Tonic-Clonic Activity at Subarachnoid Hemorrhage Onset: Impact on Complications and Outcome

Objective: Tonic-clonic activity (TCA) at onset complicates 3% to 21% of cases of subarachnoid hemorrhage (SAH). The impact of onset TCA on in-hospital complications, including seizures, remains unclear. One study associated onset TCA with poor clinical outcome at 6 weeks after SAH, but to our knowledge no other studies have confirmed this relationship. This study aims to assess the impact of onset TCA on in-hospital complications, poor functional outcome, mortality, and epilepsy at 3 months. Methods: Analysis of a prospective study cohort of 1479 SAH patients admitted to Columbia University Medical Center between 1996 and 2012. TCA within 6 hours of hemorrhage onset was identified based on accounts of emergency care providers or family witnesses. Results: TCA at onset was described in 170 patients (11%). Patients with onset TCA were younger (P = 0.002), presented more often with poor clinical grade (55% vs. 26%, P<0.001) and had larger amounts of cisternal, intraventricular, and intracerebral blood than those without onset TCA (all, P<0.001). After adjusting for known confounders, onset TCA was significantly associated with in-hospital seizures (OR 3.80, 95%-CI: 2.43–5.96, P<0.001), in-hospital pneumonia (OR 1.56, 95%-CI: 1.06–2.31, p = 0.02), and delayed cerebral ischemia (OR 1.77, 95%-CI: 1.21–2.58, P = 0.003). At 3 months, however, onset TCA was not associated with poor functional outcome, mortality, and epilepsy after adjusting for age, admission clinical grade, and cisternal blood volume. Conclusions: Onset TCA is not a rare event as it complicates 11% of cases of SAH. New and clinically relevant findings are the association of onset TCA with in-hospital seizures, pneumonia and delayed cerebral ischemia. Despite the increased risk of in-hospital complications, onset TCA is not associated with disability, mortality, and epilepsy at 3 months

Causal Structure of Brain Physiology after Brain Injury from Subarachnoid Hemorrhage

High frequency physiologic data are routinely generated for intensive care patients. While massive amounts of data make it difficult for clinicians to extract meaningful signals, these data could provide insight into the state of critically ill patients and guide interventions. We develop uniquely customized computational methods to uncover the causal structure within systemic and brain physiologic measures recorded in a neurological intensive care unit after subarachnoid hemorrhage. While the data have many missing values, poor signal-to-noise ratio, and are composed from a heterogeneous patient population, our advanced imputation and causal inference techniques enable physiologic models to be learned for individuals. Our analyses confirm that complex physiologic relationships including demand and supply of oxygen underlie brain oxygen measurements and that mechanisms for brain swelling early after injury may differ from those that develop in a delayed fashion. These inference methods will enable wider use of ICU data to understand patient physiology

Ras2, the TC21/R-Ras2 Drosophila homologue, contributes to insulin signalling but is not required for organism viability

Ras1 (Ras85D) and Ras2 (Ras64B) are the Drosophila orthologs of human H-Ras/N-Ras/K-Ras and R-Ras1-3 genes, respectively. The function of Ras1 has been thoroughly characterised during Drosophila embryonic and imaginal development, and it is associated with coupling activated trans-membrane receptors with tyrosine kinase activity to their downstream effectors. In this capacity, Ras1 binds and is required for the activation of Raf. Ras1 can also interact with PI3K, and it is needed to achieve maximal levels of PI3K signalling in specific cellular settings. In contrast, the function of the unique Drosophila R-Ras member (Ras2/Ras64B), which is more closely related to vertebrate R-Ras2/TC21, has been only studied through the use of constitutively activated forms of the protein. This pioneering work identified a variety of phenotypes that were related to those displayed by Ras1, suggesting that Ras1 and Ras2 might have overlapping activities. Here we find that Ras2 can interact with PI3K and Raf and activate their downstream effectors Akt and Erk. However, and in contrast to mutants in Ras1, which are lethal, null alleles of Ras2 are viable in homozygosis and only show a phenotype of reduced wing size and extended life span that might be related to reduced Insulin receptor signalling.Secretaría de Estado de Investigación, Desarrollo e Innovación, Grant/Award Number: BFU2015-64220-P and BFU2018-094476. We would also like to acknowledge the support from the Drosophila transgenesis and confocal microscopy CBMSO scientific services. The CBMSO enjoys institutional support from the Ramón Areces and Santander Foundatio

