Shreyansh Shah

cAMP Response Element-Binding Protein 1 Feedback Loop Is Necessary for Consolidation of Long-Term Synaptic Facilitation in Aplysia

The transcription factor cAMP response element (CRE)-binding protein (CREB) plays an essential role in the induction of many forms of long-term synaptic plasticity. Levels of CREB1, the Aplysia homolog of CREB, show sustained elevations for several hours after the induction of long-term synaptic facilitation (LTF). Furthermore, CREB1 binds to the promoter of its own gene. These results suggest the existence of a CREB1-positive feedback loop that contributes to the consolidation of LTF. In the present study, we provide a detailed, quantitative characterization of the dynamics of CREB1 mRNA and protein as well as CREB1 phosphorylation after LTF induction. Injections of CRE oligonucleotides prevented the increase in CREB1 in response to 5-HT, corroborating the existence of the CREB1 feedback loop. This loop probably sustains CRE-dependent gene transcription, which remains elevated for at least 12 h after LTF induction. LTF is blocked by injection of CREB1 antibody after the induction phase, suggesting that the CREB1-positive feedback is required for consolidation of LTF.

The SILK flow diverter in the treatment of intracranial aneurysms

The SILK flow diverter (SFD; Balt Extrusion, Montmorency, France) is a flow diverting stent used in the endovascular treatment of intracranial aneurysms. It works on the principle of redirecting flow away from the aneurysm sac, leading to occlusion over time. We present a systematic review on the clinical outcomes and complications of the SFD. A literature search for English language articles were conducted on PubMed, Medline and EMBASE for articles on the treatment of intracranial aneurysms with the SILK flow diverter. The inclusion criteria were n>10, use of SFD only, data on complications and aneurysm occlusion rate (AOR). Eight studies with 285 patients and 317 intracranial aneurysms were included. The mean age was 52.7 years and nearly 80% were women. In terms of angiographic distribution, 86.8% of aneurysms were located in the anterior circulation and 13.2% in the posterior circulation. As for the aneurysm size, 37.9% were classed as small, 44.4% as large and 17.7% as giant. Ischemic complications and parent artery occlusion each occurred in 10% of patients. Aneurysm rupture rate was 3.5%, while the cumulative mortality was 4.9%. The main outcome measure, 12 month AOR, was 81.8% with complete occlusion in 216 out of 264 aneurysms. Use of flow diverters for the treatment of intracranial aneurysm with complex morphologies has gained in popularity over the last few years. Our review suggests that SFD achieves comparable AOR to its contemporary, the Pipeline Embolization Device (ev3 Endovascular, Plymouth, MN, USA) but has a higher rate of higher rate of ischemic complications, aneurysm rupture and mortality.

Screening with MRI for Accurate and Rapid Stroke Treatment: SMART

Objective: The objective of this study was to demonstrate the feasibility of timely multimodal MRI screening before thrombolysis in acute stroke patients. Methods: Quality improvement processes were initiated in 2013 to reduce door-to-needle (DTN) time at the 2 hospitals where the NIH stroke team provides clinical care. Acute ischemic stroke (AIS) patients who received IV tissue plasminogen activator (tPA) ≤4.5 hours from last known normal were identified. Demographic and clinical characteristics and timing metrics were analyzed comparing the time periods before, during, and after the quality improvement processes. Results: There were 157 patients treated with IV tPA for AIS during 2012–2013, of whom 135 (86%) were screened with MRI. DTN time was significantly reduced by 40% during this period from a median of 93 minutes in the first half of 2012 to 55 minutes in the last half of 2013 (p < 0.0001) with a significant 4-fold increase in the proportion of treated patients with DTN time ≤60 minutes from 13.0% to 61.5%, respectively (p < 0.00001). Improvement in DTN time was associated with reduced door-to-MRI time, and there were no differences in demographic or clinical characteristics (p = 0.21–0.76). Conclusions: It is feasible and practical to consistently and rapidly deliver IV tPA to AIS patients within national benchmark times using MRI as the routine screening modality. The processes used in the SMART (Screening with MRI for Accurate and Rapid Stroke Treatment) Study to reduce DTN time have the potential to be widely applicable to other hospitals.

