Sex Differences in Perihematomal Edema Volume and Outcome After Intracerebral Hemorrhage.

BACKGROUND: Although larger hematoma volume is associated with worse outcome after intracerebral hemorrhage (ICH), the association between perihematomal edema (PHE) volume and outcome remains uncertain, as does the impact of sex on PHE and outcome. Here we aimed to determine whether larger PHE volume is associated with worse outcome and whether PHE volume trajectories differ by sex. METHODS: We conducted a post hoc analysis of the Factor VIIa for Acute Hemorrhagic Stroke Treatment (FAST) trial, which randomized patients with ICH to receive recombinant activated factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial computed tomography (CT) scans (at baseline [within 3 h of onset], at 24 h, and at 72 h). Generalized estimating equations examined interactions between sex, CT time points, and FAST treatment arm on PHE and ICH volumes. Mixed and multivariable logistic models examined associations between sex, PHE, and outcomes. RESULTS: A total of 781 patients with supratentorial ICH (mean age 65 years) were included. Compared to women (n = 296), men (n = 485) had similar median ICH (14.9 vs. 13.6 mL, p = 0.053) and PHE volumes (11.1 vs. 10.5 mL, p = 0.56) at baseline but larger ICH and PHE volumes at 24 h (19.0 vs. 14.0 mL, p < 0.001; 22.2 vs. 15.7 mL, p < 0.001) and 72 h (16.0 vs. 11.8 mL, p < 0.001; 28.7 vs. 19.9 mL, p < 0.001). Men had higher absolute early PHE expansion (p < 0.001) and more hematoma expansion (growth ≥ 33% or 6 mL at 24 h, 33% vs. 22%, p < 0.001). An interaction between sex and CT time points on PHE volume (p < 0.001), but not on ICH volume, confirmed a steeper PHE trajectory in men. PHE expansion (per 5 mL, odds radio 1.19, 95% confidence interval 1.10-1.28), but not sex, was associated with poor outcome. CONCLUSIONS: Early PHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation.

Selective amplification of ipRGC signals accounts for interictal photophobia in migraine.

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

Age Alters Prevalence of Left Atrial Enlargement and Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source.

BACKGROUND: Nonstenotic carotid plaque and undetected atrial fibrillation are potential mechanisms of embolic stroke of undetermined source (ESUS), but it is unclear which is more likely to be the contributing stroke mechanism. We explored the relationship between left atrial enlargement (LAE) and nonstenotic carotid plaque across age ranges in an ESUS population. METHODS: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried (2015 to 2021). LAE and plaque thickness were determined by transthoracic echocardiography and computed tomography angiography, respectively. Descriptive statistics were used to compare plaque features in relation to age and left atrial dimensions. RESULTS: Among the 4155 patients screened, 273 (7%) met the inclusion criteria. The median age was 65 years (interquartile range [IQR] 54-74), 133 (48.7%) were female, and the median left atrial diameter was 3.5 cm (IQR 3.1-4.1). Patients with any LAE more frequently had hypertension (85.9% versus 67.2%, P<0.01), diabetes (41.0% versus 25.6%, P=0.01), dyslipidemia (56.4% versus 40.0%, P=0.01), and coronary artery disease (22.8% versus 11.3%, P=0.02). Carotid plaque thickness was greater ipsilateral versus contralateral to the stroke hemisphere in the overall cohort (median 1.9 mm [IQR 0-3] versus 1.5 mm [IQR 0-2.6], P<0.01); however, this was largely driven by the subgroup of patients without any LAE (median 1.8 mm [IQR 0-2.9] versus 1.5 mm [IQR 0-2.5], P<0.01). Compared with patients ≥70 years, younger patients had more carotid plaque ipsilateral versus contralateral (mean difference 0.42 mm±1.24 versus 0.08 mm±1.54, P=0.047) and less moderate-to-severe LAE (6.3% versus 15.3%, P=0.02). CONCLUSIONS: Younger patients with ESUS had greater prevalence of ipsilateral nonstenotic plaque, while the elderly had more LAE. The differential effect of age on the probability of specific mechanisms underlying ESUS should be considered in future studies.

Vessel wall MR imaging of central nervous system vasculitis: a systematic review.