Medical Treatment Failure for Symptomatic Vasospasm After Subarachnoid Hemorrhage Threatens Long-Term Outcome

Background and Purpose- Symptomatic vasospasm is a common cause of morbidity and mortality after subarachnoid hemorrhage. We sought to identify predictors and the long-term impact of treatment failure with hypertensive therapy for symptomatic vasospasm. Methods- We performed a retrospective analysis of 1520 subarachnoid hemorrhage patients prospectively enrolled in the Columbia University SAH Outcomes Project between August 1996 and August 2012. One hundred ninety-eight symptomatic vasospasm patients were treated with vasopressors to raise arterial blood pressure, with and without volume expansion. Treatment response, defined as complete or near-complete resolution of the initial neurological deficit, was adjudicated in weekly meetings of the study team based on serial clinical examination after hypertensive treatment. Outcome was evaluated at 1 year with the modified Rankin Scale. Results- Twenty-one percent of the 198 patients who received hypertensive therapy did not respond to treatment. Treatment failure was associated with an increased risk of death or severe disability at 1 year (modified Rankin Scale score of 4-6; 62% versus 25%; P0.3 μg/L (64% versus 28%; P=0.001), aneurysm coiling (43% versus 20%; P=0.004), and involvement of \u3e1 symptomatic vascular territory at onset (39% versus 22%; P=0.02). In multivariable analysis, treatment failure was independently associated only with troponin I elevation (adjusted odds ratio, 4.30; 95% CI, 1.69-11.09; P=0.002). Conclusions- Failure to respond to induced hypertension for symptomatic vasospasm threatens 1-year outcome. Subarachnoid hemorrhage patients with symptomatic vasospasm who have elevated initial troponin I levels, indicative of neurogenic cardiac injury, are at twice the risk of medical treatment failure. Expedited endovascular therapy should be considered in these patients

Supplemental Material, Supp_Table_1_final - Prognostic Value of the Neurological Examination in Cardiac Arrest Patients After Therapeutic Hypothermia

<p>Supplemental Material, Supp_Table_1_final for Prognostic Value of the Neurological Examination in Cardiac Arrest Patients After Therapeutic Hypothermia by Elizabeth A. Matthews, Jessica Magid-Bernstein, Evie Sobczak, Angela Velazquez, Cristina Maria Falo, Soojin Park, Jan Claassen, and Sachin Agarwal in The Neurohospitalist</p

Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis

Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of diseases such as cancer, central nervous system (CNS) disorders, viral infections, and others. Vafidemstat (ORY-2001) is a clinical stage inhibitor of KDM1A in development for the treatment of neurodegenerative and psychiatric diseases. However, the role of ORY-2001 targeting KDM1A in neuroinflammation remains to be explored. Here, we investigated the effect of ORY-2001 on immune-mediated and virus-induced encephalomyelitis, two experimental models of multiple sclerosis and neuronal damage. Oral administration of ORY-2001 ameliorated clinical signs, reduced lymphocyte egress and infiltration of immune cells into the spinal cord, and prevented demyelination. Interestingly, ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the inflammatory gene expression signature characteristic ofEAE in the CNS of mice more potently. In addition, ORY-2001 induced gene expression changes concordant with a potential neuroprotective function in the brain and spinal cord and reduced neuronal glutamate excitotoxicity-derived damage in explants. These results pointed to ORY-2001 as a promising CNS epigenetic drug able to target neuroinflammatory and neurodegenerative diseases and provided preclinical support for the subsequent design of early-stage clinical trials

Baseline Characteristics in SAH Patients With and Without Onset TCA.

<p>Data are N (%) or median [IQR]. TCA denotes tonic-clonic activity at subarachnoid hemorrhage onset.</p>*<p>Range 0, no blood, 30 all cisterns completely filled.</p>**<p>Range 0, no IVH, 12 all ventricles completely filled with IVH.</p>†<p>Anterior circulation denotes: anterior cerebral artery, anterior communicating artery, intracranial internal carotid artery, middle cerebral artery, posterior communicating artery.</p

Complications, Length of In-hospital Stay and Outcomes According to Onset TCA.

<p>Data are N (%). TCA denotes tonic-clonic activity at subarachnoid hemorrhage onset.</p>*<p>SIRS denotes systemic inflammatory response, with range 0 lowest, 4 highest.</p>**<p>Information on DCI was not available for 81 patients.</p