Calcitonin Gene-Related Peptide Antagonists for the Prevention of Migraine: Highlights From Pivotal Studies and the Clinical Relevance of This New Drug Class.

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 galcanezumab for 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.

Relevance of the Updated Food and Drug Administration Alteplase Label for Acute Ischemic Stroke: The Estimated Impact and Current Guidelines.

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.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

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.

Optimizing Door-to-Groin Puncture Time: The Mayo Clinic Experience.

Objectives: To provide a better understanding of methods that can be used to improve patient outcomes by reducing the door-to-groin puncture (DTP) time and present the results of a stroke quality improvement project (QIP) conducted by Mayo Clinic Arizona's stroke center. Methods: We conducted a systematic literature search of Ovid MEDLINE(R), Ovid EMBASE, Scopus, and Web of Science for studies that evaluated DTP time reduction strategies. Those determined eligible for the purpose of this analysis were assessed for quality. The strategies for DTP time reduction were categorized on the basis of modified Target: Stroke Phase III recommendations and analyzed using a meta-analysis. The Mayo Clinic QIP implemented a single-call activation system to reduce DTP times by decreasing the time from neurosurgery notification to case start. Results: Fourteen studies were selected for the analysis, consisting of 2277 patients with acute ischemic stroke secondary to large-vessel occlusions. After intervention, all the studies showed a reduction in the DTP time, with the pooled DTP improvement being the standardized mean difference (1.37; 95% confidence interval, 1.20-1.93; τ2=1.09; P<.001). The Mayo Clinic QIP similarly displayed a DTP time reduction, with the DTP time dropping from 125.1 to 82.5 minutes after strategy implementation. Conclusion: Computed tomography flow modifications produced the largest and most consistent reduction in the DTP time. However, the reduction in the DTP time across all the studies suggests that any systematic protocol aimed at reducing the DTP time can produce a beneficial effect. The relative novelty of mechanical thrombectomy and the consequential lack of research call for future investigation into the efficacy of varying DTP time reduction strategies.

Identifying and Addressing Barriers to Systemic Thrombolysis for Acute Ischemic Stroke in the Inpatient Setting: A Quality Improvement Initiative.

OBJECTIVES: To identify barriers to inpatient alteplase administration and implement an interdisciplinary program to reduce time to systemic thrombolysis. PATIENTS AND METHODS: Compared with patients presenting to the emergency department with an acute ischemic stroke (AIS), inpatients are delayed in receiving alteplase for systemic thrombolysis. Institutional AIS metrics were extracted from the electronic medical records of patients presenting as an inpatient stroke alert. All patients who received alteplase for AIS were included in the analysis. A gap analysis was used to assess institutional deficiencies. An interdisciplinary intervention was initiated to address these deficiencies. Efficacy was measured with pre- and postintervention surveys and institutional AIS metric analysis. Statistical significance was determined using the Student t test. We identified 5 patients (mean age, 73 years; 100% (5/5) male; 80% (4/5) white) who met inclusion criteria for the preintervention period (January 1, 2017, to December 31, 2017) and 10 patients (mean age, 71 years; 50% male; 80% white) for the postintervention period (October 31, 2018, to July 1, 2020). RESULTS: We found barriers to rapid delivery of thrombolytic treatment to include alteplase availability and comfort with bedside reconstitution. Interdisciplinary intervention strategies consisted of stocking alteplase on additional floors as well as structured education and hands-on alteplase reconstitution simulations for resident physicians. The mean time from stroke alert to thrombolysis was shorter postintervention than preintervention (57.4 minutes vs 77.8 minutes; P=.03). CONCLUSION: A coordinated interdisciplinary approach is effective in reducing time to systemic thrombolysis in patients experiencing AIS in the inpatient setting. A similar program could be implemented at other institutions to improve AIS treatment.

Contemporary Management of Acute Ischemic Stroke Across the Continuum: From TeleStroke to Intra-Arterial Management.

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.

Are Postprocedural Blood Pressure Goals Associated With Clinical Outcome After Mechanical Thrombectomy for Acute Ischemic Stroke?

