This study reviewed data on 215 young adults aged 18-45 admitted with ischemic stroke or transient ischemic attack (TIA) to a university hospital stroke center between 2005-2010. The results showed: - High rates of traditional vascular risk factors like hypertension (20%), diabetes (11%), dyslipidemia (38%), and smoking (34%). - Extensive diagnostic testing including blood tests, echocardiograms, vessel imaging found relevant abnormalities in 136 of 203 patients on angiography and detected the likely stroke cause in nearly 90% of patients. - Common causes were cardioembolism (47%), including 17% with patent foramen ovale, and arterial lesions in the middle cerebral artery (23%),

1. ORIGINAL CONTRIBUTION
ONLINE FIRST
Ischemic Stroke and Transient Ischemic Attack
in Young Adults
Risk Factors, Diagnostic Yield, Neuroimaging, and Thrombolysis
Ruijun Ji, MD, PhD; Lee H. Schwamm, MD; Muhammad A. Pervez, MD; Aneesh B. Singhal, MD
Background: Approximately 10% to 14% of ischemic years. Relevant arterial lesions were frequently detected
strokes occur in young adults. in the middle cerebral artery (23%), internal carotid ar-
tery (13%), and vertebrobasilar arteries (13%). Cardio-
Objective: To investigate the yield of diagnostic tests, embolic stroke occurred in 47% (including 17% with iso-
neuroimaging findings, and treatment of ischemic strokes lated patent foramen ovale), and 11% had undetermined
in young adults. stroke etiology. The median National Institutes of Health
Stroke Scale score was 3 (interquartile range, 0-9) and
Design: We retrospectively reviewed data from our Get 81% had good outcome at hospital discharge. Of the 29
with the Guidelines–Stroke database from 2005 through patients receiving thrombolysis (median National Insti-
2010. tutes of Health Stroke Scale score, 14; interquartile range,
9-17), 55% had good outcome at hospital discharge and
Setting: University hospital tertiary stroke center.
none developed symptomatic brain hemorrhage.
Patients: A total of 215 consecutive inpatients aged 18
Conclusions: This study shows the contemporary pro-
to 45 years with ischemic stroke/transient ischemic attack.
The mean (SD) age was 37.5 (7) years; 51% were male. file of ischemic stroke in young adults admitted to a ter-
tiary stroke center. Stroke etiology can be determined in
Results: There were high incidence rates of hyperten- nearly 90% of patients with modern diagnostic tests. The
sion (20%), diabetes mellitus (11%), dyslipidemia (38%), causes are heterogeneous; however, young adults have
and smoking (34%). Relevant abnormalities were shown a high rate of traditional vascular risk factors. Throm-
on cerebral angiography in 136 of 203 patients, on car- bolysis appears safe and short-term outcomes are favor-
diac ultrasonography in 100 of 195, on Holter monitor- able.
ing in 2 of 192; and on hypercoagulable panel in 30 of
189 patients. Multiple infarcts were observed in 31% and Arch Neurol. Published online October 29, 2012.
were more prevalent in individuals younger than age 35 doi:10.1001/jamaneurol.2013.575
A
PPROXIMATELY 10% TO 14% advent of thrombolysis and stroke unit care,
of ischemic strokes occur in may have significantly impacted the pro-
adults ages 18 to 45 years.1-7 file of ischemic stroke in young adults. We
Stroke etiology in this studied the diagnosis, management, and
population differs by geo- outcome of ischemic stroke in young adults
graphic region and has greater heteroge- admitted to our comprehensive stroke cen-
neity than in older individuals.5,8,9 Even ter. A major objective was to determine the
within this population, the etiologic spec- yield of diagnostic tests and characterize
trum varies according to study type (hos- brain and vascular imaging findings, which,
pital based1-3 vs epidemiologic10), the ex- to our knowledge, has not been the focus
Author Affiliations: tent and availability of diagnostic evaluation, of prior studies. Author Affil
Department of Neurology, or the criteria used to ascribe etiology. To Department
Massachusetts General our knowledge, data concerning ischemic Massachuset
Hospital, Boston, Massachusetts METHODS Hospital, Bo
stroke in young adults in the United States
(Drs Ji, Schwamm, Pervez, and (Drs Ji, Schw
Singhal); and Department of
is limited to a few studies published more Singhal); and
Neurology, Capital Medical than a decade ago.2-5 Advances in stroke di- This retrospective study was approved by our Neurology, C
University, Beijing, China agnostic tests, particularly neuroimaging, re- hospital’s human research committee. We re- University, B
(Dr Ji). finement in classification schema,11 and the viewed our American Heart Association Get (Dr Ji).