PURPOSE: Beyond vessel wall enhancement, little is understood about vessel wall MR imaging (VW-MRI) features of vasculitis affecting the central nervous system (CNS). We reviewed vessel wall MR imaging patterns of inflammatory versus infectious vasculitis and also compared imaging patterns for intracranial versus extracranial arteries of the head and neck. METHODS: Studies reporting vasculitis of the CNS/head and neck and included MR imaging descriptions of vessel wall features were identified by searching PubMed, Scopus, Cochrane, Web of Science, and EMBASE up to June 10, 2020. From 6065 publications, 115 met the inclusion criteria. Data on study characteristics, vasculitis type, MR details, and VW-MRI descriptions were extracted. RESULTS: Studies used VW-MRI for inflammatory (64%), infectious (17%), or both inflammatory and infectious vasculitides (19%). Vasculitis affecting intracranial versus extracranial arteries were reported in 58% and 39% of studies, respectively. Commonly reported VW-MRI features were vessel wall enhancement (89%), thickening (72%), edema (10%), and perivascular enhancement (16%). Inflammatory vasculitides affecting the intracranial arteries were less frequently reported to have vessel wall thickening (p = 0.006) and perivascular enhancement (p = 0.001) than extracranial arteries. Varicella zoster/herpes simplex vasculitis (VZV/HSV, 45%) and primary angiitis of the CNS (PACNS, 22%) were the most commonly reported CNS infectious and inflammatory vasculitides, respectively. Patients with VZV/HSV vasculitis more frequently showed decreased or resolution of vessel wall enhancement after therapy compared to PACNS (89% versus 59%). CONCLUSIONS: To establish imaging biomarkers of vessel wall inflammation in the CNS, VW-MRI features of vasculitis accounting for disease mechanism and anatomy should be better understood.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

Ipsilateral Carotid Plaque Presence is Inversely Associated with Patent Foramen Ovale in Cryptogenic Stroke: A Multicenter CohortStudy.

BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of all strokes. Potential contributors to ESUS include patent foramen ovale (PFO) and non-stenotic plaque (<50%, NSP) of the ipsilateral internal carotid artery (ICA). To better differentiate these as unique mechanisms, we explored the prevalence of each in a multicenter observational cohort. METHODS: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a computed tomography angiography neck scan and a transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) with adequate visualization of a PFO were included. Patients with prior carotid stent, endarterectomy or alternative etiologies were excluded from the study. Descriptive statistics were used to characterize patients with and without PFO, with multivariable logistic regression used to predict the presence of a PFO based on clinicoradiographic factors as well as degree of luminal stenosis and ipsilateral plaque thickness >3mm, based on previously published thresholds of clinical relevance. RESULTS: Of the 234 included patients with unilateral anterior ESUS and adequate TTE or TEE, 17 (7.3%) had a PFO and 64 (27.4%) had ≥3mm of ipsilateral ICA plaque. Patients with PFO had significantly less NSP and less ipsilateral cervical ICA stenosis (0% [IQR 0-0%] vs. 0% [IQR 0-50%], p=0.03; Table). After adjustment for all predictors of PFO in multivariable regression (p<0.1: Hispanic ethnicity and ipsilateral plaque thickness), ipsilateral NSP was independently associated with a 62% lower odds of harboring a PFO (ORadj per 1cm of plaque 0.48, 95%CI 0.25-0.94). No patients with a PFO had ≥3mm of ipsilateral ICA plaque. CONCLUSION: Ipsilateral NSP is more common in ESUS patients without a PFO. While this study is limited by the small PFO event rate, it supports the notion that NSP and PFO may be independent contributors to ESUS.

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Acute Cerebrovascular Events in Hospitalized COVID-19 Patients.

BACKGROUND AND PURPOSE: Initial reports suggest a significant risk of thrombotic events, including stroke, in patients hospitalized with coronavirus disease 2019 (COVID-19). However, there is little systematic data on stroke incidence and mechanisms, particularly in racially diverse populations in the United States. METHODS: We performed a retrospective, observational study of stroke incidence and mechanisms in all patients with COVID-19 hospitalized from March 15 to May 3, 2020, at 3 Philadelphia hospitals. RESULTS: We identified 844 hospitalized patients with COVID-19 (mean age 59 years, 52% female, 68% Black); 20 (2.4%) had confirmed ischemic stroke; and 8 (0.9%) had intracranial hemorrhage. Of the ischemic stroke patients, mean age was 64 years, with only one patient (5%) under age 50, and 80% were Black. Conventional vascular risk factors were common, with 95% of patients having a history of hypertension and 60% a history of diabetes mellitus. Median time from onset of COVID symptoms to stroke diagnosis was 21 days. Stroke mechanism was cardioembolism in 40%, small vessel disease in 5%, other determined mechanism in 20%, and cryptogenic in 35%. Of the 11 patients with complete vascular imaging, 3 (27%) had large vessel occlusion. Newly positive antiphospholipid antibodies were present in >75% of tested patients. Of the patients with intracranial hemorrhage, 5/8 (63%) were lobar intraparenchymal hemorrhages, and 3/8 (38%) were subarachnoid hemorrhage; 4/8 (50%) were on extracorporeal membrane oxygenation. CONCLUSIONS: We found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19. Most patients with ischemic stroke had conventional vascular risk factors, and traditional stroke mechanisms were common.

