Population-based study of wake-up strokes
J. Mackey, MD
D. Kleindorfer, MD
H. Sucharew, PhD
C.J. Moomaw, PhD
B.M. Kissela, MD
K. Alwell, BSN
M.L. Flaherty, MD
D. Woo, MD
P. Khatri, MD
O. Adeoye, MD
S. Ferioli, MD
J.C. Khoury, PhD
R. Hornung, DPH
J.P. Broderick, MD
Objective: Previous studies have estimated that wake-up strokes comprise 8% to 28% of all
ischemic strokes, but these studies were either small or not population-based. We sought to
establish the proportion and event rate of wake-up strokes in a large population-based study and
to compare patients who awoke with stroke symptoms with those who were awake at time of
Methods: First-time and recurrent ischemic strokes among residents of the Greater Cincinnati/
Northern Kentucky region (population 1.3 million) in 2005 were identified using International
Classification of Diseases–9 codes 430–436 and verified via study physician review. Ischemic
strokes in patients aged 18 years and older presenting to an emergency department were in-
cluded. Baseline characteristics were ascertained, along with discharge modified Rankin Scale
scores and 90-day mortality.
Results: We identified 1,854 ischemic strokes presenting to an emergency department, of which
273 (14.3%) were wake-up strokes. There were no differences between wake-up strokes and all
other strokes with regard to clinical features or outcomes except for minor differences in age and
baseline retrospective NIH Stroke Scale score. The adjusted wake-up stroke event rate was
26.0/100,000. Of the wake-up strokes, at least 98 (35.9%) would have been eligible for throm-
bolysis if arrival time were not a factor.
Conclusions: Within our population, approximately 14% of ischemic strokes presenting to an
emergency department were wake-up strokes. Wake-up strokes cannot be distinguished from
other strokes by clinical features or outcome. We estimate that approximately 58,000 patients
with wake-up strokes presented to an emergency department in the United States in 2005.
CI ? confidence interval; ED ? emergency department; GEE ? generalized estimating equations; mRS ? modified Rankin
Scale; rNIHSS ? NIH Stroke Scale score estimated retrospectively; tPA ? tissue plasminogen activator.
IV tissue plasminogen activator (tPA) remains the only medication approved by the Food and
Drug Administration for the treatment of ischemic stroke. The original National Institute of
Neurological Disorders and Stroke study restricted tPA use to 3 hours following known symp-
tom onset,1and the recent European Cooperative Acute Stroke Study 3 study extended that
window to 4.5 hours in selected patients.2Patients who go to sleep healthy and wake up with
symptoms beyond this time window are not eligible for treatment based on these time restric-
tions. Previous studies have estimated that wake-up strokes comprise 8% to 28% of all isch-
emic strokes,3-14but these studies either were not population-based or were relatively small.
Some of these studies have suggested differences between wake-up strokes and non-wake-up
strokes, reporting that wake-up strokes had greater initial stroke severity6,13and were more
likely to have a poor outcome,10,13while other studies have found no appreciable differences.8,9
From the Departments of Neurology (J.M., D.K., C.J.M., B.M.K., K.A., M.L.F., D.W., P.K., S.F., J.P.B.) and Emergency Medicine (O.A., R.H.),
University of Cincinnati College of Medicine; and Division of Biostatistics and Epidemiology (H.S., J.C.K.), Cincinnati Children’s Hospital,
Study funding: Supported by the NIH/NINDS R01 NS030678.
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Jason
Mackey, University of Cincinnati,
Department of Neurology, 260
Stetson St, Suite 2300 ML0525,
Cincinnati, OH 45219
Copyright © 2011 by AAN Enterprises, Inc.
We sought to establish the proportion and
event rate of wake-up strokes within a large
biracial population and to evaluate possible
differences between wake-up and non-
wake-up strokes. We also sought to establish
how many patients with wake-up strokes
would have been eligible for tPA if time were
not a factor.
