Intravenous Thrombolysis in Patients With Cervical Artery Dissection

Abstract

Objectives

Cervical artery dissection (CeAD) accounts for 25% of ischemic strokes in young adults. This study evaluated the benefits and harms of intravenous thrombolysis (IVT) in patients presenting with spontaneous CeAD and acute ischemic stroke symptoms.

Methods

This analysis used data from the retrospective STOP-CAD study and included patients with spontaneous CeAD who presented within 1 day of acute ischemic stroke symptoms. Patients were dichotomized into those who received IVT and those managed without IVT. We assessed the association between IVT and 90-day functional independence (modified Rankin Scale scores 0–2) and the incidence of symptomatic intracranial hemorrhage (ICH, defined as ICH causing new or worsening neurologic symptoms within 72 hours after CeAD diagnosis).

Results

This study included 1,653 patients from the original STOP-CAD cohort of 4,023. The median age was 49 years, and 35.1% were women; 512 (31.0%) received IVT. IVT was associated with 90-day functional independence (adjusted odds ratio [aOR] = 1.67, 95% CI 1.23–2.28, p = 0.001), but not with symptomatic ICH (aOR = 1.52, 95% CI 0.79–2.92, p = 0.215).

Discussion

In patients with spontaneous CeAD and suspected ischemic stroke, IVT improved functional outcomes, without increasing symptomatic ICH risk. These findings support current guideline recommendations to consider thrombolysis for otherwise eligible patients with CeAD.

Classification of Evidence

This study provides Class III evidence that IVT significantly increases the probability of 90-day functional independence in patients with CeAD.

Introduction

Intravenous thrombolysis (IVT) effectively reduces disability in acute ischemic stroke (AIS) when administered early.¹ Cervical artery dissection (CeAD), responsible for up to 25% of AIS in young adults,² presents a unique challenge for IVT due to theoretical concerns about thrombolysis worsening dissections and increasing the risk of subarachnoid hemorrhage with concurrent intracranial CeAD.^3-6 Despite these concerns, current guidelines from the American Heart Association and European Stroke Organization suggest IVT as a reasonable option for patients with CeAD who otherwise meet criteria for IVT, acknowledging the lack of CeAD-specific safety data.^2,7

This study examined the efficacy and safety of IVT for CeAD-related AIS by addressing the primary research questions of whether IVT is associated with improved functional outcomes at 90 days and whether IVT leads to a higher incidence of symptomatic intracranial hemorrhage.

Methods

Data and Research Ethics

This study was a planned secondary analysis of the Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection (STOP-CAD) data set.⁸ Study approval was granted by the Lifespan Institutional Review Board (IRB), in line with the original STOP-CAD study protocols. Because no identifiable personal information was used, informed consent was waived. The need for additional IRB approval for this analysis was waived because of the utilization of deidentified data. Aggregate data can be shared on reasonable request to the corresponding author.

Patient Population

The patient population consisted of patients with AIS symptoms presenting within 1 day of dissection symptom onset. The population was stratified into 2 groups: patients receiving IVT and those not receiving IVT.

Study Outcomes

The primary outcome was 90-day functional independence, defined as a favorable modified Rankin Scale (mRS) score of 0–2. The safety outcome was symptomatic ICH, defined as ICH causing new or worsening neurologic symptoms within 72 hours after CeAD diagnosis.¹² Detailed data collection and validation processes are described in the main STOP-CAD study.⁸

Analytical Plan

Univariate analyses were conducted using chi-squared tests, Student t-tests, and rank-sum tests as appropriate. Unadjusted and adjusted binary logistic regression models were constructed to determine associations between IVT and outcomes. Models were adjusted for prespecified variables (age and baseline National Institutes of Health Stroke Scale [NIHSS] score). To enhance the robustness of our analyses and to address differences in outcomes related to pertinent demographic, clinical, and radiologic variables between groups, we also incorporated the inverse probability of treatment weighting (IPTW) method, using differential variables (p < 0.05) from the baseline characteristics.

We assessed effect modification of the relationship between IVT status and patient outcomes through multiplicative interaction terms with sex, stroke severity, intracranial involvement of dissection, presence of partial occlusive thrombus, and treatment with endovascular therapy. Mild stroke was defined as an NIHSS score ≤5, aligning with previous literature.⁹ Additional method details can be found in eMethods.

Results

Baseline Characteristics

From the STOP-CAD data set, 1,653 patients presented with AIS symptoms attributable to spontaneous CeAD and met the study's inclusion criteria (eFigure 1). The median follow-up duration was 288 days (interquartile range [IQR] 93–836). Overall, 512 patients (31.0%) received IVT. Table 1 summarizes the clinical characteristics of included patients stratified according to treatment with vs without IVT. The median NIHSS score at admission was higher in the IVT group (NIHSS score 11; IQR 5–18 vs 4; IQR 1–11, p < 0.001). The 90-day mRS data were available for 1,304 patients (78.9%), and baseline characteristics of patients with vs without 90-day mRS data are given in eTable 1.