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.

INTERMACS Analysis of Stroke During Support With Continuous-Flow Left Ventricular Assist Devices: Risk Factors and Outcomes.

OBJECTIVES: 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. BACKGROUND: Stroke is a major complication after LVAD. Pre-implant factors that influence stroke are not well understood. METHODS: We evaluated all patients in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) who were implanted with continuous flow LVADs from May 1, 2012, to March 31, 2015. Pre-operative risk factors for stroke and stroke incidence, morbidity, and mortality were analyzed. RESULTS: During the study period, 7,112 patients underwent continuous flow LVAD placement. Median follow-up was 9.79 months (range 0.02 to 34.96 months). Of all patients, 752 (10.57%) had at least 1 stroke, with an incidence rate of 0.123 strokes per patient-year. A total of 447 (51.38%) strokes were ischemic and 423 (48.62%) were hemorrhagic. Patients with hemorrhagic stroke had worse survival than those with ischemic strokes (30-day survival: 45.3% vs. 80.7%; p < 0.001). Of patients with a first stroke, 13% had a second stroke. Pre-implant predictors of stroke were female sex (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.25 to 1.82; p < 0.001), pre-implant systolic blood pressure (HR: 1.01; 95% CI: 1.00 to 1.01; p = 0.002), heparin-induced thrombocytopenia (HR: 3.68; 95% CI: 1.60 to 8.47; p = 0.002), intra-aortic balloon pump (HR: 1.21; 95% CI: 1.01 to 1.46; p = 0.043), and primary cardiac diagnosis (ischemic/other/unknown) (p = 0.040). CONCLUSIONS: Despite improvements in LVAD technology, stroke-related morbidity and mortality is substantial. Further investigation is necessary to decrease the risk of this devastating complication.

Acute Isolated Central Facial Palsy as Manifestation of Middle Cerebral Artery Ischemia.

BACKGROUND: Isolated central facial palsy (I-CFP) is attributed to a lacunar syndrome affecting the corona radiata region or pons. We examined our acute stroke registry for patients presenting with I-CFP and localized their symptoms to a vascular lesion. SUBJECT & METHODS: Our database of consecutive patients with symptoms of acute cerebral ischemia admitted from January 2008 to December 2012 was reviewed for NIH Stroke Scale (NIHSS) scores and subcomponents. All patients with I-CFP ± dysarthria (total NIHSS ≤ 3) had contrast-enhanced MR-angiography and transcranial Doppler as standard of care. All ischemic lesions were localized by MRI within 72 hours from symptom onset. RESULTS: Of 2,202 patients with acute cerebral ischemia, 879 patients (35%) had NIHSS score ≤ 3 points (mean age 63 + 15 years, 46 % women). Nine patients (.4%) presented with I-CFP ± dysarthria. Of these, only 1 had a lesion in the corona radiata and patent MCA, 1 had a pontine lesion without proximal vessel occlusion (2/9, or 22%). Remaining 7 patients (78%) had flow-limiting thromboembolic mid-to-distal M1/proximal M2 MCA disease. Of these, 6 (86%) patients had a prominent early anterior temporal artery on MRA and nonlacunar ischemic lesions on MRI. CONCLUSIONS: Contrary to current teaching of lesion localization for an I-CFP, our study revealed the majority of acute patients presenting with this symptom had evidence of flow-limiting thromboembolic MCA disease rather than a lacunar lesion. Our findings underscore the essential role of comprehensive vascular imaging in patients presenting with I-CFP, which is commonly associated with acute flow-limiting thromboembolic MCA disease.

Transferring Patients with Intracerebral Hemorrhage Does Not Increase In-Hospital Mortality.

