SARS-CoV-2 and Stroke Characteristics

A Report From the Multinational COVID-19 Stroke Study Group

Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc; Ghasem Farahmand, MD; Eric Koza, MD Candidate; Ashkan Mowla, MD; Alireza Vafaei Sadr, PhD; Arash Kia, MD; Alaleh Vaghefi Far, MD; Stefania Mondello, MD, PhD, MPH; Achille Cernigliaro, PhD, MPH; Annemarei Ranta, MD, PhD; Martin Punter, PhD, MBChB; Faezeh Khodadadi, PharmD; Soheil Naderi, MD; Mirna Sabra, PhD; Mahtab Ramezani, MD; Ali Amini Harandi, MD; Oluwaseyi Olulana, MS; Durgesh Chaudhary, MBBS; Aicha Lyoubi, MD; Bruce C.V. Campbell, MD; Juan F. Arenillas, MD; Daniel Bock, MD; Joan Montaner, MD; Saeideh Aghayari Sheikh Neshin, MD; Diana Aguiar de Sousa, MD, PhD; Matthew S. Tenser, MD; Ana Aires, MD; Mercedes de Lera Alfonso, MD; Orkhan Alizada, MD; Elsa Azevedo, MD, PhD; Nitin Goyal, MD; Zabihollah Babaeepour, MD; Gelareh Banihashemi, MD; Leo H. Bonati, MD; Carlo W. Cereda, MD; Jason J. Chang, MD; Miljenko Crnjakovic, MD; Gian Marco De Marchis, MD; Massimo Del Sette, MD; Seyed Amir Ebrahimzadeh, MD, MPH; Mehdi Farhoudi, MD; Ilaria Gandoglia, MD; Bruno Gonçalves, MD; Christoph J. Griessenauer, MD; Mehmet Murat Hancı, MD; Aristeidis H. Katsanos, MD; Christos Krogias, MD; Ronen R. Leker, MD; Lev Lotman, MD; Jeffrey Mai, MD; Shailesh Male, MD; Konark Malhotra, MD; Branko Malojcic, MD, PhD; Teresa Mesquita, MD; Asadollah Mir Ghasemi, MD; Hany Mohamed Aref, MD; Zeinab Mohseni Afshar, MD; Jusun Moon, MD; Mika Niemelä, MD, PhD; Behnam Rezai Jahromi, MD; Lawrence Nolan, DO; Abhi Pandhi, MD; Jong-Ho Park, MD; João Pedro Marto, MD; Francisco Purroy, MD, PhD; Sakineh Ranji-Burachaloo, MD; Nuno Reis Carreira, MD; Manuel Requena, MD; Marta Rubiera, MD; Seyed Aidin Sajedi, MD; João Sargento-Freitas, MD; Vijay K. Sharma, MD; Thorsten Steiner, MD; Kristi Tempro, MD; Guillaume Turc, MD, PhD; Yasaman Ahmadzadeh, MD; Mostafa Almasi-Dooghaee, MD; Farhad Assarzadegan, MD; Arefeh Babazadeh, MD, MPH; Humain Baharvahdat, MD; Fabricio Buchadid Cardoso, MD, MPH; Apoorva Dev, PhD; Mohammad Ghorbani, MD; Ava Hamidi, MD; Zeynab Sadat Hasheminejad, MD; Sahar Hojjat-Anasri Komachali, MD; Fariborz Khorvash, MD; Firas Kobeissy, PhD; Hamidreza Mirkarimi, MD; Elahe Mohammadi-Vosough, MD; Debdipto Misra, MS; Ali Reza Noorian, MD; Peyman Nowrouzi-Sohrabi, PhD; Sepideh Paybast, MD; Leila Poorsaadat, MD; Mehrdad Roozbeh, MD; Behnam Sabayan, MD, PhD; Saeideh Salehizadeh, MD; Alia Saberi, MD; Mercedeh Sepehrnia, MD; Fahimeh Vahabizad, MD; Thomas Alexandre Yasuda, MD; Mojdeh Ghabaee, MD; Nasrin Rahimian, MD, MPH; Mohammad Hossein Harirchian, MD; Afshin Borhani-Haghighi, MD; Mahmoud Reza Azarpazhooh, MD; Rohan Arora, MD; Saeed Ansari, MD; Venkatesh Avula, MS; Jiang Li, MD, MPH; Vida Abedi, PhD; Ramin Zand, MD, MPH

Disclosures

Stroke. 2021;52(5):e117-e130.

Abstract and Introduction

Abstract

Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale.

Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries' health expenditure on outcomes.

Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were <55 years of age, and 105 (24.4%) patients had no identifiable vascular risk factors. Among acute ischemic stroke patients, 44.5% (126 of 283 patients) had large vessel occlusion; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median National Institutes of Health Stroke Scale (8 [3–17] versus 11 [5–17]; P=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P<0.001) in countries with middle-to-high health expenditure when compared with countries with lower health expenditure. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144 (37.8%) were asymptomatic at the time of admission for SARS-CoV-2 infection.

Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.

Introduction

Since the emergence of the coronavirus disease 2019 (COVID-19) pandemic, several cases of cerebrovascular events were reported among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).^[1] Studies presented the incidence and prevalence of acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) in SARS-CoV-2–infected patients.^[2–6]

Many studies proposed coagulopathy as the underlying pathophysiological mechanism for the cerebrovascular events.^[7,8] Small case series demonstrated a higher proportion of large vessel occlusions (LVOs),^[2,9] or cryptogenic strokes,^[4,10] with elevated D-dimer level, liver enzymes, and inflammatory or renal failure biomarkers among the patients who experienced SARS-CoV-2 infection.^[4,5] Additionally, most of the studies noted a higher severity and mortality rate among stroke patients diagnosed with SARS-CoV-2 compared with others.^[4,11,12]