Table.

Comparison of Baseline Characteristics Between Patients With Spontaneous Cervical Artery Dissection and Acute Ischemic Stroke Symptoms Treated With vs Without Intravenous Thrombolysis

		No intravenous thrombolysis (N = 1,141)	Intravenous thrombolysis (N = 512)	p Value
Demographics
Median age (interquartile range)	N = 1,653	49 (39–58)	50 (42–57)	0.131
Female sex (%)	N = 1,653	421/1,141 (36.9)	159/512 (31.1)	0.021
Race (%)
White	N = 1,653	811/1,141 (71.1)	394/512 (77.0)	0.013
Black	N = 1,653	83/1,141 (7.3)	34/512 (6.6)	0.642
Asian	N = 1,653	47/1,141 (4.1)	18/512 (3.5)	0.559
Other	N = 1,653	200/1,141 (17.5)	66/512 (12.9)	0.018
Ethnicity: Hispanic	N = 1,501	110/1,039 (10.6)	19/462 (4.1)	<0.001
Comorbidities (%)
Migraine	N = 1,653	114/1,141 (10.0)	49/512 (9.6)	0.791
Hypertension	N = 1,653	437/1,141 (38.3)	201/512 (39.3)	0.711
Diabetes	N = 1,653	132/1,141 (11.6)	35/512 (6.8)	0.003
Hyperlipidemia	N = 1,653	311/1,141 (27.3)	125/512 (24.4)	0.225
Neck trauma	N = 1,652	220/1,140 (19.3)	83/512 (16.2)	0.134
Median NIH Stroke Scale score on admission (interquartile range)	N = 1,559	4 (1–11)	11 (5–18)	<0.001
Imaging characteristics (%)
Intracranial involvement of dissection	N = 1,653	165/1,141 (14.5)	57/512 (11.1)	0.067
Occlusive dissection	N = 1,636	522/1,130 (46.2)	302/506 (59.7)	<0.001
Partially occlusive thrombus	N = 1,653	152/1,141 (13.3)	73/512 (14.3)	0.608
Any vertebral artery dissection	N = 1,653	556/1,141 (48.7)	125/512 (24.4)	<0.001
Additional intervention (%)
Endovascular therapy	N = 1,653	254/1,141 (22.3)	314/512 (61.3)	<0.001

Primary Outcome

In the univariate analysis, 73.7% of patients receiving IVT achieved 90-day functional independence, compared with 76.5% in the non-IVT group (p = 0.265). In unadjusted analysis, IVT was not associated with functional independence at 90 days (odds ratio [OR] 0.86; 95% CI 0.66–1.12, p = 0.266); this changed to an adjusted OR (aOR) of 1.67 (95% CI 1.23–2.28, p = 0.001) after adjusting for covariates (Table 2).

Table 2.

Association of Intravenous Thrombolysis and Outcomes in Patients With Spontaneous Cervical Artery Dissection and Acute Ischemic Stroke Symptoms Treated With vs Without Intravenous Thrombolysis

Outcome	No thrombolysis	Thrombolysis	Main analysis		Inverse probability of treatment weighting analysisa
			Unadjusted N OR (95% CI) p value	Adjusted N OR (95% CI) p value	Unadjusted OR (95% CI) p value	Adjusted OR (95% CI) p value
90-d mRS 0-2	681/890 (76.5%)	305/414 (73.7%)	1,304 0.86 (0.66–1.12) 0.266	1,236 1.67 (1.23–2.28) 0.001	1.67 (1.21–2.29) 0.002	1.85 (1.31–2.62) 0.001
90-d mRS 0-1	510/890 (57.3%)	212/414 (51.2%)	1,304 0.78 (0.62–0.99) 0.039	1,236 1.35 (1.03–1.77) 0.031	1.32 (0.99–1.77) 0.056	1.40 (1.02–1.92) 0.039
Discharge mRS 0-2	699/1,097 (63.7%)	283/499 (56.7%)	1,596 0.75 (0.6–0.93) 0.008	1,511 1.32 (1.03–1.7) 0.028	1.35 (1.04–1.76) 0.027	1.39 (1.04–1.86) 0.028
Symptomatic intracranial hemorrhage	18/1,141 (1.6%)	21/512 (4.1%)	1,653 2.67 (1.41–5.05) 0.003	1,559 1.52 (0.79–2.92) 0.215	0.81 (0.39–1.70) 0.581	0.81 (0.38–1.70) 0.570

^aVariables used for inverse probability of treatment weighting were sex, White race, other races, Hispanic ethnicity, history of diabetes mellitus, presence of occlusive dissection, dissection involving vertebral artery, acute endovascular therapy, and baseline NIHSS score.

