Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

The European Academy of Neurology COVID-19 registry (ENERGY): an international instrument for surveillance of neurological complications in patients with COVID-19.

The COVID-19 pandemic is a global public health issue. Neurological complications have been reported in up to one-third of affected cases, but their distribution varies significantly in terms of prevalence, incidence and phenotypical characteristics. Variability can be mostly explained by the differing sources of cases (hospital vs. community-based), the accuracy of the diagnostic approach and the interpretation of the patients' complaints. Moreover, after recovering, patients can still experience neurological symptoms. To obtain a more precise picture of the neurological manifestations and outcome of the COVID-19 infection, an international registry (ENERGY) has been created by the European Academy of Neurology in collaboration with European national neurological societies and the Neurocritical Care Society and Research Network. ENERGY can be implemented as a stand-alone instrument for patients with suspected or confirmed COVID-19 and neurological findings or as an addendum to an existing registry not targeting neurological symptoms. Data are also collected to study the impact of neurological symptoms and neurological complications on outcomes. The variables included in the registry have been selected in the interests of most countries, to favour pooling with data from other sources and to facilitate data collection even in resource-poor countries. Included are adults with suspected or confirmed COVID-19 infection, ascertained through neurological consultation, and providing informed consent. Key demographic and clinical findings are collected at registration. Patients are followed up to 12 months in search of incident neurological manifestations. As of 19 August, 254 centres from 69 countries and four continents have made requests to join the study.

Subarachnoid hemorrhage guidance in the era of the COVID-19 pandemic - An opinion to mitigate exposure and conserve personal protective equipment.

Aneurysmal subarachnoid hemorrhage (SAH) patients require frequent neurological examinations, neuroradiographic diagnostic testing and lengthy intensive care unit stay. Previously established SAH treatment protocols are impractical to impossible to adhere to in the current COVID-19 crisis due to the need for infection containment and shortage of critical care resources, including personal protective equipment (PPE). Centers need to adopt modified protocols to optimize SAH care and outcomes during this crisis. In this opinion piece, we assembled a multidisciplinary, multicenter team to develop and propose a modified guidance algorithm that optimizes SAH care and workflow in the era of the COVID-19 pandemic. This guidance is to be adapted to the available resources of a local institution and does not replace clinical judgment when faced with an individual patient.

Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury.

OBJECTIVES: Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. DESIGN: A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. MAIN RESULTS: Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. CONCLUSIONS: This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.

Plasma-type gelsolin in subarachnoid hemorrhage: novel biomarker today, therapeutic target tomorrow?

There is growing interest in the potential neuroprotective properties of gelsolin. In particular, plasma-type gelsolin (pGSN) can ameliorate deleterious inflammatory response by scavenging pro-inflammatory signals such as actin and lipopolysaccharide. In a recent issue of Critical Care, Pan and colleagues report an important association between pGSN and subarachnoid hemorrhage (SAH) disease severity, and found pGSN to be a novel and promising biomarker for SAH clinical outcome. Previous research shows pGSN may be actively degraded by neurovascular proteases such as matrix metalloproteinases in the cerebral spinal fluid of SAH patients. Taken together, these results suggest that pGSN is not only a novel marker of SAH clinical outcome, but may also play an active mechanistic role in SAH, and potentially serve as a future therapeutic target.

O-GlcNAcylation is essential for therapeutic mitochondrial transplantation.

BACKGROUND: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals. METHODS: Mitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc. O-GlcNAcylated mitochondrial proteins were identified by mass spectrometry and the antiglycation ability of O-GlcNAcylated DJ1 was determined by loss-of-function via mutagenesis. Therapeutic efficacy of O-GlcNAcylated mitochondria was assessed in a mouse model of transient focal cerebral ischemia-reperfusion. To explore translational potential, we evaluated O-GlcNAcylated DJ1 in CSF collected from patients with subarachnoid hemorrhagic stroke (SAH). RESULTS: We show that isolated mitochondria are susceptible to advanced glycation end product (AGE) modification, and these glycated mitochondria induce the receptor for advanced glycation end product (RAGE)-mediated autophagy and oxidative stress when transferred into neurons. However, modifying mitochondria with O-GlcNAcylation counteracts glycation, diminishes RAGE-mediated effects, and improves viability of mitochondria recipient neurons. In a mouse model of stroke, treatment with extracellular mitochondria modified by O-GlcNAcylation reduces neuronal injury and improves neurologic deficits. In cerebrospinal fluid (CSF) samples from SAH patients, levels of O-GlcNAcylation in extracellular mitochondria correlate with better clinical outcomes. CONCLUSIONS: These findings suggest that AGE-modification in extracellular mitochondria may induce danger signals, but O-GlcNAcylation can prevent glycation and improve the therapeutic efficacy of transplanted mitochondria in the CNS.

Mitochondria are the part of a cell that generate most of its energy to perform its functions. In injury or disease, mitochondrial function can become disrupted. Transplantation of healthy mitochondria is being explored as a potential therapy to replace damaged mitochondria and restore normal cellular function. However, this approach is difficult to perform because mitochondria are not able to maintain their healthy state outside of cells. Here, we show that one of the reasons for this is due to a molecular process called advanced glycation end product modification. We show that simple modification of mitochondria with a sugar prevents this process and helps to improve the success of therapeutic mitochondrial transplantation in cells and in a mouse model of stroke. Our findings may help to guide future efforts to develop therapies based on mitochondrial transplantation.

Subarachnoid Hemorrhage.