To present a more comprehensive overview of stroke among patients infected with SARS-CoV-2, we devised a multinational multiple-phase study. In the first phase, we estimated the risk of stroke among the SARS-CoV-2–infected hospitalized patients. ^[13] In the current study, we aimed to present more details on the features and characteristics of our expanded multinational stroke cohort with prior SARS-CoV-2 infection. We further investigated the risk of LVO, stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS), and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria in the entire cohort, as well as different geographic regions.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. The Baseline Characteristics, Comorbidities, and Laboratory Findings Among SARS-CoV-2 Infected Patients With Stroke
Parameter	AIS, n=323 (74.8%)	Intracerebral hemorrhage, n=68 (15.7%)	SAH, n=23 (5.3%)	Cerebral venous/sinus thrombosis, n=18 (4.2%)
Age, y; mean (SD)	67.2±15.2	63±16	62.6±14.1	48.9±11.5
Age, y; median (IQR)	68 (58–78)	65 (54–75)	62 (54–74)	51 (39.5–55.2)
<40, n (%)	23 (7.1)	8 (12.9)	1 (4.3)	5 (27.8)
41–64, n (%)	110 (34.1)	20 (32.3)	12 (52.2)	11 (61.1)
65–74, n (%)	77 (23.8)	13 (21)	5 (21.7)	2 (11.1)
≥75, n (%)	113 (53)	21 (33.9)	5 (21.7)	0 (0)
Sex: female, n (%)	130 (40.2)	30 (44.1)	12 (52.2)	11 (61.1)
Asymptomatic for SARS-CoV-2 infection at the time of admission, n (%)	104 (36.1)	31 (53.4)	8 (36.4)	4 (22.2)
SARS-CoV-2 to stroke interval, d; mean (SD)	5±7	5±8	3±5	3±4
SARS-CoV-2 to stroke interval, d; median (IQR)	3 (0–9)	0 (0–10.3)	1.5 (0–5.3)	4.5 (0.7–10.3)
NIHSS, median (IQR)	9 (4–17)	10 (0–19)	6 (0–16)	14 (7–17)
ICH score, median (IQR)	…	3 (2–4)	…	…
Mechanical ventilation, n (%)	238 (73.7)	31 (50)	12 (52.2)	10 (55.6)
Initiation of mechanical ventilation, d; median (IQR)	2 (1–3)	2 (1–4)	5 (1–15)	1 (1–2)
Length of hospital stay, d; mean (SD)	12±12	15±18	18±20	18±14
Length of hospital stay, d; median (IQR)	7 (4–16)	8 (3–21)	11 (4.2–31)	14 (7–30)
Disposition*
Discharged home, n (%)	127 (42.8)	10 (17.9)	3 (15)	12 (66.7)
In-hospital mortality, n (%)	82 (27.6)	35 (62.5)	11 (55)	3 (16.7)
Still in hospital or dispositioned to subacute care, n (%)	88 (29.6)	11 (22)	6 (30)	3 (16.7)
Medications
Prior antiplatelet therapy, n (%)	87 (28.0)	16 (28.1)	3 (14.3)	0 (0.0)
Prior anticoagulant therapy, n (%)	28 (9.0)	6 (10.5)	2 (9.5)	4 (23.5)
Region
Middle East, n (%)	153 (47.4)	43 (63.2)	17 (73.9)	15 (83.3)
America, n (%)	6 (1.9)	0 (0.0)	0 (0.0)	2 (11.1)
Europe, n (%)	88 (27.2)	19 (27.9)	6 (26.1)	1 (5.6)
Asia, n (%)	76 (23.5)	6 (8.8)	0 (0.0)	0 (0.0)
Countries' health expenditure
Middle to high, n (%)	170 (52.6)	26 (38.2)	5 (21.7)	2 (11.1)
Low, n (%)	153 (47.4)	42 (61.8)	18 (78.3)	16 (88.9)
Comorbidities
Hypertension, n (%)	202 (63.1)	43 (63.2)	14 (60.9)	1 (5.6)
Diabetes, n (%)	111 (34.6)	21 (30.9)	4 (17.4)	2 (11.1)
Ischemic heart disease, n (%)	72 (24.3)	12 (17.6)	4 (21.1)	0 (0)
Atrial fibrillation, n (%)	45 (14.1)	3 (4.4)	2 (8.7)	0 (0)
Carotid stenosis, n (%)	38 (12.8)	2 (2.9)	0 (0)	0 (0)
Chronic kidney disease, n (%)	42 (13.1)	9 (13.2)	3 (13)	2 (11.1)
Cardiac ejection fraction <40%, n (%)	24 (8.1)	7 (10.3)	0 (0)	0 (0)
Active neoplasm, n (%)	21 (7.1)	4 (5.9)	1 (4.3)	0 (0)
Rheumatological disease, n (%)	5 (1.7)	0 (0)	1 (4.3)	0 (0)
Prior stroke or transient ischemic attack, n (%)	5 (1.7)	0 (0)	0 (0)	0 (0)
Smoking, n (%)	53 (16.6)	11 (16.2)	3 (13)	0 (0)
Laboratory findings
White blood cell count, ×109/L; mean (SD)	9.8±4.8	11.4±10.0	13.5±12.9	11.1±6.0
White blood cell count, ×109/L; median (IQR)	9 (6.8–11.2)	9.5 (7.7–12.1)	10 (8.8–12.2)	11.1 (6.7–14.8)
<4 ×109/L, n (%)	7 (2.3)	3 (5.7)	0 (0)	2 (22.2)
4–10 ×109/L, n (%)	184 (61.1)	29 (54.7)	10 (50)	4 (44.4)
10–20 ×109/L, n (%)	96 (31.9)	18 (34)	9 (45)	3 (33.3)
≥20 ×109/L, n (%)	14 (4.7)	5 (10)	1 (5)	0 (0)
Neutrophil count, ×109/L; mean (SD)	7.7±4.5	9.3±8.5	9.6±6.1	9.2±5.1
Neutrophil count, ×109/L; median (IQR)	6.8 (4.8–9.2)	7.2 (5.2–10.6)	7.3 (5.4–11)	9.4 (4.7–14.2)
<4 ×109/L, n (%)	43 (15.2)	5 (10)	1 (5)	1 (12.5)
4–10 ×109/L, n (%)	182 (64.3)	33 (66)	12 (60)	6 (75)
10–20 ×109/L, n (%)	49 (17.3)	10 (20)	6 (30)	1 (12.5)
≥20 ×109/L, n (%)	9 (3.2)	2 (4)	1 (5)	0 (0)
Lymphocyte count, ×109/L; mean (SD)	1.5±1.5	2.0±3.6	2.8±6.3	2.0±1.3
Lymphocyte, ×109/L; median (IQR)	1.3 (0.9–1.9)	1.3 (0.9–2.0)	1.3 (0.9–1.9)	1.9 (1.2–2.3)
<1 ×109/L, n (%)	93 (32.5)	21 (39.6)	6 (28.6)	1 (12.5)
1–2 ×109/L, n (%)	130 (45.5)	19 (35.8)	10 (47.6)	4 (50)
2–3 ×109/L, n (%)	41 (14.3)	9 (35.8)	3 (14.3)	2 (25)
3–4 ×109/L, n (%)	11 (3.8)	1 (1.9)	0 (0)	1 (12.5)
≥4 ×109/L, n (%)	11 (3.8)	3 (5.7)	2 (9.5)	0 (0)
Platelet count, ×109/L; mean (SD)	314.5±440.7	197.1±89.1	191.45±60.9	254.2±170.1
Platelet count, ×109/L; median (IQR)	229 (161–333.7)	178.5 (142.5–254)	183 (141–246)	237 (139–337)
<350 ×109/L, n (%)	228 (78.1)	50 (94.3)	20 (100)	8 (88.9)
350–500 ×109/L, n (%)	64 (21.9)	3 (5.7)	0 (0)	1 (11.1)
ALT, U/L; mean (SD)	63.3±86.3	50.4±66.0	67.2±78.1	120.9±231.6
ALT, U/L; median (IQR)	29.8 (10.1–90.2)	22.9 (8.0–67.7)	53 (11.6–75.2)	39 (29–107)
AST, U/L; mean (SD)	32.1±26.8	35.7±24.5	43.4±27.9	121.5±265.1
AST, U/L; median (IQR)	23.9 (14–40.5)	28.9 (20–43)	35 (21–69.8)	44 (30.5–63)
BUN, mg/dL; mean (SD)	53.1±104.2	99.9±290.8	83.1±160.6	31.9±16.3
BUN, mg/dL; median (IQR)	32 (21–50)	33.5 (21.5–51)	36 (26–60)	30 (23–37)
Creatinine, mg/dL; mean (SD)	1.5±1.7	2.2±2.6	2.57±3.12	1.46±1.21
Creatinine, mg/dL; median (IQR)	1.1 (1.1–1.5)	1.1 (0.9–1.8)	1 (0.9–2.8)	1.1 (0.9–1.6)
CRP, mg/L; mean (SD)	61±131	79±192	85±155	54±37
CRP, mg/L; median (IQR)	36 (24–57)	37 (24–54)	41 (29.5–62.5)	30 (23.5–37)
LDH, U/L; mean (SD)	604.8±1536.7	450.8±443.3	443.0±268.5	766±812.1
LDH, U/L; median (IQR)	377 (245–524)	366.5 (254.5–571)	252 (230–664)	453 (250–1115)
Fibrinogen, mg/dL; mean (SD)	463.6±989.6	706.1±418.1	…	…
Fibrinogen, mg/dL; median (IQR)	223 (3.9–490.5)	693 (303–1246)	…	…
D-dimer, ng/mL; mean (SD)	2654.8±6429.4	8668.4±16318.1	…	1080.8±1376.5
D-dimer, ng/mL; median (IQR)	1027 (551–2200)	2303 (584.5–6875)	…	…