INTRODUCTION: Comprehensive stroke centers (CSCs) accept transferred patients from referring hospitals in a given regional area. The transfer process itself has not been studied as a potential factor that may impact outcome. We compared in-hospital mortality and severe disability or death at CSCs between transferred and directly admitted intracerebral hemorrhage (ICH) patients of matched severity. MATERIALS AND METHODS: We retrospectively reviewed all primary ICH patients from a prospectively-collected stroke registry and electronic medical records, at two tertiary care sites. Patients meeting inclusion criteria were divided into two groups: patients transferred in for a higher level of care and direct presenters. We used propensity scores (PS) to match 175 transfer patients to 175 direct presenters. These patients were taken from a pool of 530 eligible patients, 291 (54.9%) of whom were transferred in for a higher level of care. Severe disability or death was defined as a modified Rankin Scale (mRS) sore of 4-6. Mortality and morbidity were compared between the 2 groups using Pearson chi-squared test and Student t test. We fit logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between transfer status and in-hospital mortality and severe disability or death in full and PS-matched patients. RESULTS: There were no significant differences in the PS-matched transfer and direct presentation groups. Patients transferred to a regional center were not at higher odds of in-hospital mortality (OR: 0.93, 95% CI: 0.50-1.71) and severe disability or death (OR: 0.77, 95% CI: 0.39-1.50), than direct presenters, even after adjustment for PS, age, baseline NIHSS score, and glucose on admission. CONCLUSION: Our observation suggests that transfer patients of similar disease burden are not at higher risk of in-hospital mortality than direct presenters.

Differences in the role of black race and stroke risk factors for first vs. recurrent stroke.

OBJECTIVES: To assess whether black race and other cerebrovascular risk factors have a differential effect on first vs. recurrent stroke events. METHODS: Estimate the differences in the magnitude of the association of demographic (age, back race, sex) or stroke risk factors (hypertension, diabetes, cigarette smoking, atrial fibrillation, left ventricular hypertrophy, or heart disease) for first vs. recurrent stroke from a longitudinal cohort study of 29,682 black or white participants aged 45 years and older. RESULTS: Over an average 6.8 years follow-up, 301 of 2,993 participants with a previous stroke at baseline had a recurrent stroke, while 818 of 26,689 participants who were stroke-free at baseline had a first stroke. Among those stroke-free at baseline, there was an age-by-race interaction (p = 0.0002), with a first stroke risk 2.70 (95% confidence interval: 1.86-3.91) times greater for black than white participants at age 45, but no racial disparity at age 85 (hazard ratio = 0.91; 95% confidence interval: 0.70-1.18). In contrast, there was no evidence of a higher risk of recurrent stroke at any age for black participants (p > 0.05). The association of traditional stroke risk factors was generally similar for first and recurrent stroke. CONCLUSION: The association of age and black race differs substantially on first vs. recurrent stroke risk, with risk factors playing a similar role.

Treatment and Outcome of Thrombolysis-Related Hemorrhage: A Multicenter Retrospective Study.

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, <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.

Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry.

BACKGROUND: There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention. METHODS: Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology. RESULTS: A total of 78 AF patients (mean age 71 ± 9years; 54% men; 81% IS, 19% TIA; median CHADS2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2-5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 ± 5 months (range 1-18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria (n = 1) and rectal bleeding (n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%). DISCUSSION: Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation.

Cdc42 and Rac1 regulate late events in Salmonella typhimurium-induced interleukin-8 secretion from polarized epithelial cells.

Salmonella typhimurium colonization 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 alpha-induced activation of NFkappaB 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.

The Salmonella typhimurium flagellar basal body protein FliE is required for flagellin production and to induce a proinflammatory response in epithelial 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. typhimurium genes. To identify novel genes that participate in this pathogen-induced proinflammatory response, we created S. typhimurium Tn-10 transposon mutants and identified a single mutant with Tn-10 insertional inactivation within the fliE flagellar 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 IkappaBalpha/NF-kappaB 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. typhimurium phenotype. Furthermore, functional down-regulation of basolateral TLR5 completely inhibited the monolayers' ability to respond to both wild-type S. typhimurium and purified flagellin but had no affect on tumor necrosis factor alpha-induced responses. We therefore conclude that S. typhimurium fliE is essential for flagellin secretion, flagellar assembly, and S. typhimurium-induced proinflammatory responses through basolateral TLR5 and is consistent with the emerging model of S. typhimurium flagellin-induced inflammation.