Safety Outcome

The rate of symptomatic ICH was higher in the IVT group, occurring in 4.1% of patients vs 1.6% in the non-IVT group (OR 2.67; 95% CI 1.41–5.05, p = 0.003). After adjustment for age and NIHSS score, IVT was not significantly associated with symptomatic ICH (aOR 1.52; 95% CI 0.79–2.92, p = 0.215) (Table 2).

Sensitivity Analysis

IPTW analysis was conducted for the unadjusted and adjusted logistic regression models including the variables sex, White race, other races, Hispanic ethnicity, history of diabetes mellitus, presence of occlusive dissection, dissection involving vertebral artery, acute endovascular therapy, and baseline NIHSS score. IPTW analysis demonstrated an association and a similar effect size between IVT and 90-day functional independence (aOR 1.85; 95% CI 1.31–2.62, p = 0.001). Treatment with IVT was not associated with symptomatic intracranial hemorrhage (aOR 0.81; 95% CI 0.38–1.70, p = 0.570) (Table 2).

Interaction Analysis

In the analysis of IVT's association with 90-day functional outcomes, no significant interactions were found across subgroups (interaction p > 0.05). However, subgroup analysis indicated a higher likelihood of 90-day functional independence in patients treated with IVT with a NIHSS score >5, those without intracranial involvement of dissection, or those without partial occlusive thrombus (Figure 1). Conversely, 90-day functional independence associated with IVT was observed irrespective of whether patients received acute endovascular therapy (Figure 1). Additional secondary outcomes and stratified analyses can be found in eResults.

Figure 1. Interaction Analysis of 90-Day Functional Outcomes in Patients With Spontaneous Cervical Artery Dissection and Acute Ischemic Stroke Symptoms Treated With vs Without Intravenous Thrombolysis.

The forest plot examines the adjusted odds ratio for achieving functional independence at 90 days (mRS 0–2). The model adjusted for age and baseline NIHSS score. mRS = modified Rankin Scale.

Discussion

This study examined the safety and efficacy of IVT in patients with CeAD presenting with AIS symptoms. A key finding is that patients with CeAD treated with IVT had significantly improved functional outcomes at discharge and at 90 days, particularly in those with nonminor stroke and those with no intracranial involvement of the dissection, and without an increased risk of symptomatic ICH.

Our analyses showed significant outcome differences between patients receiving IVT and those who did not, after adjusting for the admission NIHSS score, reflecting the considerable differences in baseline stroke severity between the 2 groups. We found that 4.1% of patients treated with IVT developed a symptomatic intracranial hemorrhage, aligning closely with the findings of previous non-CeAD thrombolysis studies in acute ischemic stroke.^4,10-12

In our analysis comparing outcomes with and without IVT in patients stratified by NIHSS score (eFigure 2), IVT was particularly effective in patients with nonminor strokes, aligning with current guidelines recommending use of thrombolysis in patients with CeAD with disabling stroke symptoms.² Furthermore, echoing the findings of recent trials on minor AIS,^9,13,14 our study found that the benefit of thrombolysis for patients with minor stroke symptoms was not statistically significant (eFigure 3). However, this lack of statistical significance may be attributed to the limited sample size.

Consistent with current guidelines advocating use of IVT before thrombectomy, our subgroup analysis demonstrated potential benefit of IVT irrespective of whether endovascular therapy was performed.¹⁵ Notably, we found no significant difference in functional outcomes among patients with intracranial involvement of dissection or partial occlusive thrombus, providing reassuring data regarding the use of IVT in these subpopulations. However, we note the small numbers of patients being compared in these subgroups, underscoring the need for further investigation in these subgroups.

The retrospective, nonrandomized, observational nature of the study may introduce indication bias, with IVT treatment decisions potentially influencing patient outcomes due to exclusion of patients with contraindications. The likelihood of residual confounding cannot be discounted because unmeasured or inaccurately measured covariates might have affected the results. Last, the outcomes were extracted from records charted by providers unblinded to the IVT status. However, the consistency of our results with previous randomized controlled trials, including the symptomatic ICH rates and the lack of benefit of IVT treatment in minor strokes, provides reassurance regarding the robustness of our findings. Still, further investigations are crucial to corroborate our results.

Conclusion

In patients with spontaneous CeAD and suspected ischemic stroke, IVT may improve functional outcomes, without significantly increasing symptomatic ICH risk. These findings support current guideline recommendations to consider thrombolysis for otherwise eligible patients with spontaneous CeAD.

