Search

Objective:To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. Data Sources:A literature search was performed in PubMed (January 2009 to November 2019) using the terms migraine, calcitonin gene-related peptide(CGRP), erenumab, fremanezumab, and galcanezumabfor clinical trials and studies. Study Selection and Data Extraction:Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. Data Synthesis:In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. Relevance to Patient Care and Clinical Practice:This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Conclusions:Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.

In this comprehensive contemporary review of acute ischemic stroke management, what is new and different will be highlighted beginning with prehospital stroke systems of care, emergency medical systems, and mobile stroke units, followed by hospital stroke teams, emergency evaluation, telemedicine, and brain and vascular imaging, and finishing with emergency treatments including thrombolysis and mechanical thrombectomy.

Mechanical thrombectomy (MT) is the standard of care for patients who present with an acute ischemic stroke within 6 hours of symptom onset, and up to 24 hours in appropriately selected patients. However, optimal postoperative management of these patients remains uncertain, especially with regard to blood pressure control. To review the existing literature to define potential blood pressure goals in the immediate postoperative period in patients who undergo MT for acute ischemic stroke. The topic was defined through a clinical scenario and the subsequent development of a targeted clinical question. A literature search was performed, with relevant articles selected, one of which, a prospective observational study, was critically appraised. Participants included neurology residents and consultants, a medical librarian, clinical epidemiologists, as well as content experts from vascular neurology and interventional neuroradiology. Permissive hypertension (defined as <220/120 or <180/105 mm Hg as per the American Heart Association/American Stroke Association guidelines) may be harmful in the postoperative period following MT, especially in patients who were successfully recanalized. Moderate blood pressure control (<160/90) was found to be a predictor of improved 3-month mortality on multivariable logistic regression analysis in patients who sustained successful reperfusion [odds ratio (OR), 0.08; 95% confidence interval (CI), 0.01-0.054; P=0.01]. A 10 mm Hg increase in systolic blood pressure was found to result in a lower OR of having a favorable 3-month functional independence (OR, 0.70; 95% CI, 0.56-0.85; P=0.001) as well as higher rates of 3-month mortality (OR, 1.49; 95% CI, 1.18-1.88; P=0.001). Blood pressure goals in the immediate postoperative period in patients who undergo MT should differ than those who do not undergo MT, with data suggesting that lower blood pressure than permissive hypertension may be related to improved outcomes, especially in cases of successful reperfusion. However, current data are derived from observational studies; further studies, preferably in the form of randomized-controlled trials, are needed to further clarify the relationship between postoperative blood pressures and outcomes in this patient population.

In 2015, the Food and Drug Administration updated the contraindications for the use of alteplase in acute ischemic stroke (AIS), potentially creating a greater impact on treatment. A history of intracranial hemorrhage and recent stroke within 3 months were removed as contraindications, increasing the number of patients eligible for alteplase. The aim of this commentary is to call attention to the updates and discuss them relative to current American Heart Association/American Stroke Association guidelines. Additionally, we estimate the clinical impact of the updates by analyzing AIS admissions to a large-volume Comprehensive Stroke Center.

Background:Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. Objective:To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Methods:Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. Results:We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P< 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing (P= 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily (P= 0.045). No seizures were reported during hospital admission in either group. Conclusions:Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

This study sought to evaluate predictors of stroke during left ventricular assist device (LVAD) support from data available prior to implantation, and quantify stroke-related morbidity and mortality.

