appraisal. This trial compared 128 patients with acute ischemic stroke and large vessel occlusion from a single center (Aarhus University Hospital, Denmark), 65 of whom received GA and 63 received CS. No significant difference was detected for the primary outcome of volume of infarct growth. The rate of successful thrombectomy and favorable clinical outcomes for the GA arm was significantly higher in the intention-to-treat analysis. CONCLUSIONS: GA does not result in worse tissue outcomes or worse clinical outcomes when compared with CS in acute stroke patients with large vessel occlusion undergoing mechanical thrombectomy.