Abstracts

Transcription

Abstracts

The International Stroke Conference welcomes these
organizations to our annual meeting:
®
AANS/CNS Cerebrovascular Section
®
American Society of Interventional and Therapeutic Neuroradiology
Nursing Symposium: February 19
Sessions: February 20-22
Exhibits: February 20-21
New Orleans, Louisiana
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Prevention
Diagnosis
Tr e a t m e n t / I n t e r v e n t i o n
Rehabilitation
Basic Science
stro
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nfer
ence
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Abstracts
528
Stroke
Vol 39, No 2
February 2008
International Stroke Conference Oral Presentations
1
Subgroup Analysis In the Fast Trial: A Subset of Intracerebral Hemorrhage
Patients That Benefit from Recombinant Activated Factor VII?
Stephan A Mayer, Columbia Univ, New York, NY; Stephen M Davis, Univ of Melbourne,
Melbourne, Australia; Kamilla Begtrup, Novo Nordisk A/S, Copenhagen, Denmark; Joseph P
Broderick, Univ of Cincinnati, Cincinnati, OH; Michael N Diringer, Washington Univ, St. Louis, MO;
Brett E Skolnick, Novo Nordisk, Inc, Princeton, NJ; Thorsten Steiner; Univ of Heidelberg,
Heidelberg, Germany
Introduction: The recombinant activated Factor VII (rFVIIa) FAST trial was a randomized,
double-blind placebo-controlled study of 821 spontaneous intracerebral hemorrhage (ICH) patients
diagnosed by computed tomography (CT) scan ⱕ3 hours after symptom onset and treated with
placebo, 20 or 80 ␮g/kg rFVIIa ⱕ1 hour after CT. FAST showed that rFVIIa (80 ␮g/kg) given ⱕ4
hours after ICH onset significantly limits hematoma growth. However, in contrast to an earlier phase
2b trial, survival and functional outcome were not improved at 90 days. In this post-hoc analysis we
hypothesized that earlier treatment and exclusion of patients with high probability of poor outcome
(massive hemorrhage volumes, substantial intraventricular hemorrhage [IVH] and advanced age)
might enhance the ability of rFVIIa to impact positively on clinical outcome. Methods: Combinations
of predictive factors for outcome after ICH were analyzed at different clinically meaningful cut-offs
to identify a candidate subgroup. The impact of treatment on outcome and volume change in this
group were analyzed by logistic regression (mRS) and linear mixed models (ICH volumes). The same
criteria were then applied to the data from the phase 2b trial to examine our hypothesis of the
assumed responder subgroup. Results: A candidate subgroup (n⫽160) was identified comprising
patients aged ⱕ70 years, with baseline ICH volume ⬍60 ml, baseline IVH volume ⬍5 ml, and time
from symptom onset to rFVIIa treatment ⱕ2.5 hours. The adjusted odds ratio (OR) for poor outcome
in patients receiving 80 ␮g/kg rFVIIa was 0.28 (95% CI 0.08 to 1.06). The reduction in hemorrhage
growth relative to placebo was almost doubled by limiting onset to treatment to 2.5 hours (-7.3 ⫾
3.2 ml [P⫽0.02] versus -3.8 ⫾ 1.5 ml in the 80 ␮g/kg group overall). The improved treatment
effect was then confirmed in an analysis of a patient subgroup (n⫽56), from the earlier phase 2b
study, which was defined by the same criteria (OR 0.02, P⫽0.02 versus OR 0.47, P⫽0.01 overall).
Conclusions: This exploratory analysis provides evidence that with an earlier treatment window and
exclusion of known determinants of poor outcome at baseline (age and magnitude of ICH and IVH),
a subpopulation of ICH patients may benefit from hemostatic therapy with rFVIIa.
2
Microbleeds Versus Macrobleeds: Evidence for Distinct Processes.
Steven M Greenberg, R. N. Kaveer Nandigam, David Schoenfeld, Hui Zhang, Massachusetts
General Hosp, Boston, MA; Rebecca A Betensky, Harvard Sch of Public Health, Boston, MA;
Jonathan Rosand, Anand Viswanathan, Eric E Smith; Massachusetts General Hosp, Boston, MA
Background and Purpose: Small, asymptomatic hemorrhagic lesions (or microbleeds) are a
commonly recognized feature accompanying larger symptomatic hemorrhages (macrobleeds). It is
unclear whether microbleeds and macrobleeds represent two extremes within a single continuum
of hemorrhage sizes, or rather two distinct processes with separate risk factors. Methods: We
determined the volumes of all 163 hemorrhages detected by gradient-echo MRI in 46 consecutive
subjects with primary lobar hemorrhage diagnosed as cerebral amyloid angiopathy and modeled
their distribution. We also analyzed the appearance of new macrobleeds and microbleeds in 94
consecutive survivors of lobar hemorrhage and a subset of 34 with additional follow-up MRI
15.8⫹-6.5 months after baseline. Appearance of new hemorrhages was modeled as a Poisson
distribution with maximum-likelihood estimation of parameters for the rate of appearance of any
new hemorrhagic lesion (R) and the probability that a given new hemorrhage would be a
symptomatic macrobleed (P). R and P were compared between categories of subjects with low or
high numbers of hemorrhages at baseline (categorized according to the group median). Results:
Hemorrhage volumes occurred in a distinctly bimodal distribution (Figure) represented as a mixture
model with peaks at 0.009 cm3 and 16.4 cm3. The optimal threshold (determined by receiver
operating characteristic) for distinguishing the two groups was 0.069 cm3, corresponding to a
spherical diameter of 0.51 cm. Subjects with more hemorrhages at baseline had a substantially
higher rate of new hemorrhage formation (R⫽0.19 versus 0.01 hemorrhages per month,
p⬍0.0001) but a lower probability that a new hemorrhagic lesion would be a symptomatic
macrobleed (P⫽0.10 versus 0.50; p⬍0.0001). Conclusion: Based on the bimodal distribution of
hemorrhage volumes and the differential risks observed for small and large hemorrhages,
microbleeds and macrobleeds appear to represent distinct pathophysiologic entities. These data are
consistent with a threshold model, whereby hemorrhagic lesions reaching a particular volume
proceed to enlarge into a full-sized macrobleed. Modeling the bleeding process as distinct initiation
and enlargement events may be a useful framework for understanding the pathogenesis of
hemorrhagic stroke.
3
Multicentre Prospective Study Demonstrates Feasibility Of CT-Angiography
In Intracerebral Hemorrhage And Validity Of “Spot Sign” For Hematoma
Expansion Prediction.
Andrew M Demchuk, Suresh Subramaniam, Jayme Kosior, Sarah Tymchuk, Christine O’Reilly,
Univ of Calgary, Calgary, Canada; Carlos Molina, Vall d’Hebron Hosp, Barcelona, Spain; Jayanta
Roy, Advance Medicare and Rsch Institute, Kolkata, India; Imanuel Dzialowski, Univ of Dresden,
Dresden, Germany; Jean-Martin Boulanger, Univ of Sherbrooke, Greenfield Park, Canada;
Mohammed Alzawahmah, Nic Weir, Michael D Hill, Univ of Calgary, Calgary, Canada; David
Gladstone, Richard Aviv, Univ of Toronto -Sunnybrook Health Sciences Cntr, Toronto, Canada;
PREDICT/Sunnybrook ICH CTA Study Group
Background: Previous hemostatic therapy trials have demonstrated efficacy against hematoma expansion but this has not translated into improved clinical outcomes. Better selection of
ICH patients at risk for hematoma expansion is needed for future hemostatic therapy trials.
Single centre ICH CT angiography (CTA) studies have detected small, enhancing foci (‘spot
sign’) within acute hematomas which appear to predict ICH expansion. The PREDICT/
Sunnybrook study is an ongoing prospective observational study that aims to determine the
validity and feasibility of contrast extravasation to predict ICH expansion in a large, multicentre
cohort. We present our preliminary findings. Methods: ICH patients enrolled in study at 6
centres since May 2006. All enrolled patients underwent acute CT angiography. Scans
reviewed for “spot sign” by 3 blinded readers. ICH/IVH volumes quantified using computer
assisted segmentation algorithm. Significant hematoma expansion defined as ⬎5 ml increase
in total hematoma volume (ICH⫹IVH). Results: 43 patients enrolled and all received baseline
CTA. Fifteen patients (35%) demonstrated 25 enhancing foci. Median onset-CTA time 213.5
minutes and median non-contrast CT to CTA time 7.5 minutes. Median baseline ICH volume
was 25.3 ml (14.6 –53 iqr) for “spot sign” positive group and 12.2 ml (5.2–34.7 iqr) for “spot
sign” negative group (p⫽0.087). Hematoma expansion analysis limited to 36 patients
(excluded 2 early deaths, 2 surgical evacuations and 3 rFVIIa all before follow-up scan; 5/7 of
these excluded patients were “spot sign” positive). Significant hematoma expansion occurred
in 6/36 patients (16%), all had “spot sign” on CTA (p⫽0.0001). For significant hematoma
expansion the positive predictive value for “spot sign” was 60% (6/10) and negative predictive
value was 100% (26/26). Mean ICH volume expansion was 12.2 ⫹/- 22.3 ml for “spot sign
positive” cases and minus 1.1 ⫹/- 4.4 ml for “spot sign” negative cases (p⫽0.006). Mean IVH
volume expansion was 13.4 ⫹/- 28.6 ml for “spot sign” positive cases and 0.6 ⫹/- 2.3 ml for
“spot sign” negative cases (p⫽0.03). Total hematoma volume expansion was 25.5 ⫹/- 32.8
ml for “spot sign” positive cases and minus 0.6 ⫹/- 3.8 ml for “spot sign” negative cases
(p⫽0.0003). Conclusions: This study demonstrates the feasibility of performing acute ICH CTA
at multiple centres with short noncontrast CT to CTA time delay. The data validates the “spot
sign” as a strong predictor of ICH, IVH and total hematoma expansion with very high negative
predictive value. “Spot sign” negative patients appear to be at very low risk for significant
hematoma expansion. The study will continue to recruit cases for further characterization.
However a clinical trial selecting ICH patients for hemostatic therapy using CTA “spot sign”
appears warranted.
4
Polymorphisms in the Aquaporin 4 and Thrombin protease-activated
receptors gene are related to Edema Volume In Patients With Acute
Intracerebral Hemorrhage.
Yolanda Silva, Sebastian Remollo, Judith Mallolas, Hosp Dr Josep of Girona, Girona, Spain;
Natalia Pérez de la Ossa, Hosp Germans Trias i Pujol, Badalona, Spain; Mar Castellanos,
Verónica Cruz, Hosp Dr Josep of Girona, Girona, Spain; Florentino Nombela, Hosp de la
Princesa, Madrid, Spain; José Castillo, Hosp Clı́nico Universitario, Santiago de Compostela,
Spain; Joaquı́n Serena; Hosp Dr Josep of Girona, Girona, Spain
Background and purpose: The expression of aquaporin 4 (APQ4), a water channel protein, has
been related to blood brain barrier (BBB) differentiation and brain edema after experimental
Abstracts and presentations are embargoed for release at date and time of presentation or time of AHA/ASA news event. Information may not be released before then.
Failure to honor embargo policies will result in the abstract being withdrawn and barred from presentation.
2008 ISC Oral Presentations
529
cerebral ischemia. On the other hand, thrombin could play a role in edema formation by
affecting the permeability of the BBB in experimental intracerebral hemorrhage. Thrombin
signalling is mediated in part by protease-activated receptors (PAR). We investigated whether
APQ4 and PAR-1 gene polymorphisms were associated with edema volume in patients with an
ICH. Methods: Genomic DNA was isolated from peripheral blood samples of 44 patients with
an acute primary supratentorial intracerebral hemorrhage. Polymorphism screening of the
AQP4 and PAR-1 gene was performed by polymerase chain reaction (PCR), single-strand
conformation polymorphism (SSCP) and sequencing analysis. A cranial CT was performed
within the first 12 hours from symptoms onset and at 72⫾12 hours. The volume of the
perihematoma edema was determined by a planimetric method. Results: Two polymorphisms,
one in the AQP4 gene and another in the PAR-1 gene were associated with the volume of
perihematomal edema at 72 hours. The first was identified in the 5’UTR of the AQP4 gene
which corresponded to an G-to-A transition at -39 bp from the transcription start site (X2⫽6.7,
p⫽0.03). The second polymorphism was found in the 5’ regulatory region of the PAR-1 gene
which corresponded to a 13-bp insertion repeating the preceding -506 sequence (X2⫽7.7,
p⫽0.02). Conclusions: The -39 G/A polymorphism in the 5’UTR of the AQP4 gene and the -506
I/D in the PAR-1 gene are associated with the volume of edema at 72 hours in patients with
acute ICH. These polymorphisms might be indicative of a higher genetic susceptibility to BBB
disruption.
7
5
Antiplatelet Medications and Hemorrhage Growth After Intracerebral
Hemorrhage.
In Vivo 11C PIB Binding is Increased in Patients with Cerebral Amyloid
Angiopathy Haemorrhage.
Lauren H Sansing, Steven R Messe, Brett L Cucchiara, Univ of Pennsylvania, Philadelphia,
PA; Stanley N Cohen, Univ of Nevada, Las Vegas, NV; Patrick D Lyden, Univ of CaliforniaSan Diego, San Diego, CA; Scott E Kasner, Univ of Pennsylvania, Philadelphia, PA; for the
CHANT Investigators
John V Ly, Geoffrey A Donnan, National Stroke Rsch Institute, Heidelberg Heights, Australia;
Victor L Villemagne, Dept of Nuclear Medicine, Cntr for PET, Austin Health, Heidelberg,
Australia, Heidelberg, Australia; Jorge A Zavala, Henry Ma, National Stroke Rsch Institute,
Heidelberg Heights, Australia; Graeme O’Keefe, Uwe Ackerman, Henri Tochon-Danguy,
Christopher C Rowe; Dept of Nuclear Medicine, Cntr for PET, Austin Health, Heidelberg,
Australia
Introduction: There has been conflicting evidence about the effect of antiplatelet medication
use on hemorrhage growth and outcome after spontaneous intracerebral hemorrhage (ICH).
Methods: The CHANT trial was a randomized, placebo-controlled trial of NXY-059 after
spontaneous ICH. We analyzed patients in the placebo arm, and correlated antiplatelet
medication use at the time of ICH with initial ICH volumes, ICH growth in the first 72 hours, and
modified Rankin Score at 90 days. Results: There were 303 patients included in this analysis
including 76 (25%) who were taking antiplatelet medications at ICH onset. Of these, 62 patients
were taking aspirin alone, 5 clopidogrel alone, 3 aspirin and clopidogrel, 2 aspirin and
dipyridamole, 2 triflusal, 1 dipyridamole alone, and 1 ibustrin. Older age and male sex were
significantly associated with antiplatelet medication use. Six patients taking antiplatelet
medications were also taking warfarin. None of the patients received platelet transfusions. Use
of antiplatelet medications at ICH onset had no effect on the volume of ICH at presentation or
on growth of ICH at 72 hours. There was also no effect on initial edema volume or edema
growth. In multivariate analysis, controlling for initial hemorrhage volume, initial Glasgow Coma
Scale score, presence of intraventricular hemorrhage, age, infratentorial location and warfarin
use, there was also no significant association of use of antiplatelet medications with either
hemorrhage growth or outcome at 90 days. Conclusions: Use of antiplatelet medications at ICH
onset is not associated with the size of the initial ICH or expansion of ICH in the first 72 hours.
There was also no association between use of antiplatelet medications and outcome at 90
days. These findings suggest that attempts to reverse antiplatelet medications after ICH may
not be warranted.
Abstract: Background: Cerebral amyloid angiopathy (CAA) is an important cause of
intracerebral haemorrhage (ICH). However, in-vivo diagnosis is difficult and usually inferred
from clinical and imaging criteria. N-methyl-[11C]2-(4’-methylaminophenyl)-6hydroxybenzothiazole ([11C]PIB) is a ligand which binds to beta-amyloid both in plaques and
vessel walls and may be imaged with PET. We tested the hypothesis that patients with a clinical
diagnosis of CAA related ICH (CAAH) will have increased PIB PET uptake. Methodology:
Patients with CAAH based on the Boston criteria were studied using PIB PET and compared to
age matched controls. Distribution Volume Ratio (DVR) maps were created using Logan
graphical analysis and the cerebellar cortex as a reference. Differences between means were
assessed by Kruskal Wallis test. Results: Eleven patients with CAAH of mean age 73.5 yrs
(58 –93) were studied at a mean of 71 days (6 –270) post-ICH and compared to 21 normal
controls of mean age 71.8 yrs (59 – 83). The mean whole Brain PIB uptake among patients was
higher compared to normal controls with mean DVR of 1.56⫾0.17 SD and 1.37⫾0.09 SD
respectively (p⫽0.002). PIB binding was particularly high in the Neocortical regions with a
mean DVR of 1.67⫾0.28 SD in patients compared to 1.34⫾0.15 SD in controls (p⫽0.003). One
patient had neocortical DVR less than the 75% percentile of controls. Conclusion: [11C]PIB
uptake is higher in patients with CAAH compared to normal aged matched controls. [11C]PIB
PET may assist the in-vivo diagnosis of CAAH. Equally important is the potential for PIB PET to
serve as a surrogate marker for future therapeutic studies.
Initial ICH volume (mean), mL
Initial ICH volume (median), mL
ICH growth at 72 hours (mean), mL
ICH growth at 72 hours (median), mL
Modified Rankin Scale ⱕ3 at 90 days
Antiplatelet
medication
No antiplatelet
medication
p value
22.5⫾24.3
13.3
8.0⫾26.2
1.0
45%
23.5⫾22.3
15.8
7.7⫾21.5
1.0
47%
0.74
0.53
0.93
0.38
0.72
6
Withdrawn
8
Long-Term Prognosis After Transient Ischemic Attack (TIA).
Anthony S Kim, UCSF, San Francisco, CA; Stephen Sidney, Div of Rsch Kaiser Permanente
Northern California, Oakland, CA; Allan L Bernstein, Kaiser Santa Rosa Med Cntr, Santa
Rosa, CA; S. Claiborne Johnston; UCSF, San Francisco, CA
OBJECTIVE. To evaluate the long-term mortality of patients after TIA BACKGROUND. Risk
factors for short-term stroke and mortality after TIA have been previously defined but the
long-term mortality after TIA has received less attention. DESIGN/METHODS. Patients diagnosed with TIA in the emergency rooms of a California managed care plan from March 1997
to May 1998 were enrolled and followed until November 1999. Patients were censored at last
known followup date or death from nonvascular cause for analyses of mortality from vascular
causes. Clinical data were abstracted from databases and medical records and mortality was
ascertained from clinical databases and public records. Kaplan-Meier life table analysis was
used to generate mortality estimates. RESULTS. Mean age was 70.1 years. Patients were
followed for an average of 503 days (median 539 days, maximum 977 days, n⫽1,706) for a
total of 2,349 person-years of followup. A total of 217 patients died during the followup period
(12.7%) at an average of 277 days (median 210 days, max 958 days) after enrollment for TIA.
Of the patients that died during the study, 68 (31.3%) died within 90 days of enrollment, a total
of 99 (45.6%) died within 180 days of enrollment, and 144 (66.4%) died within one year of
enrollment. For all patients the cause of death was listed as stroke in 50 (23.0%) and
cardiovascular disease in 32 patients (14.7%), cancer in 20 patients (9.2%), infection in 20
patients (9.2%), and other in 22 (10.1%). Cause of death was unknown in 74 (34.1%). The
overall rate of all-cause mortality was estimated at 9.1% at one year (95% confidence
interval ⫽ 7.8 –10.7%) and 16.3% at two years (14.1–18.8%). The rate of mortality for cardio
or cerebrovascular disease was 3.9% (3.0 –5.0%) at one year and 6.5% at two years
(5.1– 8.3%) and the rate of mortality from stroke alone was 1.5% at one year (1.0 –2.2%) and
3.3% at two years (2.1– 4.9%). (See figure for cumulative mortality risk curves.) CONCLUSIONS/
RELEVANCE. Mortality from stroke figures more prominently than cardiovascular risk in the
530
Stroke
Vol 39, No 2
February 2008
long-term cumulative mortality after TIA and presents a target for aggressive secondary
prevention measures. STUDY SUPPORTED BY NIH/NINDS
had a favorable outcome after 90 days. The t-PA treated patients weighing ⬎100kg were
younger (57⫾10 vs 69⫾10; p⫽0.0001) and had lower rate of atrial fibrillation (0% vs
20%;p⫽0.018), compared to their slimmer counterparts. On univariate analysis, older age,
higher baseline NIHSSS, the presence of hypodensity on initial scan, and history of
hypertension, diabetes, or heart failure were statistically associated with worse outcome 90
days after treatment with t-PA. On logistic regression, body weight ⬎100kg emerged as one
of 3 significant predictors of unfavorable outcome after t-PA (adjusted OR 5.76; p⫽0.017).
Other predictors were older age and higher baseline NIHSSS. Body weight ⬎100kg was also
associated with neurological deterioration (ⱖ 4 points on NIHSSS) 7–10 days after t-PA
(OR⫽3.4; p⫽0.07). This impact of body weight on outcome was not seen among the
placebo-treated patients. Conclusions: In the NINDS cohort, stroke patients weighting ⬎
100kg seem to derive less benefit from IV t-PA than their slimmer counterparts. The link
between obesity and higher levels of PAI-1, and restricting the maximal dose of IV t-PA in these
patients might account for our findings. The exact mechanism(s) underlying this observation
and its potential therapeutic implications require further investigations.
11
Chronic Kidney Disease is a Strong Independent Predictor of Poor Outcome
in Patients With Acute Stroke.
9
Low-Income, Low-hospital Volume And High Stroke Mortality: The Puzzling
Route Of Inequity.
Gustavo Saposnik, Univ of Toronto, Toronto, Canada; Thomas Jeerakathil, Univ of Alberta,
Edmonton, Canada; Daniel Selchen, Univ of Toronto, Missassauga, Canada; Vladimir
Hachinski, Univ of Western Ontario, London, Canada; Moira K Kapral, Univ of Toronto,
Toronto, Canada; on behalf of the Stroke Outcome Rsch Canada (SORCan) Working Group
Background: Socioeconomic status has been associated with inequality in delivery of services,
increased incidence of stroke and poor outcomes. Most prior studies have explored individual
patient factors rather than health system variables as explanations for the association between
socioeconomic status, stroke care and outcome. Objective To identify whether low-income
individuals were more likely to be admitted to facilities with low-stroke volume, and whether
this contributed to differences in outcomes. Methods: We identified all patients with ischemic
stroke admitted to acute care hospitals in Canada between April 2003, and March 2004
through the Hospital Morbidity and Mortality Database (HMDB). The HMDB is a National
database that contains patient-level socio-demographic, diagnostic, procedural and administrative information across Canada.There are 680 acute care facilities across the country
reporting to the HMDB, which covers 99.8% of all acute care hospitals. Ischemic stroke was
identified through patient’s principal diagnosis recorded using the International Classification of
Diseases. We evaluated the association between socioeconomic status and hospital admission
based on facility volume. Multivariable analysis was performed using generalized estimating
equations to account for clustering observations at institutions. Statistical analyses were
performed using SAS and STATA 8.0 . Results: Overall 25,228 patients with ischemic stroke
were included in the analysis. Lower socioeconomic status was associated with higher
admission to non-teaching, low-volume hospitals, more medical complications, and poor stroke
outcomes. Mortality at 7 days was 8.4%, 8.2%, 7.7%, 7.1, and 6.6% (p⫽0.002) for income
quintiles 1 (lowest), 2, 3, 4, and 5 (highest) respectively. Low-income patients admitted to
low-volume hospitals was associated with a higher risk-adjusted stroke mortality when
compared to high-income patients admitted to high-volume hospitals (7.8% versus 6.2% at 7
days, p⬍001; 15.2% versus 12.5% discharge mortality, p⬍0.001). In the multivariable
analysis, low-income patients admitted to low-volume hospitals had a higher mortality after
adjusting for covariates (For 7-day mortality: OR 1.26, 95%CI 1.07–1.49; and for mortality at
discharge OR 1.17, 95%CI 1.11–1.45). Conclusions: Low-income patients presenting with an
acute stroke are more likely to be seen in low-volume facilities. This subgroup of patients had
higher risk-adjusted mortality than other groups. Understanding the pathways through which
socioeconomic status affects health care may lead to strategies for quality improvement.
10
Does Stroke Patient’s Weight Influence The Response To Intravenous t-PA?
Min Lou, The 2nd Affiliated Hosp of Zhejiang Univ, Hangzhou, China; Magdy H Selim; Beth
Israel Deaconess Med Cntr, Boston, MA
Background and Purpose: The current guidelines for intravenous thrombolysis with t-PA for
ischemic stroke recommend a maximum dose of 90 mg, irrespective of patient’s weight.
Elevated levels of plasminogen-activator inhibitor-1 (PAI-1), the main inhibitor of plasminogen
activation, have been linked to obesity. Therefore, we hypothesized that stroke patients
weighting ⬎100kg may require higher doses of t-PA and thus, are less likely to benefit from
t-PA compared to patients who weigh ⱕ100Kg and receive weight-based dose of t-PA.
Methods: We queried the NINDS t-PA study database, and divided each cohort (t-PA and
placebo) into 2 groups (favorable vs. unfovarobale outcome) based on functional outcome at
day 90. We defined favorable outcome as Barthel Index (BI) ⱖ95 or NIHSSS 0 –1 or modified
Rankin scale (mRS) 0 –1 at day 90. We used univariate analyses to determine inter-group
differences in 25 demographic, clinical, laboratory, and radiological variables. Variables with
pⱕ0.2 on univariate testing were tested in a multivariate logistic regression model to analyze
the effects of weight (⬎100kg vs. ⱕ100Kg) in each cohort on functional outcomes. Results:
Twenty patients (6%) of the t-PA and 32 patients (10%) of the placebo cohorts had an actual
body weight ⬎100 kg; 168 t-PA treated patients (54%) vs. 127 placebo-treated patients (41%)
Gilad Yahalom, Roseline Schwartz, Yvonne Schwammenthal, Oleg Merzeliak, Maya Toashi,
David Orion, David Tanne; Chaim Sheba Med Ctr, Tel-Hashomer, Israel
Background and purpose: Chronic kidney disease (CKD) is increasingly recognized as an
independent risk factor for cardiovascular disease and stroke. Our aim was to examine the
prevalence of CKD and the association between CKD and its severity with stroke outcome in
a large prospective cohort of unselected patients with acute stroke. Methods: We examined the
association between baseline CKD and one year outcomes in 822 consecutive patients with
acute stroke (ischemic or hemorrhagic). Glomerular filtration rate (GFR) was estimated by 2
methods: the Modification of Diet in Renal Disease (MDRD) equation and the Mayo Clinic
qadratic equation. An eGFR rate ⱕ60 ml/min/1.73m2 defined CKD. After excluding patients with
kidney failure, ORs adjusting for age, gender, stroke type and severity, anemia, hypertension,
diabetes, cardiac disease, past stroke, malignancy, and prior disability were estimated to study
the associations between eGFR 45– 60 and 15– 44 as compared to ⬎60 ml/min/1.73m2 with
outcome. Results: CKD was present in 38% (n⫽311) of patients based on the MDRD equation
and 21% (n⫽170) based on the Mayo Clinic equation. The adjusted ORs for 1-year mortality
based on the MDRD equation were 0.7 (95%CI, 0.4 –1.2) associated with eGFR 45– 60 and 3.0
(1.6 –5.7) associated with eGFR 15– 44, while those based on the Mayo Clinic equation were
2.3 (1.2– 4.8) and 3.5 (1.7–7.4), respectively. The adjusted ORs for nursing home dwelling or
death were 0.7 (0.4 –1.3) and 2.7 (1.4 –5.5) by the MDRD equation and 2.4 (1.1– 4.9) and 3.3
(1.4 –7.9) by the Mayo Clinic equation, and for Barthel Index ⬍75, 0.9 (0.5–1.6) and 2.7
(1.2– 6.0) by the MDRD equation and 1.9 (0.9 – 4.3) and 4.2 (1.6 –11.3) by the Mayo Clinic
equation, respectively. Conclusions: CKD is a strong independent predictor of mortality and
poor outcome in patients with acute stroke. The estimation of the prevalence of CKD and the
GFR cut-off associated with poor outcome depend on the equation used to estimate GFR.
12
The Impact of Case Managed Care in Patients with Acute Stroke and
Transient Ischemic Attack.
Annette C Robertson, Jiming Fang, Institute for Clinical Evaluative Sciences, Toronto,
Canada; M P Lindsay, Canadian Stroke Network, Ottawa, Canada; Moira K Kapral, Frank L
Silver; Univ of Toronto, Toronto, Canada
Background: Nurse case managers coordinate and facilitate access to timely and appropriate
health care services. Little is known about the impact of case managed care on patients
hospitalized during the acute phase of their stroke. Methods: The Registry of the Canadian
Stroke Network (RCSN) collects data on consecutive patients presenting to designated stroke
centres in Ontario and Nova Scotia within 2 weeks of an acute stroke or TIA. We included
patients from RCSN Phase 3 who were admitted to 9 Ontario regional stroke centres between
October 2005 and March 2007. We excluded patients with in-hospital strokes and subarachnoid hemorrhages from the cohort. We compared the care delivered and the outcomes between
patients managed with and without a nurse case manager. Results: Over this period of 18
months, a total of 4,012 patients were admitted to hospital with a final diagnosis of ischemic
stroke, TIA, or intracerebral hemorrhage. Nurse case managers were involved in the care of
1787 patients (45%). Gender, age, and initial stroke severity (based on the Canadian
Neurological Score) were not significantly different between the groups. Co-morbidity as
measured by the Charlson index was lower in the case manager group (31.1% vs. 34.6%,
p⫽0.021). Allied health services provided in the acute phase including occupational therapy,
physiotherapy, speech language pathology, and nutritionist were utilized more frequently for
the case managed group (p⬍0.0001 for each). The length of hospital stays (LOS) were longer
(median 9 vs. 7, p⬍0.0001). Preventable in-hospital complications including deep vein
thrombosis, decubitus ulcer, pneumonia, fall with injury, and pulmonary embolism were not
reduced. Only urinary tract infections were reduced (12.9% vs. 15.2%, p⫽0.0328). In-hospital
deaths were reduced in the case managed group however, after adjusting for age, gender,
stroke severity and co morbidity this reduction became non-significant (4.2%; 95%CI 3.3–5.3
vs. 5.1%; CI 95% 4.3– 6.2). Functional recovery assessed by the Modified Rankin scale (mRS)
showed no significant differences between the two groups for mRS ⬎1 or ⬎2. Conclusion:
The addition of a nurse case manager increased access to allied health care but also slightly
increased the LOS. Patient outcomes were not significantly changed by the presence of a case
manager. However, the impact of case managers may be diminished by our cohort that
includes only patients managed in designated stroke centres.
13
Long-term Use of Secondary Stroke Prevention Therapies among US
Veterans.
Deborah A Levine, Monika M Safford, Jeroan J Allison, Thomas K Houston, Univ Alabama
Birmingham, Birmingham, AL; Dean M Reker, Kansas VA Med Cntr, Kansas City, MO; Peter
H King, Birmingham VA Med Cntr, Birmingham, AL; Linda S Williams, Roudebush VA Med
Cntr, Indianapolis, IN; Mark S Litaker, Catarina I Kiefe; Univ Alabama Birmingham,
Birmingham, AL
Background: Long-term use of secondary prevention therapies among stroke survivors who
use the Veterans Administration (VA) health system has not been examined. We assessed use
of secondary prevention medications in a recent national sample of US veterans hospitalized
with acute ischemic stroke (IS). Methods: We identified all consecutive patients aged 40 – 85
years discharged from all US VA Medical Centers with a primary diagnosis of IS from 10/1/01
through 9/30/03 by ICD-9 codes (434.xx and 436.xx) using VA data. Patients with atrial
fibrillation, on warfarin, or without an outpatient primary care or neurology clinic visit ⬍365
days of discharge were excluded. We measured filled prescriptions of anti-platelets, thiazide
diuretics, ACE inhibitors or angiotensin receptor blockers (ACE/ARBs), and statins, from 90 days
before to 365 days after index IS hospitalization. Results: The study cohort (n⫽5,850; mean
age 66 ⫾ 10.7 years) was mostly male (98%), and racially diverse (66% white, 23% black).
There was a 76% prevalence of hypertension, 38% of diabetes, 42% of hyperlipidemia, 33%
of coronary heart disease, and 17% of prior stroke. Contraindication rates were 8% for
ACE/ARBs, 3% for aspirin, 3% for other anti-platelets, 6% for statins, and 0.1% for thiazides.
Utilization of all drug classes increased significantly during the 90 days following index IS, and,
except for the anti-platelets, were maintained moderately up to 365 days (Table 1). Because
of underestimation of over-the-counter aspirin use, we analyzed the cumulative use of the
other 3 drug classes (Table 2). While patients used more drug classes following the index IS,
one third of IS survivors were using none of three drug classes at 365 days post-hospital
discharge. Conclusions: Use of secondary stroke preventive medications among veterans is
likely sub-optimal. Quality improvement programs to increase prescription and adherence of
these therapies are needed.
TABLE 1: USE OF SECONDARY STROKE PREVENTIVE THERAPIES, BY DRUG CLASS,
AMONG US VETERANS DISCHARGED FROM A VA MEDICAL CENTER WITH ACUTE
ISCHEMIC STROKE, OCTOBER 1, 2001 THROUGH SEPTEMBER 30, 2003
Filled Prescription Rate (%) during Specified Interval
Drug Class
Aspirin
Other anti-platelet
Total anti-platelet
Thiazide diuretic
ACE/ARB
Statin
90 days
pre-stroke
discharge
0 –90 days
post-stroke
discharge
91–180 days
post-stroke
discharge
181–270 days
post- stroke
discharge
271–365 days
post-stroke
discharge
22.2
11.4
28.8
15.3
36.4
27.2
56.9
57.7
83.6
22.3
54.0
52.7
33.6
46.5
63.2
18.8
47.0
46.1
30.1
43.1
58.1
18.8
44.3
43.9
28.3
42.7
57.2
20.2
44.0
45.0
TABLE 2: USE OF SECONDARY STROKE PREVENTIVE THERAPIES, BY NUMBER OF DRUG
CLASSES, AMONG US VETERANS DISCHARGED FROM A VA MEDICAL CENTER WITH
ACUTE ISCHEMIC STROKE, OCTOBER 1, 2001 THROUGH SEPTEMBER 30, 2003
Number of
Drug Classes
(3 maximum)
3
2
1
0
90 days
pre-stroke
discharge
3.9
18.6
30.0
47.5
531
of ischemic stroke and an NIH Stroke Scale score ⬎1. After consent and randomization,
in-hospital baseline measures were obtained. For both the intervention (n⫽190) and control
(n⫽190) groups PCPs received written patient summaries of baseline data. For the intervention
an Advanced Practice Nurse/Care Manager (APN-CM) performed an in-home assessment
within 1 week of discharge. The results of the home assessment were reviewed by an
interdisciplinary post-stroke consultation team (PSC-Team) who developed patient care plans
specific to each problem identified by the APN-CM. A copy of the care plans, evidence-based
guidelines, pertinent references, and “academic detailing” were given to the patient’s PCP. The
APN-CM worked with the PCP to implement the recommendations and provide ongoing
monitoring over the next 6 months via periodic phone calls and PRN home visits. Outcomes:
Multiple outcomes across 5 domains were used to capture both functional and management
effects. The 5 domains included 1) Neuromotor Function, 2) Institutional utilization and
death, 3) Quality of Life, 4) Medical Management for common post-stroke complications and
recurrent stroke, and 5) Self-management. Results: The two groups were highly similar at
baseline with almost all confidence intervals including zero. The effect of the treatment was
near zero standard deviations for all but domain 5. The global test for the function domains
proved non-significant at the alpha⫽0.04 level (p⫽0.53). The global test of the management
domains were significant at alpha⫽0.01 (p⫽0.002). The closed tests for the medical
management domain proved non-significant (p⫽0.62), while the one for self-management
proved significant (p⫽0.0003). Discussion The results showed no significant effect of the
intervention on the primary outcome at 6 months. Potential reasons include the effectiveness
of the stroke unit in post-discharge planning and the lack of baseline deficits in the study
population.
15
The Combined Approach To Lysis Utilizing Eptifibatide And rt-PA In Acute
Ischemic Stroke (the CLEAR Stroke Trial): Final Results From Tier I and II.
Arthur M Pancioli, Univ of Cincinnati, Cincinnati, OH; for the CLEAR Trial Investigators
The combined approach to lysis utilizing eptifibatide and rt-PA (CLEAR) stroke trial is a
multi-center, double-blind, randomized, dose-escalation and safety study. This trial was a part
of the NINDS SPOTRIAS program. Methods - The CLEAR Trial evaluated the risks and benefits
of eptifibatide, a GP llb/IIIa antagonist, combined with low-dose IV rt-PA in ischemic stroke
patients treated within 3 hours of onset (age 18 – 80 years and baseline NIHSS⬎5). Patients
were randomized 3:1 to IV eptifibatide plus low-dose rt-PA, or standard dose rt-PA. The primary
safety endpoint was the incidence of symptomatic ICH within 36 hours. The CLEAR trial studied
2 dose tiers of combined therapy compared to standard dose rt-PA. In dose tier 1 the rt-PA dose
was 0.3 mg/kg. In dose tier 2 the rt-PA dose was 0.45 mg/kg. In both tiers the eptifibatide dose
was a 75 mcg/kg bolus and a 0.75 mcg/kg/hr infusion for 2 hours. The control for both dose
tiers was standard 0.9 mg/kg rt-PA. Results - The study enrolled a total of 94 subjects; 40 in
dose tier 1 and 54 in dose tier 2. The combination cohort had a total of 69 patients with a
median age of 71, and a median baseline NIHSS of 14. The standard dose rt-PA group had 25
patients with a median age of 61 and a median baseline NIHSS of 10 (p⫽0.014 for NIHSS).
There was 1 (1.4%) symptomatic ICH in the combination group and 2 (8.0%) in the standard
treatment arm (p⫽0.17). There was a non-significant trend toward increased efficacy with the
standard dose rt-PA treatment arm. The adjusted odds ratio and associated 95% confidence
intervals for achieving a good outcome in the experimental group as compared to the control
group: 90-day mRS 0.59 (0.21, 1.67), 90-day Barthel 0.51 (0.15, 1.71) 90-day GOS 1.08 (0.36,
3.18). (Adjusted for age, baseline NIHSS and baseline Rankin) Conclusion - The combination
of eptifibatide and reduced dose rt-PA is safe enough for consideration of further dose ranging
trials in acute ischemic stroke.
Filled Prescription Rate (%) during Specified Interval
0 –90 days
91–180 days
181–270 days
271–365 days
post-stroke
post-stroke
post- stroke
post-stroke
discharge
discharge
discharge
discharge
8.2
33.4
37.5
20.9
6.9
28.2
34.8
30.1
6.4
27.4
32.9
33.3
16
Does Study Enrollment Delay Treatment with Intravenous Thrombolytics for
Acute Ischemic Stroke?
7.8
27.6
30.7
33.9
*Three drug classes are thiazide diuretics, ACE/ARBs, and statins. #
14
Randomized Controlled Trial of a Post-stroke Post-discharge Care
Management Intervention.
Kyle R Allen, Susan Hazelett, Summa Health System, Akron, OH; Dave Jarjoura, Ohio State
Univ, Columbus, OH; Kathy Wright, Janice Weinhardt; Summa Health System, Akron, OH
Background: Stroke is the leading cause of disability, the third leading cause of death, and one
of the most expensive medical problems in the United States. Acute care institutions and
rehabilitation programs that utilize a comprehensive interdisciplinary team approach to patient
care demonstrate improved patient outcomes. It is unclear whether comprehensive postdischarge care can further optimize post-stroke outcomes. Purpose: This randomized
controlled trial tested the effectiveness of a comprehensive interdisciplinary post-discharge
stroke care management intervention in improving the overall well-being of stroke survivors 6
months post-discharge. Methods: Patients were recruited from the acute stroke unit at our 963
bed community teaching hospital in Northeastern Ohio. Inclusion criteria included a diagnosis
Sheryl Martin Schild, UT Houston Health Science Cntr, Houston, TX; Karen C Albright, UCSD,
San Diego, CA; Hen Hallevi, Andrew D Barreto, Nicole R Gonzales, UT Houston Health
Science Cntr, Houston, TX; Aslam M Khaja, Univ of Illinois at Chicago, Chicago, IL; Kachi
Illoh, Elizabeth A Noser, James C Grotta, Sean I Savitz; UT Houston Health Science Cntr,
Houston, TX
Background: Enrollment in acute stroke trials at a stroke center with multiple study protocols
may delay the initiation of IV thrombolytics in patients who present within 3 hrs of symptom
onset. Some trials require enrollment and randomization before or during thrombolysis. Rapid
treatment decisions are critical in the acute setting. Delays in reperfusion not only limit tissue
salvage but also may impair the detection of potential clinical improvements from study
treatments. Methods: We prospectively studied all patients presenting to our emergency
department with acute ischemic stroke over the past 3.5 years who qualified for thrombolysis
within 3 hours of onset. We collected demographics, baseline NIHSS scores, CT findings, and
door-to-needle times and compared patients treated with IV thrombolytics in a clinical trial with
patients who received standard of care IV t-PA. Results: Out of 290 patients treated with IV
thrombolytics, 46 were enrolled in trials after starting t-PA (adjunctive therapies), 19 were
enrolled in trials prior to starting thrombolytics (comparing different thrombolytics), and 225
were treated with standard IV t-PA. There was no significant difference in age, gender, NIHSS
score, admission glucose, changes on CT, onset to arrival time, or door-to-needle time between
532
Stroke
Vol 39, No 2
February 2008
patients enrolled in clinical studies and those who received standard treatment. However,
among study patients, pre-lytic randomization led to a significantly longer door-to-needle time
by 13 minutes (p⫽.028). Discussion: Patients participating in our trials are representative of
our overall population of acute stroke patients. We found that trials requiring pre-lytic
randomization can lead to a short delay in the initiation of treatment. Future studies are needed
to determine if such a short delay is clinically significant and can be shortened by improved
enrollment strategies.
Variable
Age, median (range)
Gender (% male)
Race (%) African-American Hispanic
White Other
Admission Glucose, median (range)
Early Ischemic changes on initial CT
%
Baseline NIHSS Score, median (range)
Onset to needle, median (range)
Door to needle, median (range)
Variable
Onset to needle,
median (range)
Door to needle,
median (range)
Not enrolled
135(64–180)
n⫽225
62(20–131)
n⫽222
Not enrolled
Enrolled
p value
63 (19–91)
n⫽225
56.4 (127/225)
38.7 (87/225)
14.2 (32/225)
44.9 (101/225)
2.2 (5/225)
122 (62–536)
n⫽225
15.6 (35/225)
65 (38–91)
n⫽65
50.8 (33/65)
32.3 (21/65)
13.8 (9/65)
49.2 (32/65)
4.5 (3/65)
135 (78–414)
n⫽65
16.9 (11/65)
.285
12 (0–39)
n⫽225
135 (64–180)
n⫽225
62 (20–131)
n⫽222
13 (3–26)
n⫽65
127 (64–180)
n⫽65
61 (23–135)
n⫽63
.696
.418
.168
.170
.790
.636
.725
Studies with
post-lytic enrollment
46/65 (70.8%)
Studies with
pre-lytic enrollment
19/65 (29.2%)
126(64–180)
n⫽45
59(23–135)
n⫽45
128(92–178)
n⫽19
72(52–111)
n⫽18
18
Feasibility of Caffeinol and Hypothermia for Acute Ischemic Stroke.
Sheryl Martin-Schild, Andrew D Barreto, Hen Hallevi, UT Houston Health Science Cntr,
Houston, TX; Aslam M Khaja, Univ of Illinois at Chicago, Chicago, IL; Hashem Shaltoni,
Nicole R Gonzales, Kachi Illoh, Elizabeth A Noser, Jarek Aronowski, Sean I Savitz, James C
Grotta; UT Houston Health Science Cntr, Houston, TX
Background: Caffeinol and hypothermia have each been shown to be neuroprotective and the
combination robustly reduces infarct volume and deficits in our animal stroke model. Prior
studies also support the safety of caffeinol infusion in acute stroke patients. We tested whether
combining these two approaches is safe and feasible. Methods: In a non-randomized trial, 20
patients with acute ischemic stroke were enrolled to receive caffeinol and hypothermia.
Caffeinol IV (caffeine 8 –9 mg/kg; ethanol 0.4g/kg) was administered within 4 hrs while
hypothermia was started within 5 hrs after symptom onset and continued for 24 hrs (target
temp 33–350C) followed by 12 hrs of rewarming. The protocol included meperidine and
buspirone to treat shivering. IV t-PA was given to patients who met eligibility criteria. Results:
Fourteen of 20 patients received t-PA followed by caffeinol and hypothermia. Three of the 20
had contraindications to t-PA and the other 3 received t-PA either with hypothermia or caffeinol.
Cooling was attempted in 18 patients via endovascular (n⫽8) or surface (n⫽10) approaches;
in the other 2 patients, there was machine failure or complete resolution of deficits before
instituting cooling. Of those 18 patients enrolled in the hypothermia protocol, 5 did not reach
the target temperature. Two reached the target temperature within 1 hr, a total of 4 reached
the target temperature within 2 hrs, and 8 within 3hrs of induction. Of the 13 patients that
reached the target temperature during active cooling, the average time to target from symptom
onset was 9hrs, 43min. The last 5 hypothermia patients received iced saline and surface
cooling and their temperatures reached the target on average within 2hrs 30min. Their average
time to target from symptom onset was 6hrs 21min. One symptomatic hemorrhage occurred
in a patient who received t-PA and died. One patient died of malignant edema and a third
patient died of unrelated medical complications. No adverse events were attributed to caffeinol.
One patient had reduced respiratory drive due to meperidine, requiring BiPAP. Discussion: Our
study supports the feasibility of combining caffeinol with hypothermia in acute stroke patients.
A prospective multi-center placebo-controlled phase 2 randomized study has been designed to
test the efficacy of caffeinol, hypothermia or both in patients presenting within 3 hrs of stroke
onset.
19
17
Lack of Adherence to Guidelines for Pre-TPA Blood Pressure Levels Is
Associated with Higher Risk of Symptomatic Intracerebral Hemorrhage.
Georgios Tsivgoulis, Stroke Program, Barrow Neurological Institute, Phoenix AZ and UAB
Comprehensive Stroke Cntr, Birmingham, AL; James L Frey, Stroke Program, Barrow
Neurological Institute, Phoenix, AZ., Phoenix, AZ; Vijay K Sharma, Div of Neurology, Dept of
Medicine, National Univ Hosp, Singapore, Singapore; Annabelle Y Lao, Steven L Hoover, Wei
Liu, Murray Flaster, Stroke Program, Barrow Neurological Institute, Phoenix, AZ., Phoenix,
AZ; Anne W Alexandrov, Comprehensive Stroke Cntr, Univ of Alabama at Birmingham Hosp,
Birmingham, AL; Marc Malkoff, Stroke Program, Barrow Neurological Institute, Phoenix, AZ.,
Phoenix, AZ; Andrei V Alexandrov; Comprehensive Stroke Cntr, Univ of Alabama at
Birmingham Hosp, Birmingham, AL
Background&Purpose: Based on small pilot studies, exclusionary blood pressure parameters
for TPA treatment in the NINDS TPA trial were set at SBP ⬎185mmHg and DBP⬎110mmHg.
Current guidelines endorse these thresholds despite little data to substantiate the choice of
these specific BP values. We sought to determine if pre-treatment BP protocol violation in acute
IS patients receiving iv-TPA are related to the subsequent risk of sICH. Subjects&Methods: We
reviewed medical records of consecutive IS admissions treated with intravenous TPA over 10
year period at our tertiary care hospital. The National Institutes of Health Stroke Scale (NIHSS)
scores on admission and modified Rankin Scores (mRS) at discharge were documented as
standard of care. The closest documented BP values to the time of TPA-bolus (range 0 –10 min)
were considered as pre-treatment BP. BP protocol violation was identified as SBP⬎185 or
DBP⬎110 mmHg pre-bolus. sICH was defined as brain imaging evidence of ICH with clinical
worsening by the NIHSS score increase of ⱖ4 points. Results: Among 510 IS patients treated
with iv-TPA (282 men; mean age 65⫾15 yrs), 63 patients (12.4%) had BP protocol violations.
Patients with sICH had higher pre-treatment SBP levels (169⫾29mmHg vs. 156⫾24mmHg;
p⫽0.006) while pre-treatment DBP levels were similar in those with and without sICH
(85⫾21mmHg vs. 82⫾16mmHg; p⫽0.430). Pre-treatment BP protocol violation was more
frequent in patients with sICH (26% vs. 12%; p⫽0.019). Patients with BP protocol violation had
an absolute sICH risk of 12.7% compared to 5.1% without BP violation. The number-neededto-harm for one more patient to have sICH was 13. After adjusting for demographic
characteristics, stroke risk factors, onset-to-treatment time and baseline stroke severity,
pre-treatment BP protocol violations were independently associated with a higher likelihood of
sICH (OR: 2.49; 95%CI: 1.04 –5.97; p⫽0.040). Patients with BP violation tended to have lower
rates of functional independence (mRS 0 –1) at hospital discharge (9%) compared to patients
without BP protocol violation (14%; p⫽0.074). Conclusions: These data demonstrate an
independent association between BP protocol violation and likelihood of sICH and provide
support for current guidelines advising caution in using iv-TPA when pre-treatment BP exceeds
the pre-specified threshold.
The Metabolic Syndrome is Associated with a Higher Resistance to i.v.
Thrombolysis for Acute Ischemic Stroke in Women Than in Men.
Juan F Arenillas, Patricio Sandoval, Natalia Pérez de la Ossa, Mónica Millán, Cristina
Guerrero, Domingo Escudero, Laura Dorado, Elena López-Cancio, Ana C Ricciardi,
Neurosciences Dep. Germans Trias i Pujol Universitary Hosp, Barcelona, Spain; José
Castillo, Neurosciences Dep. General Universitary Hosp, Santiago de Compostela, Spain;
Antoni Dávalos; Neurosciences Dep. Germans Trias i Pujol Universitary Hosp, Barcelona,
Spain
Background and purpose: Metabolic syndrome (MetS) is associated with defective endogenous fibrinolysis. Previous studies suggested that MetS might confer a higher resistance to i.v.
thrombolysis in acute middle cerebral artery (MCA) ischemic stroke. As the MetS increases the
risk of stroke and coronary heart disease in women to a greater extent than in men, we aimed
to investigate whether there may be gender differences in the impact of MetS on the response
to i.v. thrombolysis for acute MCA ischemic stroke. Methods: We prospectively studied
consecutive ischemic stroke patients treated with intravenous t-PA following SITS-MOST
criteria, who showed an MCA occlusion on prebolus transcranial Doppler (TCD) examination.
TCD monitoring of the occluded MCA was performed, and resistance to thrombolysis was
defined as the absence of complete MCA recanalization 24 hours after t-PA infusion, according
to Thrombolysis in Brain Ischemia criteria. MetS was diagnosed following the criteria
established by the AHA/NHLBI-2005 statement modified for abdominal obesity, which was
defined by a body-mass indexⱖ25. Results: A total of 132 patients (82 men, 50 women, mean
age 67.6 ⫾ 11) with an acute MCA occlusion were included. Median baseline NIHSS score was
17 (interquartile range 10 –20). MetS was diagnosed in seventy-eight (60%) patients.