Appendix. Authors

Name	Location	Contribution
Liqi Shu, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Favour Akpokiere	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Daniel M. Mandel, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Thalia S. Field, MD, FRCPC, MHSc	Vancouver Stroke Program, Division of Neurology, University of British Columbia, Vancouver, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Christopher R. Leon Guerrero, MD	Department of Neurology, Atrium Health, Charlotte, NC	Drafting/revision of the manuscript for content, including medical writing for content
Nils Henninger, MD, PhD, Dr. med.	Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA	Drafting/revision of the manuscript for content, including medical writing for content
Jayachandra Muppa, MBBS	Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA	Drafting/revision of the manuscript for content, including medical writing for content
Muhammad Affan, MD	Department of Neurology, University of Minnesota, Minneapolis	Drafting/revision of the manuscript for content, including medical writing for content
Omair U. Haq Lodhi, MBBS	Department of Neurology, University of Minnesota, Minneapolis	Drafting/revision of the manuscript for content, including medical writing for content
Mirjam R. Heldner, MD, MSc	Department of Neurology, Inselspital, University hospital and University of Bern, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Kateryna Antonenko, MD, PhD	Department of Neurology, Inselspital, University hospital and University of Bern, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
David J. Seiffge, MD	Department of Neurology, Inselspital, University hospital and University of Bern, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Marcel Arnold, MD	Department of Neurology, Inselspital, University hospital and University of Bern, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Setareh Salehi Omran, MD	Department of Neurology, University of Colorado, Denver	Drafting/revision of the manuscript for content, including medical writing for content
Ross Crandall, MD	Department of Neurology, University of Colorado, Denver	Drafting/revision of the manuscript for content, including medical writing for content
Evan Lester, MD, PhD	Department of Neurology, Weill Cornell Medicine, New York	Drafting/revision of the manuscript for content, including medical writing for content
Diego López-Mena, MD	Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, Mexico City	Drafting/revision of the manuscript for content, including medical writing for content
Antonio Arauz, MD	Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, Mexico City	Drafting/revision of the manuscript for content, including medical writing for content
Ahmad Nehme, MD, MSc	Service de neurologie, Université Caen Normandie, CHU Caen Normandie, France	Drafting/revision of the manuscript for content, including medical writing for content
Marion Boulanger, MD, PhD	Service de neurologie, Université Caen Normandie, CHU Caen Normandie, France	Drafting/revision of the manuscript for content, including medical writing for content
Emmanuel Touzé, PhD	Service de neurologie, Université Caen Normandie, CHU Caen Normandie, France	Drafting/revision of the manuscript for content, including medical writing for content
João André Sousa, MD	Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra; Faculty of Medicine, University of Coimbra, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
João Sargento-Freitas, MD	Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra; Faculty of Medicine, University of Coimbra, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Vasco Barata, MD	Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra; Faculty of Medicine, University of Coimbra, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Paulo Castro-Chaves, MD	Department of Internal Medicine, São João University Hospital, Porto, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Maria T. Brito, MD	Department of Internal Medicine, São João University Hospital, Porto, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Muhib Khan, MD	Department of Neurology, Corewell Health, Grand Rapids, MI; Department of Neurology, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content
Dania Mallick, MD	Department of Neurology, Corewell Health, Grand Rapids, MI	Drafting/revision of the manuscript for content, including medical writing for content
Aaron Rothstein, MD	Department of Neurology, University of Pennsylvania, Philadelphia	Drafting/revision of the manuscript for content, including medical writing for content
Ossama Khazaal, MD	Department of Neurology, University of Pennsylvania, Philadelphia	Drafting/revision of the manuscript for content, including medical writing for content
Josefin E. Kaufmann, MMed	Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, Department of Clinical Research, University of Basel, and University Hospital Basel, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Stefan T. Engelter, MD	Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, Department of Clinical Research, University of Basel, and University Hospital Basel, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Christopher Traenka, MD	Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, Department of Clinical Research, University of Basel, and University Hospital Basel, Switzerland	Drafting/revision of the manuscript for content, including medical writing for content
Diana Aguiar de Sousa, MD	Stroke Center, Centro Hospitalar Universitário Lisboa Central, and Institute of Anatomy, Faculdade de Medicina da Universidade de Lisboa, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Mafalda D. Soares, MD, MSc	Department of Neurology, Centro Hospitalar Universitário Lisboa Central, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Sara B. Rosa, MD	Department of Neuroradiology, Centro Hospitalar Universitário Lisboa Central, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Lily Zhou, MD	Vancouver Stroke Program, Division of Neurology, University of British Columbia, Vancouver, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Preet Gandhi, MD	Vancouver Stroke Program, Division of Neurology, University of British Columbia, Vancouver, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Steven Mancini, MD	Vancouver Stroke Program, Division of Neurology, University of British Columbia, Vancouver, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Issa Metanis, MD	Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel	Drafting/revision of the manuscript for content, including medical writing for content