PURPOSE OF REVIEW: Subarachnoid hemorrhage (SAH) remains an important cause of mortality and long-term morbidity. This article uses a case-based approach to guide readers through the fundamental epidemiology and pathogenesis of SAH, the approach to diagnosis and management, the results of clinical trials and evidence to date, prognostic considerations, controversies, recent developments, and future directions in SAH. RECENT FINDINGS: Historically, management of SAH focused on prevention and treatment of subsequent cerebral vasospasm, which was thought to be the primary cause of delayed cerebral ischemia. Clinical and translational studies over the past decade, including several therapeutic phase 3 randomized clinical trials, suggest that the pathophysiology of SAH-associated brain injury is multiphasic and multifactorial beyond large vessel cerebral vasospasm. The quest to reduce SAH-associated brain injury and improve outcomes is shifting away from large vessel cerebral vasospasm to a new paradigm targeting multiple brain injury mechanisms, including early brain injury, delayed cerebral ischemia, microcirculatory dysfunction, spreading cortical depolarization, inflammation, and the brain-body interaction in vascular brain injury with critical illness.Despite multiple negative randomized clinical trials in search of potential therapeutic agents ameliorating the downstream effects after SAH, the overall outcome of SAH has improved over recent decades, likely related to improvements in interventional options for ruptured cerebral aneurysms and in critical care management. Emerging clinical evidence also suggests potential harmful impact of historic empiric treatments for SAH-associated vasospasm, such as prophylactic induction of hypertension, hypervolemia, and hemodilution (triple H therapy).With decreasing mortality, long-term SAH survivorship and efforts to reduce chronic morbidity and to improve quality of life and patient-centered outcome are growing areas of unmet need. Despite existing guidelines, significant variabilities in local and regional practices and in scientific terminologies have historically limited advancement in SAH care and therapeutic development. Large global collaborative efforts developed harmonized SAH common data elements in 2019, and studies are under way to examine how existing variabilities in SAH care impact long-term SAH outcomes. SUMMARY: Although the overall incidence and mortality of SAH is decreasing with advances in preventive and acute care, SAH remains a major cause of long-term morbidity in survivors. Significant variabilities in care settings and empiric treatment protocols and inconsistent scientific terminologies have limited advancement in patient care and therapeutic clinical studies. Large consensus efforts are under way to introduce clinical guidelines and common data elements to advance therapeutic approaches and improve patient outcome.

Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage.

OBJECTIVE: To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia. METHODS: Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied. RESULTS: sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1ß, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial-cadherin fragments. CONCLUSIONS: These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.

Effective glycemic control with aggressive hyperglycemia management is associated with improved outcome in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Hyperglycemia strongly predicts poor outcome in patients with aneurysmal subarachnoid hemorrhage, but the effect of hyperglycemia management on outcome is unclear. We studied the impact of glycemic control on outcome of patients with aneurysmal subarachnoid hemorrhage. METHODS: A prospective intensive care unit database was used to identify 332 patients with hyperglycemic aneurysmal subarachnoid hemorrhage admitted between January 2000 and December 2006. Patients treated with an aggressive hyperglycemia management (AHM) protocol after 2003 (N=166) were compared with 166 patients treated using a standard hyperglycemia management before 2003. Within the AHM group, outcome was compared between patients who achieved good (mean glucose burden <1.1 mmol/L) and poor (mean glucose burden >or=1.1 mmol/L) glycemic control. Poor outcome was defined as modified Rankin scale >or=4 at 3 to 6 months. Multivariable logistic regression models correcting for temporal trend were used to quantify the effect of AHM on poor outcome. RESULTS: Poor outcome in AHM-treated patients was lower (28.31% versus 40.36%) but was not statistically significant after correcting for temporal trend. However, good glycemic control significantly reduced the incidence of poor outcome (OR, 0.25; 95% CI, 0.08 to 0.80; P=0.02) compared with patients with poor glycemic control within the AHM group. No difference in the rate of clinical vasospasm or the development of delayed ischemic neurological deficit was seen before and after AHM protocol implementation. CONCLUSIONS: AHM results in good glucose control and significantly reduces the odds for poor outcome after aneurysmal subarachnoid hemorrhage in glucose-controlled patients. Further studies are needed to confirm these results.

Outcomes after Early Anticonvulsant Discontinuation in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Empiric use of anticonvulsant (AED) for seizure prophylaxis in aneurysmal subarachnoid hemorrhage (SAH) remains controversial and may be associated with worse SAH outcome. We determined the safety and feasibility of early discontinuation of empiric AED in a select cohort of SAH patients. METHODS: In a cohort of 166 consecutive SAH patients, a subset underwent early AED discontinuation if they were awake and following commands after aneurysm treatment. We examined the effect of AED discontinuation on seizure incidence, mortality and functional outcome at discharge using logistic regression and validated results using 70%-30% data partition. RESULTS: Seventy-three subjects underwent AED discontinuation. Patient groups had similar gender, age, Fisher grade, incidence of craniotomy, vasospasm, ischemic infarct, intraventricular and intraparenchymal hemorrhages. Hunt-Hess (HH) grade were lower in AED-discontinuation group. Clinical or electrographic seizure occurred in 1/93 (1%) patients on AED and 0/73 patient in AED-discontinuation group. Crude mortality was 24% in patients on AED and 2.7% off AED. After adjusting for age, HH grade, vasospasm, ischemic infarct, intracerebral, and intraventricular hemorrhage, AED discontinuation remains independently associated with lower mortality and higher odds of discharge to home (p=0.0002). AED use is not associated with angiographic vasospasm on exploratory analysis. CONCLUSION: AED discontinuation in SAH patients who are awake and following commands post aneurysm treatment is safe, feasible, and associated with better outcome at hospital discharge. A larger, prospective study is necessary to determine if empiric AED use in SAH leads to poorer functional status.