Resistance to complete clot lysis at 24 hours was observed in 53 (40%) patients. Two
multivariate-adjusted logistic regression models identified MetS as associated with a higher
resistance to t-PA, independently of other significant baseline variables (OR 10.1, 95% CI
[3.7–27.6], p⫽0.0006) and of the individual components of the MetS. A positive interaction
was found between MetS and gender. The MetS was associated with a significantly higher
odds of resistance to thrombolysis in women (OR 17.5, 95% CI [1.9 –163.1]) than in men (OR
5.1, 95% CI [1.6 –15.6]), (p for interaction ⫽ 0.0001). Among the subcomponents of the MetS,
obesity showed the strongest impact on the resistance to clot lysis in women, whereas blood
glucose ranked first in men. Conclusion: The effect of MetS on the resistance to i.v.
thrombolysis for acute MCA ischemic stroke appears to be more pronounced in women than
in men.
20
A Method to Predict Stroke Trial Success Based on Pooled Control Arms.
Pitchaiah Mandava, Thomas A Kent; MEDVAMC/BCM, Houston, TX
Background: Many promising phase I/II trials of treatment for stroke have not been confirmed.
While many factors have been suggested to account for this lack of success, robustness of
clinical effect may be important. Because outcome is highly dependent on baseline variables,
lack of a control group or small differences in randomization that may occur in early trials are
difficult to account for post-hoc. We hypothesized that a pooled control arm adjusted for
variables of interest and sample size would provide a more reliable predictor that could be used
for decision making prior to proceeding to full Phase III trials. Methods: All randomized
controlled trials (RCT) for acute stroke with ⬎ 10 subjects including baseline NIHSS, age and
3 month outcomes were identified. Freeman-Tukey modification of the arc-sine square-root
function was applied to the outcomes of control arms to account for the variations in the
number of patients. A locally written Matlab© program (PPREDICTS©) performed data storage,
transformation, function minimization/optimization and provided the ability to map onto,
visualize and test/validate outcomes onto the functions. The novel feature was the generation
of multi-dimensional ⫾ 95% prediction interval surfaces based on local and global statistical
factors. Here, mRS0 –2 was the outcome, and baseline NIHSS and age were selected for this
proof of principle study. Results: A function based on the control arms of 15 RCTS (n⫽5437)
was generated (mRS figure; R2⫽0.89, p⬍0.0001; mortality not shown). ABESTT and SAINT-I
treatment arm outcomes fell within prediction surface bounds and would have predicted futility
while NINDS rt-PA mRS0 –2 outcome (’N’, figure) was above the ⫹95% surface. Enlimomab
mRS0 –2 fell below the -95% surface, consistent with reported worsening. Several new
therapies were identified as promising while the failure of all others was confirmed by this
method. Conclusion: The use of a pooled placebo group function may provide an accurate
method to predict success of early trials. In addition, the degree to which an individual study’s
placebo group is representative can be checked as well. While we selected mRS0 –2 as the
outcome and NIHSS and age as predictor variables in this study, in theory this method could
employ any variable of interest provided that sufficient data was available.
533
22
Selective ETA Receptor Antagonism: Perfusion/Diffusion MRI Defines
Treatment Efficacy, Mechanism and Translatable Stroke Model for SB
234551.
Frank C Barone, Stephen C Lenhard, Robin E Haimbach, Thomas R Schaeffer, Ross G
Bentley, Matthew J McVey, Sudeep Chandra, Elaine A Irving, Andrew A Parsons, Jeffrey J
Legos; GlaxoSmithKline, King Of Prussia, PA
Background: Mismatches between tissue perfusion (PWI; an index of blood flow) and cellular
diffusion (DWI; an index of tissue injury) images allow the identification of “treatable” (i.e.,
containing salvageable penumbra) clinical stroke patients. The present pre-clinical studies
were conducted to: (a.) Determine PWI (perfusion delay) and DWI measurements in
experimental stroke models, (b.) Utilize these measurements to characterize selective ETA
receptor antagonism (i.e., determine efficacy, time-to-treatment and “treat-ability” in different
models), and (c.) Determine if increased blood flow following focal stroke is a mechanism of
neuroprotection in a “treatable” model. Methods: Permanent middle cerebral artery occlusion
(MCAO) or sham surgeries were produced in Sprague Dawley rats (SD; proximal MCAO;
hypothesized to be a slowly evolving brain injury with significant penumbra) and in
spontaneously hypertensive rats (SHR; distal MCAO; hypothesized to be a rapidly evolving brain
injury with little penumbra). At 0, 75, and/or 180 min post-surgery, SD and SHR received either
vehicle or SB 234551 (3, 10, or 30 ␮g/kg/min). The hyper intense area of perfusion delay was
measured using Gadolinium bolus contrast and the DWI hyper intense area was also measured,
and the degree of DWI-perfusion mismatch was determined. Results: Following SD proximal
MCAO, there was a significant mismatch at 60min which was maintained up to 150min. By 24
hours infarct volume was identical to the area of early perfusion deficit. SB 234551
administered within the period of peak mismatch produced a significant dose-related reduction
in cortical (penumbral) infarct volume and increased cortical tissue perfusion (p⬍0.05). When
SB-234551 was administered beyond the time of mismatch, no effect on infarct volume was
observed. Comparatively, following SHR distal MCAO there was no mismatch between
perfusion and DWI, suggesting a rapidly occurring brain injury with little penumbra. SB 234551
administered immediately at the time of MCAO did not affect infarct volume. Conclusions:
Selective ETA receptor blockade is neuroprotective in SD (i.e. a model similar to “treatable”
clinical patients). The protective mechanism appears to be due to enhanced collateral blood
flow and salvage of penumbra. Perfusion/diffusion mismatch signatures can allow selection of
a translatable stroke model, can define time to treatment protocols, and can clarify vascular
mechanism of protection in focal stroke.
23
NADPH Oxidase from Circulating Inflammatory Cells Exacerbates Injury in
Experimental Stroke.
21
Influence Of Polymorphisms Of F12 46 C/t, F7 670 A/c And F7 401/-323 On
The Outcome And The Risk Of Cerebral Hemorrhage In Patients With
Ischemic Stroke Treated With Rt-pa.
Joan Martı́-Fàbregas, Dolores Cocho, José Manuel Soria, Hosp de la Santa Creu i Sant Pa,
Barcelona, Spain; Joan Montaner, Hosp Vall d’Hebron, Barcelona, Spain; Isabel Tirado, Hosp
de la Santa Creu i Sant Pa, Barcelona, Spain; Israel Fernández-Cadenas, Hosp Vall
d’Hebron, Barcelona, Spain; Sergi Martı́nez-Ramı́rez, Eugenia Martı́nez-Hernández, Daniel
Alcolea, Marta Marquié, Jordi Fontcuberta, Josep-Lluis Martı́-Vilalta; Hosp de la Santa Creu
i Sant Pa, Barcelona, Spain
Introduction. FXII and FVII play a central role in activation of coagulation. We analyzed whether
polymorphisms of these factors influence the results of thrombolysis.Methods. A case series
of patients treated with intravenous rt-PA within the first 3 hours after symptom onset. We
genotyped the following polymorphisms: F12 46C/T, F7 670A/C and F7 G/T401/-323.
Neurological deficit was assessed with the NIHSS score. Symptomatic intracranial hemorrhage
(sICH) was diagnosed when a parenchymal hematoma (pH-2) occurred within the first 36 hours
after treatment, and was associated with an increase ⬎3 points on the NIHSS score. A
favourable outcome was defined as Rankin scale score ⬍2 at 3 months.Results. We studied
419 patients with a mean age of 70⫾10 years, and 49.4% were men. Median NIHSS score at
baseline was 16. Mean time to treatment was 142⫾30.7 minutes. A favourable outcome was
observed in 37.6% and sICH in 2.5% of patients. We detected the following polymorphisms:
F12 C46T (n⫽221, 66.5% C/C, 30.3% C/T, 3.2% T/T); F7 670A/C (n⫽204, 60.3% AA, 33.9%
AC, 5.8% CC); F7 G/T401/-323 (n⫽205, 65% G/G, 34.1% G/T, 0.9% TT). Polymorphisms
F1246 C/C and F7 670 A/A were statistically associated with an increased frequency of
asymptomatic hemorrhagic transformation (24.3% versus 11.9%, and 29.4% versus 13.1%,
respectively, p⫽0.05). Discussion. In conclusion, the polymorphisms analyzed significantly
increased the risk of asymptomatic hemorrhagic transformation, without influencing the risk of
symptomatic hemorrhage or the clinical outcome.
Xian N Tang, UCSF & SF VAMC, Stanford Univ, San Francisco, CA; Zhen Zheng, UCSF & SF
VAMC, San Francisco, CA; Nick Cairns, Combinix, Inc., Mountain View, CA; Belinda Cairns,
Combinix, Inc, Mountain View, CA; Rona G Giffard, Stanford Univ, Stanford, CA; Midori A
Yenari; UCSF & SF VAMC, San Francisco, CA
NADPH oxidase (Nox2) is a major enzyme system which generates superoxide generation in
inflammatory cells, but has recently been found in non inflammatory cells such as endothelial
cells and neurons. Here we show that Nox2 contributes to experimental stroke, especially in
circulating inflammatory cells. Experimental stroke was produced in mice by 2h transient
middle cerebral artery occlusion (tMCAO), followed by 22h reperfusion. Three different
paradigms were studied: 1) Mice treated with the Nox2 inhibitor, apocynin (Apo, 2.5 mg/kg IV
30 min prior to reperfusion) or vehicle (Veh). 2) Nox2 deficient (X-CGD, deficient in the gp91
subunit) vs wildtype (Wt) mice were studied. 3) To determine whether Nox2 in circulating cells
vs brain resident cells contribute to ischemic injury, bone marrow chimeras were generated by
transplanting bone marrow from Wt or X-CGD into X-CGD or Wt, respectively. Brains were
assessed for infarct volume, hemorrhage, in situ O.- detection, as well double labeling for O.in neurons (NeuN), endothelial cells (CD31) and microglia (CD11b). Brain tissue within
peri-infarct regions was sampled and used for Western blots. Infarct size was reduced whether
Nox2 was pharmacologically (by 37% vs vehicle, P⬍0.05) or genetically (by 54% vs Wt,
P⬍0.001) inhibited. This was also associated with reduced incidences of cerebral hemorrhage
(17% vs. 58%, Apo vs Veh; 14% vs 58%, X-CGD vs Wt). After ischemia, most of the O.- was
generated by neurons, some microglia, and rare endothelial cells. O.- was markedly reduced by
Apo treatment and in X-CGD mice in all cell types (1% vs. 448%, Apo vs Veh; 11% vs 448%,
X-CGD vs Wt). Apo treatment and X-CGD mice showed decreased MMP9 (40% vs. 86%, Apo
vs Veh; 50% vs 86%, X-CGD vs Wt) and decreased loss of ZO-1(182% vs. 27%, Apo vs Veh;
48% vs 27%, X-CGD vs Wt). Infarcts in Wt mice who received Nox2 deficient marrow
(40.1⫾6.7 mm3) were decreased significantly compared to either the Wt mice who received Wt
marrow (100.4⫾9.9 mm3, P⬍0.01) or X-CGD mice who received Wt marrow (74.5⫾6.5 mm3,
P⬍0.05). We conclude that either pharmacologic or genetic inhibition of Nox2 leads to reduced
brain injury and hemorrhage, and is correlated to decreased O.- and MMP9 expression and
prevents the loss of ZO-1. Nox2 originating from the circulating inflammatory cells contributes
more to exacerbating experimental stroke than that of the brain resident cells.
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Vol 39, No 2
February 2008
24
Mast Cells Are Early Responders After Hypoxia-ischemia In Immature Rat
Brain.
Yuxuan Jin, Susan J Vannucci, Ann-Judith Silverman; Columbia Univ Med Cntr, New York,
NY
Background and Purpose: Perinatal hypoxia-ischemia (HI) produces acute and prolonged
inflammation of the brain. Mast cells (MCs) can initiate inflammation due to pre-formed and
made-upon-demand mediators. MCs are numerous in the pia of neonatal rats and enter the
CNS on postnatal day (P) 7 with penetrating blood vessels. Using an established model of
perinatal HI, we previously reported that MCs contribute to brain damage and MC stabilization
protects through 48 hrs post-HI. Here we hypothesize that HI induces early MC migration/
activation with subsequent release of proinflammatory molecules and MC inhibition is
neuroprotective. To test this hypothesis we examined the time course of MC and neural cell
activation post HI and MC stabilization with Cromolyn. Methods: P7 rat pups were subjected
to HI according to our standard model of permanent occlusion of the right carotid artery, 75min
hypoxia (8% oxygen). Cromolyn (50 mg/kg sc) or saline was injected at 0, 1, 24 hrs after HI.
Animals were killed immediately after HI, or at 1, 2, 4, 24 hrs; 1, 2 or 4 wk after HI. Brains were
fixed, sectioned, and analyzed with histochemistry and immunocytochemistry and data
collected with standard fluorescent and scanning confocal microscopy. Results: Brain MC
numbers were elevated throughout the ipsilateral (ischemic) hemisphere immediately after HI
(P⬍0.05), and were degranulated. MC activation was observed prior to detection of cleaved
caspase-3 in apoptotic neurons (TuJ1⫹; 2hrs), or glial activation (GFAP⫹) or microglia
(OX42⫹) (4 hrs). MC numbers remained elevated for 1 week, with the largest accumulation at
48hrs (P⬍0.01). In normal CNS only MC produce TNF-alpha. Immediately following HI
TNF-alpha positive MC increased in ipsilateral hemisphere (p⬍0.01) and remained high for 24
hrs. Activated microglial TNF-alpha was evident at 4 hrs while endothelial cells had no
detectable cytokine until 48hrs post HI. Cromolyn reduced MC migration and reduced brain
damage/neuronal loss for up to 4 weeks post HI (P⬍0.05). Conclusions: These data support
our hypothesis that MCs are early responders to HI in neonatal brain. MCs are present in large
numbers in HI brain with preformed and induced proinflammatory molecules key to
inflammation. Prevention of MC activation provides lasting protection and suggests a new
target for therapeutic interventions.
25
Key Role of the Scavenger Receptor CD36 in Postischemic Inflammation
and Ischemic Brain Injury.
Alexander Kunz, Dept. of Neurology, Univ Hosp, Dresden, Germany; Takato Abe, Karin
Hochrainer, Josef Anrather, Gianfranco Racchumi, Ping Zhou, Costantino Iadecola; Div. of
Neurobiology, Weill Cornell Med College, New York, NY
Background: CD36, a scavenger receptor found in macrophages, endothelium and microglia,
contributes to ischemic brain injury (J Neurosci 25: 2504, 2005). The mechanisms of
CD36-mediated neurotoxicity are not known. In some organs, CD36 is involved in inflammatory
responses (J Clin Invest 108: 785, 2001). Therefore, we investigated whether CD36 contributes
to ischemic injury by mediating postischemic inflammation. Methods: The middle cerebral
artery (MCA) was transiently occluded in wild type mice (WT) or CD36-null mice (KO) and 72
hrs later, injury volume, mRNA expression of the inflammatory genes iNOS, ELAM, ICAM, nox2,
rac2, and neutrophil infiltration were analyzed. Results: In KO, the injury volume was reduced
(-62⫾5%; p⬍0.05; n⫽6/group) and mRNA expression of inflammatory genes was markedly
attenuated (iNOS: -74⫾3%; ELAM: -80⫾11%; ICAM: -70⫾3%; nox2: -76⫾4%; rac2:
-67⫾5%; p⬍0.05; n⫽5/group). Also, the number of neutrophils infiltrating the infarct was
reduced (KO: 281⫾93; WT: 1938⫾296; p⬍0.05; n⫽5/group). WT treated with NS398, an
agent that blocks COX2-mediated neurotoxicity, had a reduction in injury (40⫾15%; p⬍0.05;
n⫽6) not different from that of KO (p⬎0.05), but did not exhibit comparable reductions in gene
expression and neutrophils (p⬍0.05 from KO). Thus, the suppression of postischemic
inflammation in KO is not secondary to reduced injury volume. In contrast to postischemic gene
expression, brain expression of inflammatory genes induced by intracerebroventricular injection
of interleukin (IL)-1␤ was not attenuated in KO (p⬎0.05; n⫽5/group). If the protection in KO
is due to suppression of inflammation, then treatments antagonizing postischemic inflammation
should not be effective in KO. Consistent with this prediction, the iNOS inhibitor aminoguanidine
reduced infarct volume in WT (-45⫾13%; n⫽6), but not in KO (p⬎0.05 from vehicle; n⫽6).
In contrast, NS398 reduced injury both in WT (-40⫾15%) and KO (-59⫾4%; p⬍0.05;
n⫽6/group). Conclusions: The data demonstrate that CD36 is a key factor triggering
inflammatory gene expression and tissue damage following cerebral ischemia. The observation
that, contrary to ischemia, IL-1ß induces a normal inflammatory response in KO indicates that
CD36 is specifically involved in the cellular and molecular mechanisms underlying postischemic
inflammation. The identity of the ligand(s) activating CD36 during cerebral ischemia and the
signaling pathways linking CD36 to postischemic gene expression remain to be defined.
cerebral ischemia was induced by occluding the middle cerebral artery (MCAO) using an
intraluminal filament technique (ischemia duration 3 h). Our laboratory had previously
established a hypothermia model in mice. Eight C57BL/6 (wild type) mice received normothermia (37°C; NT), eight C57BL/6 mice received hypothermia (32–34°C; HT), seven
plasminogen knockout mice (Plg-/-) received normothermia, and nine Plg-/- received
hypothermia treatment during 24 hours of reperfusion. The infarct size was volumetrically
determined. Gelatine zymography was used to detect MMP-9 and MMP-2 activity. The MMP
content was measured by the ratio of the ischemic- to the non-ischemic side. The statistical
analysis was based on Scheffe’s test and the Mann-Whitney U test with SEM. The infarct size
was 69⫾8mm3 in NT and 38⫾5mm3 in HT (p⫽0.024) in C57BL/6 (wild-type) mice. MCAO
produced larger infarcts in Plg-/- mice (91⫾8mm3 NT; 52⫾6mm3 HT; p⫽0.004). Hypothermia
significantly reduced the proteolytic activity of MMP-9 in C57BL/6 (NT: 372⫾85%; HT:
203⫾35%; p⫽0,048), whereas MMP-9 in Plg-/- was not affected (NT: 1007⫾129%; HT:
767⫾182%; p⫽0.281). Furthermore, the MMP-9 level was 2.71 times higher in Plg-/- than in
C57BL/6 during normothermia (p⫽0.018); it increased by 3.77-fold during hypothermia
(p⫽0.034). The MMP-2 level remained unchanged in all conditions (C57BL/6: NT 228⫾62%,
HT 135⫾29%; Plg-/-: NT 222⫾75%, HT 167⫾36%). In conclusion, this study demonstrates
that hypothermia is as effective in Plg-/- mutants as it is in wild type mice in reducing infarct
size. A novel finding of the study is the high level of MMP-9 in PLG-/- mice, which was not
significantly affected by hypothermia. This high MMP-9 in the plasminogen knockout situation
might reflect a compensatory increase in an alternative proteolytic system, resulting in larger
infarcts. Further studies are needed to clarify the pathophysiological relevance of this
observation.
27
Timing Of MGE Cell Transplantation After Distal Middle Cerebral Artery
Occlusion Significantly Influences The Cell-host Interaction.
Hideo Shichinohe, Marcel M Daadi, Nobutaka Horie, Theo D Palmer, Tonya Bliss, Gary K
Steinberg; Stanford Univ, Stanford, CA
Introduction: Growing evidence suggests that cell transplantation holds great potential as stroke
therapy. One fundamental variable that needs to be defined is the optimal time after stroke for
transplantation. This study describes the difference that the time of transplantation makes to
the host response and graft biology. Methods: Primary medial ganglionic eminence (MGE)
neural precursors were isolated from E15 rat embryos carrying the transgene for EGFP. Stroke
was induced in rats by distal middle cerebral artery occlusion. A suspension of MGE cells was
transplanted into the rat cortex at day 2 (n⫽5) or day 14 (n⫽6) after stroke. Animals were
sacrificed at day 42 post-stroke and we had histological analysis. Results: There was a
significant difference in transplanted cell survival between the two transplant groups. Cells
transplanted at day 2 post-stroke showed very little survival at day 42; the cells in the core
appeared to be dead but a thin layer of cells survived around the periphery of the graft. In
contrast, when examined at day 42, the cells transplanted at day 14 exhibited much more
robust survival throughout the graft and formed a much more elongated graft. Furthermore, the
grafts of the day 2 group showed a greater migratory capacity towards the lesion that the day
14 grafts. The day 2 grafts had migrated 1.26 ⫾ 0.42 mm from the site of transplantation and
were close to lesion edge whereas the day 14 grafts showed little migration from the site of
transplantation (0.27 ⫾ 0.17 mm) and were thus further from the lesion. The host inflammatory
response was dependent on the timing of transplantation. The day-2 group showed a robust
inflammatory response at six weeks post-stroke, with microglia both within and surrounding
the graft. In the day-14 group at six weeks poststroke, there were very few microglia in the
graft and a dramatic lack of them immediately surrounding the graft. However, in this microglia
sparse area there were many host astrocytes which appeared to form a barrier around the graft
precluding the monocytes. Conclusions: The timing of transplantation after stroke has a
long-term effect on the host response to the graft. This response can dramatically affect the
graft’s microenvironment and ultimately determine the success of cell-based therapy.
26
Effects Of Hypothermia On Focal Cerebral Ischemia In Plasminogen
Knockout Mice.
Jan Burk, Dorothe Burggraf, Ludwig-Maximilians Univ - Dept of Neurology, Munich,
Germany; Milan Vosko, AKh Linz, Linz, Austria; Martin Dichgans, Ludwig-Maximilians Univ Dept of Neurology, Munich, Germany; Gerhard F Hamann; HSK Dr. Horst-Schmidt-Klinik Dept of Neurology, Wiesbaden, Germany
The effects of focal cerebral ischemia were studied in plasminogen knockout mice (Plg-/-)
under normothermic and hypothermic conditions, and compared to wild type animals. Focal
28
Resveratrol Preconditioning Induced Neuroprotection Is Mediated Via
Sirt1-Uncoupling Protein 2 Pathway.
David Della Morte, Kunjan R Dave, Miguel A Perez-Pinzon; Univ of Miami, Miami, FL
Ischemic preconditioning (IPC) is a phenomenon whereby an organ’s adaptive transient
resistance to a lethal insult occurs by preconditioning this organ with a sub-lethal/mild insult
of short duration. Using an in vitro model of cerebral ischemia, resveratrol mimics IPC via the
SIRT1 (member of Sirtuin family of proteins) pathway. In the present study, we show that
tolerance for cerebral ischemia can be induced by resveratrol preconditioning (RPC) in vivo. We
compared efficacy of RPC with IPC in protecting CA1 hippocampal neurons in the rat model of
asphyxial cardiac arrest (CA). IPC was induced by tightening the carotid ligatures bilaterally
following hypotension for 2 min. RPC was induced by injecting resveratrol (i.p.) at 10, 50 and
100 mg/kg. Eight minutes of CA was induced 48 hrs after IPC or resveratrol injection. Following
7 days of reperfusion, brain sections were examined for histopathological changes. Since it has
been demonstrated that SIRT1 repressed the mitochondrial uncoupling protein 2 (UCP2)
transcription by directly binding to its’ promoter, we determined if RPC induces neuroprotection
via the SIRT1-UCP2 pathway. Statistical significance was determined via ANOVA followed by
Bonferroni’s post-hoc test. The number of normal neurons in sham rats were 1328⫾23 (n⫽9)
and 70% lower in CA/vehicle rats (405⫾78, n⫽5; p⬍0.001). Normal neurons in IPC group
were higher by 88% (760⫾120, n⫽5; P⬍0.01) as compared with the CA group suggesting IPC
tolerance against CA. The number of normal neurons in 10 and 50 mg/kg resveratrol groups
were higher by 73% (702⫾54, n⫽7, p⬍0.05) and 63.4% (449⫾57, n⫽7) as compared to CA
group, respectively. No significant protection was observed at higher resveratrol concentrations
(100 mg/kg, 292⫾15, n⫽6). To determine if IPC and RPC resulted in enhanced SIRT1 activity,
we measured SIRT1 activity following IPC and RPC. IPC and RPC were able to stimulate SIRT1
activity by 29 % (n⫽4, p⬍0.02) and 36 % (n⫽4, p⬍0.01) as compared to control (n⫽4),
respectively. RPC was able to decrease levels of UCP2 by 35% (n⫽4, 65.05⫾2.08, p⬍0.05)
as compared to vehicle group (n⫽4, 100⫾13.08). In conclusion, IPC can be emulated by
pre-treating rats with low concentrations of resveratrol. Moreover, our data suggests that
resveratrol may exert its’ neuroprotective effects through activation of the SIRT1 pathway by
decreasing UCP2 levels.
29
Management of Unruptured Intracranial Aneurysm: Part 1 Natural History.
Yuichi Murayama, Toshihiro Ishibashi, Takayuki Saguchi, Masaki Ebara, Hideki Arakawa,
Koreaki Irie, Hiroyuki Takao, Toshiaki Abe; Jikei Univ, Tokyo, Japan
Purpose: We report prospective analysis of natural history of unruptured intracranial aneurysms
(UIA). Methods: Between January 2003 and August 2007, a total of 897 patients with 1084
saccular UIA were referred to our institution. The aneurysm sizes were measured by
three-dimensional computed tomography angiography (3DCTA). When patient choose conservative management, clinical and CTA follow-up were obtained every 6 months. Results: Overall
771 aneurysms followed more than 6 months with multiple CTA and clinical evaluation. Of
these 242 aneurysms received surgical or endovascular treatment and 529 aneurysms were
followed without treatment. Mean follow up duration was 679 person-year. There were sixteen
aneurysms rupture (2.4%/year) during observation. Thirteen out of 16 patients suffered
severely disabled statusor death after bleeding. Annual rupture rate of the aneurysms smaller
than 5mm and greater than 5mm were 1.2% and 5.8%, respectively. History of subarachnoid
hemorrhage (SAH) (relative risk [RR] 5.3, 95% confidence interval [CI] 1.7–16.2, P⫽0.003) and
large size were significant independent predictors for aneurysm rupture. None of ruptured
patients who had large or giant aneurysms survived in the good clinical condition. Conclusion:
The incidence of rupture of UIA may be higher than previous report. Size and history of SAH
were important factors to predict rupture of the UIA. Clinical outcome after bleeding of
incidentally found aneurysms seems worse than previous reports.
30
The Impact of Family History of Aneurysm or Subarachnoid Hemorrhage on
Aneurysm Characteristics and Outcome: Results from the International
Study of Unruptured Intracranial Aneurysms.
Robert D Brown, Jr., Irene Meissner, John Huston, III, David G Piepgras, David O Wiebers,
Mayo Clinic, Rochester, MN; Joseph P Broderick, Daniel Woo, Univ of Cincinnati, Cincinnati,
OH; Elizabeth J Cozzie, Univ of Iowa, Iowa City, MN; James C Torner; Univ of Iowa, Iowa
City, IA
Background and Purpose: Unruptured intracranial aneurysms (UIAs) occur in about 1–2% of the
population. There is a potential genetic role in the occurrence of these UIAs. The current
analysis assesses the role of family history of aneurysm and subarachnoid hemorrhage (SAH)
in the cohort of UIAs in the NIH-sponsored International Study of Unruptured Intracranial
Aneurysms (ISUIA). Methods: In 61 centers participating in ISUIA, 4,060 patients with at least
one UIA were entered into the prospective cohort. We prospectively collected family history
information, including whether there was a family history of intracranial aneurysm or SAH. For
442 patients, family history was unknown. We divided the entire cohort into 3 groups: no prior
SAH/single aneurysm; no prior SAH/multiple aneurysms; and those with prior SAH and at least
one UIA. Differences between groups were examined using contingency table tests. We
hypothesized that among patients with a UIA, demographic features, aneurysm diameter at
535
diagnosis, and outcomes may differ based on whether a family history of intracranial aneurysm
or SAH was reported. Results: Eight hundred and thirty-four patients (20.5%) reported a positive
family history of intracranial aneurysm or SAH. A positive family history was more common
among women (23.4%) than men (18.0%) in patients with no history of SAH and single
aneurysm. In patients with no prior history of SAH, a family history was more likely in 20 – 49
year olds compared to those ⬍20 years of age (p⬍0.05). The percentage of patients with a
positive family history was lower in those with prior SAH/at least one UIA (18.0%) compared
to those with no SAH/single aneurysm (19.4%) and no SAH/multiple aneurysms (25.8%). For
aneurysm characteristics, a family history was associated with a smaller aneurysm diameter
at the time of UIA diagnosis in those with no prior SAH/single aneurysm, and no prior
SAH/multiple aneurysms. In general, patients with a negative family history generally had
poorer outcomes than patients with a positive family history. Poorer outcomes were noted
among patients with no prior SAH/single aneurysm, including all-cause mortality (p⬍0.01),
non-aneurysm-related death (p⬍0.01), and aneurysm-related death (p⫽0.02). Conclusion:
One in 5 patients with a UIA reported a family history of brain aneurysm or SAH. Women were
more likely to report a family history. Patients with a UIA but without a prior SAH were more
likely to have a family history. Those with a family history were more likely to be diagnosed with
a smaller aneurysm. Patients with a negative family history generally had poorer outcomes
31
Cost-effectiveness Analysis of Endovascular Treatment versus
Neurosurgical Treatment for Ruptured Intracranial Aneurysms in the United
States.
Alberto Maud, M. Fareed K Suri, Kamakshi Lakshminarayan, Adnan I Qureshi; Zeenat
Qureshi Stroke Rsch Cntr, Univ of Minnesota, Minneapolis, MN
Introduction: The International Subarachnoid Aneurysm Trial (ISAT) demonstrated reduced
death and disability with endovascular treatment compared with neurosurgical treatment
among patients with ruptured intracranial aneurysms. However, the need for follow-up cerebral
angiography and re-treatment was higher among patients with endovascular treatment, which
may offset the cost-benefit. Objective: To determine and compare the cost-effectiveness of
endovascular and neurosurgical treatment among patients with ruptured intracranial aneurysms that could be treated with either modality. Design: The probability of poor outcome
(moderate to severe disability) and frequency of retreatment and rebleeding following
neurosurgical and endovascular treatment were obtained from ISAT population. Qualityadjusted life years (QALYs) gained was estimated by combining the frequency of each outcome
at one year (healthy, mild, moderate and severe disability) with each treatment. Net costs were
defined as the total of cost associated with moderate to severe disability, hospitalizations,
retreatment and rebleeding in each group. Costs are in 2005–2006 United States’ charges.
Incremental cost-effectiveness ratios (ICERs) were estimated over one year period following the
procedure. Results: The estimated net cost at 1 year for endovascular and neurosurgical
treated patients was $45,227 and $41,534 respectively. Overall QALY for endovascular coiling
was 0.69 and for neurosurgery it was 0.64 (ranging from 0.0 meaning death to 1.0 meaning
healthy). The cost per QALY in the endovascular treatment was $65,032 and in the
neurosurgical treatment was $64,454. The estimated ICER for endovascular treatment versus
neurosurgical treatment was 72,338 US dollars per QALY gained. Conclusions: From the United
States’ perspective, endovascular treatment costs more but appears to deliver better outcomes
than the neurosurgical alternative among patients with ruptured intracranial aneurysms that are
suitable for either therapeutic modality.
32
Long-term Follow-up Patients With Unruptured Intracranial Aneurysms.
James C Torner, Univ of Iowa, Iowa City, IA; Robert D Brown, Jr., Irene Meissner, David G
Piepgras, John Huston, III, Jack Whisnant, David O Wiebers, Mayo Clinic, Rochester, MN;
International Study of Unruptured Intracranial Aneurysms Investigators
Introduction: Few studies have examined the long-term rates of hemorrhage, mortality and
neurological outcome in patients with an unruptured intracranial aneurysm (UIA). Hypothesis:
The hypothesis was that the likelihood for hemorrhage would continue at constant rates for
observed patients, and that treatment would have decreased rates from obliteration of the
aneurysm. Methods: Patients with a UIA were prospectively entered at 61 centers for the
NIH-sponsored International Study of Unruptured Intracranial Aneurysms. In 2003 we began an
extended follow-up to add to the initial follow-up of 4060 patients. The mean follow-up was
7.2 years, with a total of 29,280 person-years. Detailed outcomes were defined in advance, and
included living/dead status and neurological assessment using the Rankin Scale and cognition
based upon the Telephone Interview for Cognitive Status. Hemorrhage, neurological change
and other endpoints were centrally adjudicated. Analysis was done with categorical analysis
and logistic regression. Results: Of the 4060 prospectively evaluated UIA patients, those with
surgical clipping included 1917 patients, endovascular treatment included 451 patients and
conservative management included 1692 patients. Loss to additional follow-up occurred in
16% of patients. At the last known follow-up, 73% of the patients were Modified Rankin Scores
0 –2. To date, 823 deaths have been reported. Nine percent of deaths were due to
subarachnoid hemorrhage (SAH); 74% in the observed patients, 3% in the surgery patients and
15% in the endovascular treated patients. The major single cause of death was cancer (20%
of deaths) and was uniformly distributed in the treatment groups. There were 72 SAHs reported
to date in the untreated group; 49 in the surgery group and 25 in the endovascular group, with
the highest risk of hemorrhage still within the first year after diagnosis in all groups. Data
collection and adjudication will continue through October and the final results will be analyzed.
536
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Vol 39, No 2
February 2008
Conclusions: Long-term outcome of patients with UIAs is important for the planning and
comparison of clinical trials of treated patients, with the goal being to prevent hemorrhage and
other adverse neurological consequences. Morbidity and mortality from intracranial aneurysms
continues longitudinally but competing risks, including other co-morbidities, also play a role
when informing patients of treatment choices.
33
Under-Treatment and Outcomes of Non-Traumatic Subarachnoid
Hemorrhage by Hospital Volume: A Multi-State Study.
p⫽0.0004), African American ethnicity (HR⫽2.91, CI⫽1.2–7.0; p⫽0.0171), and less than
90% aneurysm occlusion (HR⫽4.46, CI⫽2.0 –9.9; p⫽0.0003) were associated with increased
risk of retreatment. For surgically treated patients, only incomplete aneurysm occlusion
(⬍100%) was associated with retreatment (HR⫽11.5, CI 3.7–35.8; p⬍0.0001). Conclusions:
Aneurysm retreatment is frequently required after treatment of ruptured intracerebral
aneurysms, particularly in younger patients, those treated with coil embolization, and in those
with incomplete initial aneurysm occlusion. Although rerupture is already a strong incentive to
strive for complete aneurysm occlusion initially, a greater need for retreatment in subtotally
treated aneurysms provides some additional support.
Lucas Elijovich, UCSF, San Francisco, CA; Nancy A Dreyer, Outcome, Cambridge, MA; Jill
Van Den Bos, Milliman, Denver, CO; S. Claiborne Johnston; UCSF, San Francisco, CA
35
Background: Prior studies have suggested that outcomes of patients with complex medical
conditions, such as non-traumatic subarachnoid hemorrhage (SAH), are improved by referral to
tertiary care centers. In this study we examined the hypothesis that SAH remains under-treated
throughout the United States, particularly in centers with low volume of SAH patients, and that
outcomes are improved at high volume centers. Methods: We conducted a review of discharge
data from eighteen states throughout the United States from 2001–2004 to determine the
volume of SAH admissions at each hospital. Hospitals were subdivided into annual volume
quartiles based on the number of SAH admissions per year (1–5, ⬎ 5–12, ⬎ 12–25, ⬎
25–218). We analyzed outcomes and rates of treatment of aneurysms for patients initially
admitted through the emergency department with SAH and not transferred to another
acute-care hospital. Univariate analysis was used to calculate the rates of in-hospital mortality,
adverse outcomes (defined as in-hospital death or discharge to a nursing home or rehabilitation
hospital), treatment type, and treatment rates by quartile. Multivariable analysis with
generalized estimating equations was performed to determine the effect of these variables on
adverse outcomes. Results: A total of 23,458 patients from 1,944 hospitals were included. The
mean age of patients was 59.5 and 62.5% were female. Hospitals in the lowest quartile
comprised 75.9% of participating hospitals, while the highest quartile hospitals consisted of
4.7% of all hospitals. Only a small minority of patients had an aneurysm treated among those
admitted to hospitals in the lowest quartile hospitals (6.3% of all patients; 2.3% of patients ⬎
65) compared to the highest quartile (37.5% all patients and 24.6% of patients ⬎ 65). The
proportion of patients treated with coiling increased in the higher volume quartiles. Rates of in
hospital death decreased from 34.9% to 31.4% from the lowest to highest volume quartile. The
rate of adverse outcomes decreased successively by quartile, from 79.3% in the lowest volume
quartile to 55.2 % in the highest volume quartile; similar results were observed in patients ⬎
65 with a decrement from 87% to 78% adverse outcomes from the lowest to highest volume
quartiles. Multivariate analysis demonstrated a decrease in mortality for admissions to highest
quartile hospitals compared to the lowest, (OR 0.88 95% CI 0.81– 0.94, p⬍0.008). Significant
reductions in adverse outcomes were demonstrated comparing the highest to the lowest
volume quartiles in all patients (0.32, 0.27– 0.35, p ⬍ 0.0001) and in patients ⬎65 (0.54,
0.47– 0.63, p ⬍ 0.0001). Conclusion: Only a minority of patients with non-traumatic SAH have
an aneurysm treated, particularly among the elderly and at low-volume hospitals. Adverse
outcomes and in hospital mortality are improved at high-volume centers.
34
Predictors of Retreatment of Ruptured Intracranial Aneurysms: The
Cerebral Aneurysm Rupture After Treatment Study.
Chirag G Patil, Stanford Univ, Stanford, CA; Lucas Elijovich, Univ of California, San
Francisco, San Francisco, CA; Gary K Steinberg, Stanford Univ, Stanford, CA; Robert F
Spetzler, Cameron G McDougall, Joseph M Zabramski, Barrow Neurological Institure,
Phoenix, AZ; Daryl R Gress, Michael T Lawton, Randall T Higashida, Univ of California, San
Francisco, San Francisco, CA; Gary R Duckwiler, Univ of California, Los Angeles, Los
Angeles, CA; Phillip D Purdy, Univ of Texas, Southwestern, Dallas, TX; David G Piepgras,
Mayo Clinic, Rochester, MN; Steven L Giannotta, Univ of Southern California, Los Angeles,
CA; S. Claiborne Johnston; Univ of California, San Francisco, San Francisco, CA
Background: Rates and predictors of retreatment after endovascular and surgical treatment of
ruptured intracranial aneurysms have not been clearly established. Methods: Data from the
Cerebral Aneurysm Rupture After Treatment (CARAT) study were utilized to determine
retreatment rates after surgical clipping and coil embolization of ruptured intracranial
aneurysms. Potential predictors of retreatment were evaluated using univariate and multivariate Cox-proportional-hazards models. To aid interpretation, degree of aneurysm occlusion
after the first treatment was also evaluated as a predictor of retreatment in a univariate
Kaplan-Meier analysis (log-rank test). Results: Retreatment of the ruptured aneurysm occurred
in 45 of the 1,010 patients (4.5%) followed for a median of 4 years. Retreatment was performed
after recurrent hemorrhage in 8 (17.8%) patients and for aneurysm recurrence after complete
occlusion in 14 (31.1%) patients. Only five patients underwent recoiling of subtotally occluded
aneurysms within 1 week of initial treatment and may have been retreated as part of a planned
retreatment. Retreatment was less frequent in those treated with surgical clipping than with
endovascular coiling (2.1% versus 17.0% 5-year actuarial retreatment rate; p⬍0.0001,
log-rank test). Retreatment was strongly associated with the degree of aneurysm occlusion
after the initial treatment in univariate and multivariate analysis (5-year actuarial retreatment
rates: 2.7% for complete occlusion, 13.3% for 91–99% occlusion, 33.4% for 70 –90%
occlusion and 45.6% for ⬍70% occlusion). In multivariate analysis, older patients (HR⫽0.64
per decade, CI⫽0.49 – 0.82) and patients initially treated with surgical clipping (HR⫽0.28,
CI⫽0.12– 0.65) were less likely to be retreated. In the multivariate model of patients who
underwent endovascular treatment, younger age (HR [per decade]⫽0.57, CI⫽0.42– 0.78;
Unruptured Cerebral Aneurysms Presenting with Ischemic Events.
Nancy McLaughlin, Michel W Bojanowski; CHUM - Hopital Notre-Dame, Montreal, Canada
Background: Patients harboring an unruptured cerebral aneurysm may present with ischemic
events. The goal of this study is to assess the clinical and radiological characteristics of these
patients and the outcome following aneurysmal treatment. Methods: The study population
included 463 patients with unruptured cerebral aneurysms that were treated between 01–2000
to 11–2006. Patients with aneurysms manifesting with ischemic events were retained in this
series. Outcome was assessed 12 months following aneurysm treatment using the Modified
Rankin Scale. Results: Eleven patients were included in this series. On admission, patients were
investigated with a cerebral CT and/or MRI and angiography. An acute ischemic lesion in the
symptomatic territory was demonstrated in 6 patients. The symptomatic aneurysm was located
on the internal carotid artery (n⫽4), the middle cerebral artery (n⫽4), superior cerebellar artery
(n⫽2) and the basilar artery (n⫽1). They measured 10mm or less (n⫽7); 11–20mm (n⫽2);
more than 20mm (n⫽2). Five aneurysms were partially thrombosed on imagery. Five patients
were oriented towards endovascular treatment. Of these, one patient had an unsuccessful
coiling attempt, one had a residual neck, and three presented an aneurysmal recurrence. A
symptomatic thromboembolism occurred after endovascular re-treatment of a recurrent
aneurysm. Six patients were treated surgically. A symptomatic thromboembolism occurred
after surgery in 3 patients. Complete aneurysm exclusion was documented in 5 of 6 operated
patients. Nine of the ten treated patients had a favorable outcome.Conclusion: Aneurysms
presenting with ischemic events are often small and located on the anterior circulation. In this
series, although the risk of thromboembolic events following surgery is noteworthy, the
outcome remains favorable.
36
C-reactive Protein Gene C1444T Polymorphism Is Associated With An
Increased Risk Of Further Ischemic Events In Patients With Symptomatic
Intracranial Atherostenoses.
Juan F Arenillas, Neurosciences Dep. Germans Trias i Pujol Universitary Hosp, Barcelona,
Spain; Israel Fernández-Cadenas, Neurovascular Rsch Laboratory. Vall d’Hebron Universitary
Hosp, Barcelona, Spain; Carlos A Molina, Neurovascular Unit. Vall d’Hebron Universitary
Hosp., Barcelona, Spain; Pilar Chacón, Lipid Rsch Unit. Vall d’Hebron Universitary Hosp.,
Barcelona, Spain; Anna Rosell, Anna Penalba, Neurovascular Rsch Laboratory. Vall d’Hebron
Universitary Hosp., Barcelona, Spain; Pilar Delgado, Marc Ribó, José Álvarez-Sabı́n,
Neurovascular Unit. Vall d’Hebron Universitary Hosp., Barcelona, Spain; Joan Montaner;
Neurovascular Rsch Laboratory. Vall d’Hebron Universitary Hosp., Barcelona, Spain
Background and purpose: Symptomatic intracranial atherosclerotic disease (ICAD) is
burdened with a high risk of clinical recurrence. High blood concentration of proinflammatory
molecules, such as C-reactive protein (CRP), and raised level of inhibitors of endogenous
fibrinolysis, such as plasminogen activator inhibitor-1 (PAI-1), may be associated with an
increased risk of further ischemic events in patients affected by this disease. However, it
remains unknown to which extent this excess risk might be predetermined genetically. We
aimed to investigate whether common genetic polymorphisms of CRP and PAI-1 genes are
associated with a higher risk of suffering recurrent ischemic events in patients with
symptomatic ICAD. Methods: We studied 75 consecutive patients with a first-ever ischemic
stroke attributable to a symptomatic intracranial atherostenosis, which was confirmed
angiographically. Blood samples were drawn three months after the qualifying event. Genomic
DNA was isolated and the following single nucleotid polymorphisms (SNPs) were determined
by polymerase chain reaction: C1444T and 1059 GC of CRP gene and 4G/5G of PAI-1 promoter.
Blood concentration of CRP and PAI-1 was also measured. Patients underwent long-term
clinical follow-up to detect the occurrence of further major ischemic events. Results: During
a median follow-up time of 23 months, 18 (24%) patients suffered a major ischemic event (10
ischemic strokes, 3 transient ischemic attacks and 5 myocardial infarctions). Kaplan-Meier and
multivariate-adjusted Cox-regression analyses identified raised CRP and PAI-1 level as
predictors of further ischemic events. Patients carrying allele T of CRP C1444T SNP were
exposed to a higher risk of recurrent ischemic events during follow-up (35% vs. 12.5%,
p⫽0.02). Carriers of 4G/4G allele in the PAI-1 SNP showed a non-significant trend towards a
higher recurrence risk (35% vs. 17.4%, p⫽0.1). A Cox-regression model adjusted by age, sex
and vascular risk factors identified that the mutation in CRP gene C1444T polymorphism
predicted the occurrence of further ischemic events (HR 3.42, 95% CI [1.1–10.1], p⫽0.03).
Conclusion: A mutation in the C1444T polymorphism of CRP gene may be associated with a
higher risk of further ischemic events in patients with symptomatic ICAD.
37
Relationship of Site Experience with Clinical Outcomes in Patients
Undergoing Intracranial Stenting in the NIH Multicenter Wingspan Registry.
Fadi Nahab, Emory Univ, Atlanta, GA; Osama O Zaidat, Med College of Wisconsin/Froedtert
Hosp, Milwaukee, WI; Michael Lynn, Marc I Chimowitz, Emory Univ, Atlanta, GA; for the NIH
Multi-Cntr Wingspan Intracranial Stent Registry Study Group
Background: There are limited data on the relationship between site experience and clinical
outcomes after intracranial stenting. Hypothesis: High enrolling sites in an intracranial stenting
registry will have lower cerebrovascular complication rates within 24 hours and better long
term patient outcomes than low enrolling sites. Methods: We compared outcomes of patients
enrolled at high volume sites (enrolled ⬎ 10 patients) vs. low volume sites (enrolled ⬍ 10
patients) participating in the registry. All stented patients presented with a TIA or ischemic
stroke in the territory of a single 50 –99% stenosis of a major intracranial artery while on
antithrombotic therapy. Results: Low volume sites (10 centers that collectively enrolled 41
patients) had significantly higher cerebrovascular complications (stroke, TIA, intracerebral
hemorrhage, vasospasm, parent vessel dissection, parent vessel perforation, or stent
thrombosis) within 24 hours compared with high volume sites (6 centers that collectively
enrolled 119 patients) (29.3% vs 4.2%, p⫽0.00005). Cerebrovascular complications within 24
hours in patients done early in the sequence at a site (up to first 5 patients enrolled) remained
significantly higher at low volume vs high volume sites (32.4% vs. 6.7%, p⫽0.013). Median
follow-up in the study was 5.5 months. The rates of stroke or death within 30 days or stroke
in the territory after 30 days at 6 months was 24.1% at low volume sites vs 10.7% at high
volume sites (p⫽0.058). Conclusions: Intracranial stenting at high volume sites is associated
with lower rates of cerebrovascular adverse events within 24 hours and better 6 month patient
outcomes than at low volume sites. This difference appears to be independent of the patient
sequence at a site.
38
Analysis of Recurrent Ischemic Events Following Successful Therapy with
the Wingspan System.
Babu G Welch, UT Southwestern Med Cntr, Dallas, TX; Neuroendovascular Rsch
Collaboration
Background: Despite successful treatment of symptomatic intracranial atherosclerotic disease
with the Wingspan stent system, some patients may have recurrent ischemic events. An interim
analysis of our data was performed to determine the rate of delayed events (⬎30 days after
treatment) and any contributing factors. Methods: A prospective, intent-to-treat registry was
maintained of patients in whom the Wingspan stent system was used to treat symptomatic
ICAD at five participating US institutions. Clinical and angiographic follow-up data available
through July 2007 were analyzed. ISR was defined as ⬎50% stenosis within or immediately
adjacent (within 5 mm) to the implanted stent(s) AND ⬎20% absolute luminal loss. Results:
One-hundred and three patients who had undergone successful treatment with the Wingspan
stent system have had at least 3 months of clinic follow up. Of these, 15 have had recurrent
ischemic symptoms ipsilateral to the lesion treated - 8 strokes (7.8%) and 7 TIAs. Of the
patients with stroke, 6 were classified as minor, one as major and one as stroke with
subsequent death. In 5 of these 15 patients with recurrent symptoms the recommended dual
antiplatelet therapy regimen was interrupted. In 9, angiographic evaluation demonstrated ISR
or stent thrombosis. Conclusions: Recurrent ischemic events after successful PTAS with
Wingpsan are not uncommon, occurring in approximately 15% of patients. The vast majority
(⬎85%) of these are either TIA or minor stroke. Most recurrent ischemic events (⬎85%) can
potentially be accounted for by either ISR or interruption of the recommended dual anti-platelet
regimen. Mechanisms to maintain medication compliance and to survey for, or reduce, ISR
have the potential to substantially reduce recurrent ischemic events after therapy.
39
Safety and Efficacy of Endovascular Thrombectomy in Patients with
Abnormal Hemostasis: Pooled Analysis of the MERCI and Multi MERCI
Trials.
Raul G Nogueira, Massachusetts General Hosp, Boston, MA; on Behalf of the MERCI and
Multi MERCI Writing Committee
Background and Significance: Patients with abnormal hemostasis including INR ⬎ 1.7,
elevated PTT, and/or platelet count ⬍ 100,000/␮L are not considered candidates for
intravenous rt-PA. Similar criteria have been arbitrarily adopted by studies evaluating
intra-arterial thrombolysis including the PROACT I-II and the IMS I-II trials. Endovascular
thrombectomy obviates or lessens the use of thrombolytic drugs. Therefore, different inclusion
criteria were adopted during the MERCI and Multi MERCI trials. We performed a retrospective
analysis of the MERCI/Multi MERCI cohort as an attempt to establish the risks and benefits of
thrombectomy in patients with abnormal hemostasis. Methods: Two patient groups were
identified: Group 1 (n⫽35): patients with INR ⬎ 1.7 and/or PTT ⬎ 45 seconds and/or platelet
count ⬍ 100,000/␮L; Group 2 (n⫽270): patients with INR ⱕ 1.7, PTT ⱕ 45 seconds, and
platelet count ⱖ100,000/␮L. The rates of symptomatic intracranial hemorrhage (sICH),
vascular recanalization, good clinical outcomes (90-day mRS ⱕ 3), and mortality were
compared between the two groups. Results: Of the 35 patients in Group 1, nineteen had INR ⬎
1.7 (mean: 2.4; range: 1.8 – 4.9), 11 had PTT ⬎ 45 seconds (mean: 95; range: 46 –190), and
537
six had platelets ⬍ 100,000/␮L (mean: 63,400; range: 16,000 –94,000). Two patients had both
INR ⬎ 1.7 and PTT ⬎ 45 seconds. The two groups did not significantly differ in terms of age
(median: 71 vs. 72 years), gender (female: 60% vs. 51%; p⫽0.371), baseline NIHSS (median:
20 vs. 19), intra-arterial thrombolytic use (40% vs. 31%; p⫽0.334), or site of occlusion (ICA:
34% vs. 32%; MCA: 57% vs. 59%; Vertebrobasilar: 9% vs. 9%). Time-to-treatment was slightly
earlier in Group 1 (median: 3.6 vs. 4.3 hours; p⫽ 0.03). Forty-eight patients in Group 2 and
none of the patients in Group 1 received intravenous rt-PA (p⫽0.002). There was no significant
difference in terms of revascularization (TIMI 2–3: 60% vs. 65%; p⫽0.58) or mortality rates
(40% vs. 38%; p⫽0.85). There were three sICHs in group 1 (one PH-1 with platelet
count⫽16,000; one PH-2 with INR⫽1.8; and one SAH with INR⫽2.3). The incidence of sICH
did not differ between groups (8.6% vs. 8.5%; p⫽1.0; RR: 1.01 [95%CI: 0.33–2.87]). There
was a trend towards higher rates of good clinical outcomes in Group 2 (28% vs. 46%;
p⫽0.062). In Group 1, successful revascularization was associated with higher rates of good
clinical outcomes (44% vs. 7%; p⫽0.044; RR: 6.2 [95%CI: 1.26 –37.4]) and lower mortality
(24% vs. 64%; p⫽0.033; RR: 0.37 [95%CI: 0.17– 0.84]). Conclusion: Patients with abnormal
hemostasis who undergo thrombectomy do not appear to be at a significantly higher risk for
sICH. In this patient group, successful revascularization is associated with higher rates of good
clinical outcomes and lower mortality.