Ronen R. Leker, MD	Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel	Drafting/revision of the manuscript for content, including medical writing for content
Kelly Pan, BS	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Vishnu Dantu, BS	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Karl Baumgartne, BSr	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Tina M. Burton, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Regina Von Rennenberg, MD	Department of Neurology with Experimental Neurology, Charite Universitätsmedizin-Berlin and Center for Stroke Research, Berlin, Germany	Drafting/revision of the manuscript for content, including medical writing for content
Christian H. Nolte, MD	Department of Neurology with Experimental Neurology, Charite Universitätsmedizin-Berlin and Center for Stroke Research, Berlin, and Berlin Institute of Health, Germany	Drafting/revision of the manuscript for content, including medical writing for content
Richard Choi, DO	Department of Neurosciences, ChristianaCare, Newark, DE	Drafting/revision of the manuscript for content, including medical writing for content
Jason MacDonald, NP	Department of Neurosciences, ChristianaCare, Newark, DE	Drafting/revision of the manuscript for content, including medical writing for content
Reza Bavarsad Shahripour, MD	Department of Neurology, University of California at San Diego	Drafting/revision of the manuscript for content, including medical writing for content
Xiaofan Guo, MD	Department of Neurology, Loma Linda University, CA	Drafting/revision of the manuscript for content, including medical writing for content
Malik Ghannam, MBBCh	Department of Neurology, University of Iowa, Iowa City	Drafting/revision of the manuscript for content, including medical writing for content
Mohammad Almajali, MD	Department of Neurology, University of Iowa, Iowa City	Drafting/revision of the manuscript for content, including medical writing for content
Edgar A. Samaniego, MD, MS	Department of Neurology, University of Iowa, Iowa City	Drafting/revision of the manuscript for content, including medical writing for content
Bastien Rioux, MD, MSc	Department of Neurosciences, Université de Montréal, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Faycal Zine-Eddine, MD	Department of Neurosciences, Université de Montréal, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Alexandre Poppe, MD	Department of Neurosciences, Université de Montréal, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Ana C. Fonseca, MD, PhD	Department of Neurology, Hospital de Santa Maria, Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Maria F. Baptista, MD	Department of Neurology, Hospital de Santa Maria, Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Diana Cruz, MD	Department of Neurology, Hospital de Santa Maria, Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Michele Romoli, MD, PhD	Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy	Drafting/revision of the manuscript for content, including medical writing for content
Giovanna De Marco, MD	Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy	Drafting/revision of the manuscript for content, including medical writing for content
Marco Longoni, MD	Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy	Drafting/revision of the manuscript for content, including medical writing for content
Zafer Keser, MD	Department of Neurology, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content
Kim J. Griffin, MD	Department of Neurology, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content
Lindsey Kuohn, MD	Department of Neurology, NYU Langone Health, New York	Drafting/revision of the manuscript for content, including medical writing for content
Jennifer A. Frontera, MD	Department of Neurology, NYU Langone Health, New York	Drafting/revision of the manuscript for content, including medical writing for content
Jordan Y. Amar, MD, MSc	Department of Neurology, Washington University, Saint Louis, MO	Drafting/revision of the manuscript for content, including medical writing for content
James A. Giles, MD, PhD	Department of Neurology, Washington University, Saint Louis, MO	Drafting/revision of the manuscript for content, including medical writing for content
Marialuisa Zedde, MD	Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia	Drafting/revision of the manuscript for content, including medical writing for content
Rosario Pascarella, MD	Neuroradiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia	Drafting/revision of the manuscript for content, including medical writing for content
Ilaria Grisendi, MD	Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia	Drafting/revision of the manuscript for content, including medical writing for content
Hipolito Nzwalo, MD	Department of Internal Medicine, Centro Hospital Universitario do Algarve, Faro, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
David S. Liebeskind, MD	Department of Neurology, University of California at Los Angeles	Drafting/revision of the manuscript for content, including medical writing for content
Amir Molaie, MD, MS	Department of Neurology, University of California at Los Angeles	Drafting/revision of the manuscript for content, including medical writing for content
Annie Cavalier, MD	Department of Neurology, Duke University, Durham, NC	Drafting/revision of the manuscript for content, including medical writing for content
Wayneho Kam, MD	Department of Neurology, University of North Carolina Health Rex, Raleigh	Drafting/revision of the manuscript for content, including medical writing for content
Brian Mac Grory, MB BCh BAO, MHSc	Department of Neurology, Duke University, Durham, NC	Drafting/revision of the manuscript for content, including medical writing for content
Sami Al Kasab, MD	Department of Neurology, Medical University of South Carolina, Charleston, SC	Drafting/revision of the manuscript for content, including medical writing for content
Mohammad Anadani, MD	Department of Neurology, Medical University of South Carolina, Charleston, SC	Drafting/revision of the manuscript for content, including medical writing for content
Kimberly P. Kicielinski, MD	Department of Neurosurgery, Medical University of South Carolina, Charleston, SC	Drafting/revision of the manuscript for content, including medical writing for content
Ali Eltatawy, MD	Department of Neurology, University of Cincinnati Medical Center, OH	Drafting/revision of the manuscript for content, including medical writing for content