Disability After Minor Stroke and Transient Ischemic Attack in the POINT Trial.

Background and Purpose- While combination aspirin and clopidogrel reduces recurrent stroke compared with aspirin alone in patients with transient ischemic attack (TIA) or minor stroke, the effect on disability is uncertain. Methods- The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) randomized patients with TIA or minor stroke (National Institutes of Health Stroke Scale score ≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, myocardial infarction, or vascular death. We performed a post hoc exploratory analysis to examine the effect of treatment on overall disability (defined as modified Rankin Scale score >1) at 90 days, as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results- At 90 days, 188 of 1964 (9.6%) of patients enrolled with TIA and 471 of 2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% versus 14.3%; odds ratio, 0.97 [95% CI, 0.82-1.14]; P=0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% versus 4.0%; odds ratio, 0.73 [95% CI, 0.53-1.01]; P=0.06) and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% versus 7.4%; odds ratio, 0.78 [95% CI, 0.62-0.99]; P=0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% versus 6.0%; odds ratio, 0.74 [95% CI, 0.57-0.96]; P=0.02). In multivariate analysis, age, subsequent ischemic stroke, serious adverse events, and major bleeding were significantly associated with disability in TIA; for those with stroke, female sex, hypertension, or diabetes mellitus, National Institutes of Health Stroke Scale score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events were associated with disability. Conclusions- In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, DAPT might reduce stroke-related disability. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial.

BACKGROUND AND PURPOSE: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. METHODS: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. RESULTS: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33). CONCLUSIONS: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

A Case Series of Devastating Intracranial Hemorrhage During Venovenous Extracorporeal Membrane Oxygenation for COVID-19.

OBJECTIVE: Anticoagulation may be a challenge in coronavirus disease 2019 (COVID-19) extracorporeal membrane oxygenation due to endothelial injury and dysregulation of coagulation, which may increase the risk of thrombotic and bleeding complications. This report was created to describe the authors' single institutional experience, with emphasis on the high rate of intracranial hemorrhage for the first 10 patients with COVID-19 placed on venovenous extracorporeal membrane oxygenation (VV ECMO). DESIGN: Case series, retrospective analysis. SETTING: Single institution. PARTICIPANTS: Ten patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, mortality, stroke rate, and length of stay data were collected in all patients. In addition, laboratory values of D-dimer and C-reactive protein and standard measurements of prothrombin and activated partial thromboplastin time were collected on all patients. Ten patients, each confirmed with COVID-19 via reverse transcription-polymerase chain reaction, were supported on VV ECMO for acute respiratory distress syndrome (ARDS) for a mean duration of 9.4 ± 7 days. Four of 10 patients had hemorrhagic strokes, 3 of which resulted in death. At 30 days after initiation of VV ECMO, a total of 7 survivors included 6 patients discharged from the hospital and 1 patient who remained in the intensive care unit. CONCLUSIONS: In this small study of 10 patients, intracranial hemorrhage was a common complication, resulting in a high rate of death. The authors urge caution in the anticoagulation management of VV ECMO for patients with severe ARDS and COVID-19 patients. Close monitoring of all hematologic parameters is recommended during ECMO support while awaiting larger, multicenter studies to examine the best practice.

D-dimer and Body CT to Identify Occult Malignancy in Acute Ischemic Stroke.