40
US Multi-Center Experience with the Wingspan Stent System for the
Treatment of Intracranial Atheromatous Disease: Periprocedural Results for
156 patients.
Peter Rasmussen, Cleveland Clinic Foundation, Cleveland, OH; Neuroendovascular Rsch
Collaboration
Background and Purpose The current report details our periprocedural experience with
Wingspan (Boston Scientific/Target, Fremont CA), the first self-expanding stent system
designed for the treatment of intracranial atheromatous disease (ICAD). Methods All patients
undergoing angioplasty and stenting with the Gateway balloon-Wingspan stent system were
prospectively tracked at five participating institutions. Results Over a 20-month period, the
Wingspan stent system was successfully used to treat 156 patients with 166 intracranial
atherosclerotic lesions (average age 62.7 years; 64 women). The stent was successfully
deployed 96.5% of the time during the initial treatment session. Lesions treated involved the
internal carotid (n⫽50; 14 petrous, 15 cavernous, 16 supraclinoid segment, 5 terminus),
vertebral (n⫽32; V4 segment), basilar (BA, n⫽38), and middle cerebral (MCA, n⫽45) arteries.
Mean pretreatment stenosis, %(SD), was 75.3 (12.6), improving to 42.6 (15.2) after balloon
angioplasty and to 27.6 (15.0) after stent placement. Of the 166 lesions successfully treated,
there were nine (5.4%) major peri-procedural (within 30 days) neurological complications, four
of which ultimately led to patient death. All periprocedural complications were encountered
during the treatment of lesions within the MCA and BA. Stenosis severity did not influence the
rate of complications. Conclusions Angioplasty and stenting for symptomatic ICAD can be
performed with the Gateway balloon-Wingspan stent system with a high rate of technical
success and low peri-procedural morbidity. The severity of the stenosis treated did not
influence the complication rate.
41
Natural History of Asymptomatic Restenosis following Endovascular
Treatment of Symptomatic Intracranial Stenosis Does Not Support
Retreatment.
Haitham Hussein, Zeenat Qureshi Stroke Rsch Cntr Univ of Minnesota, Minneapolis, MN;
Mohammad Abdelmoula, UMDNJ, Newark, NJ; Adnan I Qureshi; Zeenat Qureshi Stroke Rsch
Cntr Univ of Minnesota, Minneapolis, MN
Background Restenosis is an angiographic finding that is frequently observed after angioplasty
and/or stent placement for intracranial atherosclerosis. However, due to lack of data regarding
clinical outcome of restenosis, particularly when asymptomatic, the decision to retreat is
arbitrarily based. We report on the short and intermediate clinical outcome of patients with
asymptomatic restenosis treated with medical management. Method We analyzed the data of
patients treated with either primary angioplasty or stent placement for symptomatic intracranial
atherosclerosis from 2 centers. The initial and post-procedure severity of stenosis was
estimated using Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial
criteria. We identified restenosis by target lesion stenosis ⱖ 50% or increase in severity of
stenosis by ⱖ 25% (compared with immediate post-procedure measurements) on a follow up
imaging study. All patients were followed and any new stroke or death was ascertained.
Results Of 68 patients analyzed, 37 had a follow up imaging study performed at a mean period
of 14.6 months (range 1.3–35 months). Angiographic restenosis was detected in 16 patients
and was asymptomatic in 13 patients (mean age 62⫾13; 4 were women). Restenotic lesions
were located in the middle cerebral artery (n⫽5), vertebral artery (n⫽4), basilar artery (n⫽3),
and internal carotid artery (n⫽1). The primary treatment modality had been angioplasty in 9
patients and stent placement in 4 patients. Stenosis averaged 79⫾17% pre-procedure, and
13⫾14% after treatment. Restenosis (WASID criteria) was detected using an angiogram
performed over a mean interval of 21⫾10 months from the primary procedure. Clinical follow
up period ranged from 4 to 31 months (mean 20⫾9 months). During the follow-up, only 1 event
was reported; a disabling frontal intracerebral hemorrhage at 26 months in a patient who had
undergone a stent placement in the basilar artery. Conclusion Asymptomatic angiographic
538
Stroke
Vol 39, No 2
February 2008
restenosis is associated with a low rate of stroke and death suggesting that retreatment in the
absence of clinical ischemic symptoms may not be warranted.
42
Treatment of Moyamoya Disease in the Adult Population with Indirect
Cerebral Revascularization Utilizing Pial Synangiosis.
Edward R Smith, Ronald T Grondin, R. Michael Scott; Children’s Hosp Boston, Boston, MA
Introduction: Surgical treatment of moyamoya disease in the adult population commonly
employs direct revascularization using the superficial temporal artery to middle cerebral
artery (STA-MCA) bypass. Because of small caliber scalp or middle cerebral artery
branches, it may be technically impossible to perform direct anastomosis in certain
patients. Pial synangiosis, a method of indirect revascularization, has been utilized in adult
patients treated at our institution when STA-MCA bypass has not been feasible. Although
the effectiveness of pial synangiosis has been well described in children, only limited
reports have examined its role in adult patients. Here we report on our experience with pial
synangiosis for the treatment of moyamoya in the adult population. Methods: Case series
Results: Twenty (20) adult moyamoya patients (21 y/o or older, mean ⫽31.9, median ⫽30)
were treated with pial synangiosis. Of these, 11 have 1 year follow-up imaging (MRI/A
and/or angiogram) and clinical follow-up (range⫽2–14 years). 9/11 had radiographic
evidence of significant collateral development on angiographic studies at 1 year. With
extended follow-up (2–14 years) 8 patients have all been clinically stable or improved.
2/11 patients experienced recurrent ischemic events requiring reoperation (one at 8
months, the other at 7 years postop) and 1/11 had a perioperative stroke without
reoperation. All patients have subsequently done well (3– 6 years f/u). One patient
underwent a STA-MCA bypass on one hemisphere and pial synangiosis on the opposite
side, with equally successful radiographic and clinical results (5 years follow-up).
Conclusions: Pial synangiosis is a safe and effective method of cerebral revascularization
in adult moyamoya patients. In our series, beneficial results were found to be significant
and durable, with outcomes that compare favorably to STA-MCA bypass results as reported
in the literature. Our data supports utilization of pial synangiosis as a treatment option for
moyamoya syndrome in adults, particularly when STA-MCA bypass is not technically
feasible.
43
Blood Pressure in Acute Stroke is Inversely Related to the Extent of
Collaterals.
David S Liebeskind, Sidney Starkman, Kwang D Jo, Arbi G Ohanian, James W Sayre, Susan
Yun, Doojin Kim, Latisha K Ali, Bruce Ovbiagele, Amytis Towfighi, Samir H Shah, Reza
Jahan, Gary R Duckwiler, Fernando Vinuela, Jeffrey L Saver; UCLA, Los Angeles, CA
Background: Collateral circulation strongly influences outcome in acute ischemic stroke,
improving perfusion and decreasing hemorrhagic transformation. Predicting the extent of
collaterals based on clinical variables has not been explored in detail. We hypothesized that
baseline demographics, co-morbidities, and clinical data including baseline vital parameters
may be predictive of collateral status in acute ischemic stroke. Methods: Angiographic
collaterals were graded with the ASITN/SIR scale, blinded to clinical data, on the pretreatment
injections of collateral routes in a consecutive series of mechanical thrombectomy cases.
Baseline demographics, co-morbidities, and other clinical parameters were obtained from a
prospectively maintained database. Multivariate logistic regression analyses determined
predictors of collateral grade. Results: Collateral flow was graded on angiography in 100 cases
of acute ischemic stroke (mean age 68 years, SD 17.3; 53 men, 47 women). Collateral grade
was evenly distributed across all categories of the ASITN/SIR scale. The extent of collaterals
was correlated with history of hypertension (p⫽0.003), baseline SBP (p⫽0.004) and baseline
DBP (p⫽0.028). Multivariate logistic regression analyses demonstrated a dramatic association
between baseline SBP (p⫽0.001) and history of hypertension (p⫽0.026) with extent of
collaterals. Patients with higher SBP on admission had poorer collaterals, whereas those with
lower SBP demonstrated more robust collateral flow. Collateral flow was not associated with
any other demographic or clinical variables. The presence or history of atrial fibrillation or any
other cardioembolic source had no relationship with collaterals. Collateral grade was also
unrelated to stroke mechanism. Conclusions: Blood pressure on admission is the strongest
predictor of collateral flow in acute ischemic stroke. Elevated SBP is associated with poor
collaterals, likely reflecting upregulation of angiotensin II due to attempted arteriogenesis.
Stroke patients with lower SBP demonstrate more robust collaterals and therefore may not
benefit from pressure augmentation. Contrary to traditional dogma, atrial fibrillation and
cardioembolic events have no relationship with respect to collateral flow in acute ischemic
stroke.
44
clinical trials, but its efficacy in survivors of in-hospital cardiac arrest, and arrests with
rhythms other than VT/VF, is unknown. Here we report our experience for patients treated
with MH after cardiac arrest under a wide variety of settings using a hospital-wide
protocol. Methods: We prospectively collected clinical, demographic, and outcome data on
consecutive patients treated with MH after cardiac arrest. Cooling was initiated if the
patient did not follow commands after resuscitation, regardless of initial rhythm or location
of arrest. Goal temperature was 91.4 F for 24 hours. Good outcome was defined as
discharge to home or acute rehabilitation; poor outcome was discharge to a nursing home,
or death. All patients were treated in a cardiac or medical ICU and all were assessed by
a stroke neurologist. Non-normally distributed variables were described with median
[interquartile range, IQR], and normally distributed variables as mean [Standard deviation].
Univariate predictors of outcome were explored with Mann-Whitney U, Kruskal-Wallis K, or
ANOVA, as appropriate. We performed multinomial logistic regression to evaluate
predictors of discharge disposition, coded as an ordinal variable (dead⫽0, nursing
home⫽1, rehabilitation⫽2, home⫽3), using mortality as the reference. Results: The 35
treated patients had a median age of 58 years (IQR 48 – 69), 63% were men, and 72% of
patients had initial rhythms other than VT/VF. Two thirds of patients had in-hospital cardiac
arrest. The median time to return of spontaneous circulation (ROSC) was 14 minutes [IQR
9 –27.5 min]. Good outcome was achieved in 34% of patients and mortality was 49%.
Increased time to return of spontaneous circulation and absent brainstem reflexes on day
3 both independently predicted poor outcome in a multivariate model (P⬍0.05). In patients
without brainstem dysfunction on day 3, time to ROSC was the only predictor of outcome.
Age, gender, type of arrest, and location of arrest were not associated with outcome.
Conclusion: MH is feasible, safe, and may be effective in routine clinical practice at an
academic medical center. Our data do not support limiting MH only to VT out-of-hospital
arrests, as neither initial cardiac rhythm nor location of arrest were predictive of outcome.
Our results in out-of-hospital arrests match those in randomized trials, and we found no
difference in outcome with in-hospital arrests. MH is an underused therapy with the
potential to improve outcome in many survivors of cardiac arrest.
45
Slow Initiation of Care and Poor Outcomes for Patients Having In Hospital
Ischemic Strokes.
Frank L Silver, Univ of Toronto, Toronto, Canada; Jiming Fang, Institute for Clinical
Evaluative Studies, Toronto, Canada; Annette C Robertson, M P Lindsay, Institute for Clinical
Evaluative Sciences, Toronto, Canada; Moira K Kapral; Univ of Toronto, Toronto, Canada
Background: Few studies have focused on patients with in hospital strokes. Given that
these patients are already in hospital, they should benefit from rapid access to acute
stroke care. Methods: The Registry of the Canadian Stroke Network (RCSN) collects data
on all consecutive patients presenting within 14 days of an acute stroke or TIA to 12
designated stroke centres in Ontario and Nova Scotia. After selecting patients with a final
diagnosis of ischemic stroke, patients with In Hospital Strokes between July 2003 and
March 2007 were characterized with descriptive statistics and compared to the larger
RCSN cohort of patients presenting via emergency departments. Results: Over this
45-month period there were 12,506 patients in the RCSN admitted to hospital with an
acute ischemic stroke including 535 patients who had In Hospital strokes (IHS). There was
no difference between the IHS and other patients in gender (52.1 vs. 51.4 % male) or mean
age (72.9 vs. 72.7). The IHS patients tended to have more severe initial deficits (Canadian
Neurological Score ⱕ 8 in 62.7 vs. 30.8%, p⬍0.0001) and more co-morbidities (Charlson
index ⬎ 1 in 51.0 vs. 35.2%, p⬍0.0001). After adjusting for age, gender, stroke severity
and co-morbidity the IHS patients had a higher in-hospital mortality (14.3%; 95%CI 11 18 vs. 10.9%; 95%CI 10 - 12) and worse functional outcomes (mRS ⬍3 at discharge
32.4%; 95%CI 26 –39 vs. 42.6%; 95%CI 42– 44). The use of tPA was the same (64/535;
12% vs. 1,399/11,971; 11.7%). For the tPA treated patients the median NIHSS was the
same for both groups (13). The median ED (emergency department) arrival to CT and the
median ED to tPA treatment were longer for the IHS group (61 vs. 30 minutes; p⬍0.0001
and 138 vs. 75 minutes; p⬍0.0001, respectively). (For IHS patients, the time the stroke
was first recognized was used in place of the ED arrival time). Adjusted outcomes for the
tPA treated patients were not different for the IHS group. Conclusions: Patients suffering
in hospital strokes are a unique group with overall worse hospital outcomes. IHS patients
took longer to be investigated and receive thrombolytic therapy. Education to increase the
awareness of hospital staff to recognize patients with acute stroke and special protocols
to facilitate access to acute stroke care are needed.
46
Stroke Response Nurses - Success in Ischemic Stroke Treatment Parallels
Increase in Utilization Eight Years’ Experience with 24/7 Stroke Response
Nurses.
Outcomes of Moderate Hypothermia for Survivors of In-Hospital and
Out-of-Hospital Cardiac Arrest.
Barbara L Mancini, Patricia Lane, Betsy Stagno, Debbie Healy, John W Cochran, II; Inova
Fairfax Hosp, Falls Church, VA
Richard A Bernstein, Andrew M Naidech, Northwestern Med Sch, Chicago, IL; Julie Garrett,
Robin Oakley, Deborah L Bergman, Northwestern Memorial Hosp, Chicago, IL; Mark J
Alberts, Dan J Fintel; Northwestern Med Sch, Chicago, IL
Background and Purpose: Stroke Response Nurses (SRN) have been utilized in our hospital
for more than eight years. They are to evaluate all patients coming to the Emergency
Department (ED) with symptoms of stroke, transient ischemic attack (TIA) as well as patients
already in-house for consideration of thrombolysis or other intervention. In addition they are to
screen patients with intracerebral and subarachnoid hemorrhages. Patients are considered for
inclusion in research protocols. The goal is for SRN to rapidly evaluate all patients arriving
Objectives: Moderate Hypothermia (MH) has been shown to improve neurological outcome
in survivors of out-of-hospital ventricular tachycardia/fibrillation (VT/VF) cardiac arrest in
within the three-hour window for IV tPA and the six-hour window for intra-arterial treatment.
SRN are supported by the Stroke Team consisting of neurologists and NPs who confer with the
nurse; act as consultants and see all patients treated with thrombolytics. We determined the
need to review the performance of SRN looking for any trend in these patients and to discern
why all stroke patients were not being seen. Method: The records of all SRN encounters since
1999 were reviewed and compared with the number of stroke and TIA discharges. The number
of patients seen, the diagnoses of the patients and the percent of the total stroke/TIA patient
population evaluated was tabulated. For 2007 the data reflects projections based on 6 months’
data. See Figure. Results: By 2005 most stroke patients were evaluated by SRN, the percent
seen now stands at 70%. Patients that have eluded the SRN evaluation included patients for
whom the protocol of calling the SRN was not followed, patients discovered to have had a
stroke post-operatively or in the midst of a critical illness and others who developed symptoms
of stroke while already inpatients and direct admissions. Most of the patients admitted via the
ED are now evaluated by SRN. The increase in treatment with Merci device and IV or IA
thrombolytics has closely paralleled the rise in percent of ischemic patients evaluated by SRN.
Conclusions: Over the last 8 years, SRN have been effective in screening more patients with
stroke. They now see 70% of these patients. The doubling of the number of thrombolytic/Merci
treated patients over the last few years parallels this growth. Successful deployment of SRN
has been a critical element of this improvement at our hospital. We continue to strive to have
all stroke patients seen by SRN.
47
Impact of Dedicated Stroke Response System on In-Hospital Assessment
and Outcomes of Patients with Acute Ischemic Stroke.
Gustavo J Rodriguez, Sheetal Patel, Mary DuPlessis-Tchida, Adnan I Qureshi, David C
Anderson, Kamakshi Lakshminarayan; Zeenat Qureshi Stroke Rsch Cntr, Univ of Minnesota,
Minneapolis, MN
Objective: We report the effect of system changes on various quality measures focused on the
delivery of intravenous thrombolytics in patients with acute ischemic stroke at a teaching
hospital. Methods: The following system changes were instituted in the year 2005: i) stroke
responder teams with linked pagers which could be activated by a single stroke code; ii) 24/7
neurology and radiology staff availability to assist emergency department personnel; iii) clear
established protocols of intervention in the evaluation and treatment. We evaluated the change
in the rates of the following quality parameters over a 6 year period: i) rates of intravenous
thrombolytic use in acute ischemic stroke; ii) time interval between door and treatment,and
symptom onset and treatment; and iii) in-hospital mortality. Results: A total of 75 patients
received intravenous (IV) thrombolytic therapy from 2001 through 2006. The results are
tabulated below demonstrating a significant reduction in time interval between door and
treatment following institution of a dedicated stroke response system (table) Weekends and
weekdays did not significantly differ in terms of speed of response (Door to Needle, 54.5⫾21
vs. 56.3⫾34). However, patients presenting at a public place (e.g., at work, driving, or in
public) had a significantly lower door to needle time compared with those whose event
occurred at home or at a nursing home (p⬍0.05). Conclusions System changes instituted
at our hospital have significantly improved the quality indices associated with intravenous
thrombolytic utilization in acute ischemic stroke patients. The increasing rates of utilization (the
17% treatment rate is among the highest reported) and decreasing in-hospital mortality
validate the use of indices such as door-to-needle time as performance target.
539
TABLE 1
IV thrombolytic use rate
*
Door to needle ⬍ 60
minutes
Door to needle (mean) *
Onset to needle (mean)
In-hospital mortality
2001
2002
2003
2004
7%
(8/109)
57% (4/7)
2%
(3/140)
100%
(3/3)
49 min
(3)
91 min
(3)
33%
(1/3)
6%
(6/97)
33% (2/6)
9% (8/90)
76 min (7)
120 min
(7)
25% (2/8)
2005
2006
112 min
(8)
50% (4/8) 80% (8/10)
17%
(22/126)
86%
(18/21)
67 min (6) 74 min (8)
48 min
43 min
(10)
(21)
130 min
112 min 82 min (9)
91 min
(6)
(8)
(21)
33% (5/6)
112 min 20% (2/10) 9% (2/22)
(8)
*Signifjicant at P⬍0.05.
48
A Simplified Model for the Assessment of Quality of Stroke Care in
Emerging Countries. The Argentinian National Stroke Registry (ReNACer).
Luciano A Sposato, Favaloro Foundation & Argentinian Neurological Society, Buenos Aires,
Argentina; Marı́a M Esnaola, Hosp Francés & Argentinan Neurological Society, Buenos Aires,
Argentina; Rafael Zamora, Hosp de Clı́nicas, Buenos Aires, Argentina; Marı́a C Zurru, Hosp
Italiano & Argentinian Neurological Society, Buenos Aires, Argentina; Osvaldo Fustinoni,
INEBA & Argentinian Neurological Society, Buenos Aires, Argentina; Gustavo Saposnik; St.
Michael’s Hosp, London, Canada
Background. Projections from the World Health Organization indicate that stroke incidence and
mortality will increase faster in low-income countries. Unfortunately, limited information is
available on cerebrovascular disease in emerging/low income countries, and particularly in
South America. Data on the processes of care will become crucial to improve the quality of
stroke care and subsequently reduce the stroke burden. Objectives. To measure standardized
indicators of quality of stroke care in Argentina. Our secondary goal was to compare stroke care
between teaching and non-teaching hospitals. Methods. ReNACer is a prospective, multicenter, countrywide, cooperative, hospital-based stroke registry that included different facility
types (small/large, community, teaching hospitals). We selected 9 key performance indicators
of quality of stroke care, including different domains. We used Chi-square tests to compare
categorical variables and Student’s t-tests for continuous variables. We conducted A
reabstraction study of 10% of the randomly selected charts for data quality analysis. Results.
From November 2004 to October 2006, 1991 patients with ischemic stroke were admitted to
74 institutions in Argentina. Mean age was 69.4 ⫾ 13 years, and 1100 (56%) were males.
Antithrombotic therapy was initiated within 48 hours in 79% of the patients. All patients had
a neuroimaging study during hospital stay. Median length of stay was 5 days (IQR 3–9). There
was a significant difference in average length of stay (ALOS) between teaching and
non-teaching centers (6.3 days vs 9.5 days, p⬍0.001). Only 1% of patients received
thrombolytic therapy and 5.7% were admitted to designated stroke units. The overall proportion
of patients with intranosocomial pneumonia was 14.3%, higher in non-teaching hospitals
(16.4% vs 11.4%, p 0.02). The overall adjusted in-hospital mortality rate was 9.1%, higher in
non-teaching centers (10.6% vs 7.1%, p 0.008). Antithrombotics were indicated in 90.2% and
antihypertensive agents in 63.6% of the patients, on discharge. Patients admitted to teaching
facilities had lower complication rates and ALOS that their counterparts. On the contrary,
discharge on antithrombotics and antihypertensive medications was more common in
non-teaching facilities (Table). Conclusions. Despite the lower rate of thrombolysis, admissions to stroke units, and higher rate of pneumonias, the performance of other indicators were
similar to those reported in other countries. Differences were observed in care provided at
teaching vs non-teaching institutions.
QUALITY OF STROKE CARE INDICATORS
Domains & Indicators
Acute treatment of ischemic stroke
1. Rate of thrombolysis, No. (%)
2. Rate of patients receiving
aspirin in the first 48 hours, No.
(%)
Organization and delivery of
stroke evaluation and care
3. Rate of admissions to designated
stroke units, No. (%)
4. Rate of patients with CT/MRI
performed during hospital stay,
No. (%)
4a. Computed axial tomography
4b. Magnetic resonance imaging
5a. Average length of stay, median
(interquartile range 25%,75%), d
5b. Average length of stay, mean
(SD), d
Stroke complications and
outcome
6. Intranosocomial pneumonia, No.
(%)
7. Overall in-hospital mortality,
No. (%)
Secondary Prevention
Overall
Teaching
Non-Teaching
n ⫽ 1,991
21 (1.05)
1,571 (78.9)
n ⴝ 868
10 (1.15)
673 (77.5)
n ⴝ 1,123
11 (0.98)
898 (80.0)
n ⴝ 1,991
n ⴝ 868
n ⴝ 1,123
p
0.88
0.19
113 (5.7)
74 (8.5)
36 (3.2)
⬍0.001
1,991 (100.0)
868 (100.0)
1,123 (100.0)
NA
1,904 (95.6)
357 (17.9)
5 (3–9)
805 (92.7)
207 (23.8)
4 (3–7)
1,099 (97.9)
150 (13.4)
6 (4–11)
⬍0.001
0.008
NA
8.1 (10.2)
6.3 (7.1)
9.5 (11.9)
⬍0.001
n ⴝ 1,991
n ⴝ 868
n ⴝ 1,123
164 (14.3)
55 (11.4)
109 (16.4)
0.02
181 (9.1)
62 (7.1)
119 (10.6)
0.008
n ⴝ 1,810
n ⴝ 806
n ⴝ 1,004
540
Stroke
Vol 39, No 2
Domains & Indicators
antithrombotics at discharge, No.
(%)
antihypertensive drugs discharge,
No. (%)
Overall
February 2008
Teaching
Non-Teaching
p
1,632 (90.2)
712 (88.3)
920 (91.6)
0.02
1,152 (63.6)
443 (55.0)
709 (70.6)
⬍0.001
*Intranosocomial pneumonia was evaluated during a second recruitment period in 1,148 patients (483 from
teaching centers and 665 from non-teaching centers).
49
Intravenous Tissue Plasminogen Activator Use Has a Low Risk of
Neurosurgical Intervention.
Aslam M Khaja, Univ of Illinois at Chicago, Chicago, IL; Sheryl Martin-Schild, Miriam
Morales, Andrew D Barreto, Hen Hallevi, Nicole R Gonzales, Kachi Illoh, Elizabeth A Noser,
James C Grotta; Univ of Texas - Houston, Houston, TX
Introduction: Many physicians and community hospitals are reluctant to administer intravenous (IV) tissue plasminogen activator (tPA) due to the lack of neurosurgical expertise at the
institution. We sought to determine the incidence of neurosurgical intervention in patients
treated with IV tPA for acute ischemic stroke at our institution. Methods: We prospectively
collected data on acute ischemic stroke patients treated with IV tPA at our institution. Data
included baseline demographics, stroke severity, and admission variables. In addition, we
tracked the number of patients requiring neurosurgical intervention consisting of a hemicraniectomy, ventriculostomy or hematoma evacuation. Patients were followed until discharge from
the stroke service. A favorable outcome was defined as a discharge to home or inpatient
rehabilitation. Results: Between January 2004 and December 2006 we treated 405 patients
with IV tPA for ischemic stroke. Sixteen patients underwent neurosurgical intervention (4.0%);
13/405 (3.2%) received a hemicraniectomy and 5/405 (1.2%) received a ventriculostomy. Two
patients underwent both interventions. Hematoma evacuation was not performed in any
patient. The mean time from admission to intervention was 1.4 ⫾ 1.1 days (1.5 ⫾ 1.2 days
for hemicraniectomies and 1.2 ⫾ 0.8 days for ventriculostomies). We then compared patents
that underwent neurosurgical intervention with those who did not. There were no significant
differences with respect to age, race, gender, baseline NIH Stroke Scale, symptom onset to
treatment time, and presence of early ischemic changes on CT scan. Patients receiving surgery
were more likely to have neurologic deterioration (12/16 vs. 87/389) during their hospital
admission (pⱕ.0001). Symptomatic intracranial hemorrhages occurred in 20 patients (5%);
6/16 (38%) of intervention patients versus 14/389 (4%) of non-intervention patients (pⱕ.0001).
Patients with neurosurgical intervention had a significantly longer length of hospital stay (13 vs.
6 days) (pⱕ.0001). Only 6% (1/16) patients had a modified Rankin Scale at discharge of ⱕ3
after neurosurgical intervention compared with 59% (229/388) (pⱕ.0001). Only 19% (3/16)
had a favorable outcome compared to 36% (140/389) (pⱕ.0001). Conclusion: Ischemic stroke
patients treated with IV tPA have a low probability of undergoing neurosurgical intervention.
Patients with neurologic deterioration or symptomatic hemorrhage were more likely to receive
neurosurgical intervention. On average, there is greater than one day between admission and
neurosurgical intervention. Lack of neurosurgery at an institution should not preclude the use
of IV tPA for acute ischemic stroke.
50
Chronic Intermittent Mild Hypoglycemic Episodes Exacerbate Ischemic
Damage In Streptozotocin-induced Diabetic Rats.
Kunjan R Dave, Antonello Pileggi, Isabel Saul, Miguel A Perez-Pinzon; Univ of Miami, Miami,
FL
Introduction: The American Diabetes Association estimates that stroke and heart disease are
the most serious complications of diabetes, as they account for more than 65 % mortality
among diabetics. Hyperglycemia is one of the factors responsible for a worse outcome
following stroke in diabetics. Clinical studies demonstrate that intensive therapy targeted to
control blood glucose and glycosylated hemoglobin was able to delay onset and retard the
progression of secondary complications of diabetes. The major side effect of intensive therapy
to diabetics is hypoglycemia. There are several reports describing hypoglycemic episodes in
both patients with type 1 and type 2 diabetes receiving intensive therapy. We tested the
hypothesis that chronic intermittent mild hypoglycemic (CIMH) episodes exacerbate cerebral
ischemic damage in a rodent model of diabetes. Method: Global cerebral ischemia was
induced by tightening the carotid ligatures bilaterally following hypotension (50 mmHg) for eight
minutes. We determined the extent of neuronal death at 7 days of reperfusion in CA1
hippocampus following global cerebral ischemia in control, streptozotocin (Stz)-induced
diabetic, insulin treated Stz-diabetic (ITD), and ITD rats exposed to 10 episodes of CIMH
(ITD-CIMH) compared with sham ischemic rats. Hypoglycemia (⬃55– 65 mg / dl blood glucose)
was induced twice daily for 5 days by hypoglycemic / hyperinsulinemic clamp. Cerebral
ischemia was induced 24 hours after the last CIMH treatment. The duration of diabetes was 28
- 32 days while insulin treatment was given for the last 21 days. Results: At the time of
ischemia induction, the mean blood glucose for sham, control, Stz-diabetic, ITD, and ITD-CIMH
groups was 117⫾6, 127⫾3, 613⫾46, 183⫾5, and 177⫾9 mg / dl, respectively. As expected,
Stz-diabetes (18⫾4%, n ⫽ 4) resulted in 216 % (p⬍0.001) increase in ischemic damage as
compared to control group (62⫾3 %, n⫽4). Insulin treatment (55⫾2 %, n ⫽ 3) was able to
lower ischemic damage by 41 % (p⬍0.001) as compared to diabetic group. ITD-CIMH rats
(36⫾4, n ⫽ 5) had 34 % (p⬍0.05) and 41 % (p⬍0.001) more damage as compared to ITD
or control group, respectively. Conclusion: This is the first report that CIMH episodes in
diabetic animals exacerbate cerebral ischemic damage. CIMH thus may be an unexplored but
important factor responsible for increased ischemic damage in diabetes.
51
Intracarotid Delivery Of CD49d FACS Sorted Neural Stem Cells Enhances
Angiogenesis And Improves Functional Outcome After Experimental Stroke.
Raphael Guzman, Alejandro De Los Angeles, Kevin Choo, Xavier Gaeta, Joey Cote, Samuel
Cheshier, Gary K Steinberg; Stanford Univ, Palo Alto, CA
Background: Intravascular delivery of NPC after stroke has been limited by the low efficiency
of transendothelial migration. VCAM-1 is one of the endothelial adhesion molecules known to
be upregulated early after stroke and is responsible for the firm adhesion of CD49d expressing
inflammatory cells. We hypothesized that selecting CD49d positive NPC would improve their
homing to the injured brain and improve functional outcome after stroke. Cell number and
angiogenesis were correlated to behavioral outcome. Methods: On the day of intraarterial
injection, a CD49d enriched (⬎90%) and depleted (⬍1%) NPC population was obtained by
magnetic bead enrichement and double FACS sorting. Bl6 mice (20 –25g, n⫽18) were
subjected to a left side hypoxia ischemia (20min 8% O2 ⫹ temporary right common carotid
artery (CCA) occlusion). All mice were tested by rotarod for behavioral deficits and assigned to
receive 3x105 CD49d enriched (n⫽6) or CD49d depleted (n⫽6) stem cells or vehicle (n⫽6)
injection into the right CCA 48 hours after stroke. Animals were tested by rotarod at 7 and 14
days after stroke and subsequently sacrificed and the brains processed for immunohistochemistry. Cell density was analyzed in the cortex, hippocampus and subventricular zone adjacent
to the stroke. Angiogenesis was analyzed by quantifying the lectin positive surface in the
penumbral region and the healthy contralateral hemisphere. Results: Two weeks after
intracarotid injection significantly more NPC were found in the cortex, hippocampus and
subventricular zone adjacent to the stroke in animals receiving CD49d positive as compared to
CD49d negative NPC’s (1066/cm2 vs. 583/cm2, p⬍0.05). Behavioral recovery was significantly
better for the CD49d positive cells injected group as compared to CD49d negative and vehicle
injected animals (p⫽0.031). The CD49d negative group had a better recovery than the vehicle
injected group (ns.). There was a positive correlation between the number of cells and the
behavioral performance on rotarod (r⫽0.51, p⬍0.05). Analysis of angiogenesis revealed a
significantly higher ratio of lectin positive vessels (comparing stroke penumbra to contralateral
side) in the CD49d positive group as compared to the CD49d negative and control group
(p⬍0.05). Stroke size was not significantly different between the CD49d positive and the
CD49d negative group. Conclusions: We show that enrichment of NPC by FACS sorting for the
surface integrin CD49d and intracarotid delivery promotes cell homing to the area of stroke in
mice and improves sensorimotor recovery. Behavioral improvement seems to be correlated
with higher cell numbers and increased angiogenesis. We present two concepts, functional cell
selection and intracarotid delivery, which potentially improve the efficiency of intravascular
delivery of stem cells for stroke treatment.
52
Sex Differences in micro-RNA Expression in Cerebral Ischemia.
Chad Siegel, Fudong Liu, Louise D McCullough; Univ Connecticut Health Cntr, Farmington,
CT
Introduction: Ischemic cell death pathways differ based on biologic sex. The male ischemic
cell death pathway appears to be mediated via nitric oxide, poly (ADP-ribose) polymerase, and
apoptosis-inducing factor. The female ischemic cell death pathway involves cytochrome c and
caspase activation. While sex differences in the expression of these proteins exist, there is little
data regarding the mechanism of their regulation. Micro-RNAs (miRNAs) are a class of novel,
non-coding transcripts involved in post-transcriptional gene regulation. There are no current
data regarding the role of miRNAs in either the male or the female ischemic brain. miR-15b,
miR-21, miR-23a, and miR-138 have all been implicated in cell growth and apoptosis. Current
literature suggests miR-15b inhibits Bcl-2 and miR-21 activates caspases. Three databases
utilized to determine possible miRNA binding predicted that miR-23a binds to and regulates
caspase-3, while miR-138 binds to and regulates X-linked Inhibitor of Apoptosis. We
hypothesize that sex differences exist in the expression of all four of these miRNAs in the
ischemic brain. Methods: Reversible middle cerebral artery occlusion (MCAo - 90 minute) was
performed on male and female C57Bl/6 mice (n⫽3/group). Total RNA was Trizol-extracted 4
hours after ischemic onset and quantitative RT-PCR was performed. miRNA expression was
analyzed in sham and stroke brains. Data is normalized to 5s, expressed in Ct values, and
significance is defined by p⬍0.05. Results: miR-15b expression is unchanged between the
sexes in sham animals, but female stroke animals have increased miR-15b and increased
miR-21 expression as compared to male stroke animals (miR-15: 5.03⫾0.14 vs. 5.46 ⫾ 0.20;
miR-21: 3.29⫾0.07 vs. 3.77⫾0.16). miR-23a expression is decreased in stroke males and
increased in stroke females as compared to sham (male: 1.95⫾0.09 vs. 1.51⫾0.02;
female:1.52⫾0.12 vs. 1.77⫾0.03), and increased in stroke females as compared to stroke
males (1.52⫾0.12 vs. 1.95⫾0.09). miR-138 expression is decreased in stroke males and
increased in stroke females as compared to sham (male: 4.23⫾0.04 vs. 4.68⫾0.01; female:
4.67⫾0.15 vs. 4.34⫾0.11), and increased in stroke females as compared to stroke males
(4.34⫾0.11 vs. 4.68⫾0.01). Conclusions: This is the first time any differences in miRNA
expression have been seen in the ischemic brain. Upregulation of miR-15b, miR- 21, miR-23a,
and miR-138 occurs in the ischemic female brain as compared to males. miR-23a and
miR-138 are reciprocally regulated with decreased expression in stroke males and upregulation
in stroke females. Future experiments will elucidate the specific targets of miR-21, 23a, and
138 in the ischemic brain.
53
The Role of Toll-Like Recptor(TLR) Signaling in Ischemic Precconditioning.
Bolanle M Famakin, Yongshan Mou, Ryo Ohtani, Christl A Ruetzler, John M Hallenbeck;
National Institutes, Bethesda, MD
The Role of the Toll-like Receptor (TLR) Signaling pathway in Ischemic Preconditioning.
Background and purpose: there are limited therapies for stroke despite great strides made in
this field of research. The TLR signaling pathway is evolutionarily conserved and critical in
immunity, but now appears to participate in ischemia and reperfusion. We tested the
hypothesis that the TLR signaling pathway is differentially regulated during ischemic tolerance
and cerebrovascular ischemia. Since the two major signaling pathways involved in TLR
signaling are the Myd88-dependent and Myd88-independent (TRIF) pathways, we used mice
with a mutation in the TRIF gene and mice with deletion of the MyD88 gene in our studies.
Methods: Bilateral common carotid artery occlusion (BCCAO) was used to model global
cerbrovascular ischemia. BCCAO was performed in C57BL6 mice aged 12–16 weeks with a
mutation in the TRIF gene and a deletion in the MyD88 gene. TRIF mutant and wild type
C57BL6/J mice were obtained from Jax laboratories. MyD88 breeder pairs were obtained from
the Institute for Systems Biology, Seattle, WA. Ischemic preconditioning (IP) was performed by
subjecting mice to BCCAO for 6 minutes 24 hours prior to 18 minutes BCCAO (severe global
ischemia). Mice in the control group had sham IP (exposure of bilateral common carotid
arteries, but no occlusion) followed by severe global ischemia 24 hours later. Seven days after
severe global ischemia, brains were harvested and examined for evidence of delayed neuronal
loss in the CA1 region of the hippocampus using cresyl violet staining. Results: Three (100%)
wild type C57BL6 /J mice from Jackson laboratories exhibited delayed neuronal loss in the CA1
region after 18 minutes of BCCAO without IP.. However, only 25 % (2/8) of TRIF mutant and
20% (1/5) of MyD88 -/- mice showed evidence of delayed neuronal loss under the same
conditions.. With IP, none of the TRIF (0/4) mutant mice and (1/4) 25% of the MyD88 -/- mice
showed evidence of delayed neuronal loss in the CA1 region. Conclusions: Inhibition of MyD88
or TRIF pathways appears cytoprotective. Mice with a mutation of the TRIF gene respond to IP.
However, IP does not seem effective in MyD88 -/- mice. The MyD88 pathway of the TLR
signaling pathway may play an important role in mediating responses to IP in the brain.
54
Chronic Soluble Epoxide Inhibition is Protective Against Cerebral Ischemia
During Hypertension.
Alexis N Simpkins, R D Rudic, David Stepp, Derek A Schreihofer, Siddhartha Roy, Med
College of Georgia, Augusta, GA; Bruce D Hammock, Univ of California, Davis, CA; John D
Imig; Med College of Georgia, Augusta, GA
Epoxyeicosatrienoic acids (EETs), lipid metabolites produced by CYP450 enzymes in neurons
and endothelial cells, are novel mediators with cardioprotective effects and modulate cerebral
blood flow. EETs are converted by soluble epoxide hydrolase (SEH) enzyme to less active diols,
attenuating their protective properties. We have previously shown that adamantanyl dodecanoic
acid (AUDA), an SEH inhibitor, can protect against cerebral ischemia and increase middle
cerebral artery (MCA) compliance in spontaneously hypertensive stroke prone rats (SHRSP) at
a dose of 25mg/L in the drinking water for 6 weeks without decreasing systolic blood pressure
of the SHRSPs. Here in this study, we show that 50mg/L of AUDA in the drinking water for 6
weeks does not decrease systolic blood pressure in SHR-SPs 230⫾5mmHg versus (vs.) control
SHR-SP 224⫾5mmHg, unlike 6 weeks of enalapril (10mg/kg/day) 152⫾6mmHg. However,
AUDA is as effective as enalapril in reducing percent hemispheric infarct size in the SHR-SP
with 6 hours of permanent MCA occlusion (50.3⫾2.7 n⫽16 in control, 46.2⫾4.0 n⫽10 in
enalapril treated, and 44.2⫾2.3 n⫽16 in AUDA treated, P⬍0.05), which correlates with a
smaller neurodeficit score 7.1⫾0.4 in the AUDA treated vs. 8.2⫾0.3 control (P⬍0.05). The
protection from cerebral ischemia with AUDA is associated with a reduction in the wall to lumen
ratio of the MCA in SHR-SP treated with AUDA (0.19⫾0.01 n⫽6 treated vs. 0.26⫾0.02 n⫽6
control, p⬍0.05) and an increase in the cerebral microvessel density (7127 ⫾ 211.0 ␮m2/per
mm2 n⫽3 control vs. 9656 ⫾ 598.0 ␮m2/per mm2 n⫽5 AUDA treated, p⬍0.05). Furthermore,
AUDA’s protective effects are sustained when treatment is withheld for one week (45.8⫾8.8
percent hemispheric infarct and 7.6⫾0.8 neurodeficit score, n⫽5). These results demonstrate
that chronic SEH inhibition is protective against cerebral ischemia in a model of hypertension,
and this protection is associated with a reduction in pathological vascular remodeling and a
reduction in the area at risk to ischemia. The ability of SEH inhibition to protect against cerebral
ischemia during hypertension indicates that SEH inhibition should be further investigated for its
ability to pharmacologically manage ischemic stroke.
541
(pio), reduces the incidence of stroke and myocardial infarction in diabetics, making their
neuroprotective actions clinically important. TZDs anti-inflammatory actions are believed to
mediate their neuroprotective actions. Since inflammation contributes to reperfusion injury, we
hypothesized that reperfusion influences the timewindow for TZD neuroprotection. First, we
established the importance of reperfusion using pretreatment. Pio (1mg/kg, IP) was given to
rats 24 hrs before and again at the time of 2 hr middle cerebral artery occlusion (MCAO) or
permanent MCAO using the suture model. Infarct volume was measured 24 hrs later and
expressed as the % of the contralateral hemisphere volume ⫹/- SEM. Pio treated rats receiving
2 hr MCAO had significantly reduced infarct volume (17 ⫹/- 4%;n⫽7) compared with pio
treated rats undergoing permanent MCAO (50 ⫹/- 8%;n⫽3), or vehicle treated rats undergoing
2 hr MCAO (48 ⫹/- 4%;n⫽7; p⬎0.05). Using a 2 hr MCAO model, we determined the
timewindow for TZD neuroprotection and found that post-MCAO treatment was effective only
when pio was given before reperfusion (18 ⫹/- 6%; n⫽4 as opposed to 50 ⫹/- 2%, n⫽6;
p⬍0.005). Finally, we altered the time of reperfusion and asked if the timewindow for
protection could be extended. All rats were treated with pio 3 hrs after the onset of ischemia.
Rats exposed to 3.25 hr MCAO experienced a 47% reduction in infarct volume relative to those
exposed to 2 hr MCAO (26 ⫹/-5%, n⫽7 for 3.25 hr MCAO; 50 ⫹/- 2%,n⫽ 3 for 2 hr MCAO;
p⬍0.005). Importantly, this protection occurred despite an increased duration of ischemia.
Similar results were also found for another TZD, rosiglitazone (0.1mg/kg, IP; 53% infarct
volume reduction; p⬍0.005, 18 ⫹/-7, n⫽5 for 3.25 hr MCAO; 38 ⫹/-7%, n⫽ 7 for 2 hr
MCAO). Furthermore, we find that leukocyte infiltration is reduced by over 50% in the brains
of rats receiving TZD prior to reperfusion relative to rats receiving TZD after reperfusion
(p⬍0.001; n⬎200HPF and 3 rats for all treatments) and both TZDs reduce intracellular
adhesion molecule (ICAM) mRNA, which contributes to leukocyte infiltration, by 50% relative
that seen in vehicle injected rats (p⬍0.05;n⫽3 for rosiglitazone; n⫽5 pio; n⫽4 vehicle).
Activated leukocytes gain access to ICAM at the time of reperfusion. If TZD mediated
suppression of ICAM expression has been initiated at the time of reperfusion, it is more likely
to result in a reduced infiltrate. Physicians increasingly control the timing of reperfusion through
the use of thrombolytics and other strategies. These data indicate that TZDs will be most
effective when given prior to implementing reperfusion strategies.
56
HSP27 Protects Against Neuronal Ischemia via Attenuation of Mitochondrial
Signaling Pathways.
R A Stetler, Guodong Cao, Zhongfang Wang, Feng Zhang, Univ of Pittsburgh, Pittsburgh, PA;
Yanqin Gao, Fudan Univ, Shanghai, China; Jun Chen; Univ of Pittsburgh, Pittsburgh, PA
Background: HSP27 is a member of the small heat shock protein family. In addition to its
function as a protein chaperone, HSP27 has shown potent anti-apoptotic effects in various cell
types, but the precise mechanism underlying such effects is widely debated. The expression
of HSP27 is induced after cerebral ischemia, and may have a neuroprotective role in ischemic
neurons. Therefore, the current study was conducted to determine the mechanism by which
HSP27 exerts neuroprotective effects following ischemic neuronal injury. Methods: HSP27
transgenic mice (Tg-HSP27) were created on the C57/B6 background using the human HSP27
cDNA under the control of cytomegalovirus enhancer and a chicken ␤-actin promotor. Adult
male mice were subjected to 60 min of middle cerebral artery occlusion (MCAO), during which
core temperature, blood pressure and blood gases were maintained within normal ranges.
Cortical CBF was measured using laser Doppler flowmetry. Mice were sacrificed 24 h after
MCAO, and infarct volume was measured on TTC-stained brain sections. For in vitro studies,
primary cortical cultures were infected with AAV-HSP27 or AAV-EGFP at 15 DIV for 3 d and then
subjected to 60 min of oxygen-glucose deprivation (OGD). Cell viability was measured in
cultures 24 h after OGD using Alamar blue flowmetry. Results: Tg-HSP27 mice had
significantly smaller infarct volumes than their wild-type littermates 24 h following 60 min of
MCAO (18.1 ⫾ 6.6 vs. 47.8 ⫾ 9.2 mm3, p⬍0.0001), as well as improved functional recovery
as assessed by neurobehavioral testing. Overexpression of HSP27 in vitro attenuated
OGD-induced cell death, caspase-3 and -9 activation, and mitochondrial cytochrome c release.
However, no evidence of physical interaction between HSP27 and members of the apoptosome
was detectable using co-immunoprecipitation, suggesting that HSP27 may target signaling
pathways upstream of apoptosome formation. In support of this, we found that overexpression
of HSP27 inhibited the MKK4/JNK signaling pathway following OGD. Conclusion: We have
demonstrated that transgenic overexpression of HSP27 efficiently protects against focal
ischemic brain injury, leading to improved functional recovery. Contrary to nonneuronal
systems reported in the literature, the neuroprotective effect of HSP27 occurs upstream of the
mitochondrial pro-death signaling pathway, probably by inhibiting MKK4/JNK-dependent
signaling events.
57
Ipsilateral Subventricular Zone is Activated After Acute Ischemic Stroke.
55
Extended Timewindow For Neuroprotection By Thiazolidinediones Is
Dependent On Time Of Reperfusion.
Jorge Gamboa, Univ of Kentucky, Lexington, OH; Nicole Victor, Gary Landreth, Sophia
Sundararajan; Case Western Reserve Univ, Cleveland, OH
Thiazolidinediones (TZDs) reduce infarction volume and improve long term neurologic function
in rats after focal ischemia. TZDs are used to treat type 2 diabetes and one TZD, pioglitazone
Joan Martı́-Fàbregas, Hosp de la Santa Creu i Sant Pau, Barcelona, Spain; José Manuel
Garcı́a-Verdugo, Miriam Romaguera-Ros, Ulises Gómez-Pinedo, Unidad Mixta CIPF-UVEG,
Valencia, Spain; Isidre Ferrer, Hosp de Bellvitge, L’Hospet de Llobregat, Spain; Sergi
Martı́nez-Ramı́rez, Marta Marquié, Luis Antonio Querol, Marc Suárez-Calvet, Daniel Alcolea,
Josep-Lluis Martı́-Vilalta; Hosp de la Santa Creu i Sant Pau, Barcelona, Spain
INTRODUCTION Recent animal models have shown that repair mechanisms are activated after
an ischemic stroke. One of these is the activation of the subventricular zone (SVZ) where the
astrocytes behave as stem cells and may generate new neurons. We analyzed the morphologic
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Stroke
Vol 39, No 2
February 2008
changes that occurred in the SVZ in patients who died after an acute ischemic stroke.
METHODS In patients with a first-ever cerebral non-lacunar infarction in the middle cerebral
artery territory, we evaluated the ipsilateral and contralateral SVZ with light and electron
microscopy. Immunochemistry with Ki-67 was used to detect cell proliferation and the
evaluation was done with imaging techniques (software MethaMorph 7, Molecular Devices). We
studied changes in the cyto-architecture with the aid of electron microscopy in the ependymal,
gap (hypocellular) and ribbon (astrocytes) layers. RESULTS The study included 5 patients with
a mean age of 77 ⫾ 10.4 years, 4 were men. They died after a mean of 8.4 ⫾ 7.8 days (range
2 to 21) after the ischemic stroke. Brain samples were obtained a mean of 4.7 ⫾ 2.4 hours
after death (range 2.5 a 8.5). In comparison with the contralateral SVZ, the following changes
were observed in the ipsilateral SVZ: widening of the gap layer, increased number of cells in
the gap and ribbon layers, a greater cytoplasmatic volume of the astrocytes and an increase
of cells positive for Ki-67. CONCLUSION The ipsilateral activation of the subventricular zone is
a common phenomenon after an acute ischemic stroke.
58
Improving Motor Function In Chronic Stroke Patients Using Simultaneous
Occupational Therapy And TDCS.