Lina Chervak, MD	Department of Neurology, University of Cincinnati Medical Center, OH	Drafting/revision of the manuscript for content, including medical writing for content
Roberto Chulluncuy Rivas, MD	Department of Neurology, University of Cincinnati Medical Center, OH	Drafting/revision of the manuscript for content, including medical writing for content
Yasmin N. Aziz, MD	Department of Neurology, University of Cincinnati Medical Center, OH	Drafting/revision of the manuscript for content, including medical writing for content
Eva A. Mistry, MD	Department of Neurology, University of Cincinnati Medical Center, OH	Drafting/revision of the manuscript for content, including medical writing for content
Ekaterina Bakradze, MD	Department of Neurology, University of Alabama at Birmingham	Drafting/revision of the manuscript for content, including medical writing for content
Thanh L. Tran, MD	Department of Neurology, University of Alabama at Birmingham	Drafting/revision of the manuscript for content, including medical writing for content
Marc Rodrigo-Gisbert, MD	Department of Neurology, University Hospital Vall d'Hebron, Barcelona, Spain	Drafting/revision of the manuscript for content, including medical writing for content
Manuel Requena, MD, PhD	Department of Neurology, University Hospital Vall d'Hebron, Barcelona, Spain	Drafting/revision of the manuscript for content, including medical writing for content
Faddi G. Saleh Velez, MD	Department of Neurology, University of Oklahoma	Drafting/revision of the manuscript for content, including medical writing for content
Jorge Ortiz Garcia, MD	Department of Neurology, University of Oklahoma	Drafting/revision of the manuscript for content, including medical writing for content
Varsha Muddasani, MD	Department of Neurology, Einstein-Jefferson Healthcare Network, Philadelphia, PA, USA;	Drafting/revision of the manuscript for content, including medical writing for content
Adam de Havenon, MD, MSc	Department of Neurology, University of Utah, Salt Lake City, UT; Department of Neurology, Yale New Haven Hospital, New Haven, CT	Drafting/revision of the manuscript for content, including medical writing for content
Sebastian Sanchez, MD	Department of Neurology, Yale New Haven Hospital, New Haven, CT	Drafting/revision of the manuscript for content, including medical writing for content
Venugopalan Y. Vishnu, MD (General Medicine), DM (Neurology)	Department of Neurology, All India Institute of Medical Sciences, New Delhi, India	Drafting/revision of the manuscript for content, including medical writing for content
Sridhara Yaddanapudi, MD	Department of Neurology, Thomas Jefferson University, Philadelphia	Drafting/revision of the manuscript for content, including medical writing for content
Latasha Adams, MBS	Department of Neurology, Thomas Jefferson University, Philadelphia	Drafting/revision of the manuscript for content, including medical writing for content
Abigail Browngoehl, MPH	Department of Neurology, Thomas Jefferson University, Philadelphia	Drafting/revision of the manuscript for content, including medical writing for content
Tamra Ranasinghe, MD	Department of Neurology, Wake Forest Medical Center, NC	Drafting/revision of the manuscript for content, including medical writing for content
Randy Dunston, MD	Department of Neurology, Wake Forest Medical Center, NC	Drafting/revision of the manuscript for content, including medical writing for content
Zachary Lynch, MD	Department of Neurology, Wake Forest Medical Center, NC	Drafting/revision of the manuscript for content, including medical writing for content
Mary Penckofer, BA	Department of Neurology, Cooper University, Camden, NJ	Drafting/revision of the manuscript for content, including medical writing for content
James E. Siegler, MD	Department of Neurology, Cooper University, Camden, NJ	Drafting/revision of the manuscript for content, including medical writing for content
Silvia Mayer, MD	Department of Neurology, Columbia University Medical Center, New York	Drafting/revision of the manuscript for content, including medical writing for content
Joshua Z. Willey, MD	Department of Neurology, Columbia University Medical Center, New York	Drafting/revision of the manuscript for content, including medical writing for content
Adeel S. Zubair, MD	Department of Neurology, Yale New Haven Hospital, New Haven, CT	Drafting/revision of the manuscript for content, including medical writing for content
Yee Kuang Cheng, MD	Department of Neurology, Yale New Haven Hospital, New Haven, CT	Drafting/revision of the manuscript for content, including medical writing for content
Richa Sharma, MD	Department of Neurology, Yale New Haven Hospital, New Haven, CT	Drafting/revision of the manuscript for content, including medical writing for content
João Pedro Marto, MD, PhD	Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Danna Krupka, MD	Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal	Drafting/revision of the manuscript for content, including medical writing for content
Piers Klein, BS	Department of Neurology, Boston Medical Center, MA	Drafting/revision of the manuscript for content, including medical writing for content
Thanh N. Nguyen, MD	Department of Neurology, Boston Medical Center, MA	Drafting/revision of the manuscript for content, including medical writing for content
Syed Daniyal Asad, MBBS	Department of Neurology, Hartford Hospital, CT	Drafting/revision of the manuscript for content, including medical writing for content
Zoha Sarwat, MD	Department of Neurology, Hartford Hospital, CT	Drafting/revision of the manuscript for content, including medical writing for content
Anvesh Balabhadra, MD	Department of Neurology, Hartford Hospital, CT	Drafting/revision of the manuscript for content, including medical writing for content
Shivam Patel, MD	Department of Neurology, Hartford Hospital, CT	Drafting/revision of the manuscript for content, including medical writing for content
Thais Secchi, MD	Department of Neurology, Hospital Moinhos de Vento, Porto Alegre, Brazil	Drafting/revision of the manuscript for content, including medical writing for content
Sheila C. Martins, PhD	Department of Neurology, Hospital de Clínicas de Porto Alegre, Brazil	Drafting/revision of the manuscript for content, including medical writing for content
Gabriel P. Mantovani, MD	Department of Neurology, Hospital de Clínicas de Porto Alegre, Brazil	Drafting/revision of the manuscript for content, including medical writing for content
Young Dae Kim, MD, PhD	Department of Neurology, Yonsei University, Seoul, South Korea	Drafting/revision of the manuscript for content, including medical writing for content