AIS indicates acute ischemic stroke; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CRP, C-reactive protein; ICH, intracranial hemorrhage; IQR, interquartile range; LDH, lactate dehydrogenase; NIHSS, National Institutes of Health Stroke Scale; SAH, subarachnoid hemorrhage; and SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.
*Data on patients' disposition were sparse.

Table 2. Localization and Presenting Symptoms Regarding the SARS-CoV-2 Infected Patients With ICH and Cerebral Sinus and Venous Thrombosis
Localization	n (%)	Symptoms	n (%)
ICH
SAH	23 (25.3)	Intracranial (minus subarachnoid) hemorrhage	68 (15.7)
Middle cerebral artery aneurysm	2 (8.6)	Altered level of consciousness	27 (39.7)
Posterior cerebral artery aneurysm	1 (4.3)	Limb paresis	25 (36.7)
Anterior communicating artery aneurysm	2 (8.6)	Aphasia	3 (4.4)
Basilar top aneurysm	2 (8.6)	Facial paresis	2 (2.9)
No aneurysm detected	16 (69.5)	Sensory loss	3 (2.9)
Subarachnoid and IPHs	3 (3.3)	Dysarthria	4 (2.9)
Intraventricular and IPHs	4 (4.4)	Ataxia	5 (2.9)
IPH	61 (67)	Visual field defect	1 (1.5)
Cerebellar hemorrhage	3 (7.0)	SAH	23 (25.3)
Brain stem hemorrhage	4 (9.3)	Thunderclap headache	16 (69.5)
Basal ganglia hemorrhage	19 (43.1)	Decreased level of consciousness	5 (21.7)
Thalamic hemorrhage	7 (16.3)	Cerebral herniation	1 (4.3)
Lobar hemorrhage	20 (46.5)	Seizure	1 (4.3)
Missing	17 (28.3)	Missing	21 (30.9)
Cerebral venous and sinus thrombosis
Superior sagittal sinus	6 (33.3)	Headache	9 (50)
Sigmoid sinus	6 (33.3)	Seizure	7 (38.9)
Transverse sinus	5 (27.8)	Altered level of consciousness	5 (27.8)
Lateral sinus	3 (16.7)	Increased intracerebral pressure	2 (11.1)
Straight sinus	1 (5.6)	Concomitant ICH	2 (11.1)
Cortical veins	1 (5.6)
Multiple sinus or venous involvement	5 (27.8)