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E1
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

2. Table 1. Baseline Characteristics
No. (%) No. (%)
All Male Female 18-35 y 36-45 y
(n = 215) (n = 109) (n = 106) P Value (n = 71) (n = 144) P Value
Demographics
Age, mean (SD), y 37.5 (7) 38.5 (7) 36.4 (7) .03 29.2 (5) 41.5 (3)
Sex 109 (51) 106 (49) 33 male/38 female 76 male/68 female .39
White 174 (81) 83 (76) 91 (86) .07 63 (89) 111 (77) .04
Medical history
Hypertension 42 (20) 26 (24) 16 (15) .11 6 (9) 36 (25) .004
Diabetes mellitus 23 (11) 15 (14) 8 (8) .14 3 (4) 20 (14) .03
Dyslipidemia 81 (38) 59 (54) 22 (21) Ͻ.01 26 (37) 55 (38) .82
Valvular heart disease 10 (5) 5 (5) 5 (5) Ͼ.99 3 (4) 7 (5) Ͼ.99
CAD 7 (3) 4 (4) 3 (3) Ͼ.99 0 (0) 7 (5) .10
Cardiomyopathy 7 (3) 4 (4) 3 (3) Ͼ.99 3 (4) 4 (3) .69
Atrial fibrillation 3 (1) 1 (1) 2 (2) .62 1 (1) 2 (1) Ͼ.99
CHF 2 (1) 1 (1) 1 (1) Ͼ.99 0 (0) 2 (1) Ͼ.99
Prior headaches 31 (14) 8 (7) 23 (22) .003 10 (14) 21 (15) .92
Cigarette smoking 73 (34) 37 (34) 36 (34) .99 28 (39) 45 (31) .23
Illicit drug use 26 (12) 13 (12) 13 (12) .94 13 (18) 13 (9) .05
OCP use 20 (9) 20 (19) 12 (17) 8 (6) .02
Recent pregnancy 3 (1) 3 (3) 1 (1) 2 (1) Ͼ.99
Cancer 2 (1) 1 (1) 1 (1) Ͼ.99 1 (1) 1 (1) .55
Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; OCP, oral contraceptive pill.
with the Guidelines–Stroke database12 from 2005 through 2010 ramen ovale (PFO) because of its controversial role in stroke
(n=2643 cases) to identify 215 consecutive patients ages 18 to and high detection rate in young stroke patients. Accordingly,
45 years admitted with ischemic stroke or transient ischemic PFO-associated strokes were subclassified as PFO with atrial
attack (TIA). Ischemic stroke was defined as a sudden focal neu- septal aneurysm (ASA), PFO Plus (ie, PFO and predisposing
rologic deficit with imaging-confirmed infarct, and TIA as a tran- risk for venous clot formation [eg, recent airline travel]), and
sient focal neurologic deficit without stroke on brain imaging. isolated PFO.
We excluded patients with stroke from cerebral sinovenous SPSS version 16.0 for windows was used for statistical analy-
thrombosis, subarachnoid hemorrhage, or interventions. sis. ␹2, Fisher exact, and t tests were used as appropriate. P Ͻ .05
Medical records and brain scans were reviewed by a stroke was considered statistically significant.
neurologist (R.J.), with supervision (A.B.S.). We extracted data
on patient demographics, relevant medical history (Table 1),
RESULTS
National Institutes of Health Stroke Scale (NIHSS) score at ad-
mission (obtained prospectively as per our clinical stroke pro-
tocol), diagnostic test results, in-hospital treatment, and the DEMOGRAPHICS AND RISK FACTORS
modified Rankin Scale (mRS) score at hospital discharge. A fa-
vorable outcome was defined as a mRS score of 0 to 2 at hos-
pital discharge. Of 215 patients, 203 (94%) had ischemic stroke and 12
The results of relevant blood tests were categorized as nor- (6%) had TIA. The mean (SD) age was 37.5 (7) years,
mal or abnormal based on our laboratory’s reference ranges with a nearly equal distribution of men and women in
(Table 2). Cerebrospinal fluid examination results were posi- the full cohort and in the 2 age groups. Most patients were
tive if the white blood cell count was 5/µL or greater (to con- white, as expected for our referral base in the Northeast
vert to ϫ109 per liter, multiply by 0.001) or the protein level United States. Hypertension (20%), diabetes mellitus
was greater than 0.06 g/dL (to convert to grams per liter, mul- (11%), dyslipidemia (38%), and smoking (34%) were
tiply by 10.0). Transthoracic and transesophageal echocardi- common (Table 1). There were high frequency rates of
ography reports were reviewed for cardioembolic sources, as prior headache (14%), illicit drug use (12%), and oral
described previously.11 Electrocardiography and Holter moni-
contraceptive use (9%). Hypertension and diabetes melli-
toring were considered positive if they showed atrial fibrillation/
flutter. Lower-extremity Doppler ultrasonography and pelvic tus were more common in the 36-year-old to 45-year-
magnetic resonance venography were considered positive if deep old age group, and illicit drug use more common in the
vein thrombosis was documented. 18-year-old to 35-year-old age group. Men had a higher
We reviewed diffusion-weighted imaging and fluid- frequency of dyslipidemia, while women had a higher fre-
attenuated inversion recovery sequences for lesion topogra- quency of prior headaches. Three patients had postpar-
phy. If magnetic resonance imaging was not performed, com- tum stroke, and 2 had cancer-associated strokes.