Balaji Krishnaiah, MD	Department of Neurology, University of Tennessee at Memphis	Drafting/revision of the manuscript for content, including medical writing for content
Cheran Elangovan, MD	Department of Neurology, University of Tennessee at Memphis	Drafting/revision of the manuscript for content, including medical writing for content
Sivani Lingam, MD	Department of Neurology, Kansas University Medical Center, Kansas City	Drafting/revision of the manuscript for content, including medical writing for content
Abid Y. Qureshi, MD	Department of Neurology, Kansas University Medical Center, Kansas City	Drafting/revision of the manuscript for content, including medical writing for content
Sebastian Fridman, MD, MPH	Department of Neurology, Western Ontario University, London, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Alonso Alvarado, MD	Department of Neurology, Western Ontario University, London, Canada	Drafting/revision of the manuscript for content, including medical writing for content
Farid Khasiyev, MD	Department of Neurology, Saint Louis University, MO	Drafting/revision of the manuscript for content, including medical writing for content
Guillermo Linares, MD	Department of Neurology, Saint Louis University, MO	Drafting/revision of the manuscript for content, including medical writing for content
Marina Mannino, MD	Department of Neurology and Stroke Unit, AOOR Villa Sofia-V. Cervello, Palermo, Italy	Drafting/revision of the manuscript for content, including medical writing for content
Valeria Terruso, MD	Department of Neurology and Stroke Unit, AOOR Villa Sofia-V. Cervello, Palermo, Italy	Drafting/revision of the manuscript for content, including medical writing for content
Argyro Tountopoulou, MD, PhD	First Department of Neurology, National and Kapodistrian University of Athens, Greece	Drafting/revision of the manuscript for content, including medical writing for content
Vasileios Tentolouris-Piperas, MD	First Department of Neurology, National and Kapodistrian University of Athens, Greece	Drafting/revision of the manuscript for content, including medical writing for content
Manuel M. Martinez-Marino	Department of Neurology, Centro Médico Nacional Siglo XXI IMSS., México City	Drafting/revision of the manuscript for content, including medical writing for content
Victor Carrasco Wall, MD	Department of Neurology, Centro Médico Nacional Siglo XXI IMSS., México City	Drafting/revision of the manuscript for content, including medical writing for content
Fransisca Indraswari, MD	Department of Neurology, The Miriam Hospital, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Sleiman E. El Jamal, MD	Department of Neurology, The Miriam Hospital, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Shilin Liu, MD	Department of Neurocritical Care, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology, Hefei, China	Drafting/revision of the manuscript for content, including medical writing for content
Min Zhou, MD	Department of Neurocritical Care, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology, Hefei, China	Drafting/revision of the manuscript for content, including medical writing for content
Muhammad M. Alvi, MD	Department of Neurology, West Virginia University, WV	Drafting/revision of the manuscript for content, including medical writing for content
Farman Ali, MD	Department of Neurology, West Virginia University, WV	Drafting/revision of the manuscript for content, including medical writing for content
Mohammed Sarvath, MD	Department of Neurology, West Virginia University, WV	Drafting/revision of the manuscript for content, including medical writing for content
Rami Z. Morsi, MD	Department of Neurology, University of Chicago, IL	Drafting/revision of the manuscript for content, including medical writing for content
Tareq Kass-Hout, MD	Department of Neurology, University of Chicago, IL	Drafting/revision of the manuscript for content, including medical writing for content
Feina Shi, MD	Department of Neurology, Sir Run Run Shaw Hospital of Zhejiang University Medical School, Hangzhou, China	Drafting/revision of the manuscript for content, including medical writing for content
Jinhua Zhang, MD	Department of Neurology, Sir Run Run Shaw Hospital of Zhejiang University Medical School, Hangzhou, China	Drafting/revision of the manuscript for content, including medical writing for content
Dilraj Sokhi, MD	Department of Neurology, Aga Khan University, Nairobi, Kenya	Drafting/revision of the manuscript for content, including medical writing for content
Jamil Said, MD	Department of Neurology, Aga Khan University, Nairobi, Kenya	Drafting/revision of the manuscript for content, including medical writing for content
Newnex Mongar, MBBS	Department of Neurology, Aga Khan University, Nairobi, Kenya	Drafting/revision of the manuscript for content, including medical writing for content
Alexis N. Simpkins, MD	Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA	Drafting/revision of the manuscript for content, including medical writing for content
Roberto Gomez, MD	Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA	Drafting/revision of the manuscript for content, including medical writing for content
Shayak Sen, MD	Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA	Drafting/revision of the manuscript for content, including medical writing for content
Mohammad Ghani, MD	Department of Neurology, University of Louisville, KY	Drafting/revision of the manuscript for content, including medical writing for content
Marwa Elnazeir, MD	Department of Neurology, University of Louisville, KY	Drafting/revision of the manuscript for content, including medical writing for content
Runqi Wangqin, MD, MHS	Department of Neurology, Duke University, Durham, NC	Drafting/revision of the manuscript for content, including medical writing for content
Han Xiao, PhD	Department of Economics, University of California, Santa Barbara	Drafting/revision of the manuscript for content, including medical writing for content
Narendra S. Kala, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Farhan Khan, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Christoph Stretz, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Nahid Mohammadzadeh, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Eric D Goldstein, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Karen Furie, MD, MPH	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content
Shadi Yaghi, MD	Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design