ICH indicates intracranial hemorrhage; IPH, intraparenchymal hemorrhage; SAH, subarachnoid hemorrhage; and SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Table 3. Neurological Findings Among Patients With Acute Ischemic Stroke
Parameters	n (%)	Parameters		n (%)
Imaging pattern of ischemia		Vascular territory based on imaging*
Embolic/large vessel atherothromboembolism	206 (80.5)	Anterior cerebral artery	Unilateral	7 (2.2)
Lacunar	26 (10.2)	Anterior cerebral artery	Bilateral	1 (0.3)
Borderzone	23 (9.0)	Middle cerebral artery	Unilateral	181 (56)
Vasculitis	1 (0.4)	Middle cerebral artery	Bilateral	5 (1.5)
		Posterior cerebral artery	Unilateral	33 (10.2)
TOAST criteria		Posterior cerebral artery	Bilateral	4 (1.2)
LAA	56 (32.9)	Posterior inferior cerebellar artery		9 (2.8)
Cardioembolism	46 (27.1)	Missing		64 (19.8)
Small artery occlusion	17 (10.0)	Symptoms at onset*
Other determined etiology	13 (7.6)	Hemineglect		1 (0.4)
Undetermined etiology	38 (22.4)	Limb paresis	Unilateral	168 (72.4)
		Limb paresis	Bilateral	2 (0.9)
NIHSS		Sensory loss	Unilateral	26 (11.2)
No stroke symptoms (NIHSS score, 0)	20 (7.5)	Sensory loss	Bilateral	1 (0.4)
Minor stroke (NIHSS score, 1–4)	49 (18.4)	Visual field loss	Unilateral	14 (6.0)
Moderate stroke (NIHSS score, 5–15)	117 (43.8)	Visual field loss	Bilateral	2 (0.9)
Moderate-to-severe stroke (NIHSS score, 16–20)	35 (13.1)	Gaze preference		13 (5.6)
Severe stroke (NIHSS score, 21–42)	46 (17.2)	Facial paresis		46 (19.8)
		Aphasia		56 (24.1)
LVO	126 (44.5)	Dysarthria		41 (17.7)
		Altered level of consciousness		57 (24.6)
Mechanical thrombectomy	24 (7.4)	Ataxia		21 (9.1)
		Seizure		7 (3.0)
IVT	44 (13.6)	Missing		91 (28.2)

IVT indicates intravenous thrombolysis; LAA, large artery atherosclerosis; LVO, large vessel occlusion; NIHSS, National Institutes of Health Stroke Scale; and TOAST, Trial of ORG 10172 in Acute Stroke Treatment.
*Due to multiple infarcts in some patients, the summation may exceed 100%.