Dinesh Nair, Vijay Renga, Scott Hamelin, Alvaro Pascual-Leone, Gottfried Schlaug; Beth
Israel Deaconess Med Cntr, Boston, MA
Background: In the current study, we aimed to understand the magnitude and duration of the
rehabilitative effects and the neural correlates of multiple simultaneous sessions of occupational therapy and tDCS (sham-controlled) in chronic stroke patients. Methods: Ten chronic
stroke patients (⬎ 6 months post-stroke) with moderate to severe upper extremity disability
(mean FM of 28) were randomly assigned to the treatment (receiving real-TDCS and
occupational therapy (OT) for 5 consecutive days) or sham-control (receiving sham-TDCS and
OT for 5 consecutive days) group and crossed-over after one week of assessments. Each
subject underwent 2 fMRI (performing auditorially paced flexion and extension movements of
wrist and/or elbow) and Transcranial Magnetic Stimulation (TMS) sessions (examining the
presence of motor evoked potentials, resting motor thresholds), and several motor assessments (active and passive range of motion (ROM), Fugl-Meyer scores, Wolf-Motor-Function
Tests) pre- and post-therapy. During the real-tDCS⫹OT sessions, subjects received OT (60min)
along with cathodal TDCS to the contralesional M1 under the assumption that the contralesional
M1 exerts an unmatched inhibitory influence on the lesional hemisphere which might interfere
with the recovery process. Two primary outcome measures: 1) average percentage improvement of ROM (active*100/passive) across three different joints (shoulder abduction, elbow
extension and wrist extension), and 2) Fugl-Meyer score comparing pre with post therapy (real
versus sham). Results: The mean change in ROM after real-tDCS⫹OT (7.0%) was significantly
higher (p⬍0.05) than after sham-tDCS⫹OT (2.5%). The mean improvement in Fugl-Meyer
scores was 5 points in the real-tDCS⫹OT group versus 1.2 points in the sham-tDCS⫹OT group
(p⬍0.05). These effects lasted at least 1 week. As an effect of the intervention, the mean
activation in the contralesional M1 decreased significantly comparing post with pre, while that
in the ipsilesional M1 increased. The improvement score in ROM was inversely correlated with
a decrease in the motor activation score (beta value) in the contralesional M1 (which is the
hemisphere that was treated with cathodal tDCS). Conclusions: A five consecutive-daytreatment protocol using real TDCS (cathodal) and simultaneous occupational therapy is an
effective way to enhance motor recovery in severely impaired chronic stroke patients with
effects that outlast the intervention period by at least one week. Imaging evidence indicates
that cathodal TDCS might exert its facilitating effect on motor recovery by reducing the
transcallosal inhibitory influence exerted by the contralesional, unaffected hemisphere onto the
lesional hemisphere.
treatment assignment (time X group interaction non-significant), for example: gait velocity
increase from baseline to week 9 went from 0.54 ⫹/- 0.37 to 0.72 ⫹/- 0.46 (ROP⫹PT) vs.
from 0.49 ⫹/- 0.28 to 0.69 ⫹/- 0.40 (PLAC⫹PT, p⫽0.88); and SIS-16, from 56 ⫹/- 10 to 66
⫹/- 9 vs. from 58 ⫹/- 11 to 65 ⫹/- 9 (p⫽0.72). None of the 5 serious adverse events was
attributable to drug effects. Outside therapy during the study was common, e.g., 61% patients
received outside PT (mean 12 sessions). Of patients who received ROP, 93% accurately
guessed treatment assignment. Results of serial functional MRI testing will be presented.
CONCLUSIONS: PT improves motor function in patients with chronic stroke. PT was also
commonly prescribed as standard of care outside of study-related interventions. At the doses
achieved in this trial, ROP was safe but did not show any improvement over and above the
favorable effects of PT. CLINICALTRIALS.GOV IDENTIFIER: NCT00221390
60
Prevalence And Characteristics Of Potential Subjects For Clinical Trials Of
Early Post-stroke Upper Extremity Restoration.
Alexander W Dromerick, Georgetown Univ and National Rehabilitation Hosp, Washington,
DC; Lucy E Morris, Holly Hollingsworth, Washington Univ, St. Louis, MO; Dorothy F Edwards,
Univ of Wisconsin, Madison, WI; M C Baum; Washington Univ, St. Louis, MO
Introduction: Stroke lesion location is thought to influence recovery and response to
restorative treatments; there is great interest in lesion-driven treatment strategies for motor
restoration. The utility of this approach will be limited by the number of patients who have a
specific lesion. The prevalence of any single lesion has not been well investigated, nor has the
frequency of coexisting brain lesions. We determined the prevalence of potential subjects for
a hypothetical upper extremity (UE) intervention trial, and examined clinical and neuroimaging
characteristics of that population. Methods: All patients evaluated by the Washington University
stroke service from 7/1/04 –3/31/05 meeting ICD-9 acute stroke criteria were studied (n⫽513).
Clinical data were obtained from the Cognitive Rehabilitation Research Group stroke registry.
Inclusion criteria for a hypothetical trial were applied; these included pre-stroke Barthel Index
⬎95, discharged alive, unilateral UE extremity motor impairment with minimal or no neglect
or sensory loss (NIHSS items: UE motor⬎1; Consciousness⬍1, Sensory⬍1, Neglect⫽0,
Aphasia ⬍1). CT was routinely obtained; additional MRI’s were performed if indicated. Lesion
characteristics were recorded from the MRI; otherwise, the last CT was used. Vascular
templates(Damasio) were used for major arterial territories; deep structures were scored
individually. Results: 88(17.1%) patients met clinical criteria for this hypothetical trial. The
clinical trial population was younger (60.2 ⫹ 13.6 yr.), less severely affected (NIHSS 5.7⫹0.4),
more female(56.8%) and more frequently discharged to acute rehabilitation(56.8%) than the
overall stroke registry population. MRI was available on 38 of the 88 meeting criteria, 43 has
CT only, and 7 had no imaging available. 90% of lesions were ischemic. Acute lesions were
visualized in 53 subjects; 42 had a single new lesion, 11 had ⬎2 acute lesions. Of the 42 with
single acute lesions, only 13 did not have an additional old stroke or other intra-axial pathology,
typically white matter changes. Of the 42 single acute lesions, 16/42 were deep subcortical,
13/42 were superficial cortical only, 5/42 involved both deep and superficial, 7/42 affected
brainstem, and 1 affected cerebellum. Oxfordshire scores for those without visualized acute
lesions showed lacunar syndromes (66%) and partial anterior syndromes(20%). Conclusion:
Our study has two important implications. Restorative treatments for the UE predicated on
single lesions in pristine brains in cognitively intact patients will have very limited clinical
application; only a small group of registry participants met such criteria in our hypothetical trial.
Further, to accurately model the clinical disease of stroke, animal recovery models should
incorporate multiple lesions and chronic lesions.
61
59
Ropinirole In The Treatment Of Motor Deficits After Stroke: A Randomized,
Placebo-Controlled, Double-Blind Study.
Steven C Cramer, Univ of California, Irvine, Orange, CA; Bruce H Dobkin, UCLA, L.A., CA;
Elizabeth A Noser, Univ of Texas, Houston, Houston, TX; Rachelle W Rodriguez, Univ of
California, Irvine, Orange, CA; Lori A Enney; GlaxoSmithKline, Rsch Triangle Park, NC
INTRODUCTION: Several studies suggest the potential to improve motor status in patients with
stroke by modifying the function of brain catecholamine receptors. Dopamine receptors are an
attractive target given the importance of this neurotransmitter to a multitude of processes
including attention, learning, motivation, and motor function. The current study hypothesized
that a 9-week course of the dopamine agonist Ropinirole plus physical therapy (PT) would be
a safe and effective way to increase gait velocity. METHODS: Entry criteria included stroke
1–12 mo prior, no depression (HAM-D score ⬍ 17), moderate motor deficits (arm/leg
Fugl-Meyer score 23– 83/100), and 50 foot walk ⬎ 15 sec. Patients were randomized
(double-blinded, stratified for time post-stroke) to 9 weeks of Ropinirole (ROP) or placebo
(PLAC), with doses (0.25mg - 4mg QD) titrated weekly as tolerated. All subjects received 8 PT
sessions focused on gait, leg, and arm, in weeks 5–9. Assessments extended to week 12, i.e.,
3 weeks after drug washout. The primary endpoint, gait velocity, was analyzed using repeated
measures ANOVA to examine differences in treatment groups over the 9 weeks of therapy.
RESULTS: At 3 U.S. sites, 744 patients were screened and 33 enrolled (age 61 ⫹/- 14 yr; time
post-stroke, 30 ⫹/- 15 wks; mean ⫹/- SD). Of these, 16 were randomized to PLAC⫹PT and
17 to ROP⫹PT (mean final daily ROP dose, 2.6 mg). Across all patients, significant gains were
found over time for the primary endpoint, gait velocity at week 9 (p⫽0.0001), and for most
secondary endpoints, with gains still significant at week 12. However, gains did not differ by
The Role Of The Right Hemisphere In Post-Stroke Language Recovery.
Gottfried Schlaug, Andrea Norton, Sarah Marchina; Beth Israel Deaconess Med Cntr, Boston,
MA
Introduction: The neural processes that underlie post-stroke language recovery remain largely
unknown and thus, have not been specifically targeted by aphasia therapies. Two possible
pathways to recovery may be through reactivation of perilesional areas in the left hemisphere
and/or homologous language regions in the right. Because of its potential to engage/unmask
language-capable brain regions in the unaffected right hemisphere, Melodic Intonation Therapy
(MIT), is well-suited for facilitating language recovery in non-fluent aphasic patients,
particularly those with left-hemisphere lesions encompassing large portions of the left frontal
and superior temporal lobes. In the current study, we examined the behavioral and neural
correlates of speech output after an intensive course of Melodic Intonation Therapy. Methods:
Ten patients with left-hemisphere lesions, who were at least 12 months from their first
ischemic stroke and had already received at least one course of traditional speech therapy,
have participated our Melodic Intonation Therapy trial (75 intensive MIT treatments).
Assessments consisting of speech production measures (propositional speech, standardized
confrontation naming, and automatic speech) and custom-designed fMRI-experiments using
overt speech and singing tasks, were performed twice prior to therapy to establish a stable
baseline, and repeated at specific intervals during- and post-treatment. Experimental fMRI
tasks required patients to listen to a series of spoken/melodically-intoned, bi-syllabic
words/phrases that they were capable of repeating prior to therapy, then overtly repeat each
word/phrase after an auditory cue. Experimental tasks were contrasted with control tasks and
used to assess potential changes in neural activation/speech output after therapy. Gains in
propositional speech scores were correlated with activation changes comparing post- vs.
pre-treatment fMRI studies. Results: Across all patients, post-treatment evaluations showed
significant improvement (p⬍0.001) in behavioral measures of speech output (e.g., more
meaningful words/min and increased phrase length) that correlated significantly with functional
imaging changes found in a right-hemispheric fronto-temporal network during overt speech in
post- vs. pre-treatment fMRI comparisons. Conclusion: These data suggest that intensive MIT
treatment leads to significant gains in speech production that can be maintained after therapy.
And further, that these gains are supported by functional brain changes involving primarily
right-hemispheric, language-capable brain regions. We hypothesize that MITâ€™s unique
elements (melodic intonation, rhythmic tapping, and continuous voicing) play a critical role in
facilitating recovery from non-fluent aphasia.
543
carefully been followed for 3 months. RESULTS: Human bone marrow-derived MSCs were
successfully isolated from bone marrow aspirate from all 5 stroke patients, and all were
successfully culture-expanded. Serial evaluations showed no adverse cell-related, serological,
or imaging-defined effects. CONCLUSIONS: In patients with cerebral infarcts, the intravenous
administration of autologous MSCs appears to be feasible and safe, and merits further study
as a therapy that may improve functional recovery.
64
Hypertension is Associated with Hippocampal Sclerosis.
62
Brief Psychosocial/Behavioral Intervention With Antidepressant Reduces
Post-Stroke Depression Significantly More Than Antidepressant Alone.
Pamela H Mitchell, Kyra J Becker, Ann Buzaitis, Kevin C Cain, Michael Fruin, Ruth Kohen,
Linda Teri, David Tirschwell, Richard Veith; Univ of Washington, Seattle, WA
Objective: To evaluate the short and long-term efficacy of a new brief psychosocial/behavioral
intervention adjunctive to antidepressant treatment in reducing post-stroke depression (PSD).
This paper reports short term efficacy in reducing depression. Methods: One hundred one
patients with ischemic stroke who were clinically depressed (DSM IV criteria) and within four
months of index stroke were randomly assigned to receive a 9 session, 8 week brief
psychosocial/behavioral intervention plus selective serotonin reuptake inhibitor (SSRI) antidepressant or usual care, including SSRI antidepressants. Reduction in depressive symptom
severity was measured by the Hamilton Depression Rating Scale (HDRS) at 9 weeks following
entry to the study. The psychosocial/behavioral intervention was adapted from the “Seattle
Protocols”, shown to reduce the disability associated with Alzheimer’s Disease. Our adaptation
used language pertinent to stroke and taught participants to view depressive symptoms as
observable and modifiable behaviors that are initiated and maintained by person-environment
interactions. Treatment goal was to increase the level of pleasant social and physical activity
in order to improve mood. Participants learned to use behavioral strategies to reduce or prevent
behavioral and mood disturbances characteristic of stroke. Specific problem-solving approaches were taught to participants, and solutions to behavioral challenges were individualized to meet the needs of each person. Findings: HDRS in the intervention group was
significantly lower immediately post-treatment when compared to the control group (p ⫽
⬍.001). The mean percent decrease (49% ⫹ 23% intervention versus 19% ⫹ 30% control)
and the mean absolute decrease in HDRS (9.8 ⫹ 4.9 intervention vs. 3.6 ⫹ 5.8 control) were
both clinically important and statistically significant in the intervention group compared to
control (p ⫽ ⬍.001). Responsiveness to treatment may be moderated by serotonin transporter
genotype. In 61 of the 101 participants we genotyped the 5-HTTLPR, rs25531 and STin2 VNTR
polymorphisms of the serotonin transporter. Treatment success, defined as 50% or greater
reduction in HDRS was strongest in the intervention group for those with one or two short (s)
alleles of the 5-HTTLPR polymorphism (interaction, p ⫽ .035). The interaction with STin2 VNTR
was not significant. Conclusion: A brief psychosocial/behavioral intervention is highly effective
in reducing depression in the short term and may be moderated by SERT genotype, particularly
5-HTTLPR polymorphisms.
63
Intravenous Transplantation Of Autologous Mesenchymal Stem Cells
Derived From Bone Marrow Into Stroke Patients.
Osamu Honmou, Kiyohiro Houkin, Dept. of Neurosurgery, Sapporo Med Univ, Sapporo,
Japan; Takuya Matsunaga, Forth Dept. of Internal Medicine, Sapporo Med Univ, Sapporo,
Japan; Yoshiro Niitsu, Forth Dept. of Interanl Medicine, Sapporo Med Univ, Sapporo, Japan;
Sumio Ishiai, Dept. of Rehabilitation, Sapporo Med Univ, Sapporo, Japan; Stephen G
Waxman, Jeffery D Kocsis; Dept. of Neurology, Yale Univ. Sch. of Med, New Haven, CT
BACKGROUND: Intravenous injection of mesenchymal stem cells (MSCs) prepared from adult
bone marrow has been reported to ameliorate functional deficits in several CNS diseases in
experimental animal models. Bone marrow cells can be enriched in MSCs by selecting for
plastic-adherent cells. MSCs will grow to confluency in appropriate culture conditions as
flattened fibroblast-like cells. Although MSCs may be present in different proportions in the
stromal cell fraction of various species, MSCs have a distinct cell surface antigen pattern
including SH2⫹, SH3⫹, and CD34-, and methodologies have been established to culture human
MSCs in very high purity. Although human MSCs have been clinically used for several diseases,
it is still uncertain whether MSCs may have therapeutic benefits on stroke patients.
OBJECTIVES: The objectives of this study were to examine feasibility and safety of cell therapy
using culture-expanded autologous MSCs in five stroke patients. This study was a phase I
clinical trial. METHODS: Five (male and female) patients aged ⬎/⫽50 years with stroke were
enrolled. Bone marrows from the stroke patients were obtained by aspiration from the posterior
iliac crest after informed consent was obtained; the subject’s consent was obtained according
to the Declaration of Helsinki, and this study was approved by the Institutional Review Board
at Sapporo Med. Sch. where the cells were isolated and transplanted. Bone marrow was plated
in plastic tissue culture flasks, and the adherent cells were cultured in appropriate medium in
a humidified atmosphere of 5% CO2 at 37°C. After reaching confluency, they were harvested
and cryopreserved until use. On the day of infusion cryopreserved units were thawed at the
bedside in a 37°C water bath and injected intravenously into patients over 30 min. All patients
were monitored closely during and within 48 h of MSC injections. Oxygen saturation,
temperature, blood pressure, pulse and respiratory rate were carefully monitored before and
after injection. Patients also had chest films before and after MSC injection. Patients had
Amytis Towfighi, Ling Zheng, Univ of Southern California, Los Angeles, CA; William Ellis,
Univ of California, Davis, CA; Wendy Mack, Univ of Southern California, Los Angeles, CA;
Harry V Vinters, Univ of California, Los Angeles, CA; Helena C Chui, Chris Zarow; Univ of
Southern California, Los Angeles, CA
Background: Hippocampal sclerosis (HS), severe neuronal loss and gliosis in the CA1 sector
of the hippocampus and subiculum, has been reported in 7.4% to 26% of elderly demented
individuals. The pathophysiology of HS remains controversial; the prevailing theories are
vascular and neurodegenerative. The aim of this study was to use clinical and pathological data
to further evaluate the etiology of HS. Methods: 104 autopsy cases drawn from a longitudinal
study of subjects with a clinical diagnosis of subcortical ischemic vascular dementia (SIVD),
Alzheimer’s disease (AD), and cognitively normal elderly subjects were reviewed pathologically
for Braak and Braak stage, CERAD-neuritic plaques score, Lewy Body score, cerebral amyloid
angiopathy, atherosclerosis, arteriosclerosis, and severity of cerebrovascular pathology. In all
cases, the rostral-caudal extent of both hippocampi were examined; HS was defined as
presence of focal neuronal loss with gliosis in the CA1 sector of the hippocampus, not
attributable to neurofibrillary tangles. Univariate and multivariate analyses were performed to
determine if the following historical and clinical factors correlated with HS: age at death, apoe4
genotype, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, peripheral
vascular disease, alcohol use, smoking, cerebrovascular disease, systolic blood pressure ⱖ
140, diastolic blood pressure ⱖ 90, total cholesterol ⱖ 200, high density lipoprotein ⱕ 40, low
density lipoprotein ⱖ 100, triglycerides ⱖ 200, and body mass index ⱖ 25. Results: Of 104
subjects reviewed, 29 subjects (28%) had evidence of HS. On univariate analysis, age at death
and history of hypertension were the only factors that were significantly associated with HS (OR
1.1, p⫽0.01 and OR 2.94, p⫽0.021). On multivariate analysis adjusted for age, diastolic blood
pressure ⬎90 and history of hypertension were associated with HS (OR 3.34, p⫽0.064 and OR
4.72, p⫽0.004). Conclusion: In this study of 104 elderly patients, hypertension, a key marker
of cerebrovascular disease, was significantly associated with HS, supporting a vascular etiology
of HS. Supported by grant P01 AG12435.
65
Morphological Changes of Cortical Sulci in Cerebral Small Vessel Diseases:
a 3D MRI Study in CADASIL.
Eric Jouvent, Dept of neurology, Hopital Lariboisiere, Paris, France; Jean-Francois Mangin,
Neurospin, I2BM, Saclay, France; Raphael Porcher, Dept of Biostatistics, Hopital Saint-Louis,
Paris, France; Anand Viswanathan, Dept of neurology and Clinical Trials Unit,
Massachussets General Hosp and Harvard Med Sch, Boston, MA; Mike O’Sullivan, Dept of
neurology, Klinikum Grosshadern, Ludwig-Maximilians-Univ, Munich, Germany; Jean-Pierre
Guichard, Dept of radiology, Hopital Lariboisiere, Paris, France; Martin Dichgans, Dept of
neurology, Klinikum Grosshadern, Ludwig-Maximilians-Univ, Munich, Germany;
Marie-Germaine Bousser, Hugues Chabriat; Dept of neurology, Hopital Lariboisiere, Paris,
France
Background and purpose: In cerebrovascular disorders, brain atrophy may represent a key
marker of clinical severity as reported in neurodegenerative diseases. The cortical morphological changes observed during the course of small vessel diseases remain unknown. In this
study, the depth and surface of different cortical sulci were investigated using new imaging
tools in a cohort of patients with CADASIL, a genetic model of small vessel disease. Methods:
MRI data were obtained from 54 CADASIL patients. Post-processing 3D tools were used to
identify automatically and then, calculate the depth and surface of four cortical sulci (cingular,
superior frontal, superior temporal and central). The ratio of brain to intracranial cavity volumes
(brain parenchymal fraction - BPF), volume of lacunar lesions and of white matter hyperintensities, number of cerebral microhemorrhages, and mean apparent diffusion coefficient were
also measured. Association between the depth and surface of the cortical sulci and BPF, clinical
status and subcortical MRI lesions were tested Results: The mean depth of the four sulci was
strongly related to that of BPF (p⬍0.0001), as was their mean surface (p⬍0.0001). In
multivariate analyses, the mean depth was strongly related to the Mattis Dementia Rating Scale
(p⫽0.003), and modified Rankin’s Scale (mRS) (p⬍0.0001), as was the mean surface (MDRS
: p⫽0.06, mRS: p⫽0.0002). In multivariate analyses, the depth of the different sulci was
related to the extent of subcortical lesion, whereas the surface of sulci was only related to age.
In additional analyses, the depth of the cingular sulcus was independently associated with the
volume of lacunar lesions (p⫽0.01), and the superior frontal sulcus with the mean apparent
diffusion coefficient (p⫽0.03). Conclusion: In CADASIL, important morphological changes of
cortical sulci occur in association with the progression of global cerebral atrophy. These
changes are strongly related to the clinical severity and to the extent of subcortical tissue
damage.These results suggest that the examination of cortical morphology may be of high
clinical relevance in small vessel diseases. Further studies are needed to better understand the
exact mechanisms underlying this process.
544
Stroke
Vol 39, No 2
February 2008
66
Association Between Increased Diastolic Blood Pressure Levels And
Cognitive Impairment: The Reasons For Geographic And Racial Differences
In Stroke (REGARDS) Study.
Georgios Tsivgoulis, Andrei V Alexandrov, Comprehensive Stroke Cntr, Univ of Alabama at
Birmingham Hosp, Birmingham, AL; Virginia V Wadley, Dept of Medicine, Univ of Alabama
at Birmingham, Birmingham, AL; Frederick V Unverzagt, Dept of Psychiatry, Indiana Univ
Sch of Medicine, Indianapolis, IN; Rodney C Go, Dept of Epidemiology, Univ of Alabama at
Birmingham, Birmingham, AL; Claudia S Moy, National Institute of Neurological Disorders
and Stroke, National Institutes of Health, Bethesda, MD; Brett Kissela, Dept of Neurology,
Univ of Cincinnati, Cincinnati, OH; George Howard; Dept of Biostatistics, Univ of Alabama at
Birmingham, Birmingham, AL
Background and purpose: Cross-sectional and prospective studies have shown variable and
inconsistent findings regarding the association of blood pressure (BP) levels with impaired cognitive
status. This study evaluated relationships of BP components with cognitive impairment after
adjusting for potential confounders. Methods: REGARDS is a national, longitudinal population cohort
evaluating stroke risk with telephone interviews and in-home physicals in black and white men and
women ⱖ45 years of age. Cognitive status and depressive symptoms are being assessed using
Six-Item Screener and Center for Epidemiological Studies-Depression-4-Item respectively. During
the in-home visit, BP measurements are taken as the average of two measurements using a
standard aneroid sphygmomanometer. The present analysis included 27,427 participants with
complete baseline physical and cognitive evaluations. Incremental logistic models examined
baseline relationships between BP components [systolic blood pressure (SBP), diastolic blood
pressure (DBP) and pulse pressure (PP)] and impaired cognitive status (score of ⱕ4 on Six-Item
Screener) after adjusting for demographic (age, gender, race, region) and environmental (educational level, alcohol use, smoking and exercise habits) characteristics, cardiovascular risk factors
(diabetes, hypercholesterolemia, obesity) and depressive symptoms. Results: Increased DBP levels
were associated with impaired cognitive status after adjusting for demographic and environmental
characteristics, risk factors and depressive symptoms. An increment of 10mmHg in DBP was
associated with an 8% (95%CI: 2%–15%; p⫽0.008) higher odds of cognitive impairment. No
independent association was identified between impaired cognitive status and SBP (OR: 1.02;
95%CI: 0.99 –1.06) or PP (OR 0.99; 95%CI: 0.95–1.03). There was no evidence of non-linear
relationships between any of the BP components and impaired cognitive status. There was no
interaction between age and the relationship of impaired cognitive status with SBP (p⫽0.827), DBP
(p⫽0.133), or PP (p⫽0.827) levels. Conclusions: That the association between cognitive function
was stronger for DBP than for SBP was counter to our hypothesized relationships. The linear
cross-sectional association between higher DBP and impaired cognitive status suggests that careful
monitoring and control of elevated BP may contribute to the preservation of cognitive function.
68
Tissue Microstructural Changes Are Independently Associated with
Pre-Index Cognitive Impairment in Survivors of Lobar Intracerebral
Hemorrhage.
Anand Viswanathan, Pratik Patel, Rosanna Rahman, R. N Nandigam, Catherine Kinnecom,
Massachusetts General Hosp, Boston, MA; Luc Bracoud, Bio-Imaging Technologies SAS,
Lyon, France; Jonathan Rosand, Massachusetts General Hosp, Boston, MA; Hugues
Chabriat, Dept of Neurology, CHU Lariboisière, Assistance Publique des Hôpitaux de Paris,
Paris, France; Steven M Greenberg, Eric E Smith; Massachusetts General Hosp, Boston, MA
ABSTRACT Background and Purpose: Cerebral amyloid angiopathy (CAA) is a major cause of
lobar intracerebral hemorrhage(ICH) and cognitive impairment and is associated with white
matter hyperintensities (WMH) and cerebral microbleeds (MB). MRI diffusion tensor imaging
detects microstructural tissue damage in advanced CAA even in areas that appear normal on
conventional MRI. We hypothesized that higher global mean apparent diffusion coefficient
(mean-ADC), reflecting a higher amount of chronic tissue disruption caused by CAA, and would
be independently associated with CAA-related cognitive impairment. Methods: Pre-ICH
cognitive impairment (PICI) was systematically assessed using a standardized questionnaire
(IQCODE) in 49 patients with CAA according to the Boston Criteria. Volume of WMH, number of
MB and mean-ADC were determined from MRIs obtained within 14.0 ⫾ 22.5 days of ICH.
Cortical atrophy was graded using a validated scale. WMH and mean-ADC were measured in
the hemisphere uninvolved by ICH to avoid confounding. Results: PICI was present in 10/49
subjects. Mean-ADC was the only variable associated with PICI and was elevated in those with
PICI compared to those without (12.4x10-4 versus 11.7x10-4 mm2/s; p⫽0.03) (Figure).
Mean-ADC positively correlated with age (p⫽0.0002) and cortical atrophy grade (p⫽0.004) but
not WMH or number of MB. In logistic regression controlling for age, ICH volume and amount
of cortical atrophy, only mean-ADC was independently associated with PICI (OR (per
1x10-4mm2/s increase)⫽2.45, 95%CI 1.115.40, p⫽0.04). Other MRI markers such as nWMH,
number of MB, and amount of cortical atrophy were not independently associated with PICI.
Conclusions: Mean-ADC is independently associated with pre-ICH cognitive impairment in CAA.
The lack of correlation with other MRI markers of CAA suggests that mean-ADC may be
sensitive to distinct aspects of CAA pathology and its tissue consequences. These results
suggest that global MRI diffusion changes are sensitive to clinically-relevant microstructural
alterations, and may be a useful marker of CAA-related tissue damage.
67
Heterogeneity In The Relationships Between Blood Pressure, White Matter
Lesion Volume And Cognitive Function In Patients With Small Vessel
Disease.
Jonathan Birns, King’s College London Sch of Medicine, London, United Kingdom; Jozef
Jarosz, King’s College Hosp, London, United Kingdom; Robin Morris, Institute of Psychiatry,
London, United Kingdom; Hugh Markus, St George’s, Univ of London, London, United
Kingdom; Lalit Kalra; King’s College London Sch of Medicine, London, United Kingdom
Background The inter-relationships between dynamic changes in blood pressure (BP), white matter
disease and cognitive performance have not previously been investigated in a small vessel disease
patient population whose white matter lesion (WML) volume has been quantified. Methods 88
patients (54 male, mean age 65 years) attending a neurovascular clinic with leukoaraiosis on T2 and
FLAIR MRI brain scanning were recruited. Exclusion criteria included BPⱖ160/100 mm Hg, cortical
infarct or intracranial pathology other than leukoaraiosis on MRI, or stenosis of ⬎50% of extracranial
or intracranial arteries on Doppler ultrasound. 24-hour ambulatory BP monitoring, quantitative
volumetric MRI analysis of leukoaraiosis and cognitive assessment, including tests sensitive to
attentional capacity and executive function, was undertaken. Results Subjects had a mean 24-hour
BP of 133/76 (SD13/9) mm Hg, median WML volume of 8464 (IQR 20544) mm3, mean National
Adult Reading Test (NART) error score of 25.6 (SD12.3) and mean MMSE score of 27.3 (SD 2.5).
After controlling for age and premorbid intellectual functioning, impaired perceptual processing and
attentional capacity correlated with frontal and parietooccipital WML volumes (r⫽0.3– 0.4,
p⫽0.002– 0.006), impairments of executive function and phonemic verbal fluency correlated with
parietooccipital WML volumes (r⫽0.3, p⫽0.007– 0.009) and impairments of phonemic verbal
fluency and choice reaction time correlated significantly with infratentorial WML volumes (r⫽0.5–
0.7, p⬍0.001– 0.005). There were significant correlations between daytime mean BP and improved
working memory, and between 24-hour pulse pressures and worse executive function, which were
independent of aging and premorbid intellectual functioning (r⫽0.3, p⫽0.004 – 0.009) Conclusion
In patients with small vessel disease, heterogeneous relationships existed between BP, WML
volumes and cognitive function. The neuroanatomical location of white matter tract disruption may
influence specific cognitive domains and dynamic changes in BP may affect perfusion within the
internal watershed areas differently causing diverse effects on brain structure and function.
69
The Metabolic Syndrome and Cognitive Function in Healthy Middle-Aged
and Older Adults without Diabetes.
Nicole M Gatto, USC, Los Angeles, CA; Victor W Henderson, Stanford, Stanford, CA; Jan A
St. John, Carol McCleary, Howard N Hodis, Wendy J Mack; USC, Los Angeles, CA
Recent attention has been directed towards the metabolic syndrome (MetS), a summary measure
of major cardiovascular and metabolic risk factors associated with increased risk of heart disease
and stroke. Few studies have addressed whether the metabolic syndrome and its individual
components are associated with reduced cognitive function in middle-aged and older populations,
as well as whether specific areas of cognition are more affected than others. We examined the
cross-sectional association between MetS and six areas of cognitive function in healthy cognitively
intact men and women without diabetes (n⫽853) randomized in two interventional trials. The
National Cholesterol Education Program (NCEP) criteria were used to identify subjects with MetS.
Cognitive function was assessed with a neuropsychological battery. A principal components analysis
was used to extract five uncorrelated factors interpreted to represent five areas of cognition, and a
measure of global cognition was calculated. MetS was weakly associated with decreases in verbal
memory and conceptual abilities (␤ ⫽ -0.16 [SE(␤) ⫽ 0.09], p ⫽ 0.08). As the number of MetS
criteria increased, global cognition and verbal memory and conceptual abilities decreased (p-trend
both ⫽ 0.01). Hypertension was the only MetS risk factor that was independently correlated with
decreased verbal memory and conceptual abilities (␤ ⫽ -0.26 [SE(␤) ⫽ 0.07], p ⫽ 0.0004),
semantic memory and visuospatial abilities (␤ ⫽ -0.15 [SE(␤) ⫽ 0.07], p ⫽ 0.03) and global
cognition (␤ ⫽ -0.12 [SE(␤) ⫽ 0.06], p ⫽ 0.06). This study provides evidence of an association
between MetS and reduced cognitive function among healthy middle aged and older adults without
CVD and diabetes, as well as confirms the association between hypertension and reduced cognitive
function.
TABLE 1
FIA
70
Cortical Grey Matter Volume is Reduced in Patients at High-Risk for
Vascular Events.
ANEURYSMS
Nerses Sanossian, Ling Zheng, Wendy Mack, Univ of Southern California, Los Angeles, CA;
Michael W Weiner, Univ of California San Fransisco, San Fransisco, CA; William J Jagust,
Univ of California, Berkely, Berkeley, CA; Charles C DeCarli, Dan Mungas, Univ of California,
Davis, Sacramento, CA; Bruce R Reed, Univ of California, Davis, Martinez, CA; Joel H
Kramer, Univ of California San Fransisco, San Fransisco, CA; Helena C Chui; Univ of
Southern California, Los Angeles, CA
Background: Vascular cognitive impairment is a process by which vascular risk factors (VRFs) cause
permanent effects on brain function. There are multiple mechanisms by which VRFs affect cognition;
however the mediators of this relationship are poorly understood and likely include changes in
cortical grey matter (CGM). Objective: To determine if increased vascular risk, as measured by the
Framingham Coronary Risk Profile (FCRP), is associated with reduction of relative CGM volume in
a group of community-dwelling older persons participating in an observational study. We
hypothesize that increasing FCRP scores will be independently associated with decreased CGM
volume via ischemic, inflammatory and other mechanisms. Methods: Participants were recruited
from a multicenter collaborative study of the contributions of subcortical ischemic vascular disease
and AD to cognitive impairment and dementia. All participants received a comprehensive clinical
evaluation and a standardized MRI scan of the brain at recruitment. Voxel based morphometry
followed by hand editing was used to classify brain MRI pixels into CGM, , white matter
hyperintensities (WMH), and CSF (expressed as % intracranial volume). Number and volume of
lacunes were drawn by hand. Hippocampal volume was determined using a semi-automated
method using surgical navigation technology. Results were adjusted for subject age. Results: 128
subjects had baseline FCRP and MRI available. Mean age was 75.6 (SD ⫾7.2), 42% female, 84%
white, and 9% Asian. The clinical diagnosis was normal in 49%, cognitively impaired in 22%,
Subcortical ischemic vascular dementia (SIVD) in 5%, Alzheimer’s Disease in 17% and Mixed
AD/SIVD in 7%. The mean FCRP was 21.8 (⫾13.9) and the mean percent CGM volume was 37.9
(⫾3.24). FCRP was inversely related to percent CGM volume (r⫽ -0.209, p⫽0.018). Other MRI
markers significantly associated with FCRP were number of lacunes (r⫽.250, p⫽0.0048) and
lacune volume (r⫽0.283, p⫽0.0014). Hippocampal volume showed a trend towards an inverse
relationship to FCRP(r⫽ -0.165, p⫽0.074). White matter hyperintensity volume was not associated
with FCRP (r⫽0.127, p⫽0.15). The inverse relationship of CGM and FCRP remained significant after
adjusting for age. Discussion: The cognitive effects of vascular risk factors may be mediated by loss
of CGM volume. This may have implications in the relationship of VRFs with cognitive performance
in vascular and Alzheimer disease.
71
Neurovascular Phenotypes in Children with Familial Intracranial Arterial
Aneurysms.
Todd Abruzzo, Univ of Cincinnati Med Ctr, Cincinnati, OH; L. Seranno, Cincinnati Children’s
Hosp Med Cntr, Cincinnati, OH; D. Kleindorfer, B. Jones, Univ of Cincinnati Med Ctr,
Cincinnati, OH; F. Mangano, L. Sauerbeck, Cincinnati Children’s Hosp Med Cntr, Cincinnati,
OH; A. Greely, Univ of Cincinnati Med Ctr, Cincinnati, OH; N. Zumberge, Columbus
Children’s Hosp, Columbus, OH; K. Crone, Cincinnati Children’s Hosp Med Cntr, Cincinnati,
OH; J. Broderick; Univ of Cincinnati Med Ctr, Cincinnati, OH
OBJECTIVE: Case series of intracranial arterial aneurysms (IAA) in children have shown significant
differences in phenotype as compared with adults. The formation of an IAA in the first two decades
of life suggests a more potent biological phenotype, perhaps representing the effect of strong
genetic influences. We examined the IAA phenotype in children with Familial Intracranial Aneurysms
(FIA), where strong genetic influences are known to exist. MATERIALS AND METHODS: FIA patients
under age 19 years (y) were identified by query of the FIA study database. The FIA study is a
multi-national study of families with saccular IAA in a sibling pair or ⱖ 3 first degree relatives. In
this study, IAA in children were discovered when they ruptured or when neuroimaging of a sibling
to a child with a ruptured IAA was pursued by parents. Only children with saccular aneurysms
confirmed by surgery or neuroimaging were included. An age matched cohort with non-familial,
idiopathic saccular IAA were identified by searching clinical databases at 3 tertiary referral hospitals.
We queried radiology reports, clinic registries and angiography logs from 01/93 to 11/06 using the
search term “aneurysm”. Medical records were reviewed to confirm each case. Traumatic,
infectious, neoplastic, inflammatory and flow related aneurysms were excluded. Phenotypic traits
were recorded by medical record review and compared. Differences were tested for significance
using the Fisher Exact Test. RESULTS: 8 of 441pedigrees yielded 10 FIA children with 12 IAA. In the
Non-familial cohort, there were 13 children with 16 IAA. No genetic condition or family history of IAA
was reported for any child in this cohort. Data are presented in Table 1. Analysis of children
presenting with hemorrhage showed a decreased frequency of posterior circulation aneurysms in
the FIA cohort as compared with the non-familial cohort (p ⫽ 0.03). CONCLUSIONS: The pediatric
FIA phenotype is characterized by presentation in adolescence, female predominance and small,
proximal anterior circulation aneurysms. In children presenting with hemorrhage, non-familial IAA
are commonly in the posterior circulation, while familial IAA are not. Differences between
Non-familial and Familial IAA may reflect the differential importance of environmental and genetic
factors in determining vascular segment specific vulnerability to aneurysm formation.
545
>7
< 7 mm
Size unknown
Posterior circulation
Anterior circulation
Within or proximal to
circle of Willis
Distal to circle of
Willis
CHILDREN
Average age in years
(std. dev.)
Male: Female ratio
Caucasian ethnicity
Multiple aneurysms
Non-familial
All Children
Children
presenting
with
hemorrhage
All Children
Children
presenting
with
hemorrhage
N⫽12
aneurysms
2
8
3
1
11
7
N⫽8
aneurysms
2
3
3
0
8
4
N⫽16
aneurysms
6
10
0
6
10
10
N⫽10
aneurysms
3
7
0
5
5
8
4
4
6
2
N⫽10
children
15 (⫹/- 3)
N⫽7
children
15 (⫹/- 4)
N⫽13
children
16 (⫹/- 2)
N⫽8
children
15 (⫹/- 1)
0.7
10
3
0.7
7
1
1.6
11
3
1.0
7
2
72
Bilateral Corticospinal Tract Degeneration After Unilateral Stroke in
Hemiparetic Children: A TMS and MRI Study.
Adam Kirton, Alberta Children’s Hosp, Calgary, Canada; Trish Domi, Hosp for Sick Children,
Toronto, Canada; Robert Chen, Toronto Western Rsch Institute, Toronto, Canada; Manohar Shroff,
Elizabeth Kouzmitcheva, Hosp for Sick Children, Toronto, Canada; Carolyn Gunraj, Toronto
Western Rsch Institute, Toronto, Canada; Gabrielle deVeber; Hosp for Sick Children, Toronto,
Canada
Background: Hemiparesis after childhood stroke is predicted by acute diffusion signal in the
descending corticospinal tracts (DCST-DWI), termed “pre” Wallerian degeneration (WD). Newly
described contralesional DCST-DWI appears to predict severe hemiparesis but its pathophysiology
is unstudied. Methods: We hypothesized that contralesional DCST-DWI represents acute recruitment (and chronic enhancement) of uncrossed DCST from the unlesioned hemisphere to the weak
hand and investigated this using: (1) Bilateral transcranial magnetic stimulation (TMS) in children
with contralesional DCST-DWI to evaluate for enhanced ipsilateral motor evoked potentials (iMEP),
and (2) A novel method measuring bilateral DCST areas from 29 children with chronic, unilateral
middle cerebral artery stroke to detect changes in one or both DCST areas using the ratio of ispi (I)
and contra (C) cerebral peduncle areas to a standardized brainstem area (S). Results: All children
had normal MEP contralateral to the unlesioned side. iMEP were normal for age (absent in 2, small
in 2/80 trials from other 2). Peduncle area in children with no acute DCST-DWI showed only mild
ipsilesional atrophy (C/S:I/S⫽1.38/1.26; Figure left). Children with acute ipsilesional DCST-DWI
showed marked ipsilesional DCST atrophy and the largest difference between sides (C/S:I/
S⫽1.55:1.21; middle). In contrast, those with acute contralesional signal showed evidence of
bilateral DCST atrophy with an intermediate difference between sides (C/S:I/S⫽1.36:1.10; right).
Differences between these three groups was highly significant (Kruskal-Wallis ANOVA p⫽0.004).
Conclusion: Acute DCST-DWI predicts chronic WD. Bilateral corticospinal tracts may be adversely
affected after unilateral stroke with loss of contralesional DCST associated with severe outcome.
Such novel reorganization merits further study.
546
Stroke
Vol 39, No 2
February 2008
73
Childhood Ischemic Stroke Is More Common in Boys: Findings from the
International Paediatric Stroke Study.
Male sex
Birth weight, mean (SD), g
Birth weight ⬍2500g
Birth weight ⬎4000g
Apgar score, 5 min, mean
(range)
Meredith Golomb, Riley Hosp, Indianapolis, IN; Heather Fullerton, Univ of California San
Francisco, San Francisco, CA; Gabrielle deVeber, The Hosp for Sick Children, Toronto,
Canada; and members of the International Paediatric StrokeStudy
Background: Several studies have suggested a male predominance in childhood ischemic stroke,
mirroring well-described gender differences in adult stroke, but were limited by small sample sizes
or non-validated diagnoses. The International Pediatric Stroke Study (IPSS)–a multi-centre,
multi-national prospective study of pediatric ischemic stroke initiated in 2003–provides a new
opportunity to examine this issue. Objective: To determine if a male predominance exists in children
with ischemic stroke within a large international study, and whether this gender difference is specific
to a certain stroke sub-type, age group, or underlying etiology. Methods: From 1/2003–2/2007, the
IPSS prospectively enrolled children (0 –18 years of age) with arterial ischemic stroke (AIS) or
cerebral sinovenous thrombosis (CSVT) at 30 hospitals in 10 countries. Investigators abstracted
clinical data onto standardized data collection forms. Proportions of boys were calculated for the
whole group and for subgroups defined by age (neonatal defined as first 28 days of life), stroke
sub-type (AIS versus CSVT), and etiology (as determined by the enrolling investigator using
standardized etiologic criteria). Assuming a 1:1 ratio of boys to girls in the general population, we
used chi-square tests to compare the observed proportion of boys with stroke to the expected
proportion of 50% Results: Among 965 children with ischemic stroke, 582 were boys (60%,
p⬍0.001). Male predominance persisted after stratification by age (59% for neonates N⫽289,
p⫽0.038; 61% for later childhood, N⫽676, p⬍0.001) and stroke sub-type (59% for AIS, N⫽741,
p⬍0.001; 63% for CSVT, N⫽224, p⫽0.003). It also persisted for the different etiologic subgroups:
61% for underlying cardiac disease (N⫽204, p⫽0.03); 59% for vasculopathy (N⫽185, p⫽0.09);
61% for underlying chronic disease, such as pro-thrombotic states, sickle cell anemia, and
hematological malignancies (N⫽322, p⫽0.003); and 66% for head and neck disease, such as otitis
media, pharyngitis, and head and neck trauma (N⫽205, p⫽0.001). There were no gender
differences in case fatality or deficits at discharge. Conclusion: In a large international cohort,
childhood ischemic stroke appears to be more common in boys than girls, regardless of stroke
sub-type, age group, or etiology. Further exploration of this gender difference could shed light on
stroke mechanisms in both children and adults, where a similar difference has been observed.
74
Prevalence and Predictors of Perinatal Hemorrhagic Stroke.
Jennifer Armstrong-Wells, S Claiborne Johnston, Yvonne W Wu, UC San Francisco, San
Francisco, CA; Steven Sidney, Kaiser Permanente Med Cntr, Oakland, CA; Heather J
Fullerton; UC San Francisco, San Francisco, CA
Background: Predictors for perinatal arterial ischemic stroke (PAS) include maternal factors such
as preeclampsia, prolonged rupture of membranes, and chorioamnionitis, and also intrapartum
factors, such as fetal distress and emergent cesarean delivery. Prevalence and predictors of
perinatal hemorrhagic stroke (PHS) have not been studied. Methods: We performed a case-control
study nested within the cohort of all infants born from 1993–2002 in the Northern California Kaiser
Permanente Medical Care Program, a health maintenance organization providing care for more than
3 million members. Cases of symptomatic PHS and PAS in neonates (28 weeks gestational age
through 28 days of life) were confirmed by review of medical records. Three controls per case were
randomly selected and matched on birth year and facility. This analysis included cases of PHS
(intracerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH], excluding pure intraventricular hemorrhage) and all controls. Predictors of PHS were assessed using logistic regression
techniques, adjusting for the matching criteria. Results: The population prevalence of PHS
diagnoses was 6.2 per 100,000 live births, compared to 28 per 100,000 for PAS. There were 19
cases of ICH and 1 SAH. Cases commonly presented with altered mental status (100%) and seizures
(65%). PHS was typically unifocal (74%), unilateral (83%), and seen in the parietal (47%), frontal
(37%), and less commonly, temporal regions (17%). Underlying etiologies included thrombocytopenia (n⫽3) and cavernous malformation (n⫽1); 16 (80%) were idiopathic. Univariate predictors of
PHS included fetal distress, birth by emergent cesarean delivery, and preterm or post-dates
gestational age (Table). Because of colinearity, we did not enter these predictors into a multivariate
model. Conclusions: Similar to PAS, predictors of PHS include intrapartum factors such as fetal
distress and emergent cesarean delivery. However, we found no evidence to suggest that maternal
factors predict PHS, suggesting that underlying mechanisms of PAS and PHS may differ.
UNIVARIATE PREDICTORS OF NEONATAL HEMORRHAGIC STROKE
Cases
Controls
(n⫽20)
(n⫽317)
Maternal age, mean (SD)
28.3(5.4)
28.5(6.0)
Primiparity
11/20 (55%) 149/317 (47%)
Preeclampsia
0/18
3/255 (12%)
Chorioamnionitis
0/11
3/54 (6%)
Maternal fever
1/14 (7%)
12/173 (7%)
Prolonged rupture of membranes 1/19 (5%)
16/296 (5%)
Prolonged second stage of labor
1/17 (6%)
17/204 (8%)
Gestational age, mean (SD)
38.4(3.5)
38.9(2.0)
Preterm (<36wks)
3/20 (15%)
16/312 (5%)
Post-dates (>40wks)
5/20 (25%)
39/317 (12%)
Fetal distress
7/20 (35%)
22/292 (7.5%)
Vacuum delivery
1/20 (5%)
36/312 (12%)
Emergency cesarean delivery
6/20 (30%)
35/313 (11%)
OR (95% CI)
P value
–
0.62
1.3 (0.5–3.4)
0.49
–
0.64*
–
0.44*
0.86(0.08–8.9)
0.91
1.1 (0.1–10.2)
0.86
0.7 (0.06–7.9)
0.77
–
0.89**
5.2 (1.04–25.4)
0.044
3.7 (1.08–12.5)
0.036
9.7 (2.8–33.5) <0.001
0.4 (0.05–3.1)
0.38
3.6 (1.1–12.0)
0.03
–
Cases
Controls
OR (95% CI)
P value
13/20 (65%)
3145 (934)
3/20 (15%)
3/20 (15%)
8.7(6–9)
158/317 (50%)
3377 (594)
19/316 (6%)
36/316 (11%)
9.1(5–10)
1.9 (0.7–4.8)
–
2.5 (0.59–10.8)
1.92(0.47–7.8)
–
0.2
0.95**
0.21
0.36
0.69**
Adjusted for birth year and facility of birth. P-value calculated by chi-square* or t-test**
75
Expanded Case Identification Methods Yield a Higher Incidence of Pediatric
Stroke.
Nidhi Agrawal, S. C Johnston, Yvonne W Wu, UCSF, San Francisco, CA; Stephen Sidney,
Kaiser Permanente, San Francisco, CA; Heather J Fullerton; UCSF, San Francisco, CA
Background: Prior annualized estimates of pediatric ischemic stroke incidence have ranged
from 0.5–1.2 per 100,000 U.S. children, but these studies relied purely on diagnostic code
searches to identify potential cases. We sought to estimate the incidence of pediatric ischemic
stroke using not only diagnostic code searches, but also searches of radiology reports, and to
assess the relative value of these two search strategies. Methods: Using the population of 2.3
million children (ages 0 –20 years) enrolled in a Northern California managed care plan
(1/1993–12/2003), we performed electronic searches of (1) in-patient and out-patient
diagnoses for ICD-9 codes suggestive of ischemic stroke (433– 436, 437.6) and cerebral palsy
(CP; 342–344) and (2) radiology reports for keywords suggestive of infarction. Cases were
confirmed through independent chart review by two neurologists, with adjudication by a third.
Positive predictive value (PPV) and sensitivities were calculated and stratified by etiology and
age at diagnosis. Neonatal strokes were defined as those occurring within the first 28 days of
life. Results: We identified 280 potential cases from the stroke ICD-9 code search, 863 from
the CP ICD-9 code search, and 439 from the radiology search. A total of 217 childhood
ischemic stroke cases were confirmed during 8.9 million person-years of follow-up, yielding an
annual incidence rate of 2.4 per 100,000 children. The radiology search had a higher sensitivity
than the ICD-9 code search, although both strategies had low PPVs (Table). The sensitivity of
ICD-9 codes for neonatal strokes (15%) was significantly lower than that for later childhood
strokes (53%, p⬍0.0001), as was the sensitivity of ICD-9 codes for idiopathic strokes (27%)
compared to strokes with an identified etiology (45%, p⬍ 0.006). Conclusions: Our estimate
of childhood ischemic stroke incidence is double that of prior reports, a difference at least
partially explained by our use of both ICD-9 code and radiology searches for case identification.
Studies relying purely on ICD-9 code searches may underestimate childhood stroke rates,
particularly for neonatal and idiopathic strokes.
TABLE. SENSITIVITY AND PPV BY SEARCH STRATEGY FOR ISCHEMIC STROKES
Search Strategy
Stroke ICD-9 alone
Inpatient Diagnoses
Outpatient Diagnoses
Sensitivity (%)
95% CI
PPV (%)
95% CI
34
21
13
26–42
14–29
5–15
29
18
11
23–34
14–23
7–15
Stroke ICD-9 ⫹ CP ICD-9
39
31–47
9
7–10
Radiology alone
Radiology ⫹ Stroke ICD-9
83
95
75–89
90–98
26
30
22–31
26–35
76
Nitrative Stress Induces Cerebral Microvascular Degeneration Via The
Production Of Trans-Arachidonic Acids: Role Of Hypercapnia.