METHODS The Greater Cincinnati/Northern Kentucky re-
gion includes 2 southwestern Ohio counties and 3 contiguous
Kentucky counties bordering the Ohio River. Its biracial popula-
tion of approximately 1.3 million is largely representative of the
United States in terms of age, proportion of black subjects, and
economic status.15There were 17 hospitals active in this area in
2005. While residents of surrounding counties may seek care at
these hospitals, only residents of the 5 study counties were eligi-
ble for this analysis. Previous studies have shown that residents of
these 5 counties who have a stroke seek care at these hospitals
rather than going to more distant hospitals.15
Standard protocol approvals, registrations, and patient
consents. This study was approved by the Institutional Review
Board of all participating hospitals.
A detailed description of the epidemiologic methods employed
for the Greater Cincinnati/Northern Kentucky Stroke Study has
been described previously.15-17Briefly, study nurses abstracted the
medical records of all area residents who were either inpatients or
discharged from an emergency department (ED) with primary or
secondary stroke-related International Classification of Disease,
ninth revision, discharge diagnoses 430–436 at the 17 area hospi-
tals. Strokes not found through this methodology were ascertained
via screening of all stroke-related visits to public health clinics,
hospital-based outpatient clinics, and family practice centers. Fur-
ther monitoring involved examination of records of potential stroke
cases in a random sample of 51 of the 832 primary care physicians’
offices and 25 of the 126 nursing homes in the Greater Cincinnati/
Northern Kentucky region.
To qualify as a case, a patient must have met clinical criteria
adapted from the Classification of Neurological Disorders III18
and from previous epidemiologic studies of stroke in Rochester,
MN.19Charts were screened for an additional 60 days beyond
the end of the study period to capture patients with a stroke
during the study period but not yet discharged from the hospital.
A study physician reviewed every abstract and all available neuro-
imaging studies to determine whether a stroke had occurred.
We restricted the present study group to adult patients (age
18 years and older) with acute ischemic stroke who presented to
an ED because thrombolysis outside an ED setting is difficult.
Both first-time and recurrent ischemic stroke events were in-
cluded. Transient ischemic attacks, defined as symptoms lasting
less than 24 hours without neuroradiologic evidence of infarc-
tion, were not included in this analysis. The onset of stroke
symptoms had to occur within the calendar year 2005.
The abstractors recorded the date and time of stroke onset, if
known. If onset time was unknown, the following mutually ex-
clusive options were available for estimation of onset: “awoke
with symptoms,” “presentation ?24 hours after onset time,” “af-
ter midnight” (defined as 00:01 AM to 06:00 AM), “morning”
(06:01 AM to noon), “afternoon” (12:01 PM to 18:00 PM), and
“evening” (18:01 PM to midnight). Stroke severity was repre-
sented by using a validated method20,21for estimating the NIH
Stroke Scale Score retrospectively (rNIHSS) by review of the
physician examination as documented in the emergency depart-
ment evaluation. Clinical outcome was assessed using hospital
discharge modified Rankin Scale scores (mRS) and 90-day mor-
The abstractors also recorded data corresponding to non-time-
related exclusion criteria for IV thrombolysis. Patients were consid-
ered eligible for tPA if they met the standard inclusion/exclusion
criteria as per the current standard of care.22Variables pertinent to
tPA exclusion that were not uniformly gathered in our abstracting
urinary tract hemorrhage within 3 months, arterial puncture at a
noncompressible site in the previous 7 days, and evidence of active
bleeding or acute trauma on examination.
Data were managed and analyzed using SAS®, versions 8.02
and 9.2, respectively (SAS Institute, Cary, NC). Population esti-
mates were obtained by including sampling weights in all analy-
ses. The relationships of demographic and clinical characteristics
with stroke type (wake-up and non-wake-up) were analyzed with
generalized estimating equations (GEE) to account for multiple
stroke occurrences in some patients as well as for the sampling
weights for the cases ascertained from physicians’ offices and
nursing homes.23The working correlation structure that gave the
best model fit was obtained. A binary or multinomial distribu-
tion was specified for categorical variables, as appropriate. Multi-
ple logistic regression analysis with GEE was used to examine
outcome differences between wake-up strokes and strokes that
occurred when the patient was awake after adjusting for age, sex,
race, prestroke mRS, rNIHSS, and prior atrial fibrillation. Cova-
riates were determined a priori, as having been shown to be asso-
ciated with the outcome in other studies, or if differences were
observed between wake-up and non-wake-up strokes at a p value
?0.25. We also calculated an event rate for wake-up strokes
presenting to an ED with age, sex, and race adjustment to the
2000 US Census. The event rate was calculated for adults only
(age ?18). Extrapolation to the US population was based on an
estimated total population of 296 million in 2005,24with ap-
proximately 25% of the population younger than 18.25Data are
reported as raw quantiles, raw frequencies with weighted per-
centages, and weighted means and standard errors.