Table 4. Baseline Characteristics and Neuroimaging Findings Under Each Outcome Measures
Parameters	TOAST criteria						LVO			NIHSS
Parameters	A: LAA, n=56 (32.9%)	B: cardioembolism, n=46 (27.1%)	C: small artery occlusion, n=17 (10.0%)	D: other determined, n=13 (7.6%)	E: undetermined, n=38 (22.4%)	P value	A: LVO, n=126 (44.5%)	B: other strokes, n=157 (55.5%)	P value	A: no stroke symptoms (NIHSS score, 0), n=20 (7.5%)	B: minor stroke (NIHSS score, 1–4), n=49 (18.4%)	C: moderate stroke (NIHSS score, 5–15), n=117 (43.8%)	D: moderate-to-severe stroke (NIHSS score, 16–20), n=35 (13.1%)	E: severe stroke (NIHSS score, 21–42), n=46 (17.2%)	P value
Age, y; mean (SD)	63±15	72±14 D	67±18	57±16	65±18	0.01	65.7±14.4	68±16.1	0.22	67±13	65±17	66±15	66±16	69±15	0.77
Sex: female, n (%)	19 (33.9)	21 (45.7)	3 (17.6)	9 (69.2) C	15 (39.5)	0.05	46 (36.5)	71 (45.2)	0.14	6 (30.0)	20 (40.8)	44 (37.6)	16 (45.7)	22 (47.8)	0.60
LVO, n (%)	46 (85.2) B, D, E	24 (53.3)	0 (0.0)	2 (18.2)	7 (20.0)	<0.001	…	…	…	1 (8.3)	8 (17.0)	49 (44.5) B	23 (67.6) A, B	31 (75.6) A, B, C	<0.001
IVT, n (%)	14 (25.0)	8 (17.4)	0 (0.0)	2 (15.4)	4 (10.5)	0.12	28 (22.2) B	14 (8.9)	0.002	0 (0.0)	2 (4.1)	25 (21.4) B	11 (31.4) B	5 (10.9)	<0.001
Mechanical thrombectomy; n (%)	10 (17.9)	10 (21.7)	0 (0.0)	1 (7.7)	2 (5.3)	0.07	24 (19.0)	0 (0.0)	<0.001	0 (0.0)	1 (2.0)	8 (6.8)	9 (25.7) B, C	6 (13.0)	<0.001
NIHSS, median (IQR)	9.0 (5.0–17.0)	13.0 (8.0–20.0)	4.0 (2.0–8.0)	14.0 (6.0–18.0)	7.0 (3.0–17.0)	0.10	15.0 (8.0–21.0)	6.0 (3.0–12.0)	<0.001	…	…	…	…	…	…
TOAST criteria						…			<0.001						0.03
Large artery atherosclerosis, n (%)	…	…	…	…	…		46 (58.2) A	8 (9.6)		1 (14.3)	9 (25.7)	30 (43.5)	5 (19.2)	11 (36.7)
Cardioembolism, n (%)	…	…	…	…	…		24 (30.4)	21 (25.3)		2 (28.6)	5 (14.3)	17 (24.6)	13 (50.0) B	8 (26.7)
SVO, n (%)	…	…	…	…	…		0 (0.0)	17 (20.5)		1 (14.3)	9 (25.7)	30 (43.5)	5 (19.2)	11 (36.7)
Stroke of other determined etiology, n (%)	…	…	…	…	…		2 (2.5)	9 (10.8) B		0 (0.0)	3 (8.6)	3 (4.3)	4 (15.4)	2 (6.7)
Stroke of undetermined etiology, n (%)	…	…	…	…	…		7 (8.9)	28 (33.7) B		3 (42.9)	10 (28.6)	13 (18.8)	4 (15.4)	7 (23.3)
Imaging patterns						<0.001			<0.001						<0.001
Embolic/large vessel atherothromboembolism, N (%)	54 (96.4) C, D	43 (93.5) C	4 (23.5)	9 (69.2)	34 (89.5) C		99 (88.4) B	99 (73.3)		4 (57.1)	31 (73.8)	85 (81.7)	24 (75.0)	39 (92.9)
Lacune, n (%)	0 (0.0)	1 (2.2)	13 (76.5) B, D, E	1 (7.7)	4 (10.5)		2 (1.8)	12 (17.0) B		2 (28.6)	8 (19.0)	10 (9.6)	1 (3.1)	1 (2.4)
Borderzone, n (%)	2 (3.6)	1 (2.2)	0 (0.0)	3 (23.1) A, B	0 (0.0)		11 (9.8)	12 (8.9)		0 (0.0)	3 (7.1)	9 (8.7)	7 (21.9)	2 (4.8)
Vasculitis pattern, n (%)	0 (0.0)	1 (2.2)	0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	1 (0.7)		1 (14.3)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Interval between infection onset to stroke, d; median (IQR)	4.0 (1.0–10.0)	2.0 (0.0–11.0)	2.0 (0.0–6.0)	10.0 (4.0–17.0)	4.0 (0.0–12.0)	0.12	46 (58.2) A	8 (9.6)	<0.001	3.0 (0.0–12.0)	3.0 (0.0–10.0)	4.0 (1.0–8.0)	3.0 (0.0–10.0)	1.0 (0.0–10.0)	0.64
Mechanical ventilation, n (%)	22 (29.3)	10 (21.7)	4 (23.5)	9 (69.2)	11 (28.9)	0.02	36 (28.6)	42 (26.8)	0.73	2 (10.0)	8 (16.3)	25 (21.4)	12 (34.3)	29 (63.0) A, B, C	<0.001
Disposition*						0.12			0.24						<0.001
Discharged home, n (%)	24 (42.9)	16 (34.8)	11 (64.7)	8 (61.5)	9 (24.3)		46 (37.7)	66 (44.6)		5 (62.5)	28 (62.2) D, E	52 (47.3) D, E	6 (17.6)	9 (20.5)
In-hospital mortality, n (%)	14 (25.0)	13 (28.3)	3 (17.6)	2 (15.4)	9 (24.3)		40 (32.8)	35 (23.6)		1 (12.5)	5 (11.1)	18 (16.4)	19 (55.9) B, C	23 (52.3) B, C
Still in hospital/subacute care, n (%)	18 (32.1)	17 (37.0)	3 (17.6)	3 (23.1)	19 (54.1)		36 (29.5)	47 (31.8)		2 (25.0)	12 (26.7)	40 (36.4)	9 (26.5)	12 (27.3)
Length of hospital stay, d; median (IQR)	6.0 (4.0–15.0)	7.0 (5.0 –14.0)	7.0 (5.0–16.0)	20.0 (4.0–35.0)	8.0 (6.0–26.0)	0.17	6.0 (4.0–15.0)	8.0 (5.0–17.0)	0.10	2 (10.0)	8 (16.3)	25 (21.4)	12 (34.3)	29 (63.0) A, B, C	<0.001