Neurogenic Stunned Myocardium Following Acute Subarachnoid Hemorrhage Pathophysiology and Practical Considerations

Neurogenic stunned myocardium (NSM) is a triad of transient left ventricular dysfunction, electrocardiogram changes, and elevation in cardiac enzymes, often mimicking a myocardial infarction. It has been described following acute brain injury. The purported mechanism is catecholamine excess resulting in cardiac dysfunction. From the clinical standpoint, the most frequently encountered electrocardiographic changes are QTc prolongation and ST-T changes, with modest elevations in troponin levels. Basal and mid-ventricular segments of the left ventricle are most commonly involved. NSM poses therapeutic challenges when it occurs secondary to aneurysmal subarachnoid hemorrhage, particularly in the setting of coexisting vasospasm. Overall, NSM carries good prognosis if recognized early, with appropriate management of hemodynamic and cardiopulmonary parameters.

Thrombolysis for Acute Ischemic Stroke in Patients With Cancer: A Population Study

Background and Purpose— The safety of thrombolysis for acute stroke in patients with cancer is not well established. Our aim is to study the outcomes after thrombolysis in patients with stroke with cancer. Methods— Patients with acute ischemic stroke who received thrombolysis were identified from the 2009 and 2010 Nationwide Inpatient Sample. Patients with cancer-associated strokes and noncancer strokes were compared based on demographics, comorbidities, and outcomes. Results— Of the 32 576 strokes treated with thrombolysis, cancer-associated strokes had significantly higher comorbidity indices overall, but fewer vascular risk factors than noncancer strokes. There was no difference in the rates of home discharge and in-hospital mortality, after adjusting for confounders. Subgroup analysis showed that compared with liquid cancers, patients with solid tumors had worse home discharge (odds ratio, 0.178; 95% confidence interval, 0.109–0.290; P<0.001) and higher in-hospital mortality (odds ratio, 3.018; 95% confidence interval, 1.37–6.646; P=0.006) after thrombolysis. Metastatic cancers had poorest outcomes, but intracerebral hemorrhage rates were similar. Conclusions— Thrombolytic therapy for acute stroke in patients with cancer is not associated with increased risk of intracerebral hemorrhage or in-hospital mortality. However, careful consideration of the cancer subtype may help delineate the subset of patients with poor response to thrombolysis. Prospective confirmation is warranted.

Serotonin- and training-induced dynamic regulation of CREB2 in Aplysia

Long-term memory and plasticity, including long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse, depend on the activation of transcription factors that regulate genes necessary for synaptic plasticity. In the present study we found that treatment with 5-HT and behavioral training produce biphasic changes in the expression of CREB2, a transcriptional repressor. An immediate increase in CREB2 protein was followed by a subsequent decrease. The effects of these treatments persist for at least 24 h and are observed in isolated sensory neurons. This study suggests that the dynamics of CREB2 expression could contribute to the consolidation of memory.

Decompressive Hemicraniectomy in Pediatric Patients with Malignant Middle Cerebral Artery Infarction: Case Series and Review of the Literature

OBJECTIVE Malignant middle cerebral artery infarction (mMCAI) is a life-threatening condition in pediatric patients. Despite strong evidence showing decreased morbidity and mortality in adult mMCAI patients with decompressive hemicraniectomy (DCH), there is a paucity of data on the use of DCH in children with similar conditions. Here we report experience from our center and perform a systematic review of published literature on outcomes after use of DCH in pediatric mMCAI patients. METHODS By retrospective chart review, we identified 3 children with large ischemic stroke who underwent DCH for life-threatening cerebral edema. Information was obtained about patient characteristics on admission, radiological features of the stroke, surgical procedures, complications of the DCH and cranioplasty, and functional outcomes during follow-up visits. We also reviewed the current literature on DCH in pediatric stroke. RESULTS DCH was performed in all 3 cases after development of pupillary dilatation. All 3 children survived and were ambulatory at the time of follow-up. Review of literature identified 12 other published case series describing 26 cases of DCH in pediatric patients with ischemic stroke. Descriptive statistical analysis of these cases is presented. Published reports suggest that a good outcome is possible even in the presence of signs of herniation, low preoperative Glasgow Coma Scale score, involvement of multiple vascular territories, or longer time to surgery in pediatric ischemic stroke patients. CONCLUSIONS The current data suggest a role for DCH in the management of cerebral edema in pediatric patients with mMCAI. Factors that help in prognostication for adult stroke patients undergoing DCH do not appear to convey similar information about the pediatric population. This highlights the urgent need for collaboration across institutes to further investigate this potentially life-saving procedure in pediatric stroke.