RESULTS We identified 1,778 adult area residents,
with 1,854 first-ever and recurrent ischemic strokes
that were first evaluated in an ED in 2005; 273
wake-up strokes (14.3%, 95% confidence interval
[CI] 12.7–15.9) occurred in 271 subjects. Seventy-
three patients had more than one stroke identified
during 2005; 70 patients had 2 strokes reported dur-
ing the year and 3 patients had 3 strokes. Eighteen
patients had both a wake-up stroke and a non-
wake-up stroke during the year. The exact times of
stroke onset and arrival to the ED were recorded for
637 non-wake-up strokes, of which 428 presented to
the ED within 3 hours of onset and 209 presented
beyond 3 hours of stroke onset. Of the 944 non-
wake-up strokes without a documented time of onset
to arrival, 362 had an estimated time of stroke in one
of the 6-hour windows, 358 presented to the ED
greater than 24 hours after onset, 219 had no esti-
mate of stroke onset, and 5 had no recorded time of
arrival to the ED. There were 11 cases ascertained
Neurology 76May 10, 2011
through out-of-hospital surveillance. The adjusted
event rate of wake-up strokes presenting to an ED
was 26.0/100,000 (95% CI 22.9–29.1).
A comparison of the baseline characteristics of
wake-up stroke patients with all others is found in
table 1. Compared with the non-wake-up stroke
group, wake-up stroke patients were older (72.3 ?
0.83 years vs 70.0 ? 0.48 years; p ? 0.01) and had
higher baseline rNIHSS scores (median [IQR] ? 4
[2, 8] vs 3 [2, 7]; p ? 0.004). There were no differ-
ences between the groups with regard to sex, race,
marital/partner status, residence at home, stroke risk
factors, or estimated prestroke mRS. None of the pa-
tients in the wake-up group received tPA, while 80
(4.9%) of all non-wake-up strokes received tPA.
Table 2 compares the eligibility for thrombolysis,
with time eliminated as an exclusion criterion, for the
wake-up and non-wake-up strokes. The most com-
mon exclusion in both groups was a mild stroke, as
more than half of the patients in each group had
rNIHSS scores ?5. The number with mild stroke
was significantly higher in the non-wake-up strokes
(p ? 0.004). Extreme hypertension and coagulopa-
thies were also common exclusions. In the wake-up
group, 98 (35.9%, 95% CI 30.4–41.8) patients
would have been eligible for thrombolysis, compared
with 406 (25.0%, 95% CI 22.8–27.4) in the non-
wake-up group (p ? 0.01).
With regard to short-term outcomes, there were
no significant differences in the discharge mRS scores
or 90-day mortality after adjusting for age, sex, race,
prestroke mRS, rNIHSS, and prior atrial fibrillation
between the wake-up and non-wake-up groups.
Ninety-day mortality rates were 15.8% in the
wake-up group and 15.6% in all others (p ? 0.57).
Median discharge mRS was 3 in both the wake-up
group and all others (p ? 0.94).
The previous analysis assumed that the 219
strokes with no estimate of stroke onset time were
non-wake-up strokes. In order to evaluate the poten-
tial for misclassification, the data were reanalyzed
with the assumption that the 219 were wake-up
strokes. With this reclassification, the only change
was that baseline rNIHSS was no longer significantly
different between the 2 groups (median rNIHSS
[IQR] was 4 [2, 8] for wake-up and 3 [2, 7] for
non-wake-up, p ? 0.70; the percentage with
rNIHSS ?5 was 57% for wake-up and 61% for non-
wake-up, p ? 0.20). Therefore, potential misclassifi-
cation of strokes with unknown stroke onset times
did not affect the conclusions drawn from this study.