BACKGROUND AND AIM: Patients with acute ischemic stroke associated with cancer have D-dimer elevations greater than those with acute ischemic stroke or cancer alone. While D-dimer has been proposed as a screening tool to identify such patients, its use in clinical practice to identify malignancy and to inform the use of CT scanning has not been well characterized. METHODS: We conducted a retrospective cohort study of patients with acute ischemic stroke to evaluate how D-dimer levels and CT chest, abdomen, and pelvis scanning were used in practice to screen for occult malignancy. Patients were excluded if they had known active cancer and or received tPA. RESULTS: Of 480 patients, 254 (53%) had D-dimer measured, 49 (10%) underwent CT screening for cancer, and 11 (2%) had findings concerning for malignancy. There was no difference in D-dimer level between patients who underwent CT evaluation for cancer and those who did not (median 1.01 vs 0.85 p = 0.19). Patients with CT concerning for cancer had higher D-dimer levels than those with a negative CT (median 2.52 vs 0.74 p = 0.01). D-dimer demonstrated moderate discrimination with a c-statistic of 0.77. Selecting a cut point of >1.2 ug/mL (60th percentile of our cohort and 2.4-times the upper limit of normal for our institution's D-dimer assay) provided a sensitivity of 85% and specificity of 65%, a positive likelihood ratio of 2.32, and an odds ratio of 9.6 (95% confidence interval 2.1-44.1, p = 0.004) for having a CT scan concerning for malignancy. CONCLUSIONS: Elevated D-dimer levels are suggestive of occult malignancy in acute ischemic stroke patients and should inform selective use of CT to screen for cancer.

Anticoagulation Choice and Timing in Stroke Due to Atrial Fibrillation: A Survey of US Stroke Specialists (ACT-SAFe).

OBJECTIVE: Risk of early recurrent ischemic stroke in patients with atrial fibrillation may be high. ASA/AHA guidelines provide imprecise recommendations on the timing and anticoagulant choice for this indication. We assessed current opinions of stroke neurologists. METHODS: Case scenarios describing patients with acute ischemic stroke (AIS) due to paroxysmal atrial fibrillation (AF) were presented to US board-certified stroke neurologists in an internet-based questionnaire. Questions assessed timing and choice of anticoagulation for secondary stroke prevention, factors prompting earlier anticoagulation, reasons for specific anticoagulant choice, and alternatives to anticoagulation in ineligible patients. Open-ended comments were also solicited. RESULTS: Responses were available from 238/1239 stroke neurologists surveyed. In patients with small AIS without hemorrhagic transformation (HT), 51% elected to start anticoagulation within 96 hours. With increased stroke severity and asymptomatic HT, only 29% and 26% respectively chose to anticoagulate within 7 days. Few requested stability imaging before starting anticoagulation. With symptomatic HT the majority (79%) waited >14 days. 93% would anticoagulate earlier if left atrium/left atrial appendage or acute left ventricular thrombi, or mechanical heart valve were present. Direct oral anticoagulants (DOACs) were the preferred anticoagulation strategy (64%), and the remaining 38% preferred Warfarin. Aspirin was preferred by 57% in anticoagulation ineligible. CONCLUSION: Apart from AIS with symptomatic HT, there is a remarkable lack of consensus among stroke neurologists regarding the timing of anticoagulation for secondary stroke prevention in patients with AIS due to PAF. DOACs are the preferred anticoagulation strategy. More studies are required to clarify anticoagulant management in this patient population.

Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

A web-based, branching logic questionnaire for the automated classification of migraine.

OBJECTIVE: To identify migraineurs and headache-free individuals with an online questionnaire and automated analysis algorithm. METHODS: We created a branching-logic, web-based questionnaire - the Penn Online Evaluation of Migraine - to obtain standardized headache history from a previously studied cohort. Responses were analyzed with an automated algorithm to assign subjects to one of several categories based on ICHD-3 (beta) criteria. Following a pre-registered protocol, the primary outcome was sensitivity and specificity for assignment of headache-free, migraine without aura, and migraine with aura labels, as compared to a prior classification by neurologist interview. RESULTS: Of 118 subjects contacted, 90 (76%) completed the questionnaire; of these 31 were headache-free controls, 29 migraine without aura, and 30 migraine with aura. Mean age was 41 ± 6 years and 76% were female. There were no significant demographic differences between groups. The median time to complete the questionnaire was 2.5 minutes (IQR: 1.5-3.4 minutes). Sensitivity of the Penn Online Evaluation of Migraine tool was 42%, 59%, 70%, and 83%, and specificity was 100%, 84%, 93%, and 90% for headache-free controls, migraine without aura, migraine with aura, and migraine overall, respectively. CONCLUSIONS: The Penn Online Evaluation of Migraine web-based questionnaire, and associated analysis routine, identifies headache-free and migraine subjects with good specificity. It may be useful for classifying subjects for large-scale research studies. Research study pre-registration: https://osf.io/sq9ef The following research study is a not a clinical trial.