IMPORTANCE: Treatments for symptomatic intracerebral hemorrhage (sICH) are based on expert opinion, with limited data available on efficacy. OBJECTIVE: To better understand the natural history of thrombolysis-related sICH, with a focus on the efficacy of various treatments used. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study between January 1, 2009, and April 30, 2014, at 10 primary and comprehensive stroke centers across the United States. Participants were all patients with sICH, using the definition by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), which included a parenchymal hematoma type 2 and at least a 4-point increase in the National Institutes of Health Stroke Scale score. MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality, and the secondary outcome was hematoma expansion, defined as a 33% increase in the hematoma volume on follow-up imaging. RESULTS: Of 3894 patients treated with intravenous recombinant tissue plasminogen activator (rtPA) within 4½ hours after symptom onset of ischemic stroke, 128 (3.3%) had sICH. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30-2572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12-628 minutes). The in-hospital mortality rate was 52.3% (67 of 128), and 26.8% (22 of 82) had hematoma expansion. In the multivariable models, code status change to comfort measures after sICH diagnosis was the sole factor associated with increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia (fibrinogen level, &lt;150 mg/dL) was associated with hematoma expansion, occurring in 36.3% (8 of 22) of patients without hematoma expansion vs in 25.0% (15 of 60) of patients with hematoma expansion (P = .01), highlighting a role for cryoprecipitate in reversing rtPA coagulopathy. CONCLUSIONS AND RELEVANCE: In this study, treatment of postthrombolysis sICH did not significantly reduce the likelihood of in-hospital mortality or hematoma expansion. Shortening the time to diagnosis and treatment may be a key variable in improving outcomes of patients with sICH.

Salmonella typhimuriumcolonization of the intestinal epithelium initiates biochemical cross-talk between pathogen and host that results in the secretion of chemokines, such as interleukin (IL)-8, that direct neutrophil migration to the site of infection. In nonpolarized cells, Rac1 and Cdc42 have been shown to regulate both bacterial invasion and signaling events leading to nuclear responses and IL-8 secretion. However, because the underlying actin cytoskeleton and the associated signaling machinery are distributed much differently in polarized epithelial cells, we used polarized Madin-Darby canine kidney monolayers to investigate the role of Rac1 and Cdc42 in S. typhimurium-induced pro-inflammatory responses in the more physiologically relevant polarized state. In Madin-Darby canine kidney monolayers expressing dominant-negative Rac1 or Cdc42, both Salmonella-and tumor necrosis factor α-induced activation of NFκB and mitogen-activated protein kinase signaling cascades proceeded normally, but IL-8 secretion was inhibited. We found that Rac1 and Cdc42 were not involved in early pro-inflammatory signaling events, as in nonpolarized cells, but rather regulated the basolateral exocytosis and secretion of IL-8. In contrast, dominant-negative Rac1 inhibited apical actin pedestal formation, indicating that pedestal formation and nuclear signaling for pro-inflammatory activation are not linked. These findings indicate that there are significant differences in the requirements of pathogen-induced host cell signaling pathways in polarized and nonpolarized cells.

During apical colonization by Salmonella typhimurium, intestinal epithelial cells orchestrate a proinflammatory response that involves secretion of chemoattractants, predominantly interleukin-8, which coordinate neutrophil trans-epithelial migration at the site of infection. This host-pathogen interaction requires several S. typhimuriumgenes. To identify novel genes that participate in this pathogen-induced proinflammatory response, we created S. typhimuriumTn-10 transposon mutants and identified a single mutant with Tn-10 insertional inactivation within the fliEflagellar locus that was able to adhere to and invade intestinal epithelial cells normally but was unable to induce interleukin-8 secretion in host cells. The fliE-deficient mutant failed to secrete flagellin and lacked any surface assembly of flagellae. Unlike wild-type S. typhimurium, the fliE-deficient mutant did not activate the IκBα/NF-κB signaling pathway or induce the coordinated trans-epithelial migration of isolated human neutrophils. Transcomplementation of the fliE-deficient mutant with a wild-type fliE-harboring plasmid restored all defects and produced a wild-type S. typhimuriumphenotype. Furthermore, functional down-regulation of basolateral TLR5 completely inhibited the monolayers' ability to respond to both wild-type S. typhimuriumand purified flagellin but had no affect on tumor necrosis factor α-induced responses. We therefore conclude that S. typhimurium fliEis essential for flagellin secretion, flagellar assembly, and S. typhimurium-induced proinflammatory responses through basolateral TLR5 and is consistent with the emerging model of S. typhimuriumflagellin-induced inflammation.

Atrial fibrillation is closely associated with cardioembolic stroke. Until recently, warfarin has been the gold standard for the treatment of atrial fibrillation. Since 2010 the United States Food and Drug Administration has approved three new agents for anticoagulation in patients with atrial fibrillation. The purpose of this case report is to discuss some of the practical implications for using these agents.