DISCUSSION Wake-up strokes comprised approxi-
mately 14% of ischemic stroke cases that presented
to an ED in the Greater Cincinnati/Northern Ken-
tucky population in 2005. Aside from minor differ-
ences in age and baseline rNIHSS, we did not find
significant differences between wake-up strokes and
all other ischemic strokes with regard to baseline de-
mographics, risk factor profiles, or clinical outcome.
Based upon extrapolation from our data, we estimate
that approximately 58,000 patients with wake-up
ischemic strokes presented to an ED in the United
States in 2005. Our data suggest that at least a third
of the wake-up strokes would have been eligible for
IV tPA if time were not a factor and thus represent a
group of patients that could be a focus for future
trials of acute therapy.
In the past 20 years, several large studies have re-
ported that the proportion of wake-up stroke ranges
from 14% to 28%.3,5-10,13,14The CASPR investiga-
tors reported in their survey of 11 hospitals in 5 dif-
ferent population regions of California that 8% of
strokes were wake-up.11A few smaller community-
based studies have also been performed. Investigators
included 375 patients from a single Italian territory
with a population of about 50,000. The authors
Table 1Baseline clinical characteristics of wake-up vs non-wake-up strokesa
(n ? 273)
(n ? 1,581)p Value
Age, y, mean ? SE
72.3 ? 0.8370.0 ? 0.48 0.01
Female, n (%)
156 (57.1) 876 (55.4) 0.59
White, n (%)
214 (78.4)1,202 (75.0) 0.26
Married/living with partner, n (%)
105 (39.3)658 (41.5) 0.51
Living at home, n (%)
234 (85.7)1,350 (84.2)0.56
Baseline rNIHSS, median
4 (2–8)3 (2–7) 0.004b
Baseline rNIHSS <5, n (%)
140 (51.3)950 (60.9)0.004
Prestroke estimated Rankin,
median (interquartile range)
2 (0–3)2 (0–3)0.78b
Prior infarct, n (%)
65 (23.8)353 (23.4)0.89
Prior TIA, n (%)
44 (16.1) 267 (16.3)0.94
Hypertension, n (%)
222 (81.3) 1,232 (78.2)0.25
Diabetes mellitus, n (%)
86 (31.5)527 (33.3)0.56
Elevated cholesterol, n (%)
104 (38.1) 584 (37.5)0.86
Atrial fibrillation, n (%)
51 (18.7) 240 (15.6)0.22
CAD, n (%)
91 (33.3)493 (32.2)0.72
Smoking history, n (%)
Current (within last 3 months)
64 (24.1) 398 (26.5)
83 (31.2) 397 (25.2)
119 (44.7)723 (48.3)
Given tPA, n (%)
0 (0)80 (4.9)
Abbreviations: CAD ? coronary artery disease; rNIHSS ? NIH Stroke Scale score estimated
an Refers to the number of stroke events. Denominators may vary slightly due to missing/
unknown data. Data are reported as raw quantiles, raw frequencies with weighted percent-
ages, and weighted means and standard errors.
bp Value based on ranks.
Neurology 76May 10, 2011
found that wake-up strokes occurred in 18% of their
patients but noted that many of these patients did
not have a head CT, and therefore it is unclear how
many of these cases were true acute ischemic strokes.4
Investigators in the Netherlands found that 48 of
263 patients (18%) had wake-up strokes over the
course of 3 months in a population of 520,000.12
Our study reports a similar proportion of wake-up
strokes with the advantage of a larger, biracial popu-
lation of 1.3 million.