puted tomography was reviewed. The presence, number,
location, laterality, and arterial territory of ischemic lesions were DIAGNOSTIC TESTS
noted. Transfemoral, computed tomographic, and magnetic reso-
nance angiography were reviewed for the presence of occlu-
sion or stenosis in the culprit artery. Most of the patients underwent extensive blood tests,
Stroke subtyping11 was based on information available at hos- Holter monitoring, and echocardiography (Table 2,
pital discharge. Special consideration was given to patent fo- Figure). Cerebrospinal fluid examination and toxicol-
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E2
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

3. Table 2. Diagnostic Test Results
No. (%) No. (%)
Yield,
Diagnostic Test No./No. Male Female P Value 18-35 y 36-45 y P Value
Blood
Hypercoagulable panel 30/189 10 (11) 20 (21) .05 12 (21) 18 (14) .23
Functional protein CϽ70% 2/189 1 (1) 1 (1) Ͼ.99 1 (2) 1 (1) .52
Functional protein SϽ70% 23/189 5 (5) 18 (18) .004 9 (16) 14 (11) .35
Functional antithrombin IIIϽ80% 3/189 1 (1) 2 (2) Ͼ.99 1 (2) 2 (2) Ͼ.99
Factor V Leiden mutation 4/189 3 (3) 1 (1) .37 2 (3) 2 (2) .59
Prothrombin 20210 mutation 1/189 0 (0) 1 (1) Ͼ.99 0 (0) 1 (1) Ͼ.99
Lipid panel
Total cholesterol Ͼ200 mg/dL 34/205 25 (24) 9 (9) .004 11 (17) 23 (17) .93
LDL cholesterol Ͼ130 mg/dL 28/205 21 (20) 7 (7) .006 10 (15) 18 (13) .75
HDL cholesterol Ͻ35 mg/dL 43/205 34 (33) 9 (9) Ͻ.01 12 (18) 31 (22) .58
Lipoprotein (a)Ͼ3 mg/dL 22/174 14 (16) 8 (9) .17 5 (9) 17 (14) .39
Hemoglobin A1c Ͼ6.4% 31/167 20 (23) 11 (14) .17 7 (14) 24 (21) .32
Homocysteine Ͼ1.62 mg/L 14/184 11 (12) 3 (3) .03 5 (9) 9 (7) .69
High-sensitive CRPϾ1.2 mg/L 22/203 9 (9) 13 (13) .38 5 (7) 17 (13) .22
Anticardiolipin IgGϾ15 GPL 11/207 6 (6) 5 (5) .77 4 (6) 7 (5) .74
Anticardiolipin IgMϾ15 MPL 18/207 3 (3) 15 (15) .003 5 (8) 13 (9) .73
Antinuclear antibody 3/86 2 (6) 1 (2) .59 2 (6) 1 (2) .57
Lupus antibody 1/8 0 (0) 1 (50) .25 0 (0) 1 (33) .38
Serum/urine toxicology 7/136 2 (3) 5 (8) .25 4 (8) 3 (4) .43
CSF examination 5/34 4 (27) 1 (5) .15 3 (17) 2 (13) Ͼ.99
Holter monitoring 2/192 1 (1) 1 (1) Ͼ.99 1 (2) 1 (1) .54
Echocardiography, TTE/TEE
Vegetation or mass 4/195 3 (3) 1 (1) .62 3 (5) 1 (1) .11
PFO 96/195 37 (37) 59 (62) .001 37 (57) 59 (45) .16
PFO with ASA 13/96 8 (22) 5 (8) .12 5 (14) 8 (14) Ͼ.99
Isolated PFO 83/96 29 (78) 54 (92) .12 32 (86) 51 (86) Ͼ.99
Abbreviations: ASA, atrial septal aneurysm; CRP, C-reactive protein; CSF, cerebrospinal fluid; PFO, patent foramen ovale; TEE, transesophageal
echocardiography; TTE, transthoracic echocardiography.
Conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; CRP to nanomoles per liter, multiply by 9.524; hemoglobin A1c to
proportion of total hemoglobin, multiply by 0.01; and homocysteine to micromoles per liter, multiply by 7.397.
100
90
80
70
Patients, %
60
50
40
30
20
10
0
Hypercoagulation Serum/Urine Vasculitis CSF Echocardiography Holter CT or MRI Angiography
Panel Toxicology Panel Examination Monitoring
Screening
Figure. Diagnostic tests in young adults with ischemic stroke. The lighter bars show the percentage of patients who underwent a certain test and the black bars
show the percentage of tests showing a positive result relative to stroke etiology (ie, diagnostic yield). CSF indicates cerebrospinal fluid; CT, computed
tomography; MRI, magnetic resonance imaging. See “Methods” section for individual tests included under each panel.
ogy screening were performed when clinically indi- Hypercoagulable panel screening results were posi-
cated. The diagnostic yield was relatively low for Holter tive in 16% of patients, including 3% with hereditary pro-
monitoring (1%), toxicology screening (5%), and vas- thrombin gene or factor V Leiden mutations and 13% with
culitis panel (Ͻ5%), as well as relatively high for echo- low protein C, protein S, or antithrombin III levels. The
cardiography (51%) and angiography (64%). Lipid panel most common abnormality was a low protein S level,
result abnormalities were significantly more common in mostly in women (18% vs 5%; P = .004), including 6
men. Cerebrospinal fluid examination results were ab- women taking oral contraceptives. Eight patients had per-
normal in 5 of 34 patients (15%). sistently low levels on follow-up testing.
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E3
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

4. Table 3. Brain and Vascular Imaging
No. (%) No. (%)
All Male Female 18-35 y 36-45 y
Lesion Location (n = 203) (n = 103) (n = 100) P Value (n = 69) (n = 134) P Value
Supratentorial 158 (78) 69 (67) 89 (89) Ͻ.001 53 (77) 105 (78) .80
Multiple 62 (31) 32 (31) 30 (30) .87 28 (41) 34 (25) .03
Laterality
Left side 111 (55) 52 (51) 59 (59) .22 37 (54) 74 (55) .83
Right side 77 (38) 43 (42) 34 (34) .26 26 (38) 51 (38) .96
Midline, brainstem 15 (7) 8 (8) 7 (7) .83 6 (9) 9 (7) .61
Cerebral Angiography All Male Female 18-35 y 36-45 y
(n = 212) (n = 108) (n = 104) (n = 69) (n = 143)
No significant abnormality 76 (36) 41(38) 35 (34) .57 16 (23) 60 (42) .008
Internal carotid artery 27 (13) 13 (12) 14 (13) .83 8 (12) 19 (13) .73
Origin 20 (9) 10 (9) 10 (10) Ͼ.99 4 (6) 16 (11) .21
Terminus, T lesion 7 (3) 3 (3) 4 (4) .72 4 (6) 3 (2) .22
Middle cerebral artery 59 (28) 25 (23) 34 (33) .12 24 (35) 35 (24) .12
M1/M2 48 (23) 20 (19) 28 (27) .14 20 (29) 28 (20) .13
M3/M4 11 (5) 5 (5) 6 (6) .71 4 (6) 7 (5) .75
Anterior cerebral artery 4 (2) 4 (4) 0 (0) .12 1 (1) 3 (2) Ͼ.99
Posterior cerebral artery 9 (4) 3 (3) 6 (6) .33 4 (6) 5 (3) .48
Basilar artery 5 (2) 3 (3) 2 (2) Ͼ.99 2 (3) 3 (2) .66
Vertebral artery 8 (4) 7 (6) 1 (1) .07 2 (3) 6 (4) Ͼ.99
PICA/AICA/SCA 7 (3) 5 (5) 2 (2) .45 5 (7) 2 (1) .04
Multiple arteries 17 (8) 7 (6) 10 (10) .40 7 (10) 10 (7) .43
Abbreviations: AICA, anterior-inferior cerebellar artery; PICA, posterior-inferior cerebellar artery; SCA, superior-cerebellar artery.