Jean-Claude Honore, Amna Kooli, Elsa Kermorvant-Duchemin, Sainte-Justine Rsch Cntr,
Montreal, Canada; Florian Sennlaub, INSERM U598 - Cntr des Cordeliers, Paris, France;
Michael Balazy, Dept of Pharmacology - New York Med College, Valhala, NY; Sylvain
Chemtob; Sainte-Justine Rsch Cntr, Montreal, Canada
Nitrative stress is importantly involved in microvascular degeneration notably through the
isomerisation of arachidonic acid which leads to the formation of trans-arachidonic acids (TAA).
Carbon dioxide (CO2) enhances nitration by catalyzing the conversion of peroxynitrite into the
unstable, more efficient nitrating agent nitrosoperoxocarbonate (ONOOCO2-). On the other hand,
preterm infants brain is particularly sensitive to oxidative and nitrative stress due to deficient
antioxidant defenses and polyunsaturated fatty acids enriched-cellular membranes. We thus
hypothesized that in rat pup models, increased local and/or systemic CO2 levels could favor
production of TAA and subsequent cerebral microvascular degeneration. In the cerebral
hypoxia/ischemia (HI) rat pups model (postnatal day 7; P7), our results indicate that ipsilateral
brain TAA levels are significantly increased 18 hours post-HI as compared to the contralateral
side. This phenomenon is associated with a significant decrease of the ipsilateral brain
microvascular density. Interestingly, when TAA are directly injected into cerebral lateral
ventricles, a similar decrease of microvascular density is observed. The mechanism involved
is blood pressure-independent since vascular density is also decreased in ex vivo TAA-treated
brain explants. Furthermore, using newborn rat pups directly exposed to 10% CO2 levels from
P1 to P3, we observed an increased endothelial cell nitric oxide synthase (eNOS) expression,
an increased endothelial cell 3-nitrotyrosine staining; a marker of increased nitrative stress,
and a decreased cerebrovascular density. Finally, in microvascular endothelial cells cultured in
a 10% CO2 atmosphere, a NO donor DETA NONOate (0.01 mM) enhances 3-nitrotyrosine
positive cells and cell mortality. Mechanistically, we have determined that TAA triggers
endothelial cell apoptosis through an ERK1/2 activation, and a subsequent upregulation of the
antiangiogenic factor thrombospondin-1. In conclusion, our data suggest that CO2 favors
nitrative stress and could trigger encephalopathy by eliciting production of trans-arachidonic
acids and ensuing cerebral microvascular degeneration in preterm infants.
77
Secretory Phospholipase A2 is Involved in Hypoxic Cerebrovascular Injury in
the Newborn Piglet.
Ferenc Bari, Aliz Zimmermann, Univ of Szeged, Szeged, Hungary; Jana Pardeike, Free Univ,
Berlin, Germany; Eszter Farkas, Ferenc Domoki; Univ of Szeged, Szeged, Hungary
Phospholipase A2 enzymes including secretory PLA2 (sPLA2) hydrolyze membrane phospholipids
and release arachidonic acid. Arachidonic acid is metabolised by cyclooxygenases (COX)
producing prostanoids that are key regulators in the newborn cerebral circulation. However, the
specific involvement of sPLA2 in prostanoid production is unknown. Cerebral ischemia/
reperfusion (I/R), often occurring during the neonatal period, enhances sPLA2 activity,
production of prostanoids and free redical formation. Secretory PLA2 has been implicated in
ischemic neuronal damage, but its function in cerebrovascular injury has not been addressed.
We used the novel sPLA2 inhibitor PX-18 to examine the role of the enzyme in: 1) the
hemodynamics of the systemic and cerebral circulation; 2) COX-dependent cerebrovascular
dilatory responses as hypercapnia and pituitary adenylate cyclase-activating polypeptide
(PACAP)-38, and 3) the mechanism of I/R-induced cerebrovascular dysfunction. Newborn
piglets (1–2-day old, n⫽44) were studied. The animals were anesthetized, ventilated, equipped
with arterial and venous catheters and closed cranial window. Pial arteriolar diameter was
measured by intravital microscopy. Pial arterioles were significantly dilated (16⫾5%,
mean⫾SEM) by PX-18 (10-4M) administered topically onto the brain surface, but not by lower
concentrations (10-8-10-5M). Intravenous (iv) bolus of PX-18 (6 mg/kg) transiently decreased the
mean arterial blood pressure (from 62⫾7 mmHg to 40⫾5 mmHg) and dilated pial arterioles
(32⫾1%) which both normalized in 4 – 6 min. Cerebrovascular dilation to hypercapnia was
unaffected by topical (40⫾6% vs. 50⫾7%) or iv PX-18 (51⫾5% vs. 64⫾11%). Pial arteriolar
responses to PACAP-38 (10-6M) were significantly reduced by topical PX-18 (10-5M, 67⫾11 vs.
24⫾6), but did not change after iv PX-18 (6 mg/kg in 20 min, 71⫾13 vs. 70⫾8). I/R
diminished pial arteriolar reactivity to endothelium-dependent (hypercapnia: from 44⫾4 to
25⫾7, bradykinin 10-6M: from 65⫾7 to 38⫾6) and -independent (NMDA 10-4M: from 57⫾5
to 19⫾7) vasodilators and was rescued by iv PX-18 (responses were 35⫾5%, 59⫾8% and
50⫾10%, respectively). We conclude that sPLA2 1) contributes to basal vascular tone in the
cerebral and systemic circulation; 2) may participate in COX-dependent cerebral vasodilation
and 3) is significantly involved in I/R-induced cerebrovascular injury. Therefore, PX-18 could be
the basis of novel protective pharmacological tools against I/R-induced cerebrovascular injury.
78
Single Center Experience With Combined (Thrombolytics and Mechanical
Thrombectomy) Intra-arterial Intervention In 112 Consecutive Patients With
Angiographically Confirmed Large Vessel Thromboembolic Ischemic Stroke
(1–6 hours post symptom onset) from 2003 to 2007.
Michael T Madison, James K Goddard, III., Jeffrey P Lassig, Mark E Myers; St. Paul
Radiology, Saint Paul, MN
Background: Intra-arterial thrombolytics and mechanical intervention have been shown to
recanalize acute ischemic strokes at high rates. Less data has been presented on use of these
interventions in community based settings. We wanted to see if results from our group of 4
neurointerventionalists covering acute stroke at 5 hospitals in the Minneapolis-St. Paul area
were consistent with outcomes presented in other trials. Methods: We retrospectively reviewed
112 consecutive angiographically confirmed large vessel thromboembolic ischemic stroke
patients treated with intra-arterial intervention in under 6 hours between 2003 to 2007. We
generally load the patients with 10 –20 mg of IA tPA. If this fails to recanalize the vessel, we
utilize mechanical thrombectomy, and may optionally use additional IA thrombolytics or
eptifibatide during procedure. We reviewed baseline demographics, procedural outcomes,
hemorrhage rates, and clinical outcomes. Results: The average baseline NIHSS in the cohort
was 14.2 (Range 8 –29). Average time of symptom onset to intervention 4 hours and 5 minutes
(Range 1–5.5 hours). Intra-arterial Thrombolytics were used in 101 patients (90%). Average
dose of IA tPA was 24.6 mg (Range 9 – 42 mg). Average dose of I.A. eptifibatide was 4.6 mg
(Range 0 –9.5 mg). The Merci Retriever was used in 54 patients (48%); the immediate
post-retriever recanalization was 52%. Final angiographic vessel recanalization (TIMI 2–3 Flow)
for the overall cohort was 72%. Average NIHSS (24 – 48 hours) post treatment was 7.5 (Range
0 –30). Positive clinical outcomes were observed in 59% (66/112) of the patients,and in 82%
of patients with successful vessel recanalization. In the cohort with improved outcome, the
average NIHSS prior to treatment was 13.5 (Range 8 –24) and post treatment was 4.8 (Range
0 –18). In the cohort without vessel recanalization post treatment NIHSS was 14.6 (Range
8 –30). Parenchymal contrast staining at 24 hours was observed in 29%, and symptomatic
hemorrhage was observed in 13%. Only 2 patients with complete recanalization had
symptomatic hemorrhage. Conclusions: Results from trials done at academic centers can be
successfully replicated in a private practice group of 4 neuro-interventionalists covering 5
community hospitals. High rates of final recanalization and good clinical outcomes were
observed. Further analysis of our cohort is ongoing.
547
79
Pre-ischemic Upregulation of TNF-␣ induced by Physical Exercise Reduces
Brain Inflammation via ERK1/2 Signaling in Stroke.
Alecia Curry, Brandon Leibelt, Ryan Rogers, Will Davis, Shane Sprague, David F Jimenez,
Yuchuan Ding; Univ Texas Health Science Cntr, San Antonio, TX
It has been shown that pre- ischemic physical exercise chronically upregulates TNF-␣. The
increase in TNF-␣ prior to I/R injury is associated with a decrease in MMP-9 activity and a
subsequent neuroprotective effect in rat stroke models. In this study we sought to test the
hypothesis that reduced cerebral inflammation in ischemic rats is caused by the neuroprotective action of TNF-␣ reduced matrix metalloproteinase-9 (MMP-9) activity and suppressed
adhesion molecule (ICAM-1) expression via ERK 1/2 phosphorylation. Adult male Sprague
Dawley rats were subjected to 30 minutes of exercise on a treadmill 6 days a week for 3
weeks. Stroke was induced by a 2 hour middle cerebral artery (MCA) occlusion using an
intraluminal filament. The animals in the 3 week exercised group were treated before MCA
occlusion and at reperfusion with UO126 (ERK1/2 inhibitor), TNF-␣ antibody, or both UO126
and doxycycline (MMP-9 inhibitor). Brain infarct volume was assessed using Nissl staining.
Leukocyte infiltration was evaluated using myeloperoxidase (MPO) immunostaining in cortex
and striatum. I-CAM levels were determined by real time PCR and Western blot and MMP-9
expression was evaluated using RT-PCR, Western Blot, and Zymography to evaluate mRNA
levels, protein, and enzyme activity. In exercise group, there was a significant decrease in brain
infarct volume as well as MMP-9 activity, leukocyte infiltration, and ICAM-1 expression. In the
animals treated with either TNF-␣ antibody or with UO126, an increase in the levels of the
same four parameters was observed, which neared the level detected in the non-exercise
stroke group. Furthermore, a decrease in the above mentioned parameters was seen in the
animals treated with both UO126 and doxycycline. As expected, the decrease in these
parameters was near the levels obtained in exercise ischemic rats. The results suggest that
phosphorylation of ERK 1/2 plays a major role in the decrease in brain inflammation and
subsequent neuroprotective effects seen after exercise induced upregulation of TNF-␣ prior to
I/R injury by decreasing MMP-9 activity.
80
Optimal tPA Concentration for 120 kHz Ultrasound Enhanced Thrombolysis.
George J Shaw, Jason M Meunier, Christopher J Lindsell, Christy K Holland; Univ of
Cincinnati, Cincinnati, OH
Introduction: Contraindications to tPA use for acute ischemic stroke and potential side effects
such as intra-cerebral hemorrhage (ICH) have led to interest in potential therapies such as
ultrasound enhanced thrombolysis (UET). Recently 2 MHz transcranial UET was found to
increase the recanalization rate in acute ischemic stroke patients compared with standard tPA
therapy. Lower frequency ultrasound (⬃ kHz) is of potential interest for UET as there are studies
suggesting better skull penetration and lytic efficacy than higher frequency (⬃MHz) UET.
However, a 300 kHz UET trial showed no difference in outcome and a higher ICH rate compared
with tPA alone. Clearly, the optimal UET therapy is unknown. Here, the tPA concentration
dependence of 120 kHz UET lytic efficacy is determined in an in-vitro human clot model. We
hypothesize that there is a range of tPA concentrations for which 120 kHz UET lytic efficacy is
maximal. Methods: Blood was drawn from 10 subjects after IRB approval. Clots were made in
20 ␮l pipettes, and placed in a water tank for microscopic imaging during ultrasound (US) and
tPA treatment. All treatments were at 37o C for 30 minutes. Clots were treated with tPA (tPA),
or tPA and 120 kHz US (UET) in plasma at one of 7 concentrations: 0 (control), 0.25, 0.50, 1.00,
3.15, 6 and 10 (␮g/ml). Each treatment used an average 18 clots (range 6 –31), from 4 donors
(range 3 to 10). Clot lysis was imaged and clot diameter measured over time using a previously
developed method. Average initial lytic rate, defined as the percent decrease in clot width per
minute (LR) and fractional clot loss at 30 minutes (FCL) was determined for each group. Data
are shown as mean ⫾ SEM. Results: The figure shows lytic rate vs.tPA concentration ([tPA])
for tPA and UET treated clots. There is a maximum in LR for the UET group for [tPA] ⬇ 1–3
␮g/ml. FCL (data not shown) for UET and tPA treated clots increases with [tPA] up to 1 ␮g/ml;
and is constant for larger values of [tPA] in both groups. Conclusions: LR for 120 kHz UET
treated clots exhibits a maximum for [tPA]⫽1–3 ␮g/ml, and greater FCL at all [tPA] values
compared with tPA treated clots. It may be possible to optimize UET therapy for increased lytic
efficacy while minimizing tPA dose.
548
Stroke
Vol 39, No 2
February 2008
81
Cerebral Ischemia Results In A Varying Degree Of Reduction Of Cerebral
Blood Flow In Gray And White Matter.
Quan Zhu, Duke Univ, Durham, NC; Jin-Moo Lee, Katie Vo, Washington Univ, St. Louis, MO;
Weili Lin; Univ of North Carolina, Chapel Hill, NC
Purpose The extent to which cerebral blood flow (CBF) is reduced in relationship to the normal
CBF values has been utilized as an indicator to discern ischemic injury. However, despite the
well known difference in CBF between gray and white matter, relatively little attention has been
given as to how CBF may be differently altered in gray and white matter during ischemia. The
lack of attention is most likely attributed by the inability to accurately separate gray and white
matter particularly during the hyperacute phase. To this end, we propose a new approach
capable of accurately segmenting gray (GM) and white (WM) matter separately in perfusionweighed MR images, allowing a direct and rapid assessment of CBF values in GM and WM
separately during acute cerebral ischemia. Materials and Methods MR PWI images were
obtained from 10 acute stroke patients using an EPI sequence (TR/TE/ FOV/Mat⫽2s/54ms/
220mm2/128). A model-based segmentation using unsupervised Bayes classifier with the
expectation-maximization (EM) algorithm and a mixture of multivariate Gaussians (MoMG)
based on robust principal components analysis (PCA) was developed. Specifically, the matrix
X(t⫻N) denotes the perfusion data, where N is the total voxel number in the brain. For each
time series xn (t⫻1), n⫽1,…,N, the Bayes classifier is defined as p(i| xn,␮i,⌺i␲ i)⫽p(i)p(xn|i)/
⌺ {p(i)p(xn|i)}⫽ ␲ i gxn [␮i,⌺i ]/ ⌺{␲ i gxn [␮i,⌺i ]}. Here i␮{1,…,K} represents a tissue class
label. The parameters ␮i,⌺ i and ␲ i were estimated by fitting the MoMG to maximize the
posterior probability using the EM algorithm. Robust PCA, which is less influenced by outliers,
was applied to reduce the data size prior to the clustering process. Results The proposed
approach successfully segments the entire brain into multiple components, including not only
CSF, normal GM and WM, but also abnormal GM and WM for all patients. Mean CBF values
were obtained from normal/abnormal GM and WM, separately. The ratio of normal GM/WM is
2.02⫾0.31 while this ratio is reduced to 1.63⫾0.18 for abnormal GM/WM. In addition, the ratio
between normal and abnormal gray is 1.72⫾0.31 and between normal and abnormal white is
1.38⫾0.13, respectively. Conclusions Consistent with the reported results in the literature, the
normal GM/WM CBF ratio is ⬃2. However, this ratio is significantly reduced during cerebral
ischemia, suggesting that ischemia leads to preferential reduction of CBF in GM. Specifically,
the CBF in normal GM is about 1.72 times higher than that in the abnormal GM, while the
normal WM is only 1.38 times higher than the abnormal WM. Finally, our results may suggest
that the CBF threshold values for infarction may be different between GM and WM.
82
Electrical Stimulation of the Cervical Spinal Cord Resolves Cerebral
Vasospasm following Subarachnoid Hemorrhage in Rats.
Jin-Yul Lee, Dah-Luen Huang, Richard Keep, Oren Sagher; Crosby Neurosurgical
Laboratories, Ann Arbor, MI
OBJECTIVE. Cerebral vasospasm following subarachnoid hemorrhage (SAH) remains one of the
most serious complications of aneurysmal rupture. Although the delayed cerebral vasospasm
is clinically well described, its pathogenesis is still not fully understood, and it remains difficult
to treat. Recently, increased global cerebral blood flow (CBF) ameliorating cerebral ischemia
was shown through cervical spinal cord stimulation (SCS) in a number of experimental models
as well as in anecdotal reports in humans. However, it has not been applied systematically for
use in cerebral vasospasm. The aim of this experimental study is to assess the effect of cervical
SCS during cerebral vasospasm in a double hemorrhage rat model which causes a significant
CBF reduction due to marked vasoconstriction on Day 5 after second SAH induction. METHODS.
SAH induction was performed using a double hemorrhage injection method through an
indwelling catheter in the cisterna magna. SCS was performed on Day 5 after second SAH
induction using standardized technique (unipolar stimulation with 50 Hz, pulse width of 0.2
msec, and current of 0.6 mA). Regional CBF was measured using laser Doppler flowmetry (LDF)
and 14C-IMP (14C-radiolabeled N-isopropyl-p-iodoamphetamine hydrochloride) and compared
to a SAH group on Day 5 and a sham operated control group without SCS (n⫽25). Additionally,
the effect of SCS was assessed microscopically by cross-sectional area of basilar artery (BA)
at different points (n⫽15). RESULTS. SCS caused an immediate increase in LDF values to ⬃
150% of baseline within 10 sec during delayed vasospasm. Thereafter, LDF values
progressively dropped reaching values 50% over baseline at 90 sec. and then remained
constant. Furthermore, SCS resulted in significant increase in global CBF from ⬃ 60 - 70 to ⬃
90 - 120 % of control as assessed using 14C-IMP. CBF increase was more pronounced in
cerebral regions supplied by the middle cerebral artery (MCA) to that seen in regions supplied
by the BA. Microscopically, a significant increase in cross-sectional area of BA (43% ⫾ 19 of
baseline) could be found after SCS. CONCLUSIONS. The results of this study show that cervical
SCS leads to marked vasodilation and improves significantly the regional CBF during delayed
vasospasm in a double-hemorrhage rat model. SCS may represent a useful adjunct in the
treatment of vasospasm.
delayed and sustained narrowing of the cerebral arteries that typically occurs 4 –21 days after
a SAH. Following SAH, patients fall into one of three categories: (1) approximately 30% develop
angiographic vasospasm with clinical symptoms of ischemia; (2) 50% develop angiographic
vasospasm without clinical symptoms; and (3) 20% have neither angiographic nor clinical
evidence of vasospasm. The patients who develop symptomatic vasospasm after SAH may
possess a genotypic predisposition. Since inflammation and, more specifically, leukocyteendothelial cell interactions are critical to vasospasm development, and haptoglobin (Hp)
modulates inflammation following hemorrhage, we hypothesized that an individual’s Hp
genotype may influence their risk for vasospasm. Humans, unlike other mammals, possess two
alleles for the Hp gene (Hp1 and Hp2), resulting in three possible genotypes: Hp1–1, Hp1–2,
or Hp2–2. The linear Hp1–1 protein more effectively suppresses inflammation induced by
extracorpuscular hemoglobin as compared to the cyclical Hp2–2 protein. This functional
difference may predispose Hp2–2 individuals to more severe inflammation and thus more
severe vasospasm following aneurysmal SAH. Methods: Wild-type Hp1–1 C57Bl/6J mice
(n⫽45) and genetically-modified Hp2–2 C57Bl/6J mice (n⫽45), underwent injection of either
autologous blood or normal saline solution into the cisterna magna. The animals were
sacrificed 24 hours after SAH (time of peak vasospasm in this model) and basilar artery lumen
patency and macrophage/neutrophil concentrations in the subarachnoid space were determined histologically and immunohistochemically, respectively. Activity levels were also
quantified prior to sacrifice using a 3-point scale. Results were analyzed by Kruskal-Wallis/
Student-Newman-Keuls ANOVA. Results: Hp 2–2mice, as compared to Hp1–1 mice, had
significantly lower basilar artery lumen patencies (52.9⫹1.9%vs.82.3⫹1.3% (mean⫹SEM),
p⬍0.001), higher macrophage/neutrophil concentrations (31.2⫹6.3vs.8.8⫹1.7 cells/hpf,
p⫽0.009), and lower activity scores (0.8⫹0.3vs.2.4⫹0.2, p⬍0.001). Hp2–2 mice not only had
more severe vasospasm, but also were markedly symptomatic following experimental SAH.
Conclusion: These findings suggest that the Hp2–2 genotype may predispose individuals to the
development of severe vasospasm, and that Hp2–2 may serve as a molecular marker to
prospectively identify individuals who are at increased risk for this condition. These findings
also may explain why only 30% of patients develop severe, symptomatic vasospasm with
ischemic deficits, and why current animal models of SAH (exclusively Hp1–1) have asymptomatic and typically mild vasospasm.
84
Early Inflammation after TIA or Ischemic Stroke: Different MMP-9 Time
Courses predict Stroke Severity.
Hans Worthmann, Anita B Tryc, Argyro Tountopoulou, Annemarie Goldbecker, Reinhard
Dengler, Ralf Lichtinghagen, Karin Weissenborn; Med Sch Hannover, Hannover, Germany
INTRODUCTION: The early time course of inflammatory reaction immediately following cerebral
ischemia has not been investigated in detail. Particularly a correlation with important
biomarkers of inflammation like MMP-9, TIMP-1, MCP-1 is still lacking. HYPOTHESIS: Innate
inflammation has been identified as one of the factors contributing to bad prognosis in vascular
disease. Extent and time course of inflammation as determined by circulating levels of MMP-9,
TIMP-1, S-100, IL-6, CRP and MCP-1 is correlated with stroke severity and negatively
correlated with functional outcome. METHODS: Blood samples of 87 patients with ischemic
stroke were taken at admission and 6h, 12h, 24h, 3d, 7d after symptom onset. Plasma
concentrations of biomarkers were measured by commercially available immunoassays.
Functional scores mRS (modified Rankin Scale) and NIHSS were taken at each timepoint.
RESULTS: Here we present the results of the first 51 patients. Plasma/ serum values of MMP-9,
TIMP-1, S-100, IL-6, CRP and MCP-1 show an increase which is significantly correlated with
clinical severity. Remarkably different time courses for MMP-9 levels depending on stroke
severity are detected. Patients with poor clinical outcome at day 7 show a massive increase
of MMP-9 levels as early as 3 to 6h after symptom onset followed by a progressive decline over
time (median: 6h: 119.3ng/ml; 12h: 68.2ng/ml; 24h: 80.5ng/ml). In severe stroke cases MMP-9
levels remain elevated for the days to follow. For patients with good recovery we found an
increase of MMP-9 levels as early as 3 to 6h followed by a fast decrease at 12h and 24h
followed by low and stable plasma levels at 3d and 7d (median: 6h: 68.6ng/ml; 12h: 49.1ng/ml;
24h: 38.9ng/ml). In ROC analysis for comparison of light and severe clinic with biomarkerlevels at 24 hours after symptom onset the area under the curve for MMP-9 is 0.7429. Increase
of MMP-9 levels correlates with S-100 (MMP-9 24h: r⫽0.497, p⬍0.001). Extent of tissue
damage as measured by S-100 at each time point but particularly as early as at admission
strongly correlates with worsening of functional scores at day 1 and day 7 (day1: r⫽0.795;
p⬍0.001; day7: r⫽0.586, p⫽0.022). In time course of IL-6, TIMP-1 and MCP-1 levels we
detected a rapid increase as early as 6 hours after symptom onset whereas elevation of CRP
levels is delayed with a maximum at 24 hours and 3 days after symptom onset. CONCLUSION:
Our data show important differences in early time course of inflammation after ischemia
depending on stroke severity. Strokes with full recovery in functional scores (mRS, NIHSS)
compared to completed strokes with poor clinical outcome show a different time course of
biomarkers in particular MMP-9. Further exploration of dynamics of inflammatory biomarkers
such as MMP-9 is warranted given the shown negative correlation with functional outcome.
83
The Role of the Haptoglobin Genotype in the Development of Chronic
Vasospasm After Experimental Subarachnoid Hemorrhage.
85
Neuroanatomical Basis of Swallowing Disorders after Stroke.
Kaisorn L Chaichana, Johns Hopkins Sch of Medicine, Baltimore, MD; Andrew P Levy,
Rachel Lotan-Miller, Technion-Israel Institute of Technology, Haifa, Israel; Sophia Shakur,
Rafael Tamargo; Johns Hopkins Sch of Medicine, Baltimore, MD
Marlis Gonzalez-Fernandez, Jonathan T Kleinman, Paul Ky, Jeffrey B Palmer, Argye E Hillis;
Johns Hopkins Univ Sch of Medicine, Baltimore, MD
Introduction: The leading cause of morbidity and mortality following aneurysmal subarachnoid
hemorrhage (SAH) is chronic cerebral arterial vasospasm. Chronic cerebral vasospasm is the
Background: Dysphagia is a common problem after stroke associated with significant morbidity
and mortality. Except for patients with brain stem strokes, particularly lateral medullary strokes,
it is difficult to predict which cases are likely to develop swallowing dysfunction based on their
neuroimaging. Clear models of swallowing control and integration of cortico-bulbar input have
not been defined and the role of subcortical structures is still unclear. Objective: To identify
regions of interest (ROIs) that might be related to dysphagia in acute stroke patients, with a
focus on subcortical structures. Methods: We studied 29 acute stroke cases admitted to our
institution between 2001 and 2005 with a diagnosis of a first ischemic stroke and without
history of swallowing dysfunction. Subjects had MRI within 24 hours. Cases were defined as
those subjects who were diagnosed as dysphagic after clinical evaluation by a speech language
pathologist and whose dysphagia was considered significant requiring treatment by diet
consistency modification. Controls were defined as those patients who: (1) had passed the
stroke unit’s dysphagia screening, (2) had a Clinical evaluation by a SLP that did not result in
a diagnosis of dysphagia or diet modifications, or (3) had no documented evidence of dysphagia
evaluation or treatment through their medical stay and were discharged home on a regular diet.
A trained technician, blinded to case-control status, examined 12 ROIs for dysfunctional tissue
in DWI and PWI images. The odds ratio (OR) of dysphagia was calculated for each ROI. Logistic
regression models were used to adjust for stroke severity (NIHSS) and stroke volume. Results:
Analysis of data on 14 cases and 15 controls demonstrated significant differences in the odds
of dysphagia in the following ROIs: 1) primary somatosensory, motor and motor supplementary
areas (PSSM) (OR⫽8.8, p⫽0.009); 2) orbitofrontal cortex (OFC)(OR⫽6.5, p⫽0.04); 3)
putamen, caudate, basal ganglia (PCBG)(OR⫽5.33, 0.047); and 4) internal capsule (IC)(OR⫽26;
p⫽0.005). Non-significant differences were found in the insula and temporopolar cortex.
Adjusted odds ratios for the PSSM, OFC, and PCBG were not statistically significant. Adjusted
OR of dysphagia for subjects with strokes affecting the IC was 17.8 (p⫽0.03). Conclusion:
Significantly increased odds of dysphagia were found in subjects with IC involvement. Other
areas that may play an important role include the PSSM, OFC, and PCBG. Analysis of additional
areas was limited by the number of subjects in our sample. Further studies with larger sample
size can help elucidate the swallowing control mechanism and move toward developing a full
swallowing control model.
549
limb. Results: A significant difference was found for blood flow velocity (F ⫽ 53.18, p ⫽ 0.002)
between the hemiparetic and less affected limbs. In addition, arterial diameter for the
hemiparetic limb was significantly smaller than the less affected limb (F ⫽ 475.58, p ⫽ 0.004);
see Figure 1. Conclusion: These findings suggest individuals post-stroke have vascular
changes in blood flow velocity and arterial diameter that reduce overall blood flow to the
muscle. This may influence muscle performance during exercise. .
86
The Plasticity of Swallowing Center in the Brain.
Jing Zhang, Xingquan Zhao, Chunxue Wang, Yongjun Wang; BeijingTiantan Hosp Affiliated to
Capital Med Univ, Beijing, China
Background and objective: There had no study focus on the plasticity of swallowing centers in
the brain using fMRI methods. We hypothesis that the volume of swallowing centers would
enlarged after recovery of swallowing function. Methods: Total 8 dysphagia patients after
stroke were examined under videofuloroscopy swallowing study. Then they had the fMRI study
to identify the activation situation during swallowing tasks. After treatment and the recovery of
swallowing function, the patients accepted the second fMRI study and six patients had the
second videofluoroscopy study. The fMRI were studied utilizing blood oxygenation leveldependent (BOLD) technique on a 3.0 T magnetic resonance scanner (seimens). The
parameters were TR 2620ms,TE 30ms, Flip angle 90,FOV 240⫻240cm,Slices of 36,slice thick
of 3mm,scanning time is 374s. Subjects were swallow 1 ml water boluses after it was infused
into their oral cavity through a plastic catheter placed in the midline in different interval time
from 20s⬃35s and total 12 boluses were injected. Matlab7.0 and Statistical Parametric
Mapping (SPM2) were used to postmanagement. Results: Dysphagia patients had no activation
in 4/6, ACC, parietal lobe, but brainstem, frontal lobe of 8,44,46,47, insula, temporal lobe of
21,22, occipital lobe of 18,19, post cingulate and left cerebellum were activated. After
treatment, Brodmann 4,6,3,1,2 areas had larger activation volume. Activation volume in insula
enlarged from less than 10 voxels to 56 voxels. The secondary motor areas such as BA 8,9,11
and BA 7 in the parietal lobe, PCC, puteman, brainstem and cerebellum were activated after
therapy. Conclusions: The higher centers of swallowing had plasticity. The activation volume in
the sensomotor area and insular were enlarged. The activation in ACC, parietal lobe, brainstem
and cerebellum were presented. This suggested that these areas were envolved in the
modulation of swallowing.
87
Femoral Artery Blood Flow Velocity and Diameter Changes in the
Hemiparetic Limb in Chronic Stroke.
Sandra A Billinger, Benjamin Y Tseng, Patricia M Kluding; Univ of Kansas Med Cntr, Kansas
City, KS
Purpose/Hypothesis: Physical activity levels may play a primary role in blood flow regulation.
For people post-stroke, a reduction in physical activity and a decreased demand for leg oxygen
consumption may affect blood flow to the hemiparetic lower extremity. Decreased blood flow
to the hemiparetic muscles may limit performance during functional tasks or exercise. The
purpose of this study was to characterize differences in femoral artery blood flow velocity and
arterial diameter between the hemiparetic and less affected limb. Subjects: Twelve individuals
(69.0 ⫹ 17.0 yeas of age; 8 male) with chronic stroke (6.0 ⫹ 5.0 years post-stroke; 10 with
right-side hemiparesis) participated in the study. Methods: Doppler ultrasound was used to
characterize resting femoral artery blood flow velocity and diameter between the hemiparetic
and less affected lower extremity. Femoral artery blood flow velocity was measured at a 60°
inclination angle, with the velocity gate open wide to obtain the average blood flow velocity in
the arterial wall. With the ultrasound image frozen on the screen, arterial diameter
measurements were taken just above the bifurcation of the common femoral artery at peak
systole. Repeated measures ANOVA (␣ ⬍ 0.05) was used to assess differences between
femoral artery blood flow velocity and diameter between the hemiparetic and less affected
88
One Year Follow-up Of Patients Who Are Using The Ness L300
Neuroprosthesis: Effects On Gait Performance.
Gad Alon, Univ of Maryland, Sch of M, Baltimore, MD; Jeffery M Hausdorff, Harvard Med
Sch, Boston, MA; Haim Ring; Sackler Faculty of Medicine, Tel-Aviv Univ, Tel-Aviv, Israel
OBJECTIVE: Foot drop is a common impairment that adversely affects the ability of patients
with chronic stroke to walk normally. The aim of the present study was to assess patients’
ambulation performance after one year of daily use of the NESS L300 neuroprosthesis - a radio
frequency controlled, self-administered stimulation system. SUBJECTS: Sixteen patients (mean
age: 55.7⫾14.0) with chronic hemiparesis (6.3⫾4.7yrs) and foot drop . METHODS: Gait was
evaluated at baseline without the neuroprosthesis and in four testing sessions with the
neuroprosthesis at the initial fitting, after one month, after two months and after one year. At
each testing session, subjects walked for 6 minutes wearing force-sensitive insoles. Swing and
stride durations were measured while walking speed, gait asymmetry index and stride time
variability were calculated. Gait speed was also measured during a 10 meter walk on an
obstacle course. A repeated measures model was used to analyze the neuroprosthetic effect
on each outcome measure over time. Hotelling’s T2 test compared the one year gait results with
baseline (p⬍0.05). RESULTS: Improvement over time was significant for all tested variables.
Walking speed improved from 0.62⫾0.22 m/sec to 0.91⫾0.21 m/sec (p⬍0.001). Walking time
over an obstacle course improved by 58% (from 0.40⫾0.15 m/sec to 0.63⫾0.19 m/sec;
p⬍0.001). Single limb stance (SLS) over the paretic limb increased by 25.6% (from 26.2% to
32.9%; p⫽0.02). The gait asymmetry index, a marker of inter-limb coordination, improved by
96% (from 0.51⫾0.33 to 0.26⫾0.10; p⫽0.006). Stride time variability, an indicator of gait
rhythm, decreased from 5.32⫾3.31 to 3.79⫾1.64 (p⫽0.01). Compared to the gains achieved
at 2 months, gait speed (with or without obstacle course) improved further at one year, (Figure
1) while the improvements in gait stability at 2 months were preserved at one year.
CONCLUSIONS: Daily use of the NESS L300 neuroprosthesis over 12 months enabled patients
with chronic foot drop to improve their walking ability . The self-administered stimulation
system seems to offer a favorable alternative option to over come foot drop in patients with
chronic hemiparesis. .
550
Stroke
Vol 39, No 2
February 2008
89
Efficacious Affected Arm Rehabilitation Via the Internet; Using Inexpensive,
Remote Technology to Deliver Electrical Stimulation.
Stephen Page, Valerie Hill, Peter Levine, Univ of Cincinnati, Cincinnati, OH; Amanda Herzog,
Rachel Jordan, Maura Hoefner; Xavier Univ, Cincinnati, OH
Stroke-induced hemiparesis is problematic given its impact on activities of daily living (ADLs).
Although affected arm rehabilitation is important, patients are often limited in their ability to
attend rehabilitation sessions due to limited transportation. Conventional telemedicine efforts
are also often impractical, and can require extensive and expensive technologies that are not
available to many stroke patients or rehabilitative clinics. Given the above limitations, the
current study examined the feasibility and efficacy of an Internet-based affected arm
rehabilitation program. A 62 year old male exhibiting arm hemiparesis and nonuse from an
ischemic stroke occurring 3 years before study entry was enrolled. He was administered The
Fugl-Meyer Assessment of Impairment (FM) and Action Research Arm Test (ARA) during a
single, in-person testing session. During the same session, the subject also received an
electrical stimulation machine and instructions on its use, as well as a PC-mounted
videocamera to affix to his home computer. Instructions included donning and doffing the
stimulation system, and turning the stimulation device on and off. The participant was deemed
competent with using the electrical stimulation and camera by the end of the session, by
demonstrating all aspects of the application and use of the systems independently. During the
next 4 weeks, the subject then used the system for two, 30 minute sessions per weekday.
During these times, he logged onto the PC camera at a predetermined time, and was guided
through specific exercises with the aid of the stimulation, and with guidance by a member of
the therapy team, via the Internet. After 4 weeks, he returned to the laboratory, where the
outcome measures were again administered and the devices were returned. Testing revealed
a ⫹ 8.0 increase in FM score, indicative of reduced affected arm impairment in the wrist and
fingers, and a ⫹ 4.0 increase in ARA score, indicative of new movement in the fingers during
fine movements, such as picking up a marble. Functionally, the subject exhibited new ability
to write and manipulate small objects (e.g., a zipper). These data suggest feasibility and
efficacy of this noninvasive, home-based protocol for electrical stimulation. Importantly, the
entire protocol required only two, in person visits by the subject, who lived ⬎ 100 miles away
from our rehabilitatation center.
90
Stroke Caregiver Outcomes from the Telephone Assessment and
Skill-Building Kit (TASK).
Tamilyn Bakas, Indiana Univ Sch of Nursing, Indianapolis, IN; Carol J Farran, Rush Univ Sch
of Nursing, Chicago, IL; Joan K Austin, Indiana Univ Sch of Nursing, Indianapolis, IN;
Barbara A Given, Michigan State Univ College of Nursing, East Lansing, MI; Susan M
Perkins, Indiana Univ Sch of Medicine, Indianapolis, IN; Elizabeth A Johnson, Indiana Univ
Sch of Nursing, Indianapolis, IN; Linda S Williams; Indiana Univ Sch of Medicine;
Regenstrief Institute; Roudebush Veterans Administration Med Cntr, Indianapolis, IN
Background and Purpose: Family caregivers of stroke survivors can experience depression,
social inactivity, and poor health as a result of providing care. Furthermore, stroke caregivers
often express needs for information about stroke, assistance with stroke-related care, and
follow-up after discharge. The Telephone Assessment and Skill-Building Kit (TASK) is an
8-week follow-up program based on individualized assessment of caregiver needs. The
purpose of this study was to determine the efficacy of the TASK program in improving stroke
caregiver outcomes and to estimate effect sizes for a larger study. Methods: Guided by a
conceptual model derived from Lazarus’ transactional theory of stress, 6 stroke caregiver
outcomes (optimism, task difficulty, threat appraisal, depressive symptoms, life changes,
general health perceptions) were measured in 40 family caregivers randomized to the TASK
program (n⫽21) or an attention control group (n⫽19). Data were analyzed using repeated
measures ANCOVA, controlling for baseline scores and number of minutes spent with the nurse,
with the 4-week and 8-week outcome scores as the dependent variables for each analysis.
Partial ␩2 was used to estimate effect sizes (⬍ .08 small, .09-.24 medium, ⬎.25 large).
Results: Significant improvements in caregiver optimism [F(1,36) ⫽ 6.51, p⫽.015, ␩2 ⫽.153]
and task difficulty [F(1,36) ⫽ 5.29, p⫽.027, ␩2 ⫽.128] were found with medium effect sizes
for the TASK group relative to the control group. Although not significant in this small sample,
medium size improvements in threat appraisal [F(1,36) ⫽ 3.70, p⫽.062, ␩2 ⫽.093] and
depressive symptoms [F(1,36) ⫽ 3.59, p⫽.066, ␩2 ⫽.091] were also found. Small,
non-significant improvements were noted in life changes [F(1,36) ⫽ 2.794, p⫽.103, ␩2 ⫽.072]
and general health perceptions [F(1,36) ⫽ 1.96, p⫽.170, ␩2 ⫽.052]. Conclusions: The TASK
program showed improvement in caregiver optimism, task difficulty, threat appraisal, and
depressive symptoms in this small sample. Further testing of the TASK program in a larger
randomized controlled clinical trial is warranted, with attention in subsequent studies directed
toward more distal caregiver health outcomes.
91
Costs and Rehabilitation Utilization of Stroke Patients: A Retrospective
Study of Medicare Beneficiaries.
Richard D Zorowitz, Johns Hopkins Bayview Med Cntr, Baltimore, MD; Er Chen, Kuo B
Tong; Quorum Consulting, Inc., San Francisco, CA
Objective: Long-term economic impact of stroke and stroke-related hemiparesis has not been
well characterized. Utilization of physical therapy and rehabilitation (PTR) among these patients
is not well understood. The aim of our study is to examine the costs and PTR utilization in
patients with stroke and stroke-related hemiparesis during a 3-year period following their first
stroke onset. Methods: Patients with newly diagnosed stroke who were discharged from
hospital were identified from a 5% national random sample of all Medicare beneficiaries. These
patients were followed from 2003 to 2005, and their Medicare claims were linked from
different claims databases. Patients were classified with regard to development of hemiparesis
during the study period. In-hospital mortality rate, overall Medicare reimbursements, and PTR
utilization and reimbursements were analyzed in each year. Findings: We identified 1,849
patients with newly developed stroke in the first quarter of 2003. Among them, 1,070
subsequently developed hemiparesis and 779 did not. The in-hospital mortality rate of these
stroke patients was 30.2%, 8.1% and 7.6% in 2003, 2004 and 2005, respectively. Average
Medicare payments were $75,793 for the hemiparesis cohort and $44,544 for the nonhemiparesis cohort during these 3 years. The hemiparesis cohort incurred significantly higher
costs than the non-hemiparesis cohort in the 3-year study period, and across nearly all care
settings. Hospital inpatient care incurred the highest costs, followed by physician care and
skilled nursing care. Significantly more patients in the hemiparesis cohort received some form
of PTR than those in the non-hemiparesis cohort during the 3 years. While most costs of PTR
incurred in a hospital inpatient setting in 2003 for the hemiparesis cohort, the costs of PTR
shifted to skilled nursing facilities and home health agencies in 2004 and 2005. Conclusions:
Long-term care and rehabilitation services, especially for stroke patients suffering from
hemiparesis, constitute a significant proportion of total medical costs. Costs other than those
incurred in hospital inpatient setting must be taken into account when organizing management
of post-stroke patients.
92
Insulin Resistance and Risk of Ischemic Stroke among Non-Diabetic
Individuals from the Northern Manhattan Study.
Tatjana Rundek, Dept of Neurology, Miller Sch of Medicine, Univ of Miami, Miami, FL; Qiang
Xu, Dept of Biostatistics, Joseph Miallman Sch of Public Health, Columbia Univ, New York,
NY; Ronald B Goldberg, Dept of Medicine, Miller Sch of Medicine, Univ of Miami, Miami, FL;
Bernadette Boden-Albala, Dept of Neurology and SocioMed Sciences, Mailman Sch of Public
Health, Columbia Univ, New York, NY; Norbelina Disla, Dept of Neurology, Columbia Univ,
New York, NY; Myunghee C Paik, Dept of Biostatistics, Joseph Mailman Sch of Public
Health, Columbia Univ, New York, NY; Mitchell S Elkind, Dept of Neurology, Columbia Univ,
New York, NY; Ralph L Sacco; Dept of Neurology, Epidemiology and Human Genetics, Miller
Sch of Medicine, Univ of Miami, Miami, FL
Objective: To determine the association between insulin resistance and risk of first ischemic
stroke in a multiethnic, stroke-free cohort without diagnosis of diabetes. Background: Insulin
resistance is an important underlying mechanism of metabolic syndrome, type 2 diabetes and
cardiovascular disease. Insulin resistance may affect as many as 30 – 40% of apparently
healthy subjects. Data on insulin resistance and stroke risk is controversial and limited.
Methods: The association between insulin resistance and vascular outcomes was analyzed
among 1,735 non-diabetic participants with serum available from the Northern Manhattan
Study (mean age 68.0⫾10.4 years; 63 % women; 61% Hispanics; 19% black; 19% white).
Insulin sensitivity was expressed by the Homeostatic Model Assessment of Insulin Sensitivity
(HOMA index ⫽ [fasting insulin (␮U/ml] ␨ [fasting glucose (mmol/L)] ␨ 22.5). Insulin resistance
was defined by a HOMA index ⬎3. Cox proportional hazard models were used to determine the
effect of insulin resistance on (1) the risk of first ischemic stroke and (2) the risk of combined
vascular events (MI, stroke, or vascular death). The final models were adjusted for
demographics (age, sex, race-ethnicity, education), traditional vascular risk factors (hypertension, diabetes, LDL, HDL), anthropometric (waist, BMI) and lifestyle factors (physical activity,
alcohol consumption). Results: The mean HOMA index was 2.76 ⫾ 7.42; 25% of subjects had
a HOMA index over 3 (insulin resistance). After a mean follow-up of 6.9 years, vascular events
occurred among 188 subjects; 38 had fatal or non-fatal ischemic stroke, 74 had fatal or
non-fatal MI, and 116 died of vascular causes. A HOMA index ⬎3 independently predicted the
risk of ischemic stroke [adjusted HR 2.2; 95% CI 1.2– 4.0] as well as the risk of combined
vascular events [adjusted HR 1.5; 95% CI 1.1–2.1]. This effect was independent of waist
circumference, BMI, and other components of the metabolic syndrome. Conclusion: Insulin
resistance is an important marker of increased risk of incident stroke and other vascular events
among non-diabetics. These findings emphasize the need to better characterize individuals at
increased risk of stroke, and the potential role for preventive therapies targeted at diabetes and
insulin resistance.
93
C-Reactive Protein Predicts Recurrent Stroke and Death in a
Hyperhomocyst(e)inemic Population.
Karen L Furie, Massachusetts General Hosp, Boston, MA; Annie G Howard, Lloyd E
Chambless, Stephen Campbell, Univ of North Carolina at Chapel Hill, Chapel Hill, NC; James
F Toole, Wake Forest Univ, Winston-Salem, NC; Mitchell S Elkind; Columbia Univ, New York,
NY
Background: Inflammation, measured by high sensitivity C-reactive protein (hsCRP), has been
shown to be a predictor of initial stroke and post-stroke mortality. Although both are associated
with atherosclerosis, there are conflicting data regarding the correlation between hsCRP and
homocyst(e)ine (Hcy). This study was designed to explore the association between hsCRP and
Hcy and determine the utility of hsCRP level in predicting outcome events in an ischemic stroke
population with an atherosclerotic mechanism of infarction. Methods: We analyzed data on
2230 subjects with recent non-cardioembolic ischemic stroke and mild-moderate hyperhomocyst(e)inemia aged 35– 89 enrolled in the Vitamin Intervention for Stroke Prevention (VISP) trial
for whom baseline randomization hsCRP and post-methionine load levels of Hcy were available.
Baseline values (demographics, medical comorbidities, medications, stroke characteristics)
were recorded within 120 days of stroke onset. A Cox Proportional Hazards model to predict
outcomes analyzed hsCRP as a categorical variable defined by quartiles, using hsCRP ⬍ 3
mg/L (lowest quartile) as the reference group. Results: The mean duration between stroke
onset and baseline measurement of Hcy and hsCRP was 72 days, range 9 –171 days. Mean age
was 67 years (sd 10.7). Vascular risk factors such as hypertension (73.5%), hypercholesterolemia (41.8%), diabetes (28.5%), and coronary artery disease (24.6%) were highly prevalent.
For each 4.90 umol/L higher Hcy level, hsCRP was higher by 0.27 mg/L (95% CI .076, 0.27)
after adjusting for age, gender, and race. There were 192 strokes, 133 deaths, and 383
stroke/death or coronary events during a mean follow-up of approximately 21 months. The
highest quartile of hsCRP (relative to the lowest) was predictive of recurrent stroke (p⫽.04),
death (p⫽.002), and the combined endpoint of stroke/death/coronary event (p⫽.0002) after
adjustment for age, sex, and race. Relative to the lowest quartile (⬍3 mg/L), the highest
quartile of hsCRP (⬎ 15.8 mg/L), had hazard ratios of 1.50 (95% CI 1.01, 2.23) for stroke,
2.01(95% CI 1.26, 3.21) for death, and 1.63 (95% CI 1.23, 2.15) for stroke/death/coronary
event after adjustment for age, sex, and race. Conclusion: There is an association between level
of Hcy and hsCRP in patients with predominantly atherosclerotic subtypes of ischemic stroke.
The finding that hsCRP is a strong predictor of post-stroke mortality is consistent with other
studies, however, in this population, hsCRP was also predictive of recurrent stroke and the
combined endpoint of stroke/death/coronary event. This study illustrates the importance of
inflammation as a marker of risk after atherosclerotic stroke, and provides a rationale for
exploring inflammation as a target to improve outcomes.
94
Daytime Sleepiness and Risk of Stroke and Vascular Disease: Findings
from the Northern Manhattan Study (NOMAS).
Bernadette Boden-Albala, Carl Bazil, Yeseon Moon, Janet De Rosa, Mitchell S Elkind,
Myunghee C Paik, Columbia Univ, New York, NY; Ralph L Sacco; Universoty of Miami,
Miami, FL
Objective: The aim of this study was to explore the relationship between daytime sleepiness as
a measure of an underlying sleep disorder and the risk of stroke and vascular events in a
multi-ethnic prospective cohort. Background: Sleep is an important modulator of cardiovascular
function. Recent studies have suggested poor quality and diminished quantity of sleep may be
independently linked to vascular events, though prospective studies are limited. The role of
sleep as a risk factor for stroke needs further exploration. Methods: As part of the Northern
Manhattan Study (NOMAS), the Epworth Sleepiness Scale (ESS) was collected during the 2004
annual follow-up on stroke-free community residents, identified initially through random digit
dialing. The ESS measures daytime sleepiness, which has been correlated with numerous sleep
disorders, including sleep apnea. Daytime sleepiness was trichotomized using previously
reported cut points of “no dozing” (ref), “some dozing,” and “significant dozing”. Subjects were
followed annually for a mean of 2.3 years. Cox proportional hazards models were used to
calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for total stroke, and all
vascular events (stroke, MI and vascular death). Results: We obtained the ESS on 2153
community residents. The mean age was 73 ⫾9 yrs; 64% were women; 18% white, 20% black
and 60% Hispanic. Over 44% of the cohort reported no dozing, while 47% reported “some
dozing” and 9% “significant dozing.” We detected 40 strokes and 127 vascular events. In a
multivariable Cox model with “no dozing” as the reference, “some dozing” [HR 2.6, 95% CI
1.1- 6.0] and “significant dozing” [HR 4.5, 95% 95% C.I 1.5 - 13.?] were both associated with
increased risk of stroke, adjusting for age, race-ethnicity, sex, education, systolic blood
pressure, diabetes, obesity, and physical activity. A similar dose response relationship existed
for occurrence of any vascular events: HR 1.6, 95% CI 1.0 - 2.4 for “some dozing” and HR 2.6,
95% CI 1.4- 4.8 for “significant dozing.” The impact of sleepiness did not significantly differ
by gender or race-ethnicity. Conclusions: Findings from this prospective cohort study
demonstrate that daytime sleepiness, as measured by the ESS, is an independent risk factor
for stroke as well as all vascular events. Further, the elevated risk in the highly prevalent “some
dozing” group suggests that the impact of this novel risk factor may be quite important, and
further studies of the relationship between sleep and stroke are warranted
95
Stroke in Women - Gender Differences in Stroke Incidence and Post-stroke
Disability in the Framingham Heart Study.