The limitations of time-based therapy and the
possibility that some patients with wake-up strokes
may benefit from treatment have prompted investi-
gations into possible interventions for this group of
patients. The AbESTT investigators initially in-
cluded wake-up strokes as part of the eligible study
population but stopped enrolling these patients be-
cause the rate of symptomatic ICH with study treat-
ment was unacceptably high.26Other investigators
have reported better results in small, retrospective
studies.27,28Current trials utilizing multimodal imag-
ing to better select patients beyond the standard time
window, including those who wake up with their
symptoms, are ongoing.29-32
A significant strength of this article is the
population-based methodology. Our study is the
largest population-based study of stroke incidence in
the United States, and our largely representative pop-
ulation allows us to quantify the problem of wake-up
strokes on a national scale. Studies from single cen-
ters or major academic centers are subject to referral
There are some limitations to this study. The
study is retrospective in nature and, despite best ef-
forts at complete case ascertainment, it is possible
that some cases were missed despite the surveillance
methods in place. Furthermore, this study included
only acute ischemic stroke patients who presented to
an ED and did not include those evaluated only in
other settings. Another potential problem is misclas-
sification bias with regard to timing. Approximately
12% of the strokes in our population did not have a
clear or estimated time of onset, and if some or all of
these cases were wake-up strokes the event rate could
increase substantially. Underdocumentation bias is a
potential problem in an ED setting because subjects
who were clearly not treatment candidates might not
have had as thorough neurologic examinations or rig-
orous documentation of treatment exclusions as po-
tential candidates. Finally, our estimation of patients
eligible for treatment is a conservative underestimate
of those eligible, since many treating physicians re-
gard NIHSS ?5 and elevated blood pressure (among
others) as relative rather than absolute contraindica-
tions for tPA treatment. Indeed, the 2007 acute
stroke treatment guidelines do not recommend using
a strict NIHSS cutoff for thrombolysis but rather
recommend treatment for disabling symptoms.
Our study indicates that there are no obvious dis-
tinguishing features between wake-up and non-
wake-up strokes. Wake-up strokes constitute a
significant percentage of ischemic strokes and are in-
eligible for thrombolytic therapy due to the current
time-based restrictions, which is unfortunate because
it is likely that some of these events occurred imme-
diately prior to awakening. Efforts are ongoing to
develop better methods of identifying those patients
most likely to benefit from treatment while at the
same time minimizing exposure to undue risk.
Statistical analysis was conducted by Drs. Sucharew, Khoury, and Hornung.
The authors thank the following for their participation in the Greater
Cincinnati/Northern Kentucky Stroke Study: University Hospital; Good
Samaritan Hospital; Bethesda North Hospital; Christ Hospital; St. Eliza-
beth Edgewood, Covington, Florence, and Ft. Thomas Hospitals; Mercy
Anderson, Clermont, Fairfield, Mt. Airy, and Western Hills Hospitals as
well as the Jewish Hospital; Deaconess Hospital; Cincinnati Children’s
Medical Center; and the Cincinnati Veteran Affairs Medical Center.
Table 2 Exclusions for tPA if time were not a factora
(n ? 273) n (%)
(n ? 1,581) n (%)p Value
140 (51.3) 950 (60.9) 0.004
Blood pressure, systolic >185 or
diastolic >110 mm Hg
35 (12.9)243 (14.9) 0.38
Seizure at onset
2 (0.7) 32 (2.0)0.17
20 (8.9)72 (8.5) 0.88
PTT >40 s
12 (5.9)88 (9.2) 0.17
3 (1.1)26 (1.6) 0.54
1 (0.4)19 (1.2)0.25
0 (0)2 (0.1)
11 (4.0)59 (4.5) 0.75
1 (0.4)18 (1.1)0.27
0 (0) 1 (0.1)
0 (0)5 (0.3)
ICH, SAH, IVH
0 (0) 20 (1.2)0.06b
3 (1.1) 29 (1.8)0.43
Total remaining eligible for tPA
98 (35.9) 406 (25.0)
Abbreviations: AVM ? arteriovenous malformation; ICH ? intracerebral hemorrhage; INR ?
international normalized ratio; IVH ? intraventricular hemorrhage; rNIHSS ? NIH Stroke
Scale score estimated retrospectively; PTT ? partial thromboplastin time; SAH ? sub-
arachnoid hemorrhage; tPA ? tissue plasminogen activator.
aA patient with stroke could have more than one exclusion criterion. Denominators may
vary slightly due to missing/unknown data. Data are reported as raw frequencies with
bp Value based on exact test due to zero counts in the wake-up group.