Comorbidities
Hypertension, n (%)	30 (53.6)	35 (76.1) D	10 (58.8)	4 (30.8)	25 (65.8)	0.03	79 (62.7)	106 (68.4)	0.32	14 (73.7)	34 (69.4)	78 (66.7)	23 (65.7)	29 (60.9)	0.86
Diabetes, n (%)	20 (35.7)	15 (32.6)	6 (35.3)	1 (7.7)	12 (31.6)	0.41	45 (35.7)	56 (35.9)	0.98	9 (45.0)	13 (26.5)	41 (35.0)	13 (37.1)	16 (34.8)	0.65
Ischemic heart disease, n (%)	11 (19.6)	21 (45.7) A, E	3 (17.6)	1 (7.7)	2 (5.3)	<0.001	40 (33.6) A	27 (18.2)	<0.001	1 (10.0)	2 (4.3)	33 (29.7) B	12 (36.4) B	11 (26.2) B	<0.001
Atrial fibrillation, n (%)	2 (3.6)	23 (50.0) A, E	4 (23.5)	1 (7.7)	1 (2.6)	<0.001	21 (16.7)	19 (12.3)	0.29	4 (21.1)	4 (8.2)	12 (10.3)	11 (31.4) C	9 (17.4)	0.02
Carotid stenosis, n (%)	16 (28.6) E	6 (13.0)	1 (5.9)	0 (0.0)	2 (5.3)	0.01	18 (15.1)	17 (11.5)	0.38	0 (0.0)	10 (21.7)	16 (14.4)	3 (9.1)	7 (16.7)	0.35
Chronic kidney disease, n (%)	8 (14.3)	3 (6.5)	6 (35.3) B	1 (7.7)	3 (7.9)	0.03	14 (11.1)	27 (17.4)	0.14	3 (15.8)	8 (16.3)	16 (13.7)	7 (20.0)	3 (6.5)	0.48
Cardiac ejection fraction <40%, n (%)	5 (8.9)	8 (17.4)	1 (5.9)	1 (7.7)	5 (13.2)	0.61	8.0 (6.7)	12 (8.1)	0.67	2 (20.0)	3 (6.5)	9 (8.1)	2 (6.1)	4 (9.5)	0.68
Active neoplasm, n (%)	2 (3.6)	9 (19.6) A	1 (5.9)	0 (0.0)	0 (0.0)	<0.001	9 (7.6)	8 (5.4)	0.47	0 (0.0)	0 (0.0)	11 (9.9)	3 (9.1)	3 (7.1)	0.21
Rheumatological disease, n (%)	0 (0.0)	3 (6.5)	1 (5.9)	0 (0.0)	0 (0.0)	0.32	3 (2.5)	2 (1.4)	0.48	0 (0.0)	1 (2.2)	3 (2.7)	1 (3.0)	0 (0.0)	0.83
Prior stroke or transient ischemic attack, n (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.6)	0.48	2 (1.7)	2 (1.4)	0.83	0 (0.0)	0 (0.0)	1 (0.9)	0 (0.0)	0 (0.0)	0.88
Smoking, n (%)	11 (19.6)	5 (10.9)	2 (11.8)	0 (0.0)	4 (10.5)	0.34	24 (19)	23 (14.8)	0.35	2 (10.5)	8 (16.3)	22 (18.8)	5 (14.3)	6 (13.0)	0.83
Laboratory findings
White blood cell count ×109/L, mean (SD)	10.2±5.5	10.3±4.5	9.9±2.5	11.6±8.1	8.5±3.9	0.29	10.0±5.1	9.8±4.6	0.69	8.6±3.5	9.6±5.6	9.8±4.4	9.2±4.1	11.1±5.0	0.24
Neutrophil count ×109/L, mean (SD)	8.4±4.8	7.9±4.5	8.0±2.7	9.7±7.7	6.5±3.7	0.24	7.8±4.7	7.6±4.2	0.77	7.0±3.6	7.2±5.1	7.9±4.4	7.4±3.7	8.5±4.2	0.56
Lymphocyte count ×109/L, mean (SD)	1.5±2.3	2.1±1.3	2.0±2.1	1.5±0.7	2.1±1.9	0.35	1.7±2.2	1.7±1.2	0.82	1.4±1.5	1.7±1.1	1.6±1.2	2.1±2.9	1.9±2.4	0.68
Platelet count ×109/L, mean (SD)	258.0±134.4	503.5±992.7	220.7±151.3	343.9±166.9	416.6±431.2	0.20	297.8±332.4	334.1±563.6	0.54	419.9±714.5	379.0±395.7	334.2±609.9	281.5±129.4	264.8±115.7	0.68
ALT, U/L; mean (SD)	63.5±78.4	35.5±53.3	51.0±60.0	44.9±75.5	66.5±81.2	0.29	62.9±66.5	55.5±78.6	0.43	105.6±177.7	34.5±45.9	63.9±80.3	58.0±84.3	50.1±51.2	0.04
AST, U/L; mean (SD)	36.5±34.4	30.3±23.0	25.4±13.9	34.7±38.3	24.3±19.1	0.26	31.5±28.1	31.6±24.0	0.98	30.9±22.3	23.6±20.2	33.1±26.2	28.1±23.7	41.5±32.7	0.02
BUN, mg/dL; mean (SD)	47.9±51.1	46.2±63.6	43.0±50.1	39.3±26.0	86.6±260.6	0.60	46.6±55.9	56.6±141.5	0.49	61.3±50.5	50.0±66.8	46.5±45.6	33.9±20.8	39.5±39.0	0.32
Creatinine, mg/dL; mean (SD)	1.3±0.8	1.1±0.3	1.6±1.4	1.3±1.2	1.4±1.2	0.43	1.3±0.9	1.5±1.4	0.27	1.5±1.2	1.0±0.3	1.5±1.3	1.2±0.9	1.6±1.1	0.05
CRP, mg/L; mean (SD)	47.0±52.0	49.0±58.0	35.0±18.0	42.0±25.0	107±325	0.37	47.4±54.8	71.3±183.8	0.17	57.0±41.0	46.0±52.0	50.0±51.0	45.0±31.0	47.0±40.0	0.91
LDH, U/L; mean (SD)	1064.6±2880.1	542.6±1114.4	371.2±202.7	474.7±472.4	321.5±185.6	0.53	824.1±2308.0	470.9±801.3	0.26	531.6±254.9	551.9±1136.0	457.2±707.3	511.9±412.3	1119.4±3301.0	0.57
Fibrinogen, mg/dL; mean (SD)	522.7±1054.0	674.7±1839.4	779.5±918.3	157.2±156.1	217.4±338.1	0.73	612.9±1468.5	346.3±540.8	0.33	509.3±196.3	409.1±740.9	575.3±1556.1	133.9±149.3	465.0±298.2	0.88
D-dimer, ng/mL; mean (SD)	919.6±956.4	2019.6±2694.8	820.7±593.0	1257.3±761.9	1386.8±1196.6	0.25	1909.8±2877.1	2825.8±7596.3	0.43	7020.9±11983.6	1025.6±1087.5	3277.8±9087.7	1757.3±952.1	2033.5±3027.9	0.08