Ischemic Stroke Associated With Calcitonin Gene-Related Peptide Inhibitor Therapy for Migraine: A Case Report.

Calcitonin gene-related peptide (CGRP) is involved in nociception and neurogenic inflammation in migraine, but also serves as a potent vasodilator acting on intracranial arteries. This latter effect raises concern about the possibility of drugs inhibiting CGRP precipitating cerebral ischemia. We describe a 41-year-old woman with migraine without aura who developed a right thalamic infarction following a first dose of erenumab, a CGRP-receptor blocker. Stroke onset occurred during a typical migraine. Imaging demonsrated right posterior cerebral artery near-occlusion initially with normalization of the vessel at follow-up imaging 2 months later, suggesting vasospasm as a possible mechanism. Extensive evaluation revealed no other specific cause of stroke or vascular risk factors aside from long-term use of oral contraceptive pills. CGRP inhibitors might be associated with ischemic stroke due to blockade of normal cerebral vasodilatory regulatory function.

Prevalence of Nonstenotic Carotid Plaque in Stroke Due to Atrial Fibrillation Compared to Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for about 20% of strokes. Nonstenotic cervical arterial plaque may be a mechanism of stroke in a subset of these patients. METHODS: A cohort of consecutive patients with ischemic stroke was retrospectively identified from a stroke registry. Patients with unilateral anterior circulation embolic stroke due to atrial fibrillation (AF) or consistent with ESUS who underwent computed tomographic neck angiography were included. The prespecified primary outcome was a comparison of the prevalence of carotid plaque greater than or equal to 3 mm thickness ipsilateral versus contralateral to the infarct side. RESULTS: Of 772 screened patients, 96 patients with ESUS and 99 patients with AF were included. Plaque greater than or equal to 3 mm was more frequently ipsilateral than contralateral to the infarct in patients with ESUS (41% versus 29%, P = .03), and plaque thickness was greater ipsilateral compared to contralateral (median 2.5 versus 2.2 mm, P = .02). No significant differences in plaque characteristics ipsilateral compared to contralateral were found in patients with AF. The prevalence of ipsilateral versus contralateral plaque was greater in ESUS patients less than or equal to 65 years old (48% versus 19%, P < .01), but no different in patients greater than 65 years old (35% versus 39%, P = .57). CONCLUSIONS: Nonstenotic cervical carotid plaque is more common ipislateral to the infarction in patients with ESUS, but not in patients with AF, supporting an underlying atheroembolic mechanism in a subset of ESUS patients. This association might be greater in younger ESUS patients.

Combination of Intra-Hematomal Hypodensity on CT and BRAIN Scoring Improves Prediction of Hemorrhage Expansion in ICH.

BACKGROUND: Hematoma expansion (HE) occurs in 1/3 of ICH patients and is associated with poor outcome. Intra-hematomal hypodensity (IHH) on CT has been reported to predict HE, as has the "BRAIN" score. We sought to assess the predictive value of these markers alone and in combination. METHODS: We performed a retrospective single-center study of ICH patients with CT < 6 h from onset. Two blinded neurologists assessed IHH on initial CT. Two HE definitions were examined: > 6 ml and > 6 ml or > 33%. Multivariable logistic regression was used to determine the relationship between IHH and HE. Predictive value of the BRAIN score alone and integrated with IHH was assessed. RESULTS: In 122 included patients, median ICH volume was 13 ml, median time to CT 2.0 h; HE > 6 ml occurred in 31% and > 6 ml/> 33% in 43% of subjects. IHH were identified in 61% of patients with moderate inter-rater agreement (κ = 0.59). In multivariable analysis, IHH was associated with HE using > 6 ml definition (OR 8.3, 95% CI, 2.6-32.8, P < 0.001) but not using the > 6 ml/> 33% definition (OR 1.9, 95% CI 0.84-4.3, P = 0.12). Rate of HE (> 6 ml) increased across increasing BRAIN score quartiles (Q1:11%, Q2:23%, Q3:43%, Q4:57%, P for trend < 0.001). Rate of HE > 6 ml in patients with BRAIN score ≥ 10 and IHH was 55%, with either alone was 33%, and with neither was 3%. CONCLUSIONS: Combining IHH on non-contrast CT and a simple clinical BRAIN score is a potentially powerful way to predict those patients at very high and very low risk of HE.