Rodica E Petrea, Dept of Neurology, Boston Univ Sch of Medicine, Boston, MA; Alexa S
Beiser, Sudha Seshadri, Margaret Kelly-Hayes, Carlos S Kase, Philip A Wolf; Dept of
Neurology, Boston Univ Sch of Medicine, Public Health and Framingham Heart Study,
Boston, MA
Objective: To examine gender differences in stroke incidence, severity and post-stroke
disability in the Framingham Heart Study. Background: Stroke, once considered primarily a
disease of men, is now emerging as the third cause of death and the main cause of disability
in both men and women in the US. Controversy exists regarding gender-specific rates of stroke
incidence and post-stroke outcome. Methods: Framingham Original (N⫽ 5,119, 2,829 women)
and Offspring participants (N⫽ 4,957, 2,565 women) ⬎45 years and stroke-free were followed
to first incident stroke. We compared sex-specific stroke incidence, age at first stroke, stroke
severity, and 30-day and 6-month case fatality rate. We also examined sex-specific post-stroke
551
disability, dementia prevalence and institutionalization rate in the acute phase and at 3 to 6
months post-stroke. Outcomes were adjusted for age, systolic blood pressure, antihypertensive
treatment, atrial fibrillation, current smoking, prevalent cardiovascular disease and diabetes
mellitus. Post-stroke disability analyses were also adjusted for pre-stroke disability (using the
Katz activities of daily living [ADL] scale). Results: After up to 50 years of follow-up, (249,992
person-years) we observed 1120 incident strokes (625 in women). Results are summarized in
Table 1. Conclusions: In the Framingham Heart Study women were older at initial stroke, had
a lower incidence of stroke at all age categories ⬍85 years of age and a higher incidence of
stroke above that. Women were more disabled in the acute phase of stroke, as disabled as men
at 3 to 6 months but more than 4 times as likely to be institutionalized than men. Social and
medical factors explaining these gender differences need to be explored.
All Incident Strokes
Women
Men
Age
N strokes
Incidence/1000PY
N strokes
Incidence/1000PY
45–54 55– 64 65–74
75– 84 85–94
34 76 161
223 128
0.82 1.76 5.04 12.09
21.57
41 93 182
145 34
1.16 2.58
7.59 13.40
15.51
Crude
625
4.42
495
4.56
4.07
4.96
Age-adjusted
Baseline
characteristics
and Outcome
measures
Prior to or within 72 hrs of acute stroke
6 months post-stroke
Women
Men
OR, p value
Women
Men
OR, p
value
Age at first stroke
76ⴞ11
71ⴞ10
4.6, <0.001
Severe or fatal
strokes vs. mild or
moderate
29%
23%
1.33,NS
Death in 30 days
post-stroke
22%
18%
1.48, NS
30%
27%
1.29, NS
Death in 180 days
post-stroke
Living at home
independently prior
to stroke
77%
Prevalent dementia
92%
0.31, 0.007
11%
7%
0.97, NS
12%
7%
0.68, NS
Katz scale Eating
Dressing Grooming
Bed to chair transfer
Walking
42% 60%
56% 60%
65%
30%
41%
36%
39%
52%
1.65, NS
1.88,
0.008 2.12,
0.002
2.29,⬍0.001
1.58, NS
17% 37%
34% 34%
39%
10% 23%
19% 17%
20%
0.93,NS
1.45,NS
1.84,NS
2.30,NS
1.64,NS
Institutionalized
88
84
1.09, NS
37
13
4.56,0.004
96
National Utilization of, and Outcomes following, Craniectomy for Space
Occupying Cerebral Infarction in the United States.
Mustapha A Ezzeddine, Zeenat Qureshi Stroke Rsch Cntr, Univ of Minnesota, Minneapolis,
MN; Praveen R Baimeedi, Dept of Neurosurgery, Univ of Minnesota, Minneapolis, MN; Abu
Nasar, M. Fareed K Suri, Adnan I Qureshi; Zeenat Qureshi Stroke Rsch Cntr, Univ of
Minnesota, Minneapolis, MN
OBJECTIVE: A recent meta-analysis of clinical trials suggests some therapeutic benefit with
craniectomy for space occupying cerebral infarction. However, national estimates of the
utilization of craniectomy for cerebral infarction are not available. We performed this study to
determine the frequency of craniectomy among patients with ischemic stroke in the United
States and associated in-hospital outcomes. METHODS: National estimates of craniectomy,
associated in-hospital outcomes, and hospitalization charges were obtained from Nationwide
In-patient Sample data from 2002 to 2004. Patient numbers and frequency distributions were
calculated for a nationally representative sample of patients hospitalized with a primary
diagnosis of ischemic stroke. We also determined the predictors of in-hospital mortality among
patients who underwent craniectomy. RESULTS: There were 1,470,944 admissions for
ischemic stroke between 2002 and 2004. Of these admitted patients, 682 (4.6 per 10,000
admissions) underwent craniectomy. The procedure was performed on either the first day of
admission (15%), the second day (24%), third day (16%), fourth day (9%), or later (36%).
Craniectomy was more likely to be performed in urban teaching hospitals than in urban
non-teaching or rural hospitals (p⬍0.001). The rate of death or discharge to long-term facility
was significantly higher for those patients who underwent craniectomy (86% versus 45%). The
mean days of hospitalization and total hospitalization charges were significantly higher for
patients who underwent craniectomy: 20 days (⫾16 standard deviation) versus 5 days (⫾6),
and $127,300 (⫾4234) versus $22,400 (⫾24). No significant relationship was observed
between the age of the patients treated or day of craniectomy and in-hospital mortality.
CONCLUSION: The present study provides national estimates of patients undergoing craniectomy for space occupying cerebral infarction. Considerable variations in practice patterns and
high rates of poor outcomes mandate a more standardized approach for this procedure in the
United States.
552
Stroke
Vol 39, No 2
February 2008
97
Gene Variants Previously Associated With Coronary Heart Disease:
Association With Incident Ischemic Stroke in the Cardiovascular Health
Study.
May M Luke, CELERA, Alameda, CA; Ellen S O’Meara, Univ of Washington, Seattle, WA;
Charles M Rowland, Lance A Bare, Dov Shiffman, CELERA, Alameda, CA; Thomas Lumley,
Kenneth Rice, Univ of Washington, Seattle, WA; Andre R Arellano, CELERA, Alameda, CA;
Russell P Tracy, Univ of Vermont, Colchester, VT; James J Devlin, CELERA, Alameda, CA;
Bruce M Psaty; Univ of Washington, Seattle, WA
Objective: To determine whether 74 single nucleotide polymorphisms (SNPs), which had been
associated with coronary heart disease (CHD), are associated with incident ischemic stroke.
Method: Based on antecedent studies of CHD, we prespecified the risk allele for each of the
74 SNPs. We used Cox proportional hazards models to estimate associations with incident
ischemic stroke during 13 years of follow-up in 4522 white and African American men and
women age 65 years and older in the Cardiovascular Health Study (CHS), a population-based
cohort study. Models were adjusted for age, sex, body mass index, smoking, diabetes, impaired
fasting glucose, hypertension, LDL-cholesterol, and HDL-cholesterol. Results: In white CHS
participants, the prespecified risk alleles of 7 of 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15,
FSTL4, CALM1, and BAT2) were nominally associated with increased risk of incident ischemic
stroke (one-sided P⬍0.05) and the false discovery rate (FDR) for these 7 SNPs was 0.42. In
African Americans, the prespecified risk alleles of 5 SNPs (in KRT5, LY6G5B, EDG1, DMXL2, and
ABCG2) were nominally associated with increased risk of incident ischemic stroke and the FDR
for these 5 SNPs was 0.55. The FDRs of 0.42 and 0.55 suggest that some of these associations
may be true positives. The Val12Met SNP in ABCG2 was associated in a log additive model with
incident ischemic stroke in both whites (hazard ratio 1.46, 90% CI 1.05, 2.03) and African
Americans (hazard ratio 3.59, 90% CI 1.11, 11.6). Kaplan-Meier estimates of the 10 year
cumulative incidence of stroke were lower among carriers of the Met allele than among
homozygotes of the Val allele in both whites (6% versus 10% respectively) and African
Americans (3% versus 12% respectively). Conclusion: The Val allele of the Val12Met SNP in
ABCG2 (which encodes a transporter of sterols, protoporphyrin, and anticancer drugs) was
associated with increased risk of incident ischemic stroke in both white and African American
participants of CHS.
98
99
Timing and Type of Neurologic Events prior to Carotid Artery Stenting are
Predictors of Stroke.
Seemant Chaturvedi, Wayne State Univ, Detroit, MI; Richard Atkinson, Sutter Health,
Sacramento, CA; for the CAPTURE and EXACT Executive Committees
Background: Carotid stenting with embolic protection (CAS) in patients at high surgical risk
has demonstrated comparable outcomes to endarterectomy (CEA). We sought to determine the
effect of symptom type and timing on the post-CAS stroke (S) risk. We examined this
relationship via the CAPTURE (C) Post-Market Study (PMS) and two contemporary studies,
CAPTURE 2 (C2) and EXACT (E). Methods: The study cohort includes the final patient cohort of
4225 patients enrolled in C between October 2004 and December 2006; 2070 patients in C2
(March 2006-June 2007) and 2239 patients in E (November 2005-April 2007). All patients in
whom treatment is attempted with the carotid stent with or without the embolic protection
device are included in this analysis. Neurological status is independently assessed at
pre-procedure, 24-hours and 30-days post-procedure. Baseline demographics, vessel characteristics and occurrence of S are recorded. Possible stroke events are reviewed by an
Independent Adjudication Committee. Symptomatic patients were defined as S, TIA, or
amaurosis fugax if the symptoms occurred within 180 days of the CAS. Logistic Regression
analysis was performed on timing and type of neurological event to determine predictors of
stroke for symptomatic patients. Limitations: These prospective PMS trials were run
independently and were not designed to be compared directly. Results: The 30 day endpoint
of S for all patients in C, C2 and E is 4.6%, 3.3%, and 3.5%, respectively. In C 13.8% of all
enrolled patients are symptomatic, in C2 9.9%, and in E 9.9%. For symptomatic patients the
30 day endpoint frequency of S in C (n⫽573) is 8.4%, for C2 (n⫽197) 7.1%, and for E (n⫽204)
5.9%. Data of the symptomatic patients from all three studies were combined (n⫽ 974).
Logistic regression analysis revealed that a neurological event occurring within 2 weeks prior
to the procedure is a predictor of stroke within 30 days post- procedure. Evaluation of the type
of neurologic event shows that stroke alone, TIA alone, and stroke or TIA within 2 weeks of the
procedure increases the risk for stroke in the 30 days post procedure. In this analysis there is
no evidence that amaurosis fugax alone is a predictor of stroke. The S rate for all symptomatic
patients combined (n⫽ 974) is 7.6%. Removing the recently symptomatic patients (neurological event within 2 weeks of CAS) resulted in S rate of 5.7% and a stroke and death (SD) rate
of 6.7% for the combined symptomatic cohort of C, C2 and E (n⫽720). The S rate for the
recently symptomatic patients (n⫽254) is 13.0% and the SD rate is 15.7% for the combined
symptomatic cohort. Conclusions: In general, carotid stenting is performed safely in
symptomatic patients with severe stenosis at high surgical risk. However, recent history of a
neurological event is associated with worse outcomes at 30 days. Proper patient selection for
CAS should be based on the potential risk of stenting versus the anticipated benefit.
Analysis of the Age-at-Onset Phenotype in a Pilot Genome-Wide
Association Study of Ischemic Stroke.
Bradford B Worrall, Univ of Virginia, Charlottesville, VA; W M Brown, Wake Forest Sch of
Medicine, Winston-Salem, NC; Thomas G Brott, Mayo Clinic, Jacksonville, FL; Robert D
Brown, Jr, Mayo Clinic, Rochester, MN; John Hardy, Queen Square, London, United
Kingdom; Mar Matarin, National Institute of Aging, Bethesda, MD; Stephen S Rich, Univ of
Virginia, Charlottesville, VA; Andrew Singleton, National Institute of Aging, Bethesda, MD;
James F Meschia, Mayo Clinic, Jacksonville, FL; for the Ischemic Stroke Genetics Study
(ISGS) Investigators
Our recent genome-wide association study (GWAS) in the Ischemic Stroke Genetics Study
(ISGS) identified several single nucleotide polymorphisms (SNPs) associated with ischemic
stroke and underscored the potential of this powerful tool to identify genetic stroke risk factors.
Linkage and association studies have typically treated stroke as a qualitative (affected/
unaffected) trait. However, the apoplectic and precisely identifiable onset of ischemic stroke
provides an opportunity to study “stroke latency” as a quantitative trait. Such an analysis in the
Siblings With Ischemic Stroke Study (SWISS) found incident ischemic stroke latencies
correlated significantly among siblings overall and among siblings concordant for key vascular
risk factors, consistent with genetic factors contributing to stroke latency. In a case-only
analysis from ISGS, we tested the hypothesis that there are SNPs that correlate with age at
onset of first-ever ischemic stroke, independent of known risk factors. The underlying principle
is that a gene controls when a stroke may occur, and that the age at onset of stroke is
dependent upon genotype at a SNP in that gene. Significance of association between the SNP
and age at onset was determined by the Cochran-Armitage trend test under an additive genetic
model. A series of generalized estimating equations was computed that included relevant
covariates (sex, history of hypertension, smoking status, diabetes mellitus, and coronary heart
disease) to permit estimation of the independent effect of the SNP on age at onset. Significance
was determined if P ⬍ 10 –5, a conservative threshold to account for multiple statistical tests
in the GWAS. Eighty-two SNPs met the threshold of significance. Eleven percent (9/82) of the
SNPs were significant in the unadjusted model only; 51% (42/82) were significant in the
adjusted model only, and 42% (31/82) reached significance in both the adjusted and
unadjusted models. None of these SNPs were significant in the earlier adjusted case-control
analysis of ischemic stroke risk. In summary, a case-only analysis identified 82 candidate SNPs
governing variation in age at onset of stroke in our GWAS. These SNPs differed from those
observed for stroke risk. Recent data suggest that, in addition to contributing to stroke risk per
se, genetic factors may play a role in determining specific phenotypic characteristics of
ischemic stroke such as severity, case fatality, recovery, and response to therapy. Using age
at onset as a continuous variable rather than dichotomizing stroke into early and late onset may
retain statistical power and facilitate the identification of key genetic factors contributing to the
burden of cerebrovascular disease.
100
Neuropsychological Changes After Carotid Stenting With Cerebral
Protection.
Francisco Moniche, Paloma Gonzalez-Perez, Myrta O’Valle, Jose Ramon Gonzalez-Marcos,
Alejandro Gonzalez, Aurelio Cayuela, Antonio Mayol, Alberto Gil-Peralta; Hosp. Univ. Virgen
del Rocio, Seville, Spain
Introduction: Carotid angioplasty and stenting (CAS) is an alternative to endarterectomy (CEA)
in severe carotid stenosis. Although previous studies have showed subtle neurocognitive
deficits after CEA, in up to 25% of patients, results after CAS are not well known. After CAS,
20 – 40% of patients showed new diffusion-weighted imaging lesions clinically asymptomatic.
The significance of these silent embolizations has not yet been established, but there is a
potential that they may be associated with cognitive decline. Our aim is to evaluate cognitive
and psychiatric changes after CAS. Methods: CAS with cerebral protection device was
performed in 50 consecutive patients with severe carotid stenosis. All patients were evaluated
with a battery of neuropsychological tests before and 1 and 3 months after CAS. Psychiatric
symptoms were investigated by the Neuropsychiatric Inventory (NPI). Basic and instrumental
(BADL, IADL) activities of daily living (ADL) were evaluated. Results: Apart from 4 TIA, there was
no other morbidity in 30 days after CAS. Global neuropsychological assessment significantly
improved after CAS, evaluated by Mini Mental State Examination (MMSE), Blessed Dementia
Rating Scale, and Informant Questionnaire on Cognitive Decline in the Elderly (IQ-CODE). Most
patients showed better results in visuoconstructive function, attention-concentration and
memory measured by Block Design test, Digit Symbol Coding from the Weschler Adult
Intelligence Scale III (WAIS III) and Weschler Memory Scale III (WMS III) respectively. No changes
were observed in problem solving (Matrix Reasoning, WAIS III) and language functions.
Psychiatric symptoms were scarce before CAS. Anxiety, irritability, and night-time behaviour
disturbances significantly improved after the procedure. We also found a slight improvement
in the IADL in patients after CAS. Conclusion: After CAS, neuropsychological tests showed clear
improvement in cognitive function, especially in executive function and memory, possibly
related to increased cerebral blood flow. The improvement in the quality of life of the patients
could be correlated with those changes.
RESULTS OF THE NEUROPSYCHOLOGICAL TESTS
TEST
MMSE
BLESSED
IQ-CODE
BASAL
1ST MONTH
3RD MONTH
p
24.5[21–28]
1.00[0.0–2.5]
80[78–83]
25.5[21–29]
0.50[0.0–1.5]
79.0[78–83]
26.5[22–29]
0.25[0.0–1.0]
78.0[78–81]
⬍0.0001
⬍0.0001
⬍0.0001
TEST
WAIS-III Digit
Symbol Coding
WAIS-III Block
Design Scale
WAIS-III Matriz
Reasoning
Barcelona verbal
subtest
Wechsler Memory
Scale III
Depression
Anxiety
Apathy
Disinhibition
Irritability
Nigth-time
disturbances
IDDD
BADL
IADL
BASAL
1ST MONTH
13[6–33]
18[6–35]
18.5[10–28]
18.5[10–29]
3RD MONTH
16[8.5–37.5]
18.0[12–25]
p
0.001
0.003
6.0[4–10]
5.0[4–9]
6.0[5–12]
NS
11.0[10–12]
11.0[11–12]
11.0[11–12]
NS
18.0[16–23]
20.0[16–24]
21.0[18–25]
0.002
0.0[0.0–1.0]
1.0[0.0–1.0]
0.0[0.0–1.0]
0.0[0.0–0.0]
0.0[0.0–3.0]
0.0[0.0–1.0]
33.0[33–35]
16.0[16–16]
17.0[14–18]
0.0[0.0–1.0]
0.0[0.0–1.0]
0.0[0.0–0.0]
0.0[0.0–0.0]
0.0[0.0–2.0]
0.0[0.0–0.0]
33.0[33–35]
16.0[16–16]
17.0[14–17]
0.0[0.0–1.0]
0.0[0.0–1.0]
0.0[0.0–1.0]
0.0[0.0–0.0]
0.0[0.0–1.0]
0.0[0.0–0.0]
33.0[33–35]
16.0[16–16
16.5[14–17]
NS
0.001
NS
NS
0.03
0.01
553
dyslipemic and 30.2% diabetic. Univariate analysis showed a history of diabetes (p⫽0.002),
administration of statins (p⫽0.015) and stroke subtype diagnosis (atherothrombotic and
undetermined vs. lacunar, p⫽0.036) as the only significantly different variables among those
with vascular disease extension. Baseline plasma levels of IL-6, VCAM-1 and cFn were
significantly higher in patients whith extension of their atherothrombotic disease. However, only
an increase in MMP-9 and cFn at one-year follow-up was observed among patients who
presented disease extension. In fact, an increase in MMP-9 levels ⬎26.4 ng/mL was
associated with an 8-fold increase in the risk of atherothrombotic disease extension, and that
risk increased 5-fold in patients with a cFn level increase ⬎3.1 ␮g/mL. Conclusion: The
extension of atherothrombotic disease to extracerebral territories following stroke is a frequent
vascular complication. Among those high risk patients we identified increased levels of several
cytokines, adhesion molecules and metalloproteinases suggesting that the vascular extension
process might be mediated by both inflammatory and vascular wall remodeling-related
mechanisms.
NS
NS
0.02
Values expressed in P50 [P25-P75]. IDDD indicates Interview for daily living deterioration in
dementia.
101
High Volume Centers Have Lower Complication Rates After Cea And Cas In
The Space Study.
Peter A Ringleb, Univ clinic of Heidelberg, Heidelberg, Germany; H. H Eckstein, Clinic Rechts
der Isar, Munich, Germany; Marius Hartmann, Werner Hacke, Univ clinic of Heidelberg,
Heidelberg, Germany; SPACE Investigators
Background: As a multicenter, prospective, randomized trial SPACE failed to demonstrate that
carotid artery stenting (CAS) is not inferior to carotid endarterectomy (CEA) in treating patients
with severe symptomatic carotid artery stenosis. 33 centers took part in this large trial,
recruiting together 1,214 patients. We analyzed whether the per-center complication rate was
influenced by the amount of patients included per center. Methods: Primary endpoint events
of the ITT were analyzed. A receiver operating characteristic (ROC) was done to calculate
optimal cut-off points between low- and high risk centers based on the event-rate per year.
Groups were compared with a Fisher’s exact test. Results: The number of patients included
per center ranged from 7 to 139, the rate of patients included per center and year ranged from
0.5 to 27.8. A ROC-analysis revealed a threshold of 7 interventions per year in both arms.
Centers including at least 7 CAS-patients per year (n⫽4) had a complication rate of 4.0% in
this arm, as compared to a rate of 8.7% in lower-volume centers (P⫽0.031). Centers including
at least 7 CEA-patients per year (n⫽5) had a complication rate of 3.3% in the CEA-arm,
opposed to 8.7% in lower-volume centers (Fisher’s exact test; P⫽0.008). Interpretation: In the
situation of a randomized trial the center size is of significant influence for the 30-day
complication rate both in patients treated with CAS and CEA. Centers recruiting at least 7
patients per arm and year have lower complication rates.
103
Inflammatory Markers Predicts Future Cardiovascular and Neurological
Events In Patient Undergoing Carotid Stent Implantation.
Francesco Versaci, Costantino Del Giudice, Tor Vergata Univ, Roma, Italy; Achille
Gaspardone, Sant’Eugenio Hosp, Roma, Italy; Gian Luigi Condorelli, Istituto di Ricovero e
Cura a Carattere Scientifico Multimedica, Roma, Italy; Antonio Pellegrino, Alessandro
Mauriello, Laura Liberatoscioli, Igino Proietti, Giovanni Simonetti, Claudio Cortese, Luigi
Chiariello; Tor Vergata Univ, Roma, Italy
Background. C-Reactive protein predicts cardiovascular events after coronary stenting
implantation. The aim of this study was to assess whether baseline inflammatory markers
predicts future neurological and cardiovascular events after carotid stenting and to correlate
systemic inflammation and histomorphometric analysis of the carotid plaque evaluated from
the filters utilized as protective devices during the procedure. Methods. Eighty consecutive
patients (mean age 70,8⫾8,32, 55 men) with stable severe carotid stenosis were treated with
stent implantation with distal filter devices. Levels of high-sensivity C-reactive protein (hs-CRP)
and Interleukin-6 (IL-6) levels were measured before the procedure. Histomorphometric
analysis of the debris from the filters was performed in all patients. All patients were
followed-up for 5 years and major cardiovascular events (death, myocardial infarction and
stroke) were recorded. Results. Procedural success was 98.75%. The incidence of cumulative
disabling stroke, myocardial infarction and death at the follow-up was 19%. Higher
pre-procedural levels of hs-PCR and IL-6 were associated with clinical events at follow-up
(p⫽0.0044 and 0.04 respectively). Furthermore, a significant correlation was found between
preprocedural hs-CRP and IL-6 and both the total number of particles (respectively p⫽0.03;
r⫽0.3 and p ⫽ 0.02 , r⫽ 0,3) and the mean debris area per filter (respectively p⫽0.04; R⫽0.3
and p⫽0.02, r⫽0,3). Finally mean debris area per filter was significantly associated with a
higher incidence of events at follow-up (p⫽0,048). Conclusions. Preprocedural levels of
hs-CRP and IL-6 are predictive of neurological and cardiovascular events at follow-up. Patients
with higher levels of hs-CRP and IL-6 presents a greater number of debris embolizing particles
suggesting that systemic inflammation is associated with a higher plaque instability.
102
Extension Of Atherothrombotic Disease To Extracerebral Territories
Following Stroke: Inflammation Or Vascular Remodeling Mechanisms?
Tomás Sobrino, Miguel Blanco, Dept of Neurology, Clinical Neuroscience Rsch Laboratory,
Hosp Clı́nico Universitario, Univ of Santiago de Compostela, Santiago de Compostela, Spain;
Joan Montaner, Neurovascular Rsch Laboratory, Neurovascular Unit, Vall d’Hebron Univ
Hosp, Barcelona, Spain; Marı́a M Freijó, Dept of Neurology, Hosp de Basurto, Bilbao, Spain;
Miguel A Llaneza, Dept of Neurology, Hosp Clı́nico Universitario de Salamanca, Salamanca,
Spain; Enrique Corredera, Dept of Neurology, Hosp Meixoeiro, Vigo, Spain; Blanca Fuentes,
Dept of Neurology, Hosp Universitario La Paz, Madrid, Spain; Javier Tejada, Dept of
Neurology, Hosp de León, León, Spain; David Cánovas, Dept of Neurology, Consorci Hospari
del Parc Taulı́, Barcelona, Spain; José Castillo, Dept of Neurology, Clinical Neuroscience
Rsch Laboratory, Hosp Clı́nico Universitario, Univ of Santiago de Compostela, Santiago de
Compostela, Spain; for the MITICO Study Investigators
Background and purpose: Atherothrombotic disease has an irregular and little predictable
course and its progression to other vascular territories is not well-understood. Therefore, we
aimed to study the rates and clinical profile of extension of atherothrombotic disease to
extracerebral territories following stroke as well as its possible association with an increase of
inflammatory molecular markers. Methods: Non-anticoagulated ischemic stroke patients,
recruited within 1–3 months from stroke onset were included in a multicentric prospective
study (MITICO study). Blood samples were obtained at baseline and final one-year follow-up
visit for further determination of hsCRP, IL-6, IL-10, ICAM-1, VCAM-1, MMP-9 and cellular
fibronectin (cFn). Extension of atherothrombotic disease over one year follow-up was defined
as recurrence in a different vascular territory than the cerebrovascular, in patients without
history of symptoms in other vascular territories. Results: From 742 patients with monovascular disease at the time of inclusion, 53 showed a new cerebrovascular event, 15 a coronary
event and 14 a peripheral event; therefore, 29 patients were considered to have had vascular
disease extension (3.4% of the total sample). Regarding disease extension, 18% of patients
were smokers, 34.2% ex-smokers, 19.2% alcohol users, 59.8% hypertensive, 44.5%
104
Plaque Characterization by Virtual Histology TM Intravascular Ultrasound
Analysis in Symptomatic Internal Carotid Artery Stenosis.
Shoji Matsumoto, Ichiro Nakahara, Toshio Higashi, Yasushi Iwamuro, Yoshihiko Watanabe,
Kenji Takahashi, Tetsuhiro Kikuchi, Mitsushige Ando, Masahiro Takezawa, Masahiro
Takezawa; Kokura Memorial Hosp, Kitakyushu-shi ,Fukuoka, Japan
Purpose The purpose of this study was to evaluate the in-vivo plaque composition and
characteristics in symptomatic internal carotid artery lesions using Virtual HistologyTM
intravascular ultrasound (VH -IVUS). Methods and Results In 27 patients with symptomatic
extracranial internal carotid artery stenosis in carotid artery stenting, 27 target plaque were
studied and plaque components were analyzed. Patients were divided into two groups by
history; symptomatic group (11vessels) and asymptomatic group (16 vessels). There was no
significant difference of degree of stenosis in angiography between the two groups.The plaque
volume and the fibro-fatty volume were significantly greater in the symptomatic group
compared with the asymptomatic group [Plaque volume: 595.0 mm3 (interquartile range (IQR)
548.6 ⬃641.4 mm3) vs. 389.0 mm3 (IQR:357.7⬃420.3 mm3), P⫽0.034; Fibro-fatty volume:225.3 mm3 (IQR:204.3⬃246.4 mm3) vs. 123.4 mm3(IQR:111.3⬃135. 5mm3), P⫽0.006].
There was no significant difference between both groups in regard to the ratio of fibrous,
fibro-fatty, dense calcium and necrotic core which were occupied in each plaque. Conclusions
In this series of subjects with significant internal carotid artery stenosis, both plaque volume
and fibro-fatty volume were significantly greater in symptomatic carotid plaque than
asymptomatic. VH- IVUS has a role in the evaluation of carotid artery disease beyond examining
luminal stenosis.
554
Stroke
Vol 39, No 2
February 2008
105
High-Resolution CT Imaging of Carotid Artery Atherosclerotic Plaques.
Max Wintermark, Univ California, San Francisco, CA; Sumayya S Jawadi, Univ of Missouri,
Kansas City, KS; Joseph H Rapp, San Francisco VA Med Cntr, San Francisco, CA; Tarik
Tihan, Elizabeth Tong, David Glidden, Univ California, San Francisco, CA; Sami Abedin, Univ
of Missouri, Kansas City, KS; Sarah Schaeffer, Gabriel Acevedo-Bolton, Univ California, San
Francisco, CA; Benjamin Boudignon, Univ of California, San Francisco, CA; Benjamin Orwoll,
Univ California, San Francisco, CA; XianMang Pan, San Francisco VA Med Cntr, San
Francisco, CA; David Saloner; Univ California, San Francisco, CA
PURPOSE: To evaluate the ability of multidetector-row CT-angiography (CTA) to assess the
composition and characteristics of carotid artery atherosclerotic plaques, using histology as the
gold standard. METHODS: Eight patients with transient ischemic attacks who underwent carotid
CTA and “en bloc” endarterectomy were enrolled in a prospective study. An ex-vivo micro-CT
study of each endarterectomy specimen was obtained, followed by histological examination. A
systematic comparison of CTA images with histological sections and micro-CT images was
performed to determine the CT density associated with each component of the atherosclerotic
plaques. A computer algorithm was subsequently developed that automatically identifies the
components of the carotid atherosclerotic plaques, based on the signal intensity of each pixel.
A neuroradiologist’s reading of this computer analysis was compared to the interpretation of the
histological slides by a pathologist with respect to the types and characteristics of the carotid
plaques. RESULTS: There was a 72.6% agreement between CTA and histology in terms of
carotid plaque characterization. CTA showed perfect concordance for calcifications. A
significant overlap between densities associated with lipid-rich necrotic core, connective tissue
and hemorrhage limited the reliability of individual pixel readings to identify these components.
However, CTA showed good correlation with histology for large lipid cores (kappa ⫽ 0.796,
p⬍0.001) and wide hemorrhages (kappa ⫽ 0.712, p⫽0.102). CTA performed well in detecting
ulcerations (kappa ⫽ 0.855) and in measuring the fibrous cap thickness (R2 ⫽ 0.77,
p⬍0.001). CONCLUSION: The composition of carotid atherosclerotic plaques determined by
CTA accurately reflects plaque composition defined by histology.
106
Natural History of Dural Arteriovenous Shunts.
Tommy Andersson, Karolinska Hosp, Stockholm, Sweden; Ladislav Pavic, Univ Hosp
Dubrava, Zagreb, Croatia; Göran Edner, Staffan Holmin, Michael Söderman; Karolinska Hosp,
Stockholm, Sweden
Background Dural arteriovenous shunts with cortical venous reflux or drainage (CVD) may
cause neurological symptoms and death, with or without intracranial hemorrhage. Present
knowledge about the natural history of these lesions is however limited. We investigated the
incidences of intracranial hemorrhage, progressive dementia syndrome and death in patients
diagnosed in our neurovascular center. Material and methods We evaluated the medical
records of 163 patients with dural arteriovenous shunts hospitalized in our institution from
1976 to 2007. Eighy-five of the patients had a lesion with CVD. They all had their first
angiography performed in our neurovascular unit and were included in the study. The annual
incidences of intracranial hemorrhage, progressive dementia syndrome and death were
calculated. Findings 53 patients did not have an intracranial hemorrhage as the presenting
event. One of these patients bled after diagnosis. 32 patients had an intracranial hemorrhage
as the presenting event. Three patients bled after diagnosis. One of these patients died. Apart
from deficits caused by hemorrhage, no patient reported aggravated neurological symptoms.
Conclusion The risk for hemorrhage from a dural arteriovenous shunt with cortical venous
drainage is most likely less than previously proposed and it differs between ruptured and
unruptured shunts. In patients presenting with an intracranial hemorrhage the annual risk is
about 7.4%. In patients not presenting with a hemorrhage the annual risk is about 1.5%. The
risks to develop neurological symptoms not related to hemorrhage are in all probability lower
than previously reported. In view of these novel data current management algorithms may have
to be revised.
presentation with pulsatile tinnitus, headache, or no symptoms. The time of definitive diagnosis
was recorded for each patient. The occurrence of any new hemorrhage or new or worsening
NHND from the time of diagnosis to definitive treatment (complete disconnection), if any, was
recorded. The incidence of these events was compared between groups using Fisher’s exact
test. RESULTS: Of the 12 patients with aggressive presentation, 8 were cured with surgical or
endovascular procedures that eliminated cortical venous reflux (CVR). Three received partial
treatment, with persistent CVR, and one declined treatment. For this group, the mean follow-up
from diagnosis to definitive treatment, if any, or from diagnosis to most recent follow-up, was
3.3 years. Over the follow-up period, 3 patients (25%) experienced intracranial hemorrhage; 2
(17%) experienced new or worsened NHND, which manifested as memory loss or dementia in
both patients. Four events occurred in patients with persistent CVR; one occurred before
complete treatment was achieved. In the benign presentation group, 7 patients received full
treatment, 3 received partial treatment, and 2 declined treatment. Over the mean follow-up
time of 1.8 years, there was no incidence of new hemorrhage or NHND. The observed
difference in the incidence of either hemorrhage or new or worsening NHND between
aggressive and benign presentation groups was statistically significant (Fisher’s exact test,
p⫽0.02). CONCLUSION: A hemorrhagic or NHND presentation indicates a very high risk for
further events, while the absence of these symptoms in patients with Borden type 2 or 3 dAVFs
may indicate a benign clinical course.
108
Multimodality Care of Occipital Lobe AVMs: Neurological Outcomes of A
Prospective Series of 134 Patients.
Amir R. Dehdashti, Laurent Thines, Toronto Western Hosp, Neurosurge, Toronto, Canada;
Robert Willinsky, Toronto Western Hosp, Radiology, Toronto, Canada; Michael L. Schwartz,
SunnyBrooke Hosp, Neurosurge, Toronto, Canada; Karel TerBrugge, Toronto Western Hosp,
Radiology, Toronto, Canada; Michael Tymianski, M.Christopher Wallace; Toronto Western
Hosp, Neurosurge, Toronto, Canada
Objective: The proximity of the occipital AVMs to the visual cortex and optic radiations makes
their management challenging. We studied the neurological outcomes of patients with occipital
AVMs and evaluated the role of multimodality management. Methods: A prospective analysis
was conducted for 134 patients with occipital AVMs who were managed by the Toronto
vascular malformation group between 1985 and 2007. The decision was based on the patients’
characteristics, mode of presentation and morphology of the AVM. The management modalities
were correlated with their neurological outcomes. Results: One hundred-twenty-five patients
presented with one or more symptoms, including headache in 50, seizure in 43, visual deficit
in 33 and hemorrhage in 32. Visual deficit was more common in the group of ruptured
AVMs(p ⬍ 0.002). Mean follow-up period was 4.78 years and 12 patients were lost to
follow-up. Forty-seven patients did not receive any treatment. Among the 14 patients in this
group with visual deficit at presentation, two showed improvement(14%) and two had
worsening(14%). Three patients presented with hemorrhage(6%)during follow-up with two new
visual deficits (4.2%). The two deaths in this group were unrelated to the AVM. Eighty-seven
patients were treated with embolization,surgery,radiosurgery or a combination of treatment
modalities.The final cure rate was 67%. Visual deficit at presentation improved in 7 of 32
patients(22%)and worsened in 2(9%).There were 14 new neurological deficits(16%),the
majority of which were minor. Two patients rebled after partial treatment of their AVMs. There
were three deaths (3%) related to the AVM treatment.Neurological morbidity was higher in the
treatment group(p ⬍ 0.005), but the difference in mortality did not reach statistical
significance. The visual deficit improvement was more common in the treatment group(p⬍
0.02). Among the subgroup of unruptured AVMs with treatment(45 patients), there were seven
new neurological deficits(16%) including only three new visual deficits(6.7%) and no mortality.
Conclusions:Management of occipital AVMs must be based on their natural history. Treatment
as opposed to conservative approach results in a better visual outcome in patients with visual
symptoms. There is however, a substantial risk of new but minor neurological deficit. Selected
patients with unruptured occipital AVM might be offered treatment with a low risk of new visual
deficit. The multimodality care of occipital AVMs with appropriate patient selection for each
therapeutic arm can aim for a good neurological outcome.
107
109
Benign Course of Borden Type 2 and 3 Dural Arteriovenous Fistulas
Presenting Without Neurological Symptoms.
Brainstem Arteriovenous Malformations: Natural History, Multimodality
Management And Long Term Follow-up.
James A Botros, Russell G Strom, Daniel Refai, Dept of Neurosurgery, Washington Univ Sch
of Medicine, Saint Louis, MO; Colin P Derdeyn, Depts of Neurosurgery and Neurology and
the Mallinckrodt Institute of Radiology, Washington Univ Sch of Medicine, Saint Louis, MO;
Gregory J Zipfel; Depts of Neurosurgery and Neurology, Washington Univ Sch of Medicine,
Saint Louis, MO
Laurent Thines, Amir R Dehdashti, Michael Tymianski, Karel G TerBrugge, Robert A
Willinsky, Toronto Western Hosp, Toronto, Canada; Michael Schwartz, Sunnybrook Health
Sciences Cntr, Toronto, Canada; M. C Wallace, Toronto Western Hosp, Toronto, Canada;
Univ of Toronto Brain Vascular MalformationStudy Group
INTRODUCTION: Cranial dural arteriovenous fistulas (dAVFs) with cortical venous reflux (Borden
type 2 and 3) are considered to have an aggressive clinical course. The reported risk of
hemorrhage or non-hemorrhagic neurological deficit (NHND) is high, with an annual event rate
up to 15%. The purpose of the present study is to compare the clinical course of patients with
type 2 or 3 dAVFs with benign presentation versus those presenting with hemorrhage or NHND.
METHODS: A consecutive cohort of 108 patients at our institution who presented with dAVFs
between 1997 and 2007 were evaluated and classified using the Borden scale. Twenty-four
patients with type 2 or 3 dAVFs were identified. They were divided into two groups according
to their presentation; 12 patients presented aggressively, with hemorrhage or NHND, including
seizures, ataxia, and mental status changes. The remaining 12 patients had a benign
Background and purpose: The high functional eloquence of the brain stem (BS) makes the
management of arteriovenous malformations (AVM) in this location very challenging. Our
objective was to review the results of the therapeutic management compared to the long term
outcome of BSAVM. Methods: We reviewed from our data base, a prospective series of 26
patients managed for a BSAVM between 1989 and 2007. We analyzed the demographic data,
mode of presentation, initial symptoms and early outcome. We assessed the rate of rebleeding,
the treatment results and the clinical outcome with the modified Rankin Scale (mRS). Results:
The average follow-up duration was 6.3 years. The sex ratio was 0.86 and the median age 37
years. The BSAVM was symptomatic in 92% of cases and bleeding was the revealing factor in
61%. Onset symptoms included: headache in 73%, neurological deficit in 65%, seizure in 4%.
Locations in the BS were: midbrain 8, pons 4, medulla oblongata 2, mixed 12. The initial clinical
555
examination was abnormal in 69% including: coordination and gait deficit in 48%, cranial
nerves deficit in 44%, motor or sensitive deficits in 32%, visual deficit in 16% and the initial
mRS values were: 0 to 2 in 86% and 3 to 5 in 14%. The management was conservative in 7
cases and treatment options included radiosurgery alone in 10, embolization with intent to cure
in 6, or a multimodality treatment (embolization ⫹ radiosurgery or embolization ⫹ surgery) in
5. The overall rate of rebleeding was 20%. At the end of the follow-up, the mRS values were:
0 to 2 in 78% and 3 to 6 in 22%. Among the 40% of the patients who worsened, 70% of the
complications were related to the treatment. The overall rate of occlusion was 53% after the
treatment. Conclusions: BS is a rare location of brain AVM. Their natural history doesn’t seem
so bad since most of the patients have a good early outcome after the onset of the symptoms,
60 % remained stable or improved spontaneously and only 20% presented a rebleeding. The
management, usually aiming to decrease the rebleeding risk, requires a multidisciplinary
expertise to precisely select the patients for each therapeutic option and reduce the treatment
morbidity compared with the natural course of the disease.
comparisons not significant. Log transformation gave the same result that CCMs with venous
anomaly had more B cells (FDR adjusted p⫽0.046) and clumps of B cells, and that more clumps
of anti-CD3-stained T cells/area were found in single lesions than from CCMs from subjects with
multiple lesions (p⫽0.007). Regression analysis gave a negative correlation between numbers of
clumps of T cells/area and the age at diagnosis. In conclusion, (1) inflammatory cells within a CCM
are present in all lesion types, and are not more prevalent in lesions with recent hemorrhage or
lesion growth, (2) more B cells and clumps are correlated with associated venous anomaly and (3)
more T cell clumps/area were found in single lesions than in CCMs from multiple lesions. The
specific triggers of inflammatory activity in CCM lesions require elucidation to better explain their
potential role in lesion maintenance.
110
Plasma Levels of Matrix Metalloproteinases after Treatment for Cerebral
Arteriovenous Malformations.
Helen Kim, Ludmila Pawlikowska, Charles E McCulloch, Pui-Yan Kwok, William L Young;
UCSF, San Francisco, CA
Robert M Starke, Ricardo J Komotar, Columbia Univ, New York, NY; Marc L Otten, Brian Y
Hwang, David K Hahn, Laura E Fischer, Grace H Kim, Zachary L Hickman, Mathew C
Garrett, Maxwell B Merkow, Michal A Rynkowski, Robert A Solomon, E S Connolly;
Columbia Univ, New york, NY
Introduction: Abnormal angiogenesis is thought to play a key role in the formation and
progression of cerebral arteriovenous malformations (AVMs). Previous studies have demonstrated increased local expression of angiogenic growth factors, such as matrix metalloproteinases (MMP), in resected AVM specimens. In this study, we sought to further investigate the
role of MMP-9 and abnormal angiogenesis in AVM pathogenesis by examining changes in
plasma MMP-9 levels in patients undergoing treatment for AVMs. Methods: Serial blood
samples were obtained from 15 AVM patients undergoing treatment of their AVMs at three time
points: (1) prior to embolization, (2) 24 hours post-resection, and (3) 30 days post-resection.
Blood samples were also obtained from 29 patients undergoing lumbar laminectomy surgery
who served as controls. Plasma MMP-9 concentrations were measured via commercially
available enzyme-linked immunosorbent assay (ELISA). The assay exhibits no significant
cross-reactivity with other angiogenic factors and has a sensitivity of 0.156 ng/ml. Data are
expressed as mean ⫾ SEM. Results: The mean plasma MMP-9 level in AVM patients at
baseline was 108.04⫾16.11 ng/ml, which was not significantly different than that of the
control group 104.56⫾ 12.97 ng/ml, p⫽0.872). One day after resection, plasma MMP-9 levels
increased to 230.97⫾51.00 ng/ml, which was significantly different from pre-treatment levels
(p⫽0.029). The mean plasma MMP-9 concentrations 30 days after resection decreased to
132.78⫾42.45 ng/ml which was not significantly different from control or AVM pretreatment
mean plasma MMP-9 levels (p⫽0.427 and p⫽0.590) respectively). Plasma MMP-9 levels did
not correlate with patient sex, age, AVM size, or patient presentation. Conclusions: There was
no significant difference between plasma levels of MMP-9 in our AVM patients and controls.
Plasma MMP-9 levels increased significantly after surgery and then decreased to normal levels.
These results indicate that MMP-9 levels rise during vascular surgery for AVMs rather than play
a pre-operative role in their formation. Previous studies, which found increased levels of
MMP-9 in resected AVMs, may have falsely concluded that increased MMP-9 may result in
AVM growth.
112
Transforming Growth Factor-beta1 Polymorphisms and Risk of Intracranial
Hemorrhage in Brain Arteriovenous Malformation Patients.
Background: Transforming growth factor-beta1 (TGFB1) is a pleiotropic cytokine, which plays
an important role in inflammatory response, and may be involved in brain arteriovenous
malformation (BAVM) pathogenesis. We investigated whether polymorphisms in the TGFB1
gene were associated with increased risk of intracranial hemorrhage (ICH) in the natural course
of BAVM patients. Method: Three common TGFB1 polymorphisms (-509C⬎T, Leu10Pro, and
Arg25Pro) were genotyped in 334 BAVM patients. Kaplan-Meier survival analysis of time to new
ICH after diagnosis, censoring cases at first treatment, death or last follow-up was performed.
Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox
regression analysis to adjust for covariates. Results: A total of 21 ICH events occurred during
867 person-years at risk, with a mean (standard deviation) follow-up of 2.6 (7.2) years.
Genotypes were in Hardy-Weinberg equilibrium. The Leu10Pro (⫹858C⬎T) polymorphism was
associated with risk of time to new ICH in BAVM patients (Figure). The risk of new ICH was
3.35-fold higher (95% CI⫽1.18 –9.49, P⫽0.023) in patients with the Leu10Pro TT vs. CT⫹CC
genotypes, after adjusting for age, gender and white race. Further adjustments for venous
drainage and size decreased the HR to 3.15 (95% CI⫽1.09 –9.09, P⫽0.034). The Arg25Pro
and -509C⬎T polymorphisms were not associated with ICH risk. Conclusion: A common
functional TGFB1 polymorphism (Leu10Pro) may be associated with increased risk of new ICH
in the clinical course of BAVM patients.
111
Inflammatory Cell Infiltration in Cerebral Cavernous Malformations and
Lesion Phenotype and Clinical Manifestations.
Robert Shenkar, Evanston Northwestern, Evanston, IL; Harish Raja, Duke Univ, Durham, NC;
Hongyan Du, Evanston Northwestern, Evanston, IL; Changbin Shi, Northwestern Universtiy,
Chicago, IL; H. H Batjer, Northwestern Univ, Chicago, IL; Issam Awad; Evanston
Northwestern, Evanston, IL
Introduction: Cerebral cavernous malformations (CCMs), a cause of hemorrhagic stroke, were
studied systematically for inflammatory cells. Hypothesis: We assessed the hypothesis that the
amount of inflammatory cells within CCMs correlates with specific CCM phenotype and clinical
manifestations. Methods: Formalin fixed paraffin embedded archival CCM lesions, surgically
excised from 23 subjects, were stained for plasma cells (CD138), B cells (CD20/CD79a), T cells
(CD3/CD45RO) and antigen presenting cells (HLA-DR). The number of clumps of cells/area and total
cells/area were determined for each specimen and analyzed for associations with clinical
manifestations including subject ages at surgery, first symptom and diagnosis; gender; familial
history; lesion multiplicity; seizure presence; lesion location and size; recent hemorrhage; recent
growth and venous anomaly presence. Spearman correlations were computed between outcomes.
Log transformation was applied for skew-distributed variables. Wilcoxon two-sample test, independent two-sample t test, and linear regression were used in univariate analyses. Multivariate analyses
were performed using mixed models. Two-sided p ⬍ 0.05 was considered significant, FDR (False
Discovery Rate) adjusted p values from multivariate models were reported. Results and
Conclusions: There was a wide range of clumps/area and cells/area of B, T, plasma and antigen
presenting cells within the CCMs and the data for these were skew-distributed. B cell infiltration was
correlated with T and plasma cells in the same lesions. Recent bleeding and clinical proliferation did
not correlate with inflammatory activity. In univariate analysis, CCMs with associated venous
anomaly had a larger median of clumps/sq cm (21.4 vs 5.3, p⫽0.034) and cells/sq cm (349 vs 117,
p⫽0.041) of B cells stained with anti-CD20 antibody than in CCMs without this anomaly, with other
113
Gender Differences In The Management Of Cerebrovascular Disease: The
Challenge Of Secondary Prevention.
Gustavo Saposnik, Univ of Toronto and Mobility Program Clinical Rsch Unit, Toronto,
Canada; Andrew Yan, Univ of Toronto and Canadian Heart Rsch Cntr, Toronto, Canada;
Amparo Casanova, Canadian Heart Rsch Cntr, Toronto, Canada; Anatoly Langer, Univ of
Toronto and Canadian Heart Rsch Cntr, Toronto, Canada; Shaun Goodman, Univ of Toronto
and Canadian Heart Rsch Cntr, Toronto, Canada; for the Stroke Outcome Rsch Canada
(SORCan) Working Group
Background: Female sex has been associated with poorer vascular outcomes. Limited
information is available on the achievement of guideline recommendations for lipid and blood
pressure for secondary prevention. Our goal was to analyze gender differences in attaining the
optimal LDL-cholesterol (LDL-C) and blood pressure targets among ambulatory patients with
cerebrovascular disease (CVD). Methods: We analyzed 1097 ambulatory patients with CVD
enrolled in the prospective Vascular Protection (VP) and Guidelines Oriented Approach to Lipid
Lowering (GOALL) Registries from December 2001 to December 2004. Demographic, blood
pressure, current medications, and a complete lipid profile were recorded. We examined
gender differences in the use of antithrombotic and lipid-modifying agents, and in the
attainment of blood pressure (BP) (⬍140/90 mmHg) and lipid (LDL-C ⬍ 2.5 mmol/L) targets.
Results: Among 1097 patients with CVD, 679 (62%) were male; mean (⫾SD) age was 69⫾10
years. Women had slightly higher mean baseline systolic BP (2.8 mmHg), diastolic BP (0.66
mmHg) and LDL-C (0.19 mmol/L) than their counterparts. Despite similar use of antithrombotics, antihypertensive and lipid modifying agents, women were less likely to achieve the BP
and lipid target and be on optimal care therapy (LDL ⬍2.5 mmol/L and BP ⬍ 140/90 mmHg
and on antithrombotic therapy) (table). Conclusions: Ambulatory women with history of CVD
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Stroke
Vol 39, No 2
February 2008
were less likely to attain contemporary guideline-recommended BP and lipid targets when
compared with men. Our study reveals the existence of important gender gaps in secondary
prevention of CVD. Quality improvement strategies should be implemented to optimize care in
women with CVD.
CVD patients
Outcome measures
Male
N⫽679
Female
N⫽415
p-value
Statin use (%)
78
79
0.60
Use of any lipid-modifying agent (%)
80
81
0.40
Antithrombotic therapy (%)
91
93
0.22
Use of any anti-hypertensive agent (%)
87
89
0.41
Achieved LDL-C ⬍2.5 mmol/L (%)
49
42
0.01
Achieved BP ⬍140/90 mmHg (%)
78
70
0.003
Optimized care (%) (LDL-C ⬍2.5, BP
36
30
0.01
⬍ 140/90 and on antithrombotic therapy)
TC⫽ total cholesterol, LDL-C⫽ LDL cholesterol Recommended target in the Canadian
Dyslipidemia guidelines LDL-C ⬍2.5 mmol/L equivalent to LDL-C 97mg/dL (similar to ATP III
-National Cholesterol Education Program (NCEP) Expert Panel LDL-C ⬍100 mg/dL).
Results: 1,477 patients were enrolled in AVAIL, 910 had 3 month interviews, and 663 had
these data linked to baseline medication lists and GWTG_Stroke information (mean age 67 yrs
[std 13 yrs], 83% white, 12% African American, 3% Hispanic, and 2% other). With medication
class prescribed at discharge as the denominator, adherence rates at 3 months were 95% (610
of 642) for antithrombotic, 92% (475 of 516) for anti-hypertensive, and 84.5% (437 of 517) for
lipid-lowering medications. 413 of 663 (62%) subjects were discharged on all 3 secondary
prevention medications regardless of the “qualifying” status and 322 (78%) remained on these
medications at 3 months. Of 277 “qualifying” subjects on all 3 medications, 231 (84%) were
adherent. Adherent patients were more likely to use a pill box or other reminder tool (61% vs.