The capital letters indicate a significant post hoc P value for comparison of subgroups. ALT indicates alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CRP, C-reactive protein; ICH, intracranial hemorrhage; IQR, interquartile range; IVT, intravenous thrombolysis; LAA, large artery atherosclerosis; LDH, lactate dehydrogenase; LVO, large vessel occlusion; NIHSS, National Institutes of Health Stroke Scale; SVO, small vessel occlusion; and TOAST, Trial of ORG 10172 in Acute Stroke Treatment.
*Data on patients' disposition were sparse.

Authors and Disclosures

Shima Shahjouei, MD, MPH, Georgios Tsivgoulis, MD, PhD, MSc, Ghasem Farahmand, MD, Eric Koza, MD Candidate, Ashkan Mowla, MD, Alireza Vafaei Sadr, PhD, Arash Kia, MD, Alaleh Vaghefi Far, MD, Stefania Mondello, MD, PhD, MPH, Achille Cernigliaro, PhD, MPH, Annemarei Ranta, MD, PhD, Martin Punter, PhD, MBChB, Faezeh Khodadadi, PharmD, Soheil Naderi, MD, Mirna Sabra, PhD, Mahtab Ramezani, MD, Ali Amini Harandi, MD, Oluwaseyi Olulana, MS, Durgesh Chaudhary, MBBS, Aicha Lyoubi, MD, Bruce C.V. Campbell, MD, Juan F. Arenillas, MD, Daniel Bock, MD, Joan Montaner, MD, Saeideh Aghayari Sheikh Neshin, MD, Diana Aguiar de Sousa, MD, PhD, Matthew S. Tenser, MD, Ana Aires, MD, Mercedes de Lera Alfonso, MD, Orkhan Alizada, MD, Elsa Azevedo, MD, PhD, Nitin Goyal, MD, Zabihollah Babaeepour, MD, Gelareh Banihashemi, MD, Leo H. Bonati, MD, Carlo W. Cereda, MD, Jason J. Chang, MD, Miljenko Crnjakovic, MD, Gian Marco De Marchis, MD, Massimo Del Sette, MD, Seyed Amir Ebrahimzadeh, MD, MPH, Mehdi Farhoudi, MD, Ilaria Gandoglia, MD, Bruno Gonçalves, MD, Christoph J. Griessenauer, MD, Mehmet Murat Hancı, MD, Aristeidis H. Katsanos, MD, Christos Krogias, MD, Ronen R. Leker, MD, Lev Lotman, MD, Jeffrey Mai, MD, Shailesh Male, MD, Konark Malhotra, MD, Branko Malojcic, MD, PhD, Teresa Mesquita, MD, Asadollah Mir Ghasemi, MD, Hany Mohamed Aref, MD, Zeinab Mohseni Afshar, MD, Jusun Moon, MD, Mika Niemelä, MD, PhD, Behnam Rezai Jahromi, MD, Lawrence Nolan, DO, Abhi Pandhi, MD, Jong-Ho Park, MD, João Pedro Marto, MD, Francisco Purroy, MD, PhD, Sakineh Ranji-Burachaloo, MD, Nuno Reis Carreira, MD, Manuel Requena, MD, Marta Rubiera, MD, Seyed Aidin Sajedi, MD, João Sargento-Freitas, MD, Vijay K. Sharma, MD, Thorsten Steiner, MD, Kristi Tempro, MD, Guillaume Turc, MD, PhD, Yasaman Ahmadzadeh, MD, Mostafa Almasi-Dooghaee, MD, Farhad Assarzadegan, MD, Arefeh Babazadeh, MD, MPH, Humain Baharvahdat, MD, Fabricio Buchadid Cardoso, MD, MPH, Apoorva Dev, PhD, Mohammad Ghorbani, MD, Ava Hamidi, MD, Zeynab Sadat Hasheminejad, MD, Sahar Hojjat-Anasri Komachali, MD, Fariborz Khorvash, MD, Firas Kobeissy, PhD, Hamidreza Mirkarimi, MD, Elahe Mohammadi-Vosough, MD, Debdipto Misra, MS, Ali Reza Noorian, MD, Peyman Nowrouzi-Sohrabi, PhD, Sepideh Paybast, MD, Leila Poorsaadat, MD, Mehrdad Roozbeh, MD, Behnam Sabayan, MD, PhD, Saeideh Salehizadeh, MD, Alia Saberi, MD, Mercedeh Sepehrnia, MD, Fahimeh Vahabizad, MD, Thomas Alexandre Yasuda, MD, Mojdeh Ghabaee, MD, Nasrin Rahimian, MD, MPH, Mohammad Hossein Harirchian, MD, Afshin Borhani-Haghighi, MD, Mahmoud Reza Azarpazhooh, MD, Rohan Arora, MD, Saeed Ansari, MD, Venkatesh Avula, MS, Jiang Li, MD, MPH, Vida Abedi, PhD and Ramin Zand, MD, MPH