Introduction:Acute ischemic stroke treatment is time sensitive especially for large vessel occlusion (LVO) strokes with the goal to achieve early cerebral reperfusion. Research suggests standardized protocols incorporate early notification to reduce time from arrival to mechanical thrombectomy (MT). The MT workflow at a certified stroke center required multiple phone calls to mobilize staff and resources resulting in treatment delays. The average time from neurosurgery notification (NN) to case start (CST) was 60.4 minutes (min) resulting in average door-to-puncture (DTP) time of 124.8 min further delaying early reperfusion.Purpose:Standardize MT workflows and incorporate a 1-step notification system to reduce average NN to CST by 20% to 45 min to achieve 90 min average DTP time by 90 days post implementation.Methods:Baseline data for MT cases admitted 1/1/18 - 9/2/19 arriving in the emergency room (ER) and occurring inpatient were abstracted from stroke alert logs and the electronic health record. MT transfers were excluded. A multidisciplinary group of key stakeholders completed both high level process and workflow analysis maps and mock simulations to identify gaps. Both an analysis of variance and Tukey-Kramer’s T Test were performed revealing NN to CST was most statistically significant (p<.0001) and largest root cause for overall increased DTP times. New service-specific workflows were developed including 1-step notification activated via an existing group paging system used for other purposes. Activation notified on call staff of the MT case and patient location. Data points collected were NN to CST (ED and inpatient) and DTP (ED only).Results:Average NN to CST time was 26.7 min (33.3 min decrease or 55.1%; p<.0001, n=12) resulting in DTP average of 83.4 min (41.4 min decrease or 35.3%, n=10) 90 days post-implementation. The paging system was cost-neutral due to existing licensing agreements.Conclusion:In conclusion, streamlined workflows incorporating 1-step notification reduced time from notification to staff response so MT procedures could start sooner. A multidisciplinary approach along with key stakeholder buy-in was instrumental in successful project implementation.

Background:Nearly 2 million neurons die each minute during an acute ischemic stroke (AIS). Research demonstrates patients receiving timely treatment for AIS can have more favorable outcomes. In 4thquarter (Q) 2018, a Stroke Center’s average door-to-needle (DTN) time was 54 minutes, acceptable for American Stroke Association’s (AHA/ASA) Get with the Guidelines (GWTG) quality requirement of DTN in 60 minutes or less. Nevertheless, time is brain and decreased DTN times can potentially improve patient outcomes. With this in mind, the emergency department (ED) implemented a quality improvement project (QIP) focused on DTN time reduction.Purpose:Improve the ED workflow by developing standardized roles and task prioritization to reduce DTN times by 20% from 54 minutes to 42 minutes by 4thQ 2019.Methods:Guidelines and goals were established using AHA/ASA GWTG-Stroke criteria. Included were AIS patients with symptoms occurring prior to ED arrival, met eligibility criteria, and received intravenous tissue plasminogen activator (IV t-PA). Patients with symptoms occurring after ED arrival or during the hospital stay were excluded. An interdisciplinary workgroup collaborated to formulate an evidence-based solution for workflow opportunities identified by simulations, observations, and subjective feedback. Standardized roles, similar to cardiac life support, were created. An innovative acronym, W.I.N.G.S. (weight, IV access, NIHSS, glucose, scan), was developed to strategize adoption and implementation. Education, chart reviews, and timely feedback were given to stakeholders for every stroke intervention to promote engagement.Results:In 4thQ 2019, average DTN time decreased to 35 minutes (n=16, 35.2% reduction). The average DTN time for 1stQ 2020 is 31 minutes (n=14, 42.6% reduction). Since QIP implementation, the current DTN record is 12 minutes.Conclusions:W.I.N.G.S. is now a commonly term used in the ED. The multidisciplinary approach was instrumental in implementing a feasible QIP based on evidence and did not compromise patient safety. Sustainability is dependent on continued commitment and engagement of the team to celebrate achievements and reflect, reevaluate, and revise any insufficiencies.