Contrast transthoracic echocardiography was per- (Ͼ70% by visual estimate), or underlying arteriopa-
formed in 91% of patients and transesophageal echocar- thies such as premature atherosclerosis (Table 4) or ce-
diography in 40%. A positive transthoracic echocardi- rebral artery dissection or Moyamoya disease (Table 5)
ography or transesophageal echocardiography result was were observed in 64% of patients, including 42% with
documented in 100 of 195 patients (51%). Ninety-six of angiographic abnormalities in the anterior circulation ar-
100 patients with a positive echocardiography result had teries, 14% in the posterior circulation arteries, and 8%
a PFO, including 13 with ASA and 83 without ASA. Pat- with diffuse abnormalities from conditions such as re-
ent foramen ovale was implicated as a stroke etiology in versible cerebral vasoconstriction syndrome. Proximal
76 patients and was considered incidental in cases with middle cerebral artery lesions were most common (23%),
alternate causes such as carotid dissection. followed by lesions of the internal carotid artery and the
vertebrobasilar system.
ISCHEMIC LESION TOPOGRAPHY
STROKE ETIOLOGY
Computed tomography was performed in 97% of pa-
tients and magnetic resonance imaging in 98%; 203 pa- The most common stroke subtype was cardioembolic
tients had brain infarctions. Single infarcts were ob- (47%): 5% were PFO with ASA, 14% were PFO Plus, 17%
served in 69% (Table 3). Multiple infarcts were more were isolated PFO, and 11% had established cardioem-
common in the 18-year-old to 35-year-old age group (41% bolic sources (Table 4 and Table 5). Large-artery athero-
vs 25%; P = .03). Supratentorial infarcts were more com- sclerosis and small-vessel disease were relatively uncom-
mon in women (89% vs 67%; P Ͻ .01). Patients with su- mon, and they occurred exclusively in patients older than
pratentorial infarcts had significantly higher NIHSS scores age 36 years. More than one-third of patients proved to
at admission compared with those with infratentorial in- have other well-defined causes. Multiple etiologies were
farcts (median NIHSS score, 7 vs 3, respectively; P Ͻ .001). found in 4 patients (2%). The etiology remained unde-
Of the affected arterial territories, 56% were middle ce- termined in only 9%, including 18 patients with crypto-
rebral, 3% were anterior cerebral, 7% were combined genic stroke despite a thorough workup and 1 patient
middle and anterior cerebral, 8% were posterior cere- who died before testing was completed.
bral, 21% were vertebrobasilar, and 5% were multiple.
TREATMENT AND OUTCOME
NEUROVASCULAR IMAGING
Four patients underwent hemicraniectomy for malig-
Transfemoral, computed tomographic, or magnetic reso- nant brain edema. At the time of hospital discharge, 87%
nance cerebral angiography was performed in 99% of pa- of patients were taking antiplatelet agents or anticoagu-
tients and 20% additionally underwent vascular ultraso- lants (5% were on both), and 32% were taking statins.
nography studies. Embolic occlusion, severe stenosis The median NIHSS score at admission was 3 (interquar-
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E4
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

5. Table 4. Stroke Subtypes, Treatments, and Outcomes
No. (%) No. (%)
All Male Female 18-35 y 36-45 y
(n = 215) (n = 109) (n = 106) P Value (n = 71) (n = 144) P Value
Subtype
Large-vessel atherosclerosis 4 (2) 1 (1) 3 (3) .37 0 (0) 4 (3) .31
Small-vessel disease 14 (7) 9 (8) 5 (5) .29 0 (0) 14 (10) .006
Cardioembolism 100 (47) 44 (40) 56 (53) .07 39 (55) 61 (42) .08
Other determined etiology 74 (34) 39 (36) 35 (33) .67 24 (34) 50 (35) .89
Multiple etiologies 4 (2) 2 (2) 2 (2) Ͼ.99 3 (4) 1 (1) .11
Undetermined 18 (8) 14 (13) 4 (4) .02 4 (6) 14 (10) .31
Incomplete evaluation 1 (1) 0 (0) 1 (1) .49 1 (1) 0 (0) .33
In-hospital treatment
Antiplatelet 133 (62) 61 (56) 72 (68) .07 46 (65) 87 (60) .53
Anticoagulant 65 (30) 34 (31) 31 (29) .76 24 (34) 41 (29) .42
Statins 68 (32) 39 (36) 29 (27) .24 22 (31) 46 (32) .77
Intravenous thrombolysis 19 (11) 15 (14) 8 (8) .14 10 (14) 13 (9) .26
Intra-arterial recanalization 10 (6) 7 (6) 5 (5) .59 3 (4) 9 (6) .76
Hemicraniectomy 4 (2) 4 (4) 0 (0) .12 1 (1) 3 (2) Ͼ.99
Discharge mRS score
0-2 174 (81) 85 (78) 89 (8) .26 62 (87) 112 (78) .09
3-4 12 (6) 6 (6) 6 (6) .96 2 (3) 10 (7) .35
5-6 29 (14) 18 (17) 11 (10) .19 7 (10) 22 (15) .27
Abbreviation: mRS, modified Rankin Scale.
had good clinical outcome (mRS score, 0-2). Poor out-
Table 5. Cardioembolic and Other Determined Etiologies come (mRS score, 5-6) was documented in 29 patients,
including 7 who died (Table 4).