Study Funding

The authors report no targeted funding.

Disclosure

Disclosures provided by T. Nguyen in compliance with American Heart Association annual Journal Editor Disclosure Questionnaire are available at https://www.ahajournals.org/editor-coi-disclosures; M. Arnold reports compensation from Boehringer Ingelheim, AstraZeneca, Bayer, Bristol-Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Sanofi, Pfizer, Medtronic, Novo Nordisk, and Amgen for consultant services. E. Lester reports a provisional patent for Methods and compositions for disrupting tau aggregates. E. Touze reports compensation from Elsevier for other services and employment by Caen. J.E. Kaufmann reports grants from Goldschmidt Jacobson-Stiftung. C. Traenka reports travel support from Bayer Healthcare. D. Aguiar de Sousa reports compensation from Daiichi Sankyo, Bayer, AstraZeneca, Johnson & Johnson, and Fundação Bial for other services, compensation from the University of British Columbia for data and safety monitoring services, and compensation from Organon & Co for consultant services. S. Rosa reports grants from Merck Sharp & Dohme Corporation. T. Field reports compensation from HLS Therapeutics, AstraZeneca Canada, and Roche for consultant services, service as a board member for Destine Health, compensation from the Canadian Medical Protective Association for expert witness services, and grants from Bayer. R. Leker reports compensation from Medtronic, Ischemaview, Bayer, Abbott Diabetes Care, Biogen, Janssen Biotech, and Boehringer Ingelheim for other services. C. Nolte reports compensation from Daiichi Sankyo Europe GmbH, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Alexion Pharmaceuticals for consultant services and compensation from AstraZeneca, Abbott Canada, Deutsches Zentrum für Neurodegenerative Erkrankungen, Novartis, Portola Pharmaceuticals, Deutsches Zentrum für Herz-Kreislaufforschung, and Novartis for other services. A. Poppe reports grants from Foundation Brain Canada, Heart and Stroke Foundation of Canada, and Stryker and compensation from Roche for other services. D. Liebeskind reports compensation from Medtronic, Genentech, Cerenovus, Stryker, and Rapid Medical Ltd, for consultant services. B. Mac Grory reports grants from the National Institutes of Health, employment by Duke University Medical Center, compensation from Bayer for other services, and grants from the American Heart Association, Duke Bass Connections, and the Duke Office of Physician Scientist Development. S. Al Kasab reports compensation from Stryker for other services and employment by Medical University of South Carolina. K. Kicielinski reports compensation from Stryker, Penumbra Inc., Medtronic, and MicroVention Inc., for other services, travel support from MicroVention Inc., and employment by Medical University of South Carolina and Elsevier. A. de Havenon reports stock options in TitinKM and Certus, grants from the National Institutes of Health, and compensation from Novo Nordisk for consultant services. J. Siegler reports grants from Philips and employment by the University of Chicago. J.Z. Willey reports compensation from Edwards Lifesciences Corporation and Abbott Fund for end point review committee services, compensation from UpToDate for other services, and compensation from the Abbott Laboratories for consultant services. R. Sharma reports a provisional patent for a stroke etiology classifier algorithm and grants from the National Institutes of Health Clinical Center. S. Martins reports compensation from Pfizer, Medtronic, Servier Affaires Medicales, Daiichi Sankyo, Bayer, Novo Nordisk, Novartis, Penumbra Inc., and Boehringer Ingelheim for other services. A.N. Simpkins reports grants from the National Institutes of Health. C. Stretz reports grants from Massachusetts General Hospital. K. Furie reports compensation from Janssen Biotech for consultant services. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.