35% of non-adherent; p⫽0.0002). Adherence rates did not vary by age, race, education,
household income, financial hardship, understanding how or why medications are taken, or
provider type. In a logistic regression model adjusted for 3 month modified Rankin scores,
female gender (OR 2.26; 95% CI 1.10 – 4.615), dyslipidemia (2.52; 1.27– 4.98), lack of visual
deficits (2.50; 1.23–5.26) and use of a pill box/reminders (2.70; 1.34 –5.44) were all
independently associated with adherence. Conclusions: Patient adherence to prescribed
secondary stroke prevention medications was quite high in this cohort, but about 20% were
non-adherent at 3 months. Stroke related deficits such as visual problems may be a barrier to
adherence. However, use of simple interventions such as a patient pill box or reminder tool
appears to facilitate adherence.
116
114
Does Differential Prophylactic Aspirin Use Contribute to Racial and
Geographic Disparities in Stroke?
Atorvastatin is Similarly Effective in All Ischemic Stroke Subtypes:
Secondary Analysis of the SPARCL Trial.
Stephen P Glasser, Univ of Alabama Birmingham, Birmingham, AL; Mary Cushman, Univ of
Vermont, Burlington, VT; Ronald J Prineas, Wake Forest Univ, Winston-Salem, NC; Dawn
Kleindorfer, Univ of Cincinnati College of Medicine, Cincinnati, OH; Valerie Prince, Samford
Univ McWhorter Sch of Pharmacy, Birmingham, AL; Zhiying You, Virginia J Howard, George
Howard, Univ of Alabama Birmingham, Birmingham, AL; for the REGARDS Investigators
Pierre Amarenco, Denis Diderot Univ, Paris, France; Oscar Benavente, Univ of Texas Health
Science Cntr, San Antonio, TX; Larry B Goldstein, Duke Univ Med Cntr, Durham, NC; Alfred
Callahan, III, Saint Thomas Hosp, Nashville, TN; Michael G Hennerici, Universitat Heidelberg,
Mannheim, Germany; Henrik Sillesen, Univ of Copenhagen, Copenhagen, Denmark; K M
Welch, Rosalind Franklin Univ of Medicine and Science, Chicago, IL; Justin Zivin, Univ of
California, San Diego, San Diego, CA; on behalf of the SPARCL Investigators
Context. Aspirin use may reduce the risk of stroke and coronary heart disease (CHD).
Differential use for vascular prophylaxis may contribute to racial and geographic disparities in
stroke and CHD morbidity or mortality. Design and Setting. Cross-sectional analysis of 16,908
participants from a population-based national cohort study (REasons for Geographic And Racial
Differences in Stroke) enrolled from February 2003-August 2006 with oversampling from the
southeastern Stroke Belt and African Americans. Individuals with a prior stroke or CHD, or
regular use of aspirin for pain relief were excluded from analyses. Main Outcome Measures.
Aspirin use and reasons for use were assessed using a computer-assisted telephone interview.
Results. Prophylactic aspirin use was substantially higher among whites (34.7%) than African
Americans (27.2%; p ⬍ 0.0001). There was a higher prevalence of aspirin use for prophylaxis
in the Stroke Belt (32.1%) than in the rest of the nation (30.8%; p⫽0.07). After adjustment for
measures of socio-economic status, the odds ratio of aspirin use in the rest of the nation
compared to Stroke Belt was 0.90 (95% CI 0.84,0.97). There was a higher likelihood of
prophylactic aspirin use among participants who were white, male, older, past cigarette
smokers, or of higher socioeconomic status (higher income or education). Participants who had
hypertension, diabetes, or a higher Framingham Coronary Risk Score or higher Framingham
Stroke Risk Score also had a higher likelihood of prophylactic aspirin use. Among aspirin users,
white participants were more likely to be taking low dose aspirin (⬍180 mg daily) than African
Americans (77.3% versus 70.8%), and there was no evident difference in aspirin dose between
regions (p ⫽ 0.79). Conclusions. In this study, aspirin use to prevent stroke and CHD was
higher among whites than African Americans, raising the possibility that differential aspirin use
could contribute to the racial disparities in vascular disease mortality. Counter to our
hypothesis, aspirin use was more common in the Stroke Belt than the rest of the country, so
differential aspirin use in the Stroke Belt is unlikely to contribute to geographic disparities in
stroke.
Background: The Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL)
trial showed that atorvastatin 80 mg/day reduced the risk of stroke and other cardiovascular
events in patients with recent stroke or TIA. In this post hoc analysis, we tested the hypothesis
that the benefit of treatment varied based on the type of index event. Methods: Subjects with
stroke or TIA within the prior 1– 6 months and LDL-C of 100 –190 mg/dL without known CHD
(n⫽4731) were randomized to atorvastatin 80 mg/d or placebo. Those with prosthetic heart
valves, a history of atrial fibrillation, or significant mitral stenosis were excluded. The type of
index event and outcome stroke subtype were classified by investigators based on their clinical
judgement without independent adjudication. The primary end point was occurrence of a first
fatal or non-fatal stroke. Secondary endpoints included major cardiovascular events (stroke
plus major coronary events) and revascularization procedures. Potential differences in efficacy
based on type of entry event were assessed by testing for an interaction with treatment
assignment using Cox regression models. Results: Among 4,731 participants, 15.8% were
classified as having large vessel disease (LVD) (reference category), 29.8% small vessel
disease (SVD), 21.5% ischemic stroke of unknown cause, 30.9% TIA, and 2% as hemorrhagic
stroke (HS) at baseline. There was no difference in the efficacy of treatment for either the
SPARCL primary (LVD HR: 0.70 [0.49 –1.02], TIA HR: 0.81 [0.57–1.17], SVD HR: 0.85
[0.64 –1.12], unknown cause HR: 0.87 [0.61–1.24]) or secondary endpoints based on entry
event except for patients randomized with a HS (HR⫽ 3.24 [1.01–10.4]). Patients with SVD
strokes on atorvastatin had a higher incidence of outcome hemorrhage than those with SVD on
placebo (0.61 vs. 0.12/100 p-y, p⫽0.0031). As compared to subjects with LVD strokes, those
with SVD had similar major coronary event rates (4.1 vs. 5.1% over the course of the trial,
p⫽0.569), and similar overall reductions in stroke (p⫽0.493) and major coronary events
(p⫽0.322). Conclusion: Atorvastatin 80 mg/d is effective in preventing strokes and other
cardiovascular events, irrespective of baseline ischemic stroke subtype.
115
Adherence eValuation After Ischemic stroke Longitudinal (AVAIL):
Identifying Facilitators of Adherence to Stroke Prevention Medications.
117
Assessing the Net Clinical Benefit of Warfarin by Ischemic Stroke Risk in
Atrial Fibrillation: The ATRIA Study.
Cheryl Bushnell, Wake Forest Univ Health Sciences, Winston-Salem, NC; Mark Alberts,
Northwestern Univ, Chicago, IL; Michael Frankel, Emory Univ, Atlanta, GA; Larry B Goldstein,
Duke Univ, Durham, NC; Philip Gorelick, Univ of Illinois at Chicago, Chicago, IL; S. Claiborne
Johnston, Univ of California at San Francisco, San Francisco, CA; Chelsea Kidwell,
Georgetown Univ, Washington, DC; Lee Schwamm, Harvard Univ, Boston, MA; Linda
Williams, Indiana Univ, Indianapolis, IN; Eric Peterson; Duke Univ, Durham, NC
Daniel E Singer, Yuchiao Chang, Massachusetts General Hosp, Boston, MA; Margaret C
Fang, Univ of California, San Francisco, CA; Leila H Borowsky, Massachusetts General Hosp,
Boston, MA; Niela K Pomernacki, Kaiser Permanente of Northern California Div of Rsch,
Oakland, CA; Natalia Udaltsova, Alan S Go; Kaiser Permanente of Northern California Div of
Rsch, Oakland, CA
Background: There are only limited data available related to adherence to secondary stroke
prevention medications after hospital discharge. As a result, potential barriers and facilitators
of adherence are poorly understood. Methods: AVAIL is a multi-center, longitudinal registry of
101 U.S. hospitals participating in the AHA’s Get With The Guidelines - Stroke (GWTG_Stroke)
program, and was designed to evaluate 3 month and 1 year adherence to stroke prevention
medications. For this first interim analysis, we assessed 3 month adherence to antithrombotic,
antihypertensive, and lipid-lowering medications among ischemic stroke and TIA patients
enrolled from July 1, 2006 through August 1, 2007 (follow-up rates 97% complete). Patients
were contacted via telephone questionnaires administered by trained centralized interviewers.
Self-reported adherence was defined as the use of antithrombotic, anti-hypertensive and
lipid-lowering therapy in all subjects and also among “qualifying” subjects (i.e. those with
hypertension and hypercholesterolemia or an LDL ⬎ 100) at 3 months. Logistic regression
modeling was used to identify the major clinical predictors of 3 month composite adherence.
INTRODUCTION: Warfarin anticoagulation is highly effective in preventing stroke and systemic
thromboembolism in patients with atrial fibrillation (AF). However, current anticoagulation
guidelines are (1) based solely on risk of thromboembolism off warfarin therapy, (2) do not
incorporate the increased risk of intracranial hemorrhage (ICH) due to warfarin therapy, and (3)
rely on stroke rate data from older studies. We examined the net clinical benefit of warfarin in
a contemporary cohort of patients with AF. METHODS: The ATRIA cohort consists of 13,559
patients with nonvalvular AF enrolled in an integrated healthcare delivery system with 66,754
person-years of follow-up accumulated between 1996 and 2003. Warfarin exposure was
determined using algorithms based on warfarin prescriptions and outpatient international
normalized ratio (INR) values. Patient characteristics and outcome events (ischemic stroke,
systemic embolism and ICH) were ascertained from health plan databases. Outcome events
were validated by chart review. We defined the net clinical benefit of warfarin therapy as
ischemic strokes and systemic emboli prevented versus ICH induced (since ICH is the only
bleeding complication comparable in clinical impact to ischemic stroke). Net clinical benefit
was assessed according to standard stroke risk factors in AF and the CHADS2 stroke risk
scheme. Anticoagulation quality was good with an aggregate time in therapeutic INR range of
65%. RESULTS: Overall, the annual rate of thromboembolic events was 1.27% on warfarin
therapy compared to 2.1% off warfarin therapy. The annual rate of ICH on warfarin therapy was
0.58% as compared to 0.32% off warfarin therapy. For the entire cohort over the entire
observation period, the net clinical benefit of warfarin (thromboembolism prevented vs. ICH
induced), was 0.58% per year (95% CI, 0.28 – 0.90). The point estimate of net clinical benefit
was negative in patients ⬍ 60 years old, close to zero in those 60 – 69, and increased to ⬎2%
per year for those ⬎ 80. Among those with prior ischemic stroke, the net clinical benefit was
3.7% per year vs. 0.57% per year among those without a prior stroke. The net clinical benefit
of warfarin increased from a negative value in CHADS2 category 0 to 2.34% in combined
CHADS2 categories 4 – 6. These findings were largely unchanged after multivariable analysis
including all stroke and ICH risk factors. CONCLUSIONS: In this large cohort of AF patients, we
provide a model for evaluating the net clinical benefit of warfarin therapy, taking into account
the increased absolute risk of ICH on warfarin and the lower absolute risk of stroke in recent
years. Net clinical benefit increases with age and is higher in the presence of any of the
established stroke risk factors. Risk assessment incorporating both risk of thromboembolism
and risk of ICH provides a more quantitatively informed basis for the anticoagulation decision
in AF patients.
118
Closure of the Lead-in Phase of CREST (Carotid Revascularization
Endarterectomy Vs. Stenting Trial): 30-day And One Year Analyses.
Robert W Hobson, II, Univ. Medicine & Dentistry of New Jersey/ NJ Med Sch, Newark, NJ;
Thomas G Brott, Mayo Clinic, Jacksonville, FL; Gary S Roubin, Krishna Kathir, Lenox Hill,
New York, NY; Alice J Sheffet, Univ. Medicine & Dentistry of New Jersey/ NJ Med Sch,
Newark, NJ; Pierre Leimgruber, Deaconess Med Cntr, Spokane, WA; Christopher White,
Ochsner Clinic, New Orleans, LA; Munier Nazzal, Univ of Toledo, Toledo, OH; Elie
Chakhtoura, St. Michael’s Med Cntr, Newark, NJ; B. K Lal, Univ. of Medicine & Dentistry of
New Jersey/ NJ Med Sch, Newark, NJ; MeeLee Tom, Susan E Hughes, Univ. Medicine &
Dentistry of New Jersey/ NJ Med Sch, Newark, NJ; Mary Longbottom, Mayo Clinic,
Jacksonville, FL; George Howard, Univ. of Alabama at Birmingham, Birmingham, AL;
Stephanie Martin, Univ. of Alabama at Brimingham, Birmingham, AL; Jenifer H Voeks; Univ.
of Alabama at Birmingham, Birmingham, AL
BACKGROUND AND PURPOSE: The benefit of carotid endarterectomy (CEA) or stenting (CAS)
is dependent upon periprocedural risk and the incidence of subsequent neurological events.
Safety and clinical results for CAS have varied. Closure of the CREST lead-in registry (2007)
provides an opportunity for comparison of data with published randomized clinical trial (RCT)
CEA results at 30-days and one year. METHODS: Interventionalists were CREST approved
based on low morbidity and mortality of audited cases by a multi-specialty Interventional
Management Committee. Prior to randomization approval, interventionalists performed up to 20
CAS for symptomatic (⬎50%) and asymptomatic (⬎70%) stenosis in patients at conventional
or higher risk using the ACCULINKTM Carotid Stent and ACCUNETTM Embolic Protection Systems.
Patients were pretreated with aspirin and clopidogrel, continued for at least 30-days
post-procedurally. Neurological examinations and NIH Stroke Scales were performed by CREST
neurologists pre-procedure, 24-hours and 30-days post CAS. Study primary endpoints were
any stroke, death or MI within 30-days and ipsilateral stroke after 30-days, as reviewed by an
independent clinical events committee. RESULTS: Completion of the lead-in registry of CREST
(n⫽1552 CAS procedures) resulted in analysis of 30-day and one year event rates for all
patients as well as symptomatic and asymptomatic patients. Within the first 30 days, 67 (4.3%)
patients had a stroke (60 (3.9%) ischemic infarcts and 7 hemorrhagic), 13 (⬍1%) had an MI
and 5 (⬍1%) died. The combined 30-day event rate was 4.4% (95% CI: 3.4%–5.4%) with
6.0% (95% CI: 3.7%– 8.4%) for symptomatic patients and 3.8% (95% CI: 2.6%–5.0%) for
asymptomatic patients. The one-year event rate was 5.0% (95% CI: 3.8%– 6.2%) and 6.9%
(95% CI: 4.4%–9.5%) for symptomatic patients and 4.2% (95% CI: 3.0%–5.4%) for
asymptomatic patients. CONCLUSIONS: The 30-day and one year event rates for symptomatic
patients were similar to rates reported for CEA in symptomatic RCTs. For asymptomatic
patients, despite inclusion of higher risk subsets (⬎80y/o) the 30-day and one year event rates
for CAS approached rates reported for CEA in asymptomatic RCTs. Data from this registry
confirm that most events occur within the first 30 days, while subsequent ipsilateral stroke
rates (⬍1%) suggest durability of CAS to at least one year after the procedure.
557
of women and men in the Aerobics Center Longitudinal Study. Methods - 46,405 men and 15,282
women without known CVD at baseline completed a maximal treadmill exercise test between 1970
and 2001. CRF was grouped as quartiles of the sex-specific distribution of maximal metabolic
equivalents (METs) achieved. Mortality follow-up was through December 31, 2003 using the
National Death Index. Nonfatal stroke, defined as physician-diagnosed stroke, was ascertained from
surveys during 1982–2004. Cox regression models quantified the pattern and magnitude of
association between CRF and stroke. Results - Over 18 years of follow-up there were 692 strokes
during 813,944 man-years of exposure and 171 strokes during 248,902 woman-years of exposure.
In men, age-adjusted rates of total stroke decreased across quartiles representing increasing CRF
(Ptrend ⬍0.0001). This negative association remained significant after further adjusting for
examination year, smoking, alcohol intake, family history of CVD, and abnormal exercise ECG
responses (P trend ⬍0.0001). Further adjustment for BMI, HTN, diabetes, and hypercholesterolemia
did not materially change the association (P trend ⫽ 0.003). Similar inverse patterns of association
also were seen between CRF and both nonfatal and fatal stroke. In women, total stroke rates were
also inversely associated with CRF (P trend ⫽0.006). The inverse association remained significant
after adjusting for the covariates (Ptrend ⫽ 0.001). Further adjustment for risk factors did not
significantly alter the association (Ptrend ⫽ 0.007). A similar pattern and magnitude of the association
was observed between CRF and nonfatal stroke. There was some evidence that the risk of fatal
strokes for women may have decreased across increasing quartiles of CRF, although this trend was
not statistically significant in either multivariate model (P trend ⬎.05) Lack of statistical significance
may be attributable to relatively few fatal strokes in women (N⫽55). A CRF threshold of 7– 8 METs
was associated with a substantially reduced rate of total stroke in both men and women.
Conclusions - These findings suggest that CRF is an independent determinant of stroke incidence
in initially asymptomatic and CVD-free adults, and the strength and pattern of the association is
similar for men and women. It also appears that a modest level of CRF confers significant reduction
in the risk of stroke for both men and women.
120
Americans Have Higher Prevalence Of Stroke Than Europeans: Results
From An International Study.
Mauricio Avendano, Dr.; Erasmus MC -Public Health, Rotterdam, The Netherlands
Introduction and hypothesis: Stroke mortality varies across countries, but no studies have
examined cross-national variations in stroke prevalence. The prevalence of many stroke risk factors
is higher in the US than in Europe. Therefore, we hypothesized that the prevalence of stroke is higher
in the US as compared to European countries. Methods: Data came from recent nationally
representative and fully comparable surveys of adults ages ⬎50 in the United States (n⫽13,667)
and 11 European countries (n⫽30,120). Comparable data were collected on stroke prevalence,
demographics, socioeconomic status, and major risk factors for stroke including smoking, obesity,
diabetes, physical activity and alcohol consumption. Stroke prevalence was modeled as a function
of country, demographics and conventional risk factors using logistic regression. Results: Women
had a lower prevalence of stroke as compared to men (OR⫽0.73, 95%CI 0.67, 0.80). The age
adjusted prevalence of stroke varied considerably across countries (figure) and was highest in the
US (7.4, 95%CI 6.9 –7.9 in men; 6.5, 95%CI 6.0 –7.0 in women), and lowest in Southern
Mediterranean European countries (Spain, Italy, Greece) and Switzerland. As compared to European
men, US men had higher odds of stroke (OR⫽1.61, 95%CI 1.41, 1.83). Similarly, US women had
about twice the odds of stroke than European women (OR⫽1.98, 95%CI 1.74, 2.25). Higher stroke
prevalence was associated with lower socioeconomic status as measured by wealth, income and
education, but these associations were stronger in the US as compared to most European countries.
Risk factors explained only a small fraction of the higher prevalence of stroke in the US as compared
to European populations. Conclusion: Adults in the US have a higher prevalence of stroke and larger
stroke disparities as compared to adults in Europe. Risk factors do not account for these differences,
which points at the role of broader healthcare and structural policies in determining stroke
prevalence.
119
Cardiorespiratory Fitness as a Predictor of Fatal and Nonfatal Stroke in
Asymptomatic Women and Men.
Steven P Hooker, Prevention Rsch Cntr, Univ of South Carolina, Columbia, SC; Xuemei Sui,
Dept of Exercise Science, Univ of South Carolina, Columbia, SC; Natalie Colabianchi, Dept of
Epidemiology and Biostatistics and Prevention Rsch Cntr, Univ of South Carolina, Columbia,
SC; John Vena, James Laditka, Dept of Epidemiology and Biostatistics, Univ of South
Carolina, Columbia, SC; Michael J LaMonte, Dept of Social and Preventive Medicine, Univ at
Buffalo, Buffalo, NY; Steven N Blair; Depts of Exercise Science and Epidemiology and
Biostatistics, Univ of South Carolina, Columbia, SC
Purpose - Prospective data on the association between cardiorespiratory fitness (CRF) and stroke
are largely limited to studies in men, or do not separately examine risks for fatal and nonfatal stroke.
This study examined the association between CRF and fatal and nonfatal stroke in a large cohort
558
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Vol 39, No 2
February 2008
121
Left Atrial Diameter Predicts Atrial Fibrillation in Ischemic Stroke Patients.
Fabricio Lima, Massachusetts General Hosp, Boston, MA; Michael K Parides, Columbia Univ,
New York, NY; David M Greer, Massachusetts General Hosp, Boston, MA; Peter J Kelly, Mater
Misericordiae Univ Hosp, Dublin, Ireland; Karen L Furie; Massachusetts General Hosp, Boston,
MA
Background: Stroke of undetermined etiology, which accounts for 30 – 40% of all ischemic stroke,
remains a diagnostic conundrum despite widespread use of sophisticated imaging and physiologic
studies. A proportion of these “cryptogenic” stroke patients may have undetected paroxysmal atrial
fibrillation, a hypothesis supported by a trend toward a beneficial effect of warfarin in the cryptogenic
subgroup in the Warfarin Aspirin Recurrent Stroke Study. It is well established that left atrial (LA) size
is associated with risk of atrial fibrillation (AF), a condition which warrants anticoagulation for stroke
prevention. We sought to determine whether LA diameter at the time of stroke could be a useful
predictor of subsequent AF in stroke patients presenting without a known history of AF. Methods:
Using a prospective database collected on consecutive ischemic stroke patients at the Massachusetts General Hospital, patients with no history of atrial fibrillation on admission were identified, and
all subsequent parenchymal and cerebrovascular imaging, electrocardiography (ECG), transthoracic
echocardiography, and Holter monitoring data analyzed. All echocardiograms were performed in a
single laboratory. LA diameter was analyzed as a dichotomous variable (⬍ or ⬎ 38 mm), based on
the upper limit of normal for the laboratory. All stroke subytyping was performed by a single stroke
neurologist using the TOAST classification. Final determination of AF was based on analysis of
aggregate cardiac monitoring data available at 6 months. Results: Data on 645 patients with no
previous history of atrial fibrillation were analyzed. Of these, 66 (10.2%) were discovered to have
atrial fibrillation within 6 months of stroke onset. The mean age was 67.0 (⫹/-12.1) and 32% were
female. All patients had at least 24-hour cardiac monitoring in addition to an admission ECG. LA
diameter⬎ 38 mm was present in 31% of “cryptogenic” strokes and 69% of those with
documented AF. Patients with an LA diameter ⬎ 38 mm had an OR of 3.0 [95%CI 1.8, 5.1] for being
diagnosed with AF at 6-months compared to those with LA diameter ⬍ 38 mm. Every one
millimeter increase in LA diameter was associated with a 10% higher risk of being diagnosed with
atrial fibrillation. Conclusion: In patients without a clear high risk cardioembolic source at time of
presentation, left atrial enlargement (⬎ 38 mm diameter) identified a population with a 3-fold higher
rate of atrial fibrillation. In cases of cryptogenic stroke, even in the absence of AF on ECG, left atrial
enlargement may identify a subset of patients with PAF who would benefit from more extensive
cardiac monitoring and consideration of warfarin therapy for secondary stroke prevention.
123
Validation of a Swallow Screening Tool in Acute Neuroscience Patients.
Tessa Goldsmith, Elizabeth Cadogan, Karen L Furie, Lee H Schwamm, Aneesh B Singhal,
Carmen Vega-Barachowitz, Hang Lee, Audrey Kurash Cohen; Massachusetts General Hosp,
Boston, MA
Introduction: Early identification of aspiration risk before administration of oral intake (food, fluids
or medications) in acute stroke patients is an initiative to reduce morbidity from aspiration
pneumonia that is shared by all the national stroke quality improvement programs (JCAHO, CDC,
AHA). There is a paucity of validated, simple screening tools that permit detection of aspiration risk
and suspected oropharyngeal dysphagia. Methods: We developed the Massachusetts General
Hospital-Swallow Screening Tool (MGH-SST), a weighted 6-item test of dysphagia using factors
known to predict aspiration risk with high sensitivity (tongue mobility, vocal quality, pharyngeal
sensation, cough and water swallow). The MGH-SST, which requires less than 5 minutes to perform
and score, was administered by trained research nurses. Results were compared to a reference
standard of dysphagia assessment, namely fiberoptic endoscopic evaluation of swallowing (FEES)
performed within 1 hour of MGH-SST by a speech-language pathologist (SLP). Three SLPs reviewed
each FEES video-recording and classified subjects by consensus as either “safe” or “unsafe” to eat
according to pre-specified criteria. Both the nurses and the SLPs were blinded to the patient’s
diagnosis and each others test results during testing and interpretation. Intraclass coefficients (ICC)
were calculated for Nurse interrater reliability on 30 independent, non-study patients. Results: Of
1868 consecutive admissions to the neurological and neurosurgical services screened from
8/06 – 4/07, 253 patients who had acute neurological injury with risk for dysphagia and were
appropriate to undergo FEES were approached. Of 124 who consented to participate, 100 subjects
were able to fully cooperate with FEES. They were 37% male, aged 23– 88 yr, 38% neurosurgical.
There were no significant differences between raters for MGH-SST, and the level of concordance
was high (ICC, 0.92; analysis of variance F⫽1.3). The MGH-SST performed with high rates of
sensitivity among the stroke subjects and the entire subject population. Discussion: The MGH-SST
is an easy-to-use, reliable and effective screening tool for dysphagia when done by trained nurses.
It rapidly identifies patients who are safe to eat, and protects those with questionable swallowing
function so that limited SLP resources can be devoted to those in most need of further assessment
and treatment. Further validation is needed in larger cohorts and at other centers.
All Patients (n⫽100)
Dysphagia
FEES-
(FEES) ⫹
FEES-
41
5
21
33
24
3
10
17
(MGH-SST) Positive
(MGH-SST) negative
122
Ability of the ABCD2 Clinical Prediction Rule to Identify Low-Risk TIA
Cases in Community-Based Emergency Departments.
Mathew J Reeves, Julia Warner Gargano, Susan Wehner, Michigan State Univ, East
Lansing, MI; Michael Brown, MERC, Michigan State Univ, Grand Rapids, MI; Ted Glynn,
Mary Hughes, Arshad Majid, Michigan State Univ, East Lansing, MI; Rashmi Kothari;
Michigan State Univ, Kalamazoo, MI
Introduction: The ABCD2 clinical prediction rule was developed to risk stratify TIA patients in order
to inform treatment and management decisions. In the emergency department (ED) setting, the
ability to identify the sub-group of patients who are at low-risk of stroke and other adverse events
has the most potential clinical utility. Our objective was to prospectively validate the ABCD2 rule in
4 community-based EDs and determine its ability to identify low-risk TIA cases. Methods: Over a 12
month period TIA cases were prospectively identified by trained research staff in 4 universityaffiliated community-based EDs. Eligible cases had to have an ED-based diagnosis of TIA or an
acceptable equivalent label (i.e., rule out TIA or stroke, or description of acute onset focal unilateral
symptoms), a total duration of symptoms of ⬍24 hours, and no alternative final discharge diagnosis.
Data required to calculate the ABCD2 score (i.e., age, blood pressure, clinical feature of unilateral
weakness or speech impairment, duration of symptoms, and diabetes) were abstracted from the
charts. Cases were categorized into 2 risk groups based on their ABCD2 score i.e., moderate-high
risk (ABCD2 ⫽ 4 –7) or low risk (ABCD2 ⱕ 3). All eligible cases consented to provide follow-up
information 90-days post discharge. The sensitivity, specificity and predictive values of the
dichotomized risk score (moderate-high risk versus low risk) were estimated based on a composite
90-day outcome measure of stroke, recurrent TIA, other cardiovascular hospitalization, or death.
Results: A total of 358 eligible cases were enrolled, and 90-day outcomes data were available for
338 subjects (94%). Overall, 32% of the cases were under 60 years of age, 54% were women, and
31% were non-white. The overall composite 90-day event rate was 14.5% (n⫽ 49), while the
90-day event rates for stroke, recurrent TIA, cardiovascular hospitalization, and death were 2.4%,
10.4%, 2.7%, and 1.2%, respectively. The sensitivity, specificity, positive and negative predictive
values for the composite event were 84% (95% confidence interval (95% CI) ⫽ 71–92%), 30%
(95% CI⫽ 25–35%), 17% (95% CI⫽ 12–22%), and 92% (95% CI⫽ 86 –97%), respectively. Among
the 95 subjects (28%) who were categorized into the low risk group, there were no stroke events
and only 8 (8.4%) other relevant end points during follow-up. Conclusions: In this series of TIA cases
prospectively enrolled in 4 community-based EDs, the ABCD2 prediction rule was able to accurately
identify the sub-set of cases that were at low risk of clinical events over a 90-day follow-up period.
The ABCD2 rule has potential utility in identifying low risk TIA cases that could be considered for
expedited outpatient management.
All Subjects
Stroke pts.
Stroke Subjects (n⫽54)
FEES ⫹
Sensitivity
[95% CI]
Specificity
[95% CI]
Pos Predict Val
[95% CI]
Neg Predict Val
[95% CI]
0.89[0.80,0.95]
0.89[0.77,0.96]
0.61[0.53,0.66]
0.63[0.51,0.70]
0.66[0.59,0.70]
0.71[0.61,0.76]
0.87[0.76,0.94]
0.85[0.69,0.94]
124
Neurovascular Phenotypes Among Children with Ruptured Idiopathic
Intracranial Arterial Aneurysms, and Comparison with the Adult Phenotype.
Todd Abruzzo, Univ of Cincinnati Med Cntr, Cincinnati, OH; Lynn Serrano, Cincinnati
Children’s Med Cntr, Cincinnati, OH; H Kocaeli, Univ of Cincinnati Med Cntr, Cincinnati, OH;
B Jones, Cincinnati Children’s Med Cntr, Cincinnati, OH; N Zumberge, Columbus Children’s
Hosp, Columbus, OH; F Mangano, Cincinnati Children’s Med Cntr, Cincinnati, OH; M
Zuccarello; Univ of Cincinnati Med Cntr, Cincinnati, OH
INTRODUCTION: The vascular pathology literature conceptualizes intracranial arterial aneurysms
(IAA) as chronic degenerative lesions that develop over decades due to hemodynamic wear and tear.
Although IAA of childhood are a rare entity, they are a contradiction to this model and may represent
the product of a different pathogenetic process. To address this possibility, we investigated whether
ruptured IAA phenotypes seen in childhood differ from those in adults. MATERIALS AND METHODS:
Part 1Patients under age 19 years (y) with ruptured IAA were retrospectively identified by searching
clinical registries and databases from 01/93 to 11/06 at 3 tertiary referral hospitals We queried
hospital radiology reports, clinic and angiography logs using the search term “aneurysm. Patients
with traumatic, infectious, neoplastic, inflammatory and flow related aneurysms were excluded from
analysis. Pathogenetic risk factors were documented. Part 2- A published study of 5358 adult
patients with ruptured IAA was reviewed. Epidemiological data, as well as, IAA anatomical and
metric characteristics were available for 3521 patients in this study. Aneurysm morphology was
available for all 5358 adult patients. We compared these adult patients to the pediatric patients.
RESULTS: 33 children with 40 idiopathic IAA were initially confirmed. Among these, 16 children with
21 IAA presented with rupture. Comparison data for the pediatric and adult cohorts are presented
in Table 1. Pediatric patients are subcategorized: 19 school age children ⬍ age 13y (subgroup A)
and 15 adolescents ⱖ 13 y (subgroup B). Fusiform lesions accounted for 4/10 IAA in subgroup A,
2/11 IAA in subgroup B and 59/5358 IAA in the adult group. CONCLUSIONS: Unique characteristics
of the ruptured idiopathic IAA phenotype seen in children include increased male predominance,
predilection for the posterior circulation, and greater frequency of giant and fusiform aneurysms.
Comparison of IAA phenotypes between adults, adolescents and school age children demonstrates
a stepwise trend toward increasing multiplicity, and decreasing frequency of giant and fusiform
aneurysms with advancing age. Although IAA in children may represent a unique biological
phenotype, it is possible that absence of traditional vascular risk factors such as smoking, and
long-term cumulative exposure to hemodynamic stress, select more potent forms of the same
functional variants in vessel wall biology for clinical expression. References for Adult Study Series
Kassell, NF. The International Cooperative Study on the Timing of Aneurysm Surgery. J Neurosurg
73:37– 47, 1990.
TABLE 1
Age, Gender,
Size & Location
Average Age (y)
Male/Female Ratio
Multiplicity
Giant ⬎25mm
Large 13–24mm
Sm/Med ⬍12mm
Anterior Cerebral Circulation
Posterior Circulation
Totals
N⫽ 16 n⫽21
School age
children
(Subgroup A)
N⫽ 7 n⫽10
Adolescents
(Subgroup B)
N⫽ 9 n⫽11
Adult
n⫽3521
N⫽3521
10.4
1.3
3 (.13)
3 (.14)
5 (.24)
13 (.62)
13 (.62)
8 (.38)
5.3
1.3
1 (.10)
2 (0.20)
1 (0.10)
7 (0.70)
7 (.70)
3 (.30)
15.4
1.3
2 (.18)
1 (.09)
4 (.36)
6 (.54)
6 (.55)
5 (.45)
50.4
.6
668 (.19)
70 (.02)
703 (.20)
2748 (.78)
3211 (.92)
266 (.08)
n ⫽ number of aneurysms, N⫽ number of patients.
125
Stroke Risk Factors Are Predictive of Cognitive Decline in the Absence of
Clinically Diagnosed Incident Stroke.
George Howard, Virginia G Wadley, Univ Alabama Birmingham, Birmingham, AL; Frederick W
Unverzagt, Indiana Univ Sch of Medicine, Indianapolis, IN; Nancy Jenny, Univ of Vermont,
Burlington, VT; Rodney C Go, Univ Alabama Birmingham, Birmingham, AL; Mary Cushman, Univ
of Vermont, Burlington, VT; Claudia S Moy, National Institute of Neurological Disorders and
Stroke, Bethesda, MD; for the REasons for Geographic and Racial Differences in Stroke
(REGARDS) Investigators
Introduction: While it is reasonable to hypothesize that stroke risk factors contribute to cognitive
decline, the literature to date is inconsistent. In order to direct prevention efforts, it is important to
identify which stroke risk factors are most closely associated with cognitive decline. Methods: We
assessed these relationships in REGARDS, a national longitudinal cohort study currently recruiting
30,000 African American and white participants aged 45 and older from the 48 contiguous states.
Cognitive function is being assessed by several scales, including the Six-Item Screener of global
cognitive status, conducted by telephone at baseline and annually during follow-up. 17,626
participants (mean baseline age 65.7) were stroke free at baseline and had at least two cognitive
function assessments (9,256 with two, 7,034 with three, and 1,336 with four). Observation time was
censored after a suspected stroke during follow-up (censoring 524 assessments in 369 participants). Relationships between “traditional” Framingham stroke risk factors (see table) and change
in cognitive status were assessed using a mixed model statistical approach. The difference in the
annual change in the age-race-sex adjusted number of items correctly answered on the Six-Item
Screener (0 - 6) between those with and without each risk factor were estimated. Results: The
average age, race, sex adjusted annual change in cognitive score (number of items correctly
answered) was -0.059 items. Participants at higher risk for subsequent stroke as indexed by the
Framingham Stroke Risk Score (FSRS) had significantly (p ⬍ 0.0001) more rapid decline in cognitive
performance, with a 10% higher FSRS associated with an annual change of -0.028 ⫹ 0.004 (see
Table), a difference approximately a 50% as great as the annual average rate of decline in cognitive
scores (-0.059). Individual FSRS components of left ventricular hypertrophy (LVH) (0.036 ⫹ 0.014
larger annual decline for those with LVH; p ⫽ 0.01), diabetes (0.019 ⫹ 0.009 larger annual decline
for those with diabetes; p ⫽ 0.03), and higher systolic blood pressure (0.008 ⫹ 0.003 larger decline
for each 10 mmHg; p ⫽ 0.01) were associated with more rapid declines in cognitive function.
Discussion: Even in the absence of clinically diagnosed incident stroke, in a general population
stroke risk factors were strongly related to more rapid cognitive decline. Further study is needed on
whether interventions for stroke risk factors, in particular LVH, hypertension and diabetes, may
decrease rates of cognitive decline.
DIFFERENCE IN THE ANNUAL CHANGE IN AVERAGE SIX-ITEM SCORE ATTRIBUTABLE TO
THE RISK FACTOR
Risk Factor
Framingham Stroke Risk Function (1
SD difference)
SBP (1 SD change)
Current BP Medications
Diabetes
Current Smoking
Hx Heart Disease
Atrial Fibrillation
Left Ventricular Hypertrophy
Estimate
Standard Error
p-Value
-0.028
0.004
⬍0.0001
-0.008
-0.005
-0.019
0.018
-0.011
-0.021
-0.036
0.003
0.007
0.009
0.010
0.008
0.013
0.014
0.015
0.49
0.033
0.077
0.20
0.11
0.0090
For the FSRS and each component individually, the table provides the age, race and sex adjusted estimated
difference in the annual change in the number of questions in the 6-item screener correctly answered.
126
Variants in The Monocyte Chemoattractant Protein-1 (MCP-1) and
Chemokine Receptor-2 (CCR2) Genes Act Synergistically to Increase the
Risk of Carotid Atherosclerosis.
Paul A Nyquist, Johns Hopkins, Baltimore, MD; Cherie A winkler, National Cancer Institute,
Frederick, MD; Louise M McKenzie, National Cancer Institute, Baltimore, MD; Lisa R Yanek,
Lewis C Becker, Diane M Becker; Johns Hopkins, Baltimore, MD
Background: MCP-1 mediates recruitment of macrophages into atherosclerotic plaque. CCR2 is its
receptor. Recently an independent association has been noted between the single nucleotide
559
polymorphism (SNP) in the MCP-1 promoter region rs1024611 with myocardial infarction. A Similar
relationship has been observed for the biologically active SNP in CCR2 known as CCR2 V64I.
Because MCP-1 is important in the development of atherosclerosis, we explored the region around
the MCP-1 gene and its receptor CCR2, to identify synergy between the two regions in the
development of carotid atherosclerosis. Methods: Five SNPs were genotyped around the MCP-1
region: rs1024611, rs1024610, rs2857656, rs2857657, rs4586. One SNP in CCR2 was genotyped:
CCR2 V64I. All SNPs were characterized using Taqman. The study population included 465 healthy
brothers (37%) and sisters (63%) (mean age, 46 ⫾ 7 years) of 280 probands with premature CAD
(⬍ 60 years of age). Carotid artery duplex ultrasonography demonstrated echogenic evidence of
carotid plaque (densities ⬎1mm) in 95 subjects (20%). Using unadjusted ␹2 analyses, we examined
associations between each chosen individual SNP and the presence of carotid plaque. We then
constructed a multivariable logistic model adjusting for age, sex, race, education, diabetes, smoking,
hypertension, obesity, LDL-cholesterol, and non-independence within families. We incorporated
SNPs that were associated with carotid atherosclerosis in the unadjusted analysis into the model.
This was done individually and in combination to identify individual as well as synergistic
associations between genes. Results: In the unadjusted analyses, only the MCP-1 rs2857656 SNP
and the CCR2 V64I were individually associated with carotid plaque (P⫽0.05 and P⫽0.03,
respectively). In the multivariable adjusted analysis two associations were identified. The homozygous CC genotype at rs2857656 was independently associated with carotid artery plaque, O.R. 2.02
(95% CI 1.02– 4.03, P⫽ 0.04) (N⫽14). In addition we observed a significant epistatic interaction
between MCP1 and CCR2. Patients with a combination of homozygous MCP1 CC rs2857656 and
heterozygous CCR2 V64I had a significantly higher risk of carotid atherosclerosis OR⫽7.21, (95%
CI⫽1.83–28.33, P⫽0.0048) (N⫽13). Conclusion: The homozygous MCP1 CC rs2857656 genotype
independently predicts the risk for the development of carotid plaque. The combination of a
homozygous (MCP1 CC rs2857656) genotype in the ligand and a heterozygous (CCR2 V64I)
genotype in the receptor act synergistically to predict the risk of preclinical carotid artery plaque.
127
Timing Of Microbubble-enhanced Sonothrombolysis Strongly Predicts
Intracranial Hemorrhage In Acute Ischemic Stroke.
Lavinia Dinia, Marta Rubiera, Marc Ribo, Estevo Santamarina, Olga Maisterra, Raquel
Delgado-Mederos, Jorge Pagola, Jose Alvarez-Sabin, Joan Montaner, Carlos A Molina; Hosp
Vall D Hebron, Barcelona, Spain
Background. Although ultrasound-activated microbubbles (MB) accelerates clot lysis, MB
activation has shown to promote blood barrier disruption and hemorrhagic transformation in
animal models. We conducted a case-control study aimed to investigate the risk of HT after
MB-enhanced sonothrombolysis in acute stroke. Patients and Methods We prospectively
evaluated 188 patients with acute stroke related to MCA occlusion and treated with i.v. tPA ⬍
6 hours of stroke onset. Patients received continuous 2-hour TCD monitoring plus 3 doses of
2.5 g of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These
patients were compared with 98 historical stroke patients treated with tPA plus 2-hour TCD
monitoring (control group). Both timing and degree of recanalization during first 12 hours of tPA
bolus were recorded. Presence and extend of HT on 24-h CT was blinded assessed as HI1,HI2,
PH1 and PH2. Results: Median baseline NIHSS was 17. Age, baseline NIHSS, clot location,
early CT findings, stroke subtype and time to treatment were similar between MB and control
group. Recanalization rates at 1h (32.2% vs 21%) , 2h (50.0% vs 36.7%), 6 h (63.8%/
44.5%)and 12 h (74.3%/56.2%) were significantly higher in the MB compared to the control
group (p⬍0.05). MB administration was significantly associated with an increased risk of
HI1-H2 ( 21% vs 12% , p⫽0.026 OR 5.8 95% IC 2.1– 65 ), and higher degree of clinical
improvement at 24 h (54.9% / 31.1%, p⫽0.004). PH1-PH2 (3.3% vs 3.8%; p⫽0.8) and
symptomatic ICH rates (2.9% / 2.1%, p⫽0.580) were comparable in both groups. Moreover,
the extend of bleeding after MB-enhanced sonothrombolysis was linked to the time-toreperfusion. Early (⬍6h) recanalization independently predicted HI in the MB group (OR 6.3
95% IC 2.3–56) but not in the control group. Delayed (⬎6h) or no recanalization (⬎6h) was
significantly associated with PH1-PH2 in both MB ( p⫽ 0.024) and control group (p⫽ 0.045)),
respectively. Conclusion: The extend of bleeding after MB-enhanced sonothrombolysis is
linked to the time-to-reperfusion. MB administration is associated with early recanalization and
high rate of HI1-HI2 , but it does not increase the risk of symptomatic ICH.
128
The Clinical Effect of Mild Hemorrhagic Transformation after Acute
Intra-arterial Revascularization Therapy: An Exploratory Analysis.
Pooja Khatri, Univ of Cincinnati, Cincinnati, OH; Renee’ Martin, Med Univ of South Carolina,
Charleston, SC; Thomas A Tomsick, Univ of Cincinnati, Cincinnati, OH; Yuko Y Palesch, Med
Univ of South Carolina, Charleston, SC; Michael D Hill, Univ of Calgary, Calgary, Canada;
Joseph P Broderick, Univ of Cincinnati, Cincinnati, OH; for the IMS I and II Investigators
BACKGROUND: Recent intra-arterial (IA) trials have reported higher rates of mild hemorrhagic
transformation (HT) compared to IV trials. In addition, acute stroke trials have varied in their
assessment and recording of asymptomatic hemorrhage subtypes. To our knowledge, the clinical
effects of mild HT have not been addressed in the context of IA or combined IV/IA stroke therapy.
We hypothesized that patients with mild HT after IV/IA therapy would have similar rates of poor
clinical outcome (modified Rankin Score 3– 6 at 3 months) compared to those with no HT.
METHODS: The Interventional Management (IMS) I and II trials used low-dose IV tPA (0.6 mg/kg),
followed by IA tPA (up to 22 mg), for large ischemic strokes (NIHSSⱖ10) within 3 hours of onset
(n⫽161). In IMS II, low-energy ultrasound via the EKOS MicroLysus® Catheter was also used
whenever possible. Routine CT was done at 24 ⫾ 6 hours. Varied definitions of mild ICH (using
ECASS criteria) were considered in this analysis: (1) hemorrhagic infarction (HI)-1, (2) combined HI-1
and HI-2, and (3) asymptomatic ICH, defined as not associated with clinical deterioration per the
560
Stroke
Vol 39, No 2
February 2008
local investigator. Stepwise logistic regression models were developed. Age, baseline NIHSS score,
sex, history of prior stroke, diabetes, baseline glucose, baseline systolic blood pressure, time to IV
treatment, and infarct volume were tested as covariates. RESULTS: Mild HT cases consisted of 60
asymptomatic ICHs (20 HI-1, 19 HI-2, 19 PH-1, and 2 PH-2), and 1 symptomatic HI-2. In unadjusted
analysis, all three definitions (HI-1, combined HI-1 and HI-2, and asymptomatic) were significantly
associated with poor clinical outcome (OR 4.08, 95% CI 1.43–11.67; OR 4.61, 95% CI 2.04 –10.46;
4.92, 95% CI 2.40 –10.08, respectively), compared to cases with no HT. In adjusted analyses, we
saw no association between HI-1 or combined HI-1 and HI-2 with clinical outcome. However,
asymptomatic HT was associated with poor clinical outcome (OR 2.57; 95% CI 1.07– 6.19), as were
gender (OR 2.72; 95% CI 1.16 – 6.45), baseline glucose (OR 1.01; 95% CI 1.00 –1.02; p⫽0.03), and
infarct volume (OR 1.02; 95% CI 1.01–1.03). CONCLUSIONS: We did not show an independent
association between HI-1 and HI-2 after IA therapy and clinical outcome. Whether this is due to a
lack of association or the small sample size cannot be determined from this exploratory analysis.
This analysis also suggests that the broad definition of asymptomatic HT, which includes PH-1 and
PH-2, may be independently associated with poor outcome. Our data indicate that trials should
continue to monitor asymptomatic HT, particularly PH-1 and PH-2, as a secondary safety endpoint
based on routine 24-hour imaging. PH-1 and PH-2 may affect outcome and be missed by monitoring
only variably defined “symptomatic” HT. The hypothesis that subtypes of asymptomatic HT after IA
revascularization are relevant to clinical outcome will be tested in the IMS III trial.
baseline NIHSS score, sex, and baseline glucose– using stepwise logistic regression. RESULTS:
Fifty-four cases were identified with ICA-T (n⫽8) and M1 (n⫽46) occlusions and reperfusion.
⌬TReperfuse ranged from 208 to 395 minutes. Mean baseline NIHSS scores were 18.6 (range
10 –28) for these 54 cases, compared to 19.9 (range 10 –27) for the 38 cases without
reperfusion (TICI 0 –1). Only ⌬TReperfuse (OR 0.981; 95% 0.967– 0.995) and age (OR 0.949; 95%
CI 0.903– 0.998) independently predicted good clinical outcome after reperfusion. Both
adjusted and unadjusted analyses showed that the probability of good clinical outcome
decreased as ⌬TReperfuse increased (p⫽0.009 and p⫽0.02, respectively). The graph below
shows the probability of a good clinical outcome over time (with 95% prediction bands) for
cases with reperfusion, and a horizontal line depicting the rate of good clinical outcome for
cases without reperfusion as a reference: CONCLUSIONS: We provide the first angiographic
evidence in a clinical trial that good clinical outcome following reperfusion with IA therapy is
strongly time-dependent. Opening an artery is not enough; time matters. At later times,
reperfusion may be associated with a poor risk-benefit ratio.
129
Implant For Augmentation Of Cerebral Blood Flow Clinical Trial-(ImpACT-1).
An Interim Analysis Of Safety And Effectiveness Of The Neuropath Is
System In The Treatment Of Acute Ischemic Stroke.
Subhash Kaul, Nizam’s Institute of Med Sciences, Nizam, India; Dheraj Khurana, Postgraduate
Institute of Med Education & Rsch, Chandigarh, India; Attila Csáni, Petz Hosp, Gyor, Hungary;
Nasli Ichaporia, Jehangir Hosp, Pune, India; Dietmar Schneider, Univ of Leipzig, Leipzig,
Germany; Christoph Lichy, Heidelberg Univ Clinic, Heidelberg, Germany; Sagit Weiss, David Katz,
Avinoam Dayan, BrainsGate LTD, Caesarea, Israel; Yoram Solberg, Brainsgate LTD, Caesarea,
Israel; Menashe Levy, BrainsGate LTD, Caesarea, Israel; David Tanne, Chaim Sheba Med Cntr,
Tel-Hashomer, Israel; David Yarnitsky, Rambam Hosp, Haifa, Israel; Marc Fisher, Univ of
Massachusetts Med Sch, Worcester, MA; Werner Hacke, Heidelberg Univ Clinic, Heideleberg,
Germany; Natan Bornstein; Tel Aviv Med Cntr, Tel Aviv, Israel
Background: In rat stroke models, sphenopalatine ganglion (SPG) stimulation up to 24 hours
after stroke onset augments cerebral blood flow, reduces the infarct volume and improves
neurological deficits. We present preliminary safety and effectiveness data of SPG stimulation with
the NeuroPath IS System in patients with acute ischemic stroke (AIS). Design: This is an ongoing
multi-national open label study recruiting 70 patients with AIS, age 18 – 85 years, NIHSS 7–20,
treatment initiated within 24 hours following stroke onset. The NeuroPath IS System is implanted
adjacent to the SPG via the greater palatine canal by a minimally invasive surgery (20 min., local
anesthesia). The therapeutic regimen consists of 3hr/d of stimulation over 7 days. The primary
endpoint is the incidence of AE and SAE, the secondary endpoint is the effectiveness of SPG
stimulation as measured by NIHSS, mRS and BI at day 90. Results: To date 48 patients have been
enrolled. Among the 23 who completed the study, mean age is 53 yrs, mean time to treatment is
17.7 hr, mean baseline NIHSS 11.7 with a mean baseline motor score of 6.1. Twenty-three patients
having completed treatment per protocol and having the 60 day and 90 day follow-up data were
compared to NINDS tPA control patients (with a baseline NIHSS 7–20): 57% of patients had a
favorable outcome (mRS: 0 –2) compared to 29% among the NINDS control patients (p⫽0.0087).
When the range of mRS distributions were compared, the SPG group also had a significantly better
outcome (p⫽ 0.0135, CMH test). In the whole population (n⫽48), there were 7 deaths; none was
related to study treatment: among them, one patient had no system implanted, 3 patients had
massive stroke, 2 died during follow-up and 1 patient had his treatment interrupted after 4 days.
There was an additional SAE, (recurrent stroke with hemorrhagic transformation) and 5 AE’s (1 brain
edema associated with a 1 point worsening on NIHSS; 2 wound dehiscence and 2 mal-positioning).
Conclusion: This interim analysis suggests that SPG stimulation appears to be safe and potentially
promising for the treatment of AIS when initiated within 24hours after symptom onset. In this pilot
study the NeuroPath IS System was easily and safely implanted. Further recruitment is ongoing.
130
Good Outcome after Technically Successful Intra-Arterial Therapy is
Time-Dependent.