Neurology Department, Neuroscience Institute, Geisinger Health System, PA (S. Shahjouei, A. Mowla, D.C., C.J.G., R.Z.). Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, "Attikon" University Hospital, Greece (G. Tsivgoulis, A.H.K.). Iranian Center of Neurological Research, Neuroscience Institute (G.F., S.R.-B., M. Ghabaee, M.H.H.), Neurology Department (G.F., A.V.F., M. Ghabaee), Department of Neurosurgery (S.N.), Imam Khomeini Hospital, and Neurology Department, Sina Hospital (G.B., F.V.), Tehran University of Medical Sciences, Iran. Geisinger Commonwealth School of Medicine, Scranton, PA (E.K., O.O.). Division of Stroke and Endovascular Neurosurgery, Department of Neurological Surgery, Keck School of Medicine, University of Southern California, CA (A. Mowla, M.S.T.). Department de Physique Theorique and Center for Astroparticle Physics, University Geneva, Switzerland (A.V.S.). Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, Institute for Healthcare Delivery Science, New York City, NY (A.K.). Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Italy (S. Mondello). Regional Health Authority of Sicily, Palermo, Italy (A.C.). Department of Neurology, Wellington Hospital, New Zealand and Department of Medicine, University of Otago, New Zealand (A.R., M.P.). PES University, Bangaluru, Karnataka, India (F. Khodadadi, A.D.). Neurosciences Research Center, Lebanese University/Medical School, Beirut, Lebanon (M. Sabra, F. Kobeissy). Neurology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran (M. Ramezani, A.A.H.). Neurology Department, Delafontaine Hospital, Saint-Denis, France (A.L.). Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia (B.C.V.C.). Department of Neurology, University of Valladolid, Spain (J.F.A., M.D.L.A.). Department of Cardiology, Klinikum Frankfurt Höchst, Germany (D.B.). Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain (J. Montaner). Neurology Department, Poursina Hospital, Rasht, Guilan, Iran (S.A.S.N., A.S.). Department of Neurology (D.A.d.S.) and Department of Internal Medicine (N.E.C.), Hospital de Santa Maria, University of Lisbon, Portugal. Department of Neurology, Hospital de Santa Maria, University of Lisbon, Portugal (D.A.d.S.). Department of Neurology, Centro Hospitalar Universitário de São João, Porto, Portugal (A.A., E.A.). Department of Medicine, University of Porto, Portugal (A.A., E.A.). Neurosurgery Department, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Turkey (O.A., M.M.H.). Department of Neurology, University of Tennessee (N.G., A.P., S.A.). Neurology Ward, Valiasr Hospital, Borujen, Iran (Z.B.). Department of Neurology and Stroke Unit, University Hospital Basel, Switzerland (L.H.B.). Stroke Center, Neurocenter of Southern Switzerland, Lugano (C.W.C.). Department of Critical Care Medicine, MedStar Washington Hospital Center, Washington, DC (J.J.C.). Intensive Care Unit, Department of Neurology, Clinical Hospital Dubrava, Zagreb, Croatia (M.C.). Neurorehabilitation Unit, University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, University of Basel, Switzerland (G.D.M.). Neurology Unit, Galliera Hospital, Genova, Italy (M.D.S., I.G.). Department of Radiology, Yasrebi Hospital, Kashan, Iran (S.A.E.). Neurosciences Research Center, Tabriz University of Medical Sciences, Iran (M.F.). Department of Neurology, GHU Paris Psychiatrie et Neurosciences, Université de Paris, INSERM U1266, France (B.G., G. Turc). Division of Neurology, McMaster University/Population Health Research Institute, Hamilton, ON, Canada (A.H.K.). Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Germany (C.K.). Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (R.R.L.). Department of Neurology, Albany Medical Center, NY (L.L., L.N., K.T.). Department of Neurosurgery, Georgetown University and MedStar Washington Hospital Center, DC (J. Mai). Department of Neurosurgery, Vidant Medical Center, Greenville, NC (S. Male). Department of Neurology, Allegheny Health Network, Pittsburgh, PA (K.M.). Department of Neurology, TIA Clinic, University Hospital Centre Zagreb, Zagreb School of Medicine, University of Zagreb, Croatia (B.M.). Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal (T.M., J.P.M.). Department of Anesthesiology, University of Ottawa, Canada (A.M.G.). Department of Neurology, Ain Shams University, Cairo, Egypt (H.M.A.). Infection Disease Research Center, Kermanshah University of Medical Sciences, Iran (Z.M.A.). Department of Neurology, National Medical Center, Seoul, South Korea (J. Moon). Department of Neurosurgery, Helsinki University and Helsinki University Hospital, Finland (M.N., B.R.J.). Department of Neurology, Myongji Hospital, Hanyang University College of Medicine, South Korea (J.-H.P.). Department of Neurology, Hospital Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, Spain (F.P., N.R.C.) Stroke Unit, Department of Neurology, Hospital Vall d'Hebron Barcelona, Spain (M. Requena, M. Rubiera). Department de Medicina, Universitat Autònoma de Barcelona, Spain (M. Requena, M. Rubiera). Department of Neurology, Neuroscience Research Center, Golestan University of Medical Sciences, Iran (S.A.S.). Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal (J.S.-F.). Division of Neurology, University Medicine Cluster, National University Health System, Singapore (V.K.S.). Department of Neurology, Klinikum Frankfurt Höchst, Germany (T.S.). Department of Neurology, Heidelberg University Hospital, Germany (T.S.). Hospital for Special Surgery, New York City, NY (Y.A.). Divisions of Vascular and Endovascular Neurosurgery (M.A.-D., M. Ghorbani) and Neurology (M.A.-D.), Firoozgar Hospital, Iran University of Medical Sciences, Tehran. Divisions of Vascular and Endovascular Neurosurgery (M.A.-D.) and Neurology (M.A.-D.), Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran. Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Iran (A.B.). Neurosurgical Department, Ghaem Hospital, Mashhad University of Medical Sciences, Iran (H.B.). Neurology Department, Centro Médico de Campinas, São Paulo, Brazil (F.B.C., T.A.Y.). Neurology Ward, Gheshm Hospital, Iran (A.H.). Department of Neurology, Imam Hosein Hospital, Shahid Beheshti Medical University, Tehran, Iran (Z.S.H., M. Sepehrnia). Department of Neurology, Pirooz Hospital, Gilan University of Medical Sciences, Lahijan, Iran (S.H.-A.K.). Neurology Department, Isfahan University of Medical Sciences, Iran (F. Khorvash). Program of Neurotrauma, Neuroproteomics and Biomarker Research, University of Florida (F. Kobeissy). Neurology Department, Modarres Hospital, Kashmar, Iran (H.M., E.M.-V.). Steele Institute of Health and Innovation, Geisinger Health System, PA (D.M.). Department of Neurology, Southern California Permanente Medical Group, Irvine, CA (A.R.N.). Student Research Committee (P.N.-S.) and Clinical Neurology Research Center (A.B.-H.), Shiraz University of Medical Sciences, Iran. Department of Neurology, Bou Ali Hospital, Qazvin University of Medical Sciences, Iran (S.P.). Department of Neurology, Arak University of Medical Sciences, Iran (L.P.). Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran (M. Roozbeh). Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (B.S.). Neurology Department, Salahadin Ayubi Hospital, Baneh, Iran (S. Salehizadeh). Department of Neurology, Yasrebi Hospital, Kashan, Iran (N.R.). Neurology Department, Western University, Canada (M.R.A.). Department of Neurology, Long Island Jewish Forest Hills, Queens, NY (R.A.). Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA (V. Avula, V. Abedi, J.L.). Biocomplexity Institute, Virginia Tech, Blacksburg, VA (J.L., V. Abedi).

Correspondence to
Ramin Zand, MD, MPH, Geisinger Neuroscience Institute, 100 N Academy Ave, Danville, PA 17822. Email rzand@geisinger.edu; ramin.zand@gmail.com

Disclosures
The coauthors report the following supports outside the current study: Dr Punter reports personal fees from Alexion Pharmaceuticals. Dr Arenillas reports personal fees from Boehringer Ingelheim, Pfizer, Bayer, Amgen, Daiichi-Sankyo, and Medtronic. Dr Aguiar de Sousa reports nonfinancial support from Boehringer Ingelheim. Dr Bonati reports grants from Swiss National Science Foundation, Swiss Heart Foundation, Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung, and AstraZeneca and personal fees from Claret Medical and InnovHeart. Dr Cereda reports other supports from iSchemaView and Bayer. Dr De Marchis reports other supports from Bayer and Pfizer. Dr Gonçalves reports grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil. Dr Leker reports other supports from BI, Abbott, and iSchemaView. The other authors report no conflicts.