In-hospital outcomes of thrombolysis for acute ischemic stroke in patients with primary brain tumors

Data on thrombolysis outcomes in patients with primary brain tumors are limited. Our aim was to study stroke outcomes following thrombolysis in these patients in a population-based study. Patients with acute ischemic stroke who received thrombolysis were identified from the 2002-2011 USA Nationwide Inpatient Sample. We compared demographics, comorbidities, and outcomes between primary brain tumor-associated strokes (BTS) and non-brain tumor associated strokes (NBTS). The main outcomes were inpatient mortality, home discharge and intracranial hemorrhage (ICH) rate. Of the 124,083 thrombolysis-treated stroke patients, 416 (0.34%) had brain tumors. In adjusted analysis, inpatient mortality (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.77-1.26, p=0.918), rate of home discharge (OR: 1.15; 95% CI: 0.87-1.53, p=0.40) and rate of ICH (OR: 0.94; 95% CI: 0.62-1.44, p=0.801) were similar between BTS and NBTS. Analysis of brain tumor subtypes showed that compared to NBTS, malignant BTS were independently associated with higher in-hospital mortality (OR: 2.51; 95% CI: 1.66-3.79, p<0.001), lower home discharge (OR: 0.36, 95% CI: 0.18-0.72, p=0.004), and increased risk of ICH (OR: 2.33, 95% CI: 1.49-3.65, p<0.001). Additionally, among the BTS, intraparenchymal location of tumor was associated with higher mortality (OR: 2.51; 95% CI: 1.20-5.23, p=0.014) and lower home discharge (OR: 0.26; 95% CI: 0.13-0.53, p<0.001). Thrombolytic therapy for acute stroke appears to be safe in patients with primary brain tumors, with similar rates of ICH. Malignant BTS have worse outcomes, while benign BTS have outcomes comparable to NBTS. Careful consideration of tumor pathology may aid selection of patients with poor thrombolysis outcomes.

Clinical and radiologic spectrum of corpus callosum infarctions: clues to the etiology.

Infarctions of the corpus callosum are rare. The clinical picture varies from an acute onset to slow evolving symptoms, frequently with poor localizing signs; however, the location of the infarct in the callosum often correlates with a specific etiology. We describe three patients with varying degrees of callosal infarction, each corresponding to a particular etiology.

Improving early clinical trial phase identification of promising therapeutics

This review addresses decision-making underlying the frequent failure to confirm early-phase positive trial results and how to prioritize which early agents to transition to late phase. While unexpected toxicity is sometimes responsible for late-phase failures, lack of efficacy is also frequently found. In stroke as in other conditions, early trials often demonstrate imbalances in factors influencing outcome. Other issues complicate early trial analysis, including unequally distributed noise inherent in outcome measures and variations in natural history among studies. We contend that statistical approaches to correct for imbalances and noise, while likely valid for homogeneous conditions, appear unable to accommodate disease complexity and have failed to correctly identify effective agents. While blinding and randomization are important to reduce selection bias, these methods appear insufficient to insure valid conclusions. We found potential sources of analytical errors in nearly 90% of a sample of early stroke trials. To address these issues, we recommend changes in early-phase analysis and reporting: (1) restrict use of statistical correction to studies where the underlying assumptions are validated, (2) select dichotomous over continuous outcomes for small samples, (3) consider pooled samples to model natural history to detect early therapeutic signals and increase the likelihood of replication in larger samples, (4) report subgroup baseline conditions, (5) consider post hoc methods to restrict analysis to subjects with an appropriate match, and (6) increase the strength of effect threshold given these cumulative sources of noise and potential errors. More attention to these issues should lead to better decision-making regarding selection of agents to proceed to pivotal trials.