No. (%) Thrombolysis was administered to 29 patients (13.5%),
Cardioembolic 100 (47) including 19 who received intravenous tissue plasmino-
PFO associated 76 (35.3) gen activator therapy alone, 6 who received intra-
PFO with ASA 11 (5.1) arterial thrombolysis, and 4 who received combined in-
PFO Plus 29 (13.5)
Isolated PFO 36 (16.7)
travenous/intra-arterial thrombolysis. Their median NIHSS
Cardiomyopathy 10 (4.7) score at admission was 14 (interquartile range, 9-17) and
Valvular heart disease 7 (3.3) mean (SD) length of stay was 7.1(5) days (range, 1-20
Fibroelastoma 3 (1.4) days). Angiographic occlusion was documented in 93%.
Infective endocarditis 1 (0.5) Sixteen patients (55%) had good outcome, and none de-
Myocardial infarction/left ventricular thrombus 2 (0.9) veloped symptomatic intracerebral hemorrhage.
Ventricular septal aneurysm 1 (0.5)
Other determined 74 (34)
Dissection 29 (13.5) COMMENT
Carotid 20 (9.3)
Vertebral/basilar 9 (4.2)
Reversible cerebral vasoconstriction syndromes 11 (5.1)
Moyamoya disease 7 (3.3)
Our study shows the contemporary profile of ischemic
Hypercoagulable state 6 (2.8) stroke in young adults in a tertiary referral center in the
Factor V Leiden mutation 3 (1.4) Northeast United States. The age and sex distribution in
Protein S deficiency 2 (0.9) our cohort is similar to that of other US-based studies
Antithrombin III deficiency 1 (0.45) with a similar age range.2,3 However, studies with a
Primary angiitis of central nervous system 5 (2.3) higher age cutoff have found a higher proportion of
Drug-induced stroke 5 (2.3)
Migrainous infarction 3 (1.4)
males.1 Similar to recent studies,1,7 there were high inci-
Antiphospholipid antibody syndrome 2 (0.9) dence rates (compared with young individuals without
Thrombosed aneurysm 2 (0.9) stroke13) of modifiable stroke risk factors such as dyslip-
Hyperhomocysteinemia, 176 µmol/L, MTHFR 1 (0.45) idemia, hypertension, diabetes mellitus, and smoking,
gene mutation which contribute to higher rates of recurrent vascular
Radiation arteriopathy 1 (0.45) events.14 Despite the relatively high incidences of modi-
Essential thrombocytosis 1 (0.45)
Cancer 1 (0.45)
fiable risk factors, stroke etiology was attributed to large-
artery atherosclerosis and small-vessel disease in less
Abbreviations: ASA, atrial septal aneurysm; PFO, patent foramen ovale. than 10%, suggesting that vascular risk factors increase
the susceptibility to stroke from other causes. These data
re-emphasize the need to implement evidence-based
tile range, 0-9). The mean (SD) length of stay was 6.2 stroke prevention targeting traditional risk factors in
(6) days (range, 1-54 days). More than 80% of patients young adults.1,7
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E5
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

6. A novel feature is that 99% of patients were adjudi- stroke in young individuals.23 These data justify routine
cated as having a complete diagnostic workup. An ex- cerebrovascular imaging in young adults with stroke-
tensive battery of tests was routinely performed, which like symptoms.
might explain why we found a relatively low rate of un- In our study, nearly 15% of patients required con-
determined stroke etiology compared with other stud- stant nursing care or died before hospital discharge.