Neurology 76 May 10, 2011
Dr. Mackey receives research support from the NIH. Dr. Kleindorfer has
served on a scientific advisory board for Boehringer Ingelheim; serves on
the speakers’ bureau for Genentech, Inc.; serves on the editorial board of
Stroke; receives research support from the NIH/NINDS and AAMC/
CDC; and has provided medico-legal case review. Dr. Sucharew receives
research support from the NIH. Dr. Moomaw receives research support
from the NIH/NINDS. Dr. Kissela has served on scientific advisory
boards for Allergan, Inc. and Northstar Neuroscience, Inc.; has received
funding for travel and speaker honoraria from Allergan, Inc.; serves as a
consultant for NexStim, receives research support from the NIH; and has
provided medico-legal case review. K. Alwell receives research support
from the NIH/NINDS. Dr. Flaherty has served as a consultant to Boehr-
inger Ingelheim; receives research support from the NIH/NINDS and is
PI of an NIH-funded study for which study drug is supplied by Novo
Nordisk; and has provided medico-legal case review. Dr. Woo receives
research support from the NIH/NINDS. Dr. Khatri has served on a scien-
tific advisory board for Otsuka Pharmaceutical Co., Ltd.; serves as an
Associate Editor for Frontiers in Clinical Trials in Neurology; receives pub-
lishing royalties from Informa Inc. and for The Stroke Center Handbook
(Informa, 2006); receives research support from the NIH/NINDS; and
serves on the Executive Committee of the IMS III Trial NINDS
U01NS052220, for which drugs and devices are provided by EKOS Cor-
poration, Concentric Medical, Penumbra, Inc., and Genentech, Inc. Dr.
Adeoye serves on speakers’ bureaus for and has received speaker honoraria
from Genentech, Inc. and EKR Therapeutics, Inc.; and receives research
support from EKR Therapeutics, Inc. and the NIH (NINDS, NIBIB).
Dr. Ferioli reports no disclosures. Dr. Khoury receives research support
from the NIH and has served as a consultant for Mead-Johnson. Dr.
Hornung serves on a scientific advisory board for and has received funding
for travel and speaker honoraria from the National Cancer Institute
(NCI); and serves as an Associate Editor for Public Health Reports and Plos
Medicine. Dr. Broderick has served on scientific advisory boards for John-
son & Johnson, Wyeth, and PhotoThera; holds patents re: Method for
controlling the lysis of coagulated blood with apolipoprotein e4 pheno-
type; has served as a consultant for Novo Nordisk and Genentech, Inc. (all
consulting fees and honoraria are placed in an education/research fund in
Dr. Broderick’s department of his institution); has received research sup-
port in the form of materials from Genentech, Inc., Novo Nordisk,
Schering-Plough Corp., Concentric, EKOS Corporation, and Johnson &
Johnson; and receives institutional research support from Boehringer In-
gelheim, Genentech, Inc., Schering-Plough Corp., and the NIH/NINDS.
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Historical Abstract: October 1, 1970
ELECTROPHORETIC MORPHOLOGY OF GAMMA GLOBULINS IN CEREBROSPINAL FLUID OF MULTIPLE
SCLEROSIS AND OTHER DISEASES OF THE NERVOUS SYSTEM
E. C. Laterre, A. Callewaert, J. F. Heremans, and Z. Sfaello
CSF protein electrophoresis in agar gel was performed in 2,043 patients. Among them, 323 patients were classified as having MS. The
essential feature of the gamma globulins in CSF from MS patients and other inflammatory CNS diseases resided in their restricted
heterogeneity distribution. This peculiar electrophoretic pattern occurs in 75.2 to 86.9% of MS patients, depending upon the diagnostic
category (possible, probable, or definite). The differences were significant. In MS patients there was also a positive correlation
between the degree of disability and the frequency of gamma pattern when Grade I and Grade III were compared, but no correlation
was found between the duration and course of the disease on the one hand and the CSF gamma globulin changes on the other hand.
In the other patients, this frequency varied between 2. to 5.1%, except for the group with inflammatory CNS diseases in which it
reached 39.6%. The diagnostic value of the method employed is discussed and emphasized.
Free Access to this article at www.neurology.org/content/20/10/982
Comment from Richard M. Ransohoff, MD, Associate Editor: This report presaged the observation that oligoclonal bands in
CSF typify MS and other inflammatory CNS disorders.
Neurology 76May 10, 2011