ies.1,3,8 The use of a validated algorithm11,15 to classify eti- Young stroke survivors are known to develop substan-
ology into standard TOAST (Trial of Org 10172 in Acute tial emotional and socioeconomic issues,24 and more
Stroke Treatment) subtypes lends confidence to our re- than 10% develop recurrent vascular events within 5
sults. Patent foramen ovale–associated strokes were con- years.14 From the perspective of secondary prevention, it
sidered cardioembolic, as per TOAST criteria.16 Unlike is reassuring that 92% of our patients received antiplate-
prior publications, 1 7 we further classified PFO- let or anticoagulant therapy, or both, at hospital dis-
associated strokes based on the presumed risk level (ie, charge. However, the ideal duration, safety, and efficacy
PFO with ASA, PFO Plus, and isolated PFO). This sub- of these medications in young stroke patients is not
classification was justified by the high detection rate of clear. Cholesterol-lowering medications were adminis-
PFO in our study, the possible significance of transient tered to only 32% of patients, possibly reflecting uncer-
hypercoagulable panel abnormalities in patients with PFO, tainties in exposing young adults with nonatheroscle-
and existing uncertainties about PFO treatment,17 as well rotic stroke to long-term statin therapy. A relatively
as the relationship between PFO and stroke. This level large number received thrombolysis, and no patient
of detail will allow reclassification of isolated PFO or PFO developed hemorrhagic complications; however, to our
Plus from cardioembolic to undetermined, if the stroke knowledge, there is little data concerning the safety and
risk attributable to PFO changes in the future. efficacy of thrombolysis in young adults or those with
Young adults with stroke typically undergo a wide spec- relatively uncommon stroke etiologies. Such knowledge
trum of diagnostic tests, but there is little knowledge about gaps need to be addressed in prospective studies, and
the tests’ yield or cost-effectiveness. We found a low yield treatment and prevention guidelines that specifically
for inpatient Holter monitoring, serum/urine toxicol- address stroke in young adults need to be developed.
ogy, and vasculitis panel tests. Hypercoagulable panel re- In conclusion, this study provides contemporary in-
sults at admission were positive in 30 patients, 17 of whom formation on risk factors, diagnostic tests, imaging, throm-
had transient hypercoagulable states; the rest had per- bolysis, and secondary prevention of ischemic stroke in
sistent abnormalities or inherited mutations. Conceiv- young adults. The clinical setting in a tertiary stroke cen-
ably, transient reductions in the levels of these clotting ter limits the generalizability of our results. Neverthe-
cascade proteins elevate stroke risk, particularly in pa- less, our data may prove useful in developing cost-
tients with PFO, which further justifies the PFO Plus cat- effective diagnostic strategies, understanding the
egory used in our study. We note that the association be- pathophysiology, and refining the management of ische-
tween thrombophilia and stroke remains controversial, mic stroke in young adults.
and the consequences of treating young adults with an-
ticoagulants based on such results needs to be carefully Accepted for Publication: May 16, 2012.
considered.18 Cardiac ultrasonography was positive in 100 Published Online: October 29, 2012. doi:10.1001
patients (51%), including 96 with a PFO. The true diag- /jamaneurol.2013.575
nostic yield of cardiac ultrasonography is probably much Correspondence: Aneesh B. Singhal, MD, ACC-729C, De-
lower because PFO was deemed incidental in patients with partment of Neurology, Massachusetts General Hospi-
alternate etiologies and because the significance of an tal, Boston, MA 02114 (asinghal@partners.org).
isolated PFO remains uncertain.19 Our data reflect the Author Contributions: Study concept and design: Sing-
diagnostic yield of tests in a real world academic stroke hal. Acquisition of data: Ji, Schwamm, Pervez, and Sing-
setting. Further studies are warranted to determine cost- hal. Analysis and interpretation of data: Ji, Schwamm, Per-
effectiveness and design appropriate stroke diagnostic al- vez, and Singhal. Drafting of the manuscript: Ji, Pervez,
gorithms in young adults. and Singhal. Critical revision of the manuscript for impor-
The detailed analysis of brain and vascular imaging tant intellectual content: Ji, Schwamm, Pervez, and Sing-
provides insights into the pathophysiology of stroke in hal. Statistical analysis: Ji and Singhal. Administrative, tech-
this population. Single infarctions were more common nical, and material support: Schwamm. Study supervision:
in the 36-year-old to 45-year-old age group, consistent Schwamm, Pervez, and Singhal.
with the higher incidence of small-vessel disease and ath- Conflict of Interest Disclosures: Dr Schwamm has served
erosclerosis in this age group. Both age groups showed as a consultant for the Massachusetts Department of
a similar distribution of supratentorial vs infratentorial Health and Lundbeck International Steering Commit-
infarcts. In contrast, Putaala et al1 found no significant tee, and as an unpaid chair for the American Heart As-
difference in the number of single infarcts between age sociation’s Get with the Guidelines–Stroke program.
groups, and older individuals had a higher incidence of Funding/Support: This study was funded by grants
anterior-circulation lesions. These differences may be ex- R01NS051412 and R21NS077442 from the National In-
plained by the distinct populations and different age stitutes of Health/National Institute of Neurological Dis-
groups being studied. We found a high yield of vascular orders and Stroke; grant 30700240 from the National Na-
imaging (substantially higher than in the general stroke ture Science Foundation of China; and grant 2008B30
population20,21 or thrombolysed patients22), and arte- from the Nova Program, Beijing Science and Technol-
riopathies are known to be the most common cause of ogy Commission.
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E6
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

7. 12. Schwamm LH, Fonarow GC, Reeves MJ, et al. Get With the Guidelines–Stroke is
REFERENCES associated with sustained improvement in care for patients hospitalized with acute
stroke or transient ischemic attack. Circulation. 2009;119(1):107-115.
1. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 13. Cheng YC, O’Connell JR, Cole JW, et al. Genome-wide association analysis of
15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke. ischemic stroke in young adults. G3 (Bethesda). 2011;1(6):505-514.
2009;40(4):1195-1203. 14. Putaala J, Haapaniemi E, Metso AJ, et al. Recurrent ischemic events in young
2. Adams HP Jr, Kappelle LJ, Biller J, et al. Ischemic stroke in young adult: expe- adults after first-ever ischemic stroke. Ann Neurol. 2010;68(5):661-671.
rience in 329 patients enrolled in the Iowa Registry of stroke in young adults. 15. Arsava EM, Ballabio E, Benner T, et al; International Stroke Genetics Consor-
Arch Neurol. 1995;52(5):491-495. tium. The Causative Classification of Stroke system: an international reliability
3. Kittner SJ, Stern BJ, Wozniak M, et al. Cerebral infarction in young adults: the and optimization study. Neurology. 2010;75(14):1277-1284.
Baltimore-Washington Cooperative Young Stroke Study. Neurology. 1998; 16. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute
50(4):890-894. ischemic stroke: definitions for use in a multicenter clinical trial: TOAST: Trial of
4. Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the north-
Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35-41.
ern Manhattan stroke study. Stroke. 2002;33(12):2789-2793.
17. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or
5. Qureshi AI, Safdar K, Patel M, Janssen RS, Frankel MR. Stroke in young black
medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med.
patients: risk factors, subtypes, and prognosis. Stroke. 1995;26(11):1995-
2012;366(11):991-999.
1998.
18. Morris JG, Singh S, Fisher M. Testing for inherited thrombophilias in arterial stroke:
6. Naess H, Nyland HI, Thomassen L, Aarseth J, Nyland G, Myhr KM. Incidence
can it cause more harm than good? Stroke. 2010;41(12):2985-2990.
and short-term outcome of cerebral infarction in young adults in western Norway.
19. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke:
Stroke. 2002;33(8):2105-2108.
7. George MG, Tong X, Kuklina EV, Labarthe DR. Trends in stroke hospitalizations incidental or pathogenic? Stroke. 2009;40(7):2349-2355.
and associated risk factors among children and young adults, 1995-2008. Ann 20. Maas MB, Furie KL, Lev MH, et al. National Institutes of Health Stroke Scale score
Neurol. 2011;70(5):713-721. is poorly predictive of proximal occlusion in acute cerebral ischemia. Stroke. 2009;
8. Varona JF, Guerra JM, Bermejo F, Molina JA, Gomez de la Camara A. Causes of
´ 40(9):2988-2993.
ischemic stroke in young adults, and evolution of the etiological diagnosis over 21. Shrier DA, Tanaka H, Numaguchi Y, Konno S, Patel U, Shibata D. CT angiogra-
the long term. Eur Neurol. 2007;57(4):212-218. phy in the evaluation of acute stroke. AJNR Am J Neuroradiol. 1997;18(6):
9. You RX, McNeil JJ, O’Malley HM, Davis SM, Thrift AG, Donnan GA. Risk factors 1011-1020.
for stroke due to cerebral infarction in young adults. Stroke. 1997;28(10):1913- 22. Lee KY, Han SW, Kim SH, et al. Early recanalization after intravenous adminis-
1918. tration of recombinant tissue plasminogen activator as assessed by pre- and post-
10. Kristensen B, Malm J, Carlberg B, et al. Epidemiology and etiology of ischemic thrombolytic angiography in acute ischemic stroke patients. Stroke. 2007;38
stroke in young adults aged 18 to 44 years in northern Sweden. Stroke. 1997; (1):192-193.
28(9):1702-1709. 23. Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral
11. Ay H, Furie KL, Singhal A, Smith WS, Sorensen AG, Koroshetz WJ. An evidence- arteriopathies. Cephalalgia. 2011;31(10):1067-1070.
based causative classification system for acute ischemic stroke. Ann Neurol. 2005; 24. Leys D, Bandu L, Henon H, et al. Clinical outcome in 287 consecutive young adults
´
58(5):688-697. (15 to 45 years) with ischemic stroke. Neurology. 2002;59(1):26-33.
ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COM
E7
©2012 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012