Pooja Khatri, Todd Abruzzo, Univ of Cincinnati, Cincinnati, OH; Sharon D Yeatts, Med Univ of
South Carolina, Charleston, SC; Joseph P Broderick, Thomas A Tomsick, Univ of Cincinnati,
Cincinnati, OH; for the IMS I and II Investigators
BACKGROUND: IV thrombolysis trials have taught us that “time is brain,” specifically the time
from stroke onset to the initiation of therapy. Transcranial doppler studies support the
importance of timing. We sought to determine how time from stroke onset to technically
successful reperfusion (⌬TReperfuse) affects clinical outcome in the context of intra-arterial (IA)
treatment and angiographic assessment in the Interventional Management of Stroke (IMS) I and
II trials. METHODS: The IMS trials used low-dose IV rt-PA (0.6 mg/kg), followed by IA rt-PA (up
to 22 mg), for large ischemic strokes (NIHSSⱖ10) within 3 hours of onset. In IMS II, low-energy
ultrasound via the EKOS MicroLysus姞 Catheter was also used whenever possible. To isolate the
effect of ⌬TReperfuse, we only analyzed angiographic M1 and ICA-T occlusions reperfused (TICI
2–3) during the interventional procedure (ⱕ7 hours). ⌬TReperfuse was defined as time from
stroke onset to procedure termination. Good clinical outcome was defined as modified Rankin
Score 0 –2 at 3 months. Adjustments were made for known predictors of clinical outcome–age,
131
Number Needed To Treat Estimates For tPA Per 90-minute Time Interval.
Maarten G Lansberg, Stanford Univ, Palo Alto, CA; Erich Bluhmki, Boehringer Ingelheim,
Ingelheim, Germany; Jeffrey L Saver; UCLA, Los Angeles, CA
Introduction: Number needed to treat to benefit (NNTB) and number needed to treat to harm
(NNTH) estimates provide physicians and patients with a statistically valid summary measure
that they may use intuitively to determine if a treatment effect is clinically worthwhile. When
NNT estimates are based on a dichotomization of an ordinal outcome scale, they may
underestimate the true treatment effect size. Objective: The aim of this study was to
determine, using the entire range of the modified Rankin Scale (mRS) as the outcome variable,
NNTB and NNTH estimates for tPA therapy administered within 90 minutes of symptom onset,
between 91–180 minutes, between 181–270 minutes, and between 271 and 360 minutes.
Methods: Data from the pooled analysis of the NINDS Part 1 and 2, ECASS I and II, and
ATLANTIS A and B trials were used. Two experts generated for each 90-minute treatment time
window joint distribution outcome tables in model samples of 1000 patients assigned to
placebo and tPA therapy. Results: Average NNTB estimates for patients treated in the 0 –90
minute time-window, the 91–180 minute time-window, the 181–270 time-window, and the
271–360 minute time-window were 3.6, 4.7, 6.0, and 16.5. NNTH estimates for these timewindows were 69, 43, 27 and 14. When the mRS was condensed to six strata (combining mRS
scores 5– 6) or five strata (combining mRS scores 4 – 6) NNTB estimates did not change, whereas
NNTH estimates increased. With the mRS reduced to five strata the NNTH estimates for the four
90-minute time-windows were 167, 97, 68 and 25 respectively. Conclusions: When 100 patients
are treated with intravenous tPA within 90 minutes of symptom onset 28 experience a treatment
benefit and one is harmed. With longer time-to-treatment windows the benefit gradually declines
and the potential for harm increases. In the 271–360 minute time-window, out of 100 patients
treated with tPA, only six experience a benefit and seven are harmed.
132
Quality Indicators For Primary Stroke Centers.
Anna Bersano, Monica Gattinoni, Dept of Neurological Sciences Fondazione Ospedale
Maggiore Policlinico, Milan, Italy; Alberto Morabito, Cattedra di Statistica medica, Univ of
Milan, Milan, Italy; Roberto Sterzi, SC Neurologia, Ospedale Niguarda Ca’ Granda, Milan,
Italy; Giuseppe Micieli, UO Neurologia I/Stroke unit, Istituto Clinico Humanitas,Rozzano,
Milan, Italy; Pierluigi Baron, Livia Candelise; Dept of Neurological Sciences Fondazione
Ospedale Maggiore Policlinico, Milan, Italy
Background/Objective: The creation of Primary Stroke Center (PSCs) is strongly recommended (Class I, Level of Evidence B) by the recent AHA guidelines (Stroke2007;38:1655–
711.). Brain Attack Coalition (BAC) group identified six qualifying major elements for PSC: stroke
unit, acute stroke team, written protocol, emergency medical service, emergency department
and neurosurgery service (JAMA 2000;283:3102–3109). We aim to assess the prognostic value
of these six quality indicators for acute stroke care. Methods: We evaluated 11572 stroke
patients hospitalised within 48 h of symptoms onset recruited in the PROSIT study (Lancet
2007;369:299 –305). Multifactorial logistic regression analysis was performed to assess the
association between the six quality indicators and long term outcome (two year death or
disability condition) adjusting for patients characteristics (age, sex, time from stroke onset,
intracranial haemorrhage, atrial fibrillation, level of consciousness). Results: Overall 6723
patients were dead or disabled at the two years follow-up. Stroke unit care was associated with
a reduced probability of unfavourable outcome [OR 0.81 (95%CI: 0.72– 0.91; p⫽0.0001)]. None
of the other five PSCs qualifying elements was statistically significant associated with stroke
outcome: acute stroke team [OR 0.76 (95%CI 0.47–1.22)], written protocol [OR 0.82 (95%CI
0.51–1.31], emergency medical service [OR 0.99 (95%CI 0.65–1.52)], emergency department
[OR 1.06 (95%CI 0.49 –2.29)] and neurosurgery service [OR 1.27(95%CI 0.84 –1.89]. Moreover
any specific element of setting, staffing, process of care and diagnostic exams availability was
associated with outcome except for MRI scan 24 h a day, 7 days a week [OR 0.69 (95%CI
0.51– 0.89]. Conclusion: These results should be considered before beginning a formal
process of PSCs certification.
561
white women. F1.2 and TAT were highly correlated with each other (r⫽0.652, p⬍0.0001). With
the exception of PAI-1 (no relationship), markers of thrombin generation and fibrinolysis were
associated with the 90-day NIHSS in AA women (TAT: r⫽0.58, p⫽0.0002; F1.2: r⫽0.332;
p⫽0.045; D-dimer: r ⫽ 0.545, p⫽0.001). There were no relationships between any of these
markers and outcome in white women (TAT: r ⫽ 0.02, p⫽0.9; F1.2: r ⫽ -0.263, p⫽0.146;
D-dimer: r ⫽ 0.28, p ⫽ 0.13). The correlation coefficients were different between AA and white
women for TAT (z score ⫽ 2.50, p⫽0.012), but not F1.2 or D-dimer. In AA women (n⫽37),
atrial fibrillation (p⫽ 0.035), TAT (p⫽0.058) and D-dimer (p⫽0.053) were independently
associated with 90-day NIHSS (model R2 ⫽ 0.67 with adjustment for initial NIHSS). An
otherwise identical model including F1.2 instead of TAT yielded similar results. In white women
(n⫽32), increasing age (p⫽0.001) and the presence of coronary heart disease (p⫽0.026) were
independently associated with 90-day NIHSS (model R2 ⫽ 0.76). Conclusions: Factors
associated with greater stroke severity at 90 days differed between African American and white
women with ischemic stroke. Elevated markers of thrombin generation and fibrinolysis were
associated with outcome in African American but not white women. Differences in thrombin
generation and fibrinolysis may in part explain race-ethnic differences in outcome in women
after ischemic stroke.
133
AX200 (G-CSF) for the Treatment of Acute Ischemic Stroke (AXIS).
Wolf R Schäbitz, Dept of Neurology, Univ, Münster, Germany; Rico Laage, Sygnis
Bioscience, Heidelberg, Germany; Stefan Schwab, Dept of Neurology, Univ, Erlangen,
Germany; Dietmar Schneider, Dept of Neurology, Univ, Leipzig, Germany; Gerhard Hamann,
Dept of Neurology, Wiesbaden, Germany; Michael Rosenkranz, Dept of Neurology, Univ,
Hamburg, Germany; Roland Veltkamp, Dept of Neurology, Univ, Heidelberg, Germany; Marc
Fisher, Dept of Neurology, Univ, Massachusetts, Worcester, MA; Jim Grotta, Dept of
Neurology, Univ, Texas, Houston, TX; Werner Hacke, Dept of Neurology, Univ, Heidelberg,
Germany; Armin Schneider, Sygnis Bioscience, Heidelberg, Germany; for the AXIS study
group
Background: The hematopoietic factor G-CSF (AX200) inhibits apoptotic cell death and
stimulates neural progenitor differentiation in the ischemic brain. In a number of different
animal stroke models G-CSF (AX200) robustly decreased infarct volume and enhanced
functional recovery. To date, more than a dozen animal stroke studies have been published that
show efficacy of G-CSF in experimental ischemia. To translate these experimental results into
the clinic, a national, multicenter, randomized, placebo-controlled phase IIa trial (AXIS) was
initiated in December 2004. Methods: G-CSF (AX200) was administered in 4 increasing doses
(30, 90, 135, 180 ␮g/kg bodyweight over 72 h) as i.v. infusion (30 patients) and compared to
placebo (14 patients). Inclusion criteria included onset of stroke symptoms within the last 12
hours, and presence of DWI/PWI mismatch on MRI. Primary endpoints assessed potential
thromboembolic complications and distribution of serious adverse events. Secondary endpoints
included occurrence of severe infections, intracranial hemorrhage, or changes in hematocrit
and thrombocyte count. Exploratory efficacy analyses aimed at clinical outcome (NIHSS, mRS,
BI), and ischemic lesion volume based on MRI. Results: Baseline characteristics (age, gender,
neurological deficit) were similar between verum and placebo groups. As expected, G-CSF
(AX200) dose-dependently increased white blood cell count with levels not exceeding
85.000/␮l even in the highest dose group. WBC count dropped rapidly 24 h after end of
treatment. The primary and secondary endpoints were reached. G-CSF (AX200) was generally
well tolerated with no increase in serious adverse events. Importantly, stenoses of extra- and
intracranial arteries were not negatively affected by G-CSF (AX200) treatment. Simple
comparison of clinical or imaging outcome variables did not yield differences between placebo
and verum groups. However, using age, NIHSS and diffusion volume at baseline as factors in
an exploratory multiple regression model, we detected a positive influence of AX200 on all
clinical outcome parameters in patients with larger strokes. Conclusion: We have conducted a
randomized and controlled dose-escalation study on G-CSF, a novel stroke drug with
multimodal modes of action. Intravenous G-CSF (AX200) even at high doses is well tolerated
in stroke patients. Exploratory efficacy analyses suggest a beneficial effect on neurological
outcome in patients with larger strokes. The results of the AXIS study will serve as a valuable
basis for the further clinical development of G-CSF (AX200) in ischemic stroke.
134
Elevated Levels of Thrombin-Antithrombin (TAT) are Associated with
Greater Stroke Severity in African American but not White Women.
Cheryl Bushnell, Wake Forest Univ Health Sciences, Winston-Salem, NC; Thomas Ortel,
Larry Goldstein; Duke Univ, Durham, NC
Background/Objective: African American women have poorer outcomes after stroke than
white women. We prospectively examined stroke the relationships between markers of
thrombin generation and fibrinolysis and stroke severity in African American and white women
with ischemic stroke. Methods: Women presenting within 24 hours of an acute ischemic stroke
presenting within 24 hours of onset were prospectively enrolled. NIH Stroke Scale (NIHSS)
scores were obtained acutely and after 90 days. Markers of coagulation thrombin generation
(thrombin antithrombin III [TAT], prothrombin F1.2) and fibrinolysis (plasminogen activator
inhibitor-1 [PAI-1] , and D-dimer) were measured after 90 days in subjects from whom blood
could be obtained. Results: A total of 133 women were enrolled, 67 (50%) white, 65 (49%)
African American (AA), and 1 (1%) Hispanic.Markers were obtained for 70 (53%) women at 90
days. Hypertension was more common in AA women (83% vs. white 64%; p ⫽ 0.01), and atrial
fibrillation was less common (6% vs. white 18%; p⫽0.04). The numbers of recurrent strokes,
MIs, or venous thromboses during follow-up were similar. There were no differences in initial
or 90-day NIHSS scores, or median levels of TAT, F1.2, D-dimer, or PAI-1 at 90 days in AA vs.
135
Higher Inflammatory Status in Patients with Posterior Circulation Stroke
than in Those with Anterior Circulation Stroke.
A-Hyun Cho, Catholic Univ, St.Mary’s Hosp, Seoul, Republic of Korea; Sang Beom Jeon,
Hyun-Sook Chi, Seongsoo Jang, Young-Uk Cho, Eugene Lee, Jong S. Kim; Asan Med Cntr,
Seoul, Republic of Korea
Background: It has been shown that pathogenesis and stroke mechanisms are different
between anterior circulation stroke and posterior circulation stroke. We hypothesized that the
role of inflammation might be different between anterior circulation stroke and posterior
circulation stroke. Methods: We studied consecutive, ischemic stroke patients in their chronic
(⬎3 months) stage and classified stroke subtypes according to modified TOAST classification.
Anterior circulation stroke included infarction in the territories of middle cerebral artery and
anterior cerebral artery, while posterior circulation stroke included infarctions occurring in the
territories of posterior cerebral artery, basilar artery, and vertebral artery. Patients with
uncertain territorial infarction (e.g. multiple territories) were excluded. For comparison, 107 age
and sex matched controls were included. Levels of high-sensitivity C-reactive protein (hsCRP),
intercellular adhesion molecule, vascular cell adhesion molecule, and E-selectin were
measured in all included patients and controls. Results: Of 238 patients, 81 patients (34%) had
posterior circulation stroke. Regarding the stroke subtype, large vessel disease tended to occur
more frequently in posterior circulation stroke than in anterior circulation stroke (64.2% vs.
45.9%, p⫽0.057). Stroke risk factors were similarly present between the two groups. The
hsCRP level was higher in posterior circulation stroke patients than in anterior circulation stroke
patients (0.26 ⫾ 0.49 mg/dl vs. 0.16 ⫾ 0.11 mg/dl, p⫽0.024). The hsCRP level was also
marginally higher in posterior circulation stroke patients than in control subjects (p⫽0.054).
After adjusting other factors including age, sex, hypertension, diabetes, hyperlipidemia,
smoking, TOAST classification and the use of statin, the level of hsCRP in posterior circulation
stroke patients was still higher than those that in anterior circulation stroke (OR 3.26, 95% CI
1.20 to 8.83, p⫽0.02). There was no significant difference in the levels of intercellular
adhesion molecule, vascular cell adhesion molecule, and E-selectin between anterior and
posterior circulation strokes. Conclusion: The hsCRP level was higher in patients with posterior
circulation stroke than that in patients with anterior circulation stroke. The high inflammatory
status may play a more significant role in the development of posterior circulation stroke.
136
Cerebral Autoregulation And CO2 Reactivity In Small Vessel Disease Is
Affected By Blood Pressure And Not By White Matter Disease Load.
Jarosz, King’s College Hosp, London, United Kingdom; Hugh Markus, St George’s, Univ of
London, London, United Kingdom; Lalit Kalra; King’s College London Sch of Medicine,
London, United Kingdom
Background Adequate perfusion of the deep white matter of the brain depends on the
relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation. It has
been suggested that cerebral vasoreactivity and autoregulation may be impaired in patients
with white matter disease and the purpose of this study was to investigate the interrelationships between these variables. Methods 64 patients (41 male, mean age 64 years)
attending a hypertension clinic with leukoaraiosis on T2 and FLAIR MRI brain scanning were
recruited. Exclusion criteria included BPⱖ160/100 mm Hg, cortical infarct or intracranial
pathology other than leukoaraiosis on MRI, or stenosis of ⬎50% of extracranial or intracranial
arteries on Doppler ultrasound. 24-hour ambulatory BP monitoring and quantitative volumetric
MRI analysis of leukoaraiosis was undertaken. Transcranial Doppler ultrasound techniques
were used to calculate CO2 reactivity and dynamic cerebral autoregulatory index (ARI). Results
Subjects had a mean 24-hour BP of 133/76 mmHg (SD 13/9), median white matter lesion
(WML) volume of 7169 (IQR 20497) mm3, mean CO2 reactivity of 83.6 (SD 37.4) % and mean
ARI of 5.6 (SD 1.4) (range 0 –9). ARI correlated significantly with 24-hour systolic BP (r⫽0.327,
p⫽0.030) and mean BP (r⫽0.350, p⫽0.020) but not with diastolic BP, pulse pressure, or WML
volume. In those individuals with a history of hypertension for more than 10 years, ARI also
correlated significantly with nocturnal BP dipping (r⫽0.806, p⫽0.002). CO2 reactivity was not
affected by patients’ BP levels or WML volume but correlated negatively with duration of
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Vol 39, No 2
February 2008
hypertension (r⫽-0.292, p⫽0.027). No significant relationships existed between ARI and CO2
reactivity. Conclusion Cerebral autoregulation and CO2 reactivity are two distinct processes
which are not related to WML volume but are related to BP levels and duration of hypertension
respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting the
possibility of adaptive changes in patients with increased vulnerability to reduced cerebral
perfusion.
137
Vulnerability Of Infratentorial White Matter To Nocturnal Decreases In
Blood Pressure.
Jarosz, King’s College Hosp, London, United Kingdom; Hugh Markus, St George’s, Univ of
London, London, United Kingdom; Lalit Kalra; King’s College London Sch of Medicine,
Background Cerebral hypoperfusion has been shown to correlate with severity of leukoaraiosis
and increased progression of leukoaraiosis has been associated with lower night-time blood
pressure (BP). Regional heterogeneity of the relationships between BP and cerebral blood flow
has been demonstrated previously. We investigated the relationships between regional white
matter disease load and 24-hour BP levels. Methods 88 patients (54 male, mean age 65 years)
attending a hypertension clinic with leukoaraiosis on T2 and FLAIR MRI brain scanning were
recruited. Exclusion criteria included BPⱖ160/100 mm Hg, cortical infarct or intracranial
pathology other than leukoaraiosis on MRI, or stenosis of ⬎50% of extracranial or intracranial
arteries on Doppler ultrasound. BP was assessed with 24-hour ambulatory monitoring. Location
of white matter lesions (WMLs) (frontal, pariteooccipital, temporal, basal ganglia, infratentorial)
was defined according to the Age-Related White Matter Changes rating scale (Wahlund et al.,
2001) and quantitative volumetric analysis of WMLs was undertaken. Results Subjects had a
mean 24-hour BP of 133/76 (SD13/9) mm Hg and median WML volume of 8464 (IQR 20544)
mm3. 25 patients had evidence of ‘nocturnal dipping’ (nocturnal reduction of BP by ⬎10% of
daytime BP) and 5 patients had evidence of ‘extreme dipping’ (nocturnal reduction of BP by
⬎20% of daytime BP). Infratentorial WML volume increased with dipper status (F⫽3.57,
p⫽0.04). After controlling for age and gender, infratentorial WML volume correlated negatively
with night-time BP and positively with nocturnal dipping (r⫽0.6, p⬍0.01). Regression analyses
demonstrated reduced night-time BP to be an independent predictor of infratentorial WML load
(t⫽2.9, p⬍0.01). No such relationships existed for supratentorial WMLs. Conclusion Infratentorial white matter is particularly vulnerable to nocturnal decreases in BP. This may be related
to metabolic activity, vascularisation and circadian rhythm of cerebral blood flow velocity.
Reference Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, Wallin A, Ader
H, Leys D, Pantoni L, Pasquier F, Erkinjutti T, Scheltens P; on behalf of the European Task Force
on Age-Related White Matter Changes. A new rating scale for age-related white matter changes
applicable to MRI and CT. Stroke. 2001; 32: 1318 –22
139
Albumin Treatment Improves Microvascular Hemodynamics and Augments
the Effect of Thrombolytic Therapy in Arteriolar Thrombosis: a Two-Photon
Microscopy Study.
Myron D Ginsberg, Hee-Pyoung Park, Anitha Nimmagadda, Richard A DeFazio, Raul Busto,
Ricardo Prado; Univ Miami Sch of Medicine, Miami, FL
High-dose human albumin is robustly neuroprotective in preclinical models of ischemic stroke.
The results of the recent ALIAS (Albumin in Acute Stroke) pilot clinical trial suggest that the
efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the
co-administration of high-dose albumin. This result guided the design of the ALIAS phase III
multicenter clinical trial, currently in progress. Here, we explored the intravascular component
of albumin’s protective effect by studying microvascular hemodynamics in a model of
laser-induced cortical arteriolar thrombosis, and we assessed combined therapy with albumin
and the thrombolytic agent, reteplase. The cortical microcirculation of anesthetized, physiologically monitored Sprague-Dawley rats was studied in vivo via a fronto-parietal cranial
window by two-photon laser-scanning microscopy (TPLSM) after plasma labeling with
fluorescein-dextran. Focal thrombosis was produced in 30 –50 ␮m cortical arterioles by laser
irradiation. Arteriolar flow velocity was measured repeatedly by line-scanning. At 30 min after
thrombus induction, rats of Series #1 received either human albumin, 2.5 g/kg (n⫽8), or saline
control (n⫽6), and rats of Series #2 received reteplase (1.84 –3.68 g/kg) co-administered with
either albumin (2.5 g/kg, n⫽12) or saline (n⫽9). Baseline arteriolar flow velocity, which
averaged 3.6 ⫾ 1.0 mm/sec, was reduced to 10 –25% of control by thrombosis, which also
led to focal vasodilatation. In Series #1, saline treatment at 30 min failed to influence arteriolar
flow velocity, which remained depressed at 10 –22% of control throughout the 60 –90 min
observation period. By contrast, albumin treatment induced a prompt rise in median flow
velocity to 38% of control by 10 min post-treatment, and to 61– 67% of control by 50 – 60 min
(p⬍0.05 vs. saline). In Series #2, sub-thrombolytic doses of reteplase combined with saline led
to a median increase in flow velocity to 37% of control distal to the thrombus (p⫽NS vs.
pre-treatment). By contrast, reteplase combined with albumin therapy resulted in a prompt,
highly significant increase of median flow velocity to 58% of control levels (p ⫽ 0.013 vs.
reteplase ⫹ saline), which remained significantly higher than the reteplase ⫹ saline group at
multiple time-points over the subsequent hour. We conclude that albumin, administered alone,
induces a prompt, sustained improvement in microvascular hemodynamics distal to arteriolar
thrombosis, and when co-administered with a thrombolytic agent, markedly enhances the
latter’s beneficial hemodynamic effect. These results support an important intravascular
component to albumin’s anti-ischemic effect and have important clinical implications for the
management of acute ischemic stroke.
140
Scanning Electron Microscopy Analysis of Thromboembolic Material
Retrieved from Cerebral and Cervical Arteries of Patients with Acute
Ischemic Stroke.
138
Magnitude And Time Course Of Platelet Inhibition With Extended Release
Dipyridamole With Or Without Aspirin In Healthy Japanese Volunteers: The
Japanese Aggrenox Versus Aspirin Therapy Evaluation (JAGATE).
Victor L Serebruany, Alex Malinin, Osler Med Cntr, Towson, MD; Dan Hanley; Johns Hopkins
Univ, Baltimore, MD
Background: Randomized trials showed greater stroke prevention with extended release
dipyridamole in combination with low dose aspirin than either with aspirin or dipyridamole
alone. However, most studies with this formulation (Aggrenox) were done in Europe and North
America. Considering potential inter-racial differences in drug response, we conducted a small
randomized study in healthy Japanese volunteers to compare antiplatelet regimens with regard
to the changes in the platelet biomarkers. Methods: Thirty healthy volunteers (18 – 40 years old,
15 male and 15 female) of Japanese descend were randomized to Aggrenox (n⫽17) or aspirin
81 mg (n⫽13 volunteers) for 30 days. Platelet function was assessed at baseline, and days 15,
and 30 by conventional aggregometry, whole blood flow cytometry, and cartridge-based
analyzer. Results: Both Aggrenox and aspirin provided sustained platelet inhibition at Day 15
and Day 30. Therapy with Aggrenox, however, was associated with more prominent and
significant inhibition of collagen-induced aggregation (p⫽0.08, Day 15), as well as prolongation
of the closure time (p⫽0.001, Day 30); diminished expression of platelet endothelial cell
adhesion molecule-1 (PECAM-1) (p⫽0.02, Day 30), glycoprotein IIb (GPIIb) antigen (p⫽0.001
and 0.024 for Day 15 and Day 30), and GPIIb/IIIa activity by PAC-1 antibody (p ⫽ 0.014 and
0.03), CD62 (P-selectin) (p ⫽ 0.03 for Day 15 and Day 30), as well as inhibition of protease
activated receptors (PAR-1) associated with intact WEDE-15 (p ⫽ 0.002 and 0.003) and
SPAN-12 (p ⫽ 0.002 and 0.04) thrombin receptors when compared with aspirin. Conclusion:
The magnitude and durability of platelet response after Aggrenox in healthy Japanese is similar
to those effects observed in Caucasians and African-Americans. Larger study to assess drug
efficacy and safety in the Japanese post-stroke patients is warranted.
Raul G Nogueira, Massachusetts General Hosp, Boston, MA; Sivaprasad Sukavaneshvar,
Med Device Evaluation Cntr, Salt Lake City, UT; James D Rabinov, Guilherme Dabus, Albert
J Yoo, Ferdinando S Buonanno, Johnny C Pryor, Lee H Schwamm, Joshua A Hirsch;
Massachusetts General Hosp, Boston, MA
BACKGROUND: Greater knowledge about the composition of thromboembolic material
underlying the vascular occlusion in stroke patients may provide the means for developing new
treatments. Previous studies have given important insights about the histology of these lesions.
However, these studies were limited by their inability to analyze the ultra-structure of the
thrombus. We report on the scanning electron microscopy (SEM) analysis of thrombi retrieved
from 18 stroke patients. METHODS: Thrombi were fixed in either Karnovsky’s fixative or
formalin and processed intact for SEM by dehydration with graded ethyl-alcohol. The samples
were then sputter coated with gold, and examined in a JEOL-35 Scanning Electron Microscope
(set at 25KeV with working distance of 39). RESULTS: Samples were retrieved with the Merci
device (n⫽16), Accunet device (n⫽1), or by direct tromboaspiration with a guide catheter
(n⫽1). The occlusion sites included the ICA (cervical: n⫽2; intracranial: n⫽7; both n⫽1), MCA
(n⫽5), and basilar artery (n⫽3). The samples were diverse in size, morphology, and
fragmentation. Most thrombi had some regions that were predominantly red and other regions
that were predominantly white, which was suggestive of the exposure of those regions to shear
flow or to stasis. The organization of the thrombotic elements, i.e. fibrin, platelets, and red cells
was also diverse both within each thrombus and across the various thrombi. Two distinct
structural patterns could be recognized: (1) thrombus exhibiting advanced maturity where all
the thrombotic elements were so densely integrated that individual entities were not clearly
discernible (Fig.1) suggesting a well aged and stable location that had sustained exposure to
shear flow; (2) thrombus displaying distinct fibrin strands and trapped red cells suggestive
relatively loose cross-linking characteristic of an active region where the thrombus is still in the
process of maturing and possibly of formation in regions of stasis and recirculation (Fig.2).
These patterns were seen at different proportions in different patients. CONCLUSION: Different
ultra-structural patterns can be recognized in thrombi causing cerebrovascular occlusion in
acute stroke patients. Correlation of such patterns with the presumed etiology underlying the
stroke is currently under way.
563
600 –1200J sonications were delivered to the clot, 90% of which, was liquefied with 10
seconds of pulsed sonication. The treatment produced no heat at the target. There was a direct,
non-linear correlation between clot liquefication and power of sonication. These parameters
were successfully applied using the 220KHz HIFU system - a single 750J, 10% duty cycle pulse
sonication resulted in clot liquefication. Conclusion In this pilot study, we have demonstrated
an efficient way to liquefy a blood clot utilizing a MR guided clinical HIFU system. Further
studies will be necessary to explore potential clinical application of this novel technique, such
as the treatment of ICH.
143
Stent Or Surgery In Symptomatic Carotid Artery Stenosis - Age Is An
Important Factor To Consider.
Robert Stingele, Karsten Alfke, UKSH Kiel, Kiel, Germany; The SPACE Study Group
141
TNK Induces Faster MCA Recanalization and leads to Better Short- and
Long-term Clinical Outcome Than Native tPA. The TNK-TPA Reperfusion
Stroke Study.
Carlos A Molina, Marc Ribo, Marta Rubiera, Estevo Santamarina, Raquel Delgado-Mederos,
Olga Maisterra, Pilar Delgado, Lavinia Dinia, Octavio Pontes, Joan Montaner, José
Alvarez-Sabin; Hosp Vall d’Hebron, Barcelona, Spain
Aim Tenecteplase (TNK) is a modified form of tPA, with longer half-life and greater fibrin
specificity. Although an open-label, dose-escalation study of TNK showed that doses of 0.1 to
0.4 mg/kg are safe in ischemic stroke, comparative safety and efficacy data of TNK and native
tPA is needed. We aimed to compare the effects of two thrombolytic regimen (TNK vs standard
tPA) on MCA recanalization, early clinical course and long-term outcome. Methods We
evaluated 122 consecutive stroke patients due to MCA occlusion who fulfilled criteria for iv
thrombolysis. Patients were allocated to receive standard iv tPA 0.9mg/Kg (10% bolus, 90%
1-h infusion) or iv TNK 0.4 mg/Kg (bolus), All patients underwent multiparametric MRI studies
including diffusion (DWI), perfusion (PWI), and MRA before treatment. All patients included
showed a DWI/PWI mismatch ⬎ 20% of DWI lesion. Site of arterial occlusion before treatment
and 2-hour recanalization was assessed by TCD. NIHSS scores were obtained at baseline and
24h. Symptomatic and asymptomatic ICH were assessed on CT scan performed at 24 –36h.The
mRS score was used to assess outcome at 3 months. Results Median baseline NIHSS score
was 17 points. Eighty-five (69%) patients had a proximal and 37 (31%) a distal MCA occlusion
on TCD. Eighty (66%) patients received tPA and 42 (33%) were treated with TNK. Stroke
severity, time to treatment, location of MCA occlusion, extend of initial DWI lesion and
percentage of DWI/PWI mismatch were similar in both groups. At 2h of treatment,
recanalization was significantly (p⫽0.028) higher in TNK group (n⫽29/69%) as compared to
tPA (n⫽43/53%) group. Complete recanalization at 2h was seen in 18 (42.4%) and 27 (33.4%)
patients treated with TNK and tPA, respectively (p⫽0.014). The time to beginning of
recanalization after bolus was comparable in TNK (27⫾19 min) and tPA (35⫾24 min) groups
(p⫽0.11). SICH occurred in one (2.3%) and 3 (3.7%) TNK and tPA patients, respectively.
Asymptomatic ICH on 24 –36h CT was seen in 28% of TNK and 21% of tPA treated patients
(p⫽0.089). At 24h, 63% and 51% of TNK and tPA improved ⬎ 4 points in the NHSS score
(p⫽0.041). TNK increased in 2.5-fold the rate of dramatic clinical recovery at 24h as compared
to tPA (24.5% vs 11%). At 3 months, 66% and 52% (p⫽0.039) of TNK and tPA patients,
respectively, became independent (mRS score ⬍ 2). Conclusion Compared to native tPA, TNK
(0.4 mg/Kg) administration is associated with faster and more complete MCA recanalization,
and better short-and long-term outcome without increasing the risk of SICH.
142
Mr Guided Focused Ultrasound Surgery For The Treatment Of Intra Cerebral
Hemorrhage: In Vitro Proof Of Concept.
Sagi Harnof, Univ of Virginia, Charlottesville, VA; Arik Hananel, Gilat Schiff, Javier Grinfeld,
Eyal Zadicario, Insightec, Haifa, Israel; Neal Kassell; Univ of Virginia, Charlottesville, VA
Introduction Intracranial hemorrhage (ICH) is the most lethal type of stroke with a mortality
rate of up to 50%. Surgical evacuation of the hematoma in order to reduce mass effect and
secondary insult has failed to be of proven benefit, probably due to the effects of the surgical
insult. However, minimally invasive approaches such stereotactic guided and endoscopic
evacuations have shown initial encouraging results. MR Guided High Intensity Focused
Ultrasound (MRgHIFU) is an evolving and promising non invasive technology which enables the
delivery of high energy in the form of thermal or mechanical forces to a precise point defined
by high resolution MRI imaging. We have conducted a series of in vitro, phantom based studies
to evaluate the feasibility of lysing ICH utilizing MRgHIFU, and to establish appropriate
sonication parameters. Methods All sonications were done utilizing Insightec MRgHIFU clinic
system (both the FDA approved body unit and the experimental brain unit). Phantoms consisted
of customized gel filled with clotted procaine blood. Each sonication was followed by T2
imaging. 10 cc clots were treated with escalating doses of power starting at 600w up to 1200w
of pulsed sonication for 1 to 20 seconds using a 10%–20% duty cycle, with and without
electrical steering mode. Volume analysis was done using 500 –1200 w pulsed sonication of
a 1 sec 10% duty cycle. Volumes were measured from the T2 images. 500 to 1000 w of 10%
duty cycle pulsed sonications were preformed utilizing the head system. Results A total of
Introduction: Carotid artery stenting (CAS) and carotid thrombarterectomy (CEA) are therapeutic
options for symptomatic carotid artery stenoses. Populations at a high procedural risk might be
different for CAS or CEA due to technical differences between these methods. We therefore
identified risk factors associated with a high procedural risk in patients treated within the
‘Stent-supported angioplasty versus carotid endarterectomy’ (SPACE)-trial. SPACE to date is the
largest randomized clinical trial comparing CAS and CEA in 1214 patients with symptomatic
carotid artery stenosis. Methods: Multivariate statistical methods and regression tree analysis
were used to identify risk factors for a high incidence of the primary study endpoint of the
SPACE-study (ipsilateral stroke or death within 30 days of randomization). The covariates under
investigation were defined pre-hoc in the study protocol of SPACE and consisted of age, sex,
type of qualifying event (ocular, TIA, stroke), side of intervention, degree of stenosis and
presence of relevant contralateral stenosis. Results: 1) Age: There was an age-dependent
increase of the periprocedural risk in patients treated by CAS (p ⫽ 0.008) but not with CEA (p ⫽
0.446). The optimal separator-age between low and high procedural risk was 68 years for CAS
patients. For CEA patients, such a separator could not be identified. 2) Contralateral carotid
stenosis or occlusion was present in 7.1% of CAS patients and 7.5% of CEA patients. CAS
patients with and without contralateral stenosis had similar event rates (5 vs. 7.1%), in
CEA-treated patients there was an increased risk if contralateral stenosis was present (13 vs.
5.9%). There was a trend for interaction between type of therapy and presence of contralateral
sternosis or occlusion (ITT: p⫽0.1, PP: p⫽0.042) 3) For the other covariates (sex, type of
qualifying event, side of intervention, degree of stenosis), no between-group differences could
be detected. Conclusions:In younger patients (⬍68 years), CAS had a lower procedure related
risk for stroke and death than CEA whereas older patients had a lower risk if treated with CEA.
In patients with contralateral stenosis, there was a trend for a lower risk in CAS patients.
144
VECTORS (Very Early Constraint Therapy for Recovery from Stroke) Phase II
RCT: Results of Secondary Analyses.
Dorothy F Edwards, Univ of Wisconsin, Madison, WI; Catherine E Lang, Rebecca
Birkenmeier, Washington Univ, Saint Louis, MO; William J Powers, Univ of North Carolina,
Chapel Hill, NC; Alexander W Dromerick; Georgetown Univ and National Rehabilitation Hosp,
Washington, DC
Introduction: Results from VECTORS have called into question the superiority of ConstraintInduced Therapy (CIT) over traditional therapy in promoting upper extremity (UE) recovery after
stroke. The primary analyses of VECTORS found no difference between dose-matched CIT and
control groups during acute rehabilitation. The purpose of this study was to confirm the primary
result using secondary efficacy measures from the Phase II RCT. Methods: Subjects were
assigned using adaptive randomization into control (2 hrs traditional OT), dose matched CIT (2
hrs shaping, 6h day constraint), or high intensity CIT (3 hrs shaping, 90 % waking hrs
constraint) groups at inpatient rehabilitation admission. Inclusion criteria included ischemic or
hemorrhagic stroke within 28 days of onset; no prior stroke-related neurologic impairment;
need for inpatient rehabilitation; NIH Stroke Scale (NIHSS) aphasia, command, consciousness
and sensory items ⱕ 1; NIHSS neglect ⫽ 0; and persistently hemiparetic UE with some
residual voluntary movement. Blinded raters evaluated subjects at randomization, end of
treatment (14d), and the primary endpoint (90d). Prespecified secondary measures were the
Wolf Motor Function Test (WMFT) Function and Time scores and the Motor Activity Log (MAL)
for the affected UE. Mixed model analyses were performed. Results: 52 participants (mean age
63.9⫾14 yrs) were randomized 9.65⫾4.5 days after onset. Mean NIHSS was 5.3⫾1.8; 77 %
had ischemic stroke. Groups were equivalent at baseline on all randomization and dependent
variables. As expected, all groups improved over time on the WMFT- Function scale(p⬍.0001),
WMFT-Time scale (p⬍.0001) and MAL (p⬍.0001). Significant Time x Group interactions were
found for WMFT Function (F⫽3.29; p⬍.008), and MAL (F⫽2.21; p⬍.05), such that the high
intensity CIT group had significantly worse function scores at Day 90. No significant Time x
Group interaction in timed motor performance (WMFT-Time) was found, indicating that the
three groups had equivalent time scores at Day 90. Further, no significant differences were
found between the dose-matched CIT and control groups at Day 90 on any of the three
measures. Conclusions: Analyses of secondary efficacy measures are consistent with our
previous finding that CIT was not superior to equal doses of conventional therapy in the acute
inpatient rehabilitation setting. We again observed an inverse dose response relationship,
where a higher dose was associated with lower function assessed by both objective (WMFT)
and subjective measures (MAL). Our results support the need for controlled clinical trial designs
examining the effects of timing and dose on motor recovery during acute rehabilitation.
564
Stroke
Vol 39, No 2
February 2008
145
Withdrawn
min-reperfusion ischemia model, r (rat) ASCs were isolated from fresh subcutaneous fat tissue
of each rat, and incubated under endothelial growth medium for seven days. At 8 days,
autologous rASCs (0.5 million cells in 0.5 cc PBS) or vehicle were intravenously administered.
Behavioral recovery, cerebral perfusion, brain atrophy, and angiogenesis were assessed till 35
days. Results: hASCs expressed VEGF, BDNF, CXCR4, Flk1, Flt1, vimentin, and nestin. When
cultured in hypoxic condition (1% oxygen) for 72 hours, hASCs increased the expressions of
GM-CSF, BDNF, FGF, p75, and Flt1. Intravenous transplantation of hypoxia-treated hASCs
enhanced cerebral endothelial proliferation (BrdU⫹ endothelial cells), and cerebral perfusion
state in rats with cerebral ischemia. Rats transplanted with hASCs showed better neurologic
recovery and also revealed lesser lesion volume. Conditioned media of hASCs protected
cerebral neuronal cells from hypoxic and oxidative injury. In the autologous transplantation, the
yield of rASCs in each animal was about 5 million cells per 1g fat. Autologous rASCstransplanted rats showed better functional outcome measured by modified limb placing test
compared to the vehicle group. Autologous ASCs increased angiogenesis after cerebral
ischemia. Conclusion: In summary, ASCs expressed multiple growth factors and growth factor
receptors, especially in hypoxic condition, and enhanced angiogenesis and neurologic recovery
in a cerebral ischemia model. Autologous ASCs were easily obtained and exerted functional
recovery. Neuroprotective and regenerative effects induced by intravenous hASCs seem to be
results of the orchestration of secretary and bystander effects.
148
18
FDG-PET Imaging Of Human Carotid Arteries Prior To Endarterectomy
Confirms It Is A Bilateral Disease.
146
High Resolution Copy Number Variation Analysis of Sporadic and Familial
CCM Patients.
Yasar Bayri, Winson S Ho, Kaya Bilguvar, Michael DiLuna, Mohamad Bydon, Lindsay A
Collins, Fatih Bayrakli, Christopher E Mason, Matthew W State, Murat Gunel; Yale Univ Sch
of Medicine, New Haven, CT
Introduction: Cerebral Cavernous Malformations (CCM) are a central nervous system vascular
disorder characterized by abnormally dilated vascular channels lined by a single layer of
endothelium, that are prone to cerebral hemorrhage. Three causative genes have been
identified to date that, when mutated, lead to the severe genetic phenotype of this disease. To
identify whether genetic aberrations other than the three known loci may underlie the sporadic
and familial form of this disease, single nucleotide polymorphism (SNP) based high resolution
genotyping and copy number variation (CNV) analysis of 30 sporadic and familial patients with
CCM (for whom linkage excluded the three known loci) were performed. Methods: Patient DNA
was analyzed using 250K Sty SNP chips (Affymetrix). The Affymetrix Chromosome Copy
Number Analysis Tool (CNAT) and Circular Binary Segmentation (CBS) were used to identify
significant CNVs based on derived Log2 ratios using 270 HapMap control. Results: Out of 30
patients, 23 loci with large numbers of consecutive probes demonstrating statistically
significant Log2 ratios consistent with either heterozygous or homozygous deletions not within
known CNV-rich intervals. One deletion in a sporadic case included the CCM2 interval.
Excluding the X chromosome, the two algorithms called a total number of 376 CNVs, with
NegLog10PValue larger than 2.6, that are not observed in 30 separate controls. Of the putative
CNVs, 160 and 216 are deletions and amplifications respectively. These putative CNVs are to
be validated with qPCR. Conclusions: Additional genes other than Krit1, malcavernin and
PDCD10 may account for the CCM phenotype as de-novo mutations in sporadic patients or
additional linkage loci in familial cases. The further characterization of the genes within these
loci may provide further insight into the CCM pathway and lesion pathogenesis.
147
Transplantation Of Adipose Tissue-derived Stem Cells In Cerebral Ischemia:
Enhanced Angiogenesis By Functional Stem Cells And Feasibility Of
Autologous Transplantation.
Kon Chu, Soon-Tae Lee, Keun-Hwa Jung, Eun-Cheol Song, Hee-Kwon Park, Jeong-Min Kim,
Jin-Hee Kim, Jae-Sung Lim, Kyung-Mook Kang, Nan-Hyung Hong, Jun-Young Chang, Sang
Kun Lee, Manho Kim, Jae-Kyu Roh; Seoul National Univ Hosp, Seoul, Republic of Korea
Background: Adipose-derived stem cell (ASC) is a multipotent mesenchymal stem cell
population with easy accessibility, and known to secrete multiple growth factors, thereby
showing cytoprotective effects in ischemic injury. Given the feasibility of ASCs transplantation
in cerebral ischemia, we investigated the “bystander” protection and neuro-regenerative effect
induced by ASCs in a rodent cerebral ischemia model. Methods: In the first experiment, we
cultured human ASCs (hASCs) from subcutaneous adipose tissue which was acquired from
elective surgery with patients’ consent. We investigated the cytokine transcription levels
between normoxia and hypoxia culture conditions. hASCs (3 million cells per animal) or vehicle
(PBS) were intravenously injected at 24 hours after the induction of middle cerebral artery
occlusion in rats (90 minutes, ischemia-reperfusion model), and BrdU was injected for next 14
days. Behavioral recovery, cerebral perfusion, brain atrophy, and angiogenesis were assessed
till 35 days. Conditioned media of hASCs were tested for neuroprotective effects. In the second
experiment, we tested the feasibility of autologous ASCs transplantation. On the next day of 90
M.Angels Font, Hosp Universitari de Bellvitge, Barcelona, Spain; Alex Fernandez, Cristina
Gamez, Hosp Universitari de Bellvitge, IDI, Barcelona, Spain; Mark Slevin, Manchester
Metropolitan Univ, Manchester, United Kingdom; Ramon Vila, Elena Iborra, Hosp Universitari
de Bellvitge, ACV, Barcelona, Spain; Francisco Rubio, Jerzy Krupinski; Hosp Universitari de
Bellvitge, Barcelona, Spain
Introduction: It is still unclear whether patients with unilateral carotid disease are at higher risk
of contralateral carotid artery progression. Both carotid vulnerability to rupture and asymptomatic progression is linked to plaque inflammatory cells which can be detected in vivo with
18-FDG-PET imaging. Hypothesis: Our hypothesis was that 18FDG-PET imaging can identify
inflammation in contralateral carotids with low to moderate stenosis. Methods: We studied 15
patients with symptomatic or asymptomatic unilateral carotid artery stenosis (i.e. contralateral
carotid stenosis less than 50%) scheduled for carotid endarterectomy (CEA). 18-FDG-PET was
performed prior to CEA and 116 ⫾ 22 days following surgery. All patients received an
integrated FDG-PET/CT using a Discovery ST scanner. Two-centimeter circular regions of
interest were drawn on CT images around the area including carotids in each slice, and then
transferred onto the corresponding co-registered PET image to enable FDG-uptake values
based on maximum standardized uptake value. The analysis included a vascular region 56 mm
over and below the level of the carotid bifurcation, and slice-activity curves were calculated in
order to visualize plaque and basal metabolism. Results: Carotid plaques with inflammatory
infiltrates had the highest 18-FDG uptake (p⬍0.05). We found significant correlation between
the degree of FDG accumulation in the ipsilateral carotids scheduled for CEA and contralateral
asymptomatic carotids (R⫽0,9 p⬍0.001). The FDG uptake rates in the contralateral arteries
remained increased on the follow-up imaging (1.15⫾ 0.2 vs. 1.14⫾0.1; R⫽0,7 p⫽0,006). No
significant correlation was found between the degree of 18-FDG uptake and time from
symptoms to PET imaging, symptomatic or asymptomatic patients and degree of carotid
stenosis. Diabetic patients, although normoglycemic, had lower FDG uptakes (p⬍0,01). Statin
treatment was associated with a more pronounced decrease in 18-FDG-uptake on second PET
(p⬍0.05). Conclusions This is the first in vivo study using 18-FDG-PET imaging demonstrating
that carotid atherosclerosis is a bilateral disease. Identification of inflammatory regions in the
contralateral carotids has the potential to offer early aggressive medical treatment to these
patients.
149
CT and MRI Early Vessel Signs Reflect Clot Composition in Acute Stroke.
David S Liebeskind, William H Yong, Nerses Sanossian, Sidney Starkman, Michael P Tsang,
Antonio L Moya, David D Zheng, Doojin Kim, Latisha K Ali, Samir H Shah, Amytis Towfighi,
Bruce Ovbiagele, UCLA, Los Angeles, CA; Chelsea S Kidwell, Georgetown Univ, Washington,
DC; Satoshi Tateshima, Reza Jahan, Gary R Duckwiler, Fernando Vinuela, Noriko Salamon,
J P Villablanca, Victor J Marder, Jeffrey L Saver; UCLA, Los Angeles, CA
Background: Noncontrast CT depicts some MCA occlusions as linear increased density, the
hyperdense MCA sign (HMCAS). Gradient echo (GRE) MRI may also delineate some MCA
occlusions as ovoid regions of hypointensity or blooming artifact (BA), often extending beyond
vessel margins. Prior studies of the HMCAS and BA have analyzed their prognostic significance
and prediction of response to thrombolysis, but not their pathologic substrate. Methods:
Noncontrast CT and GRE MRI studies performed immediately prior to mechanical thrombectomy in consecutive cases of acute MCA ischemic stroke were reviewed by 2 readers, blinded
to clinical and pathology data. Presence and density (HU) of the HMCAS, and presence or
absence of BA were assessed. Occlusions subsequently retrieved by embolectomy underwent
histopathologic analysis, including automated quantitative and qualitative rating of proportion
composed of red blood cells (RBC), white blood cells, and fibrin based on microscopy of
sectioned thrombi. Results: Among 51 patients, mean age was 65 years and 49% were
female. Across all retrieved thrombi, mean (SD) proportion that was RBC was 33% (⫾23) RBC,
WBC 6% (⫾14), and fibrin 62% (⫾23). Of the retrieved clots, 22 (43%) were fibrin dominant,
12 (24%) RBC dominant and 17 (33%) mixed. HMCAS was noted in 10/20 MCA stroke cases
with CT, with a mean HU of 61 (SD⫾8). BA was noted in 18/34 cases with GRE MRI. HMCAS
was more commonly seen with RBC dominant and mixed than fibrin dominant clot pathology
(100% vs. 62.5% vs. 22%, p⫽0.043). Mean percent RBC composition was higher in clots with
HMCAS (45% vs. 19%, p⫽0.030), although HU density was not correlated with clot
composition. BA was also more common in RBC dominant and mixed clots compared to fibrin
dominant clots (100% vs. 60% vs. 37%, p⫽0.020). Mean percent RBC was greater with BA
(43% vs. 22%, p⫽0.011). Conclusions: The CT HMCAS and GRE MRI BA reflect the pathology
of the occlusive thrombus. Strong correlation with RBC content suggests that RBC x-ray density
is a principal factor of the HMCAS and RBC hemoglobin deoxygenation an influential
determinant of BA. Absence of HMCAS or BA may indicate the presence of fibrin predominant
clots.
150
Evaluation Of Patients With Suspected Cardioembolic Stroke Using
Cardiovascular Mri - A Comparative Study With Echocardiography.
John J Sheehan, Northwestern Memorial Hosp, Chicago, IL; George Lin, Northwestern Univ,
Chicago, IL; Jim Connors, Mark J Alberts, Karin Dill, Reed A Omary, Richard Bernstein,
James C Carr; Northwestern Memorial Hosp, Chicago, IL
Introduction: The aim of our study was to compare Cardiovascular MRI (CVMR) and
Echocardiography (TTE and TEE) used in the detection of intracardiac thrombi in patients with
suspected cardioembolic stroke (CES). This study examined the utility of CVMR for the detection
of non-thrombotic additional findings. Methods: Over a 12 month period between September
2005 and September 2006, 106 consecutive patients with a suspected CES had CVMR for the
detection of intracardiac thrombi. All CVMR examinations were performed on a 1.5T MR
scanner using CINE trueFISP, contrast enhanced MR angiography, delayed enhanced inversion
recovery trueFISP and first pass imaging. The clinical information and study reports of
echocardiography, CVMR, MR Brain and Carotids was retrospectively reviewed. Results &
Discussion: Of the 106 patients who had a CVMR study for suspected CES, CVMR revealed 10
thrombi in n⫽9 (9.7%) patients. The thrombi were located in the LAA (n⫽3), left ventricle
(n⫽4) and right atrial appendage (n⫽3). Of these 9 patients echocardiography was positive in
n⫽2 (22%), indeterminate in n⫽2 (22%) and negative in n⫽5 (56%) (Fig. 7). One of the 5
patients with an negative echocardiograms was obese leading to technical difficulties during
the TTE. TTE and TEE was performed in 3 of the 5 negative echocardiographic studies. No
thombi were detected echocargraphy that were not seen on CVMR. CVMR reported 103 non
thrombotic additional findings in n⫽53 (57%) of patients compared to echocardiography. Sixty
of these were considered significant in n⫽38 (40.9%) of patients. When all significant findings
including thrombi were calculated there were 67 additional significant findings in n⫽42 (45%).
Additional findings associated with thrombus formation (acute infarction, scarring and LV
aneurysms) were n⫽19(20%) for CVMR and n⫽7(7%) for echocardiography. Conclusion: CVMR
is a non invasive, reproducible method for the detection of intracardiac thrombi and is clinically
advantageous in the detection of important non thrombotic findings, including prothrombotic
conditions. CVMR should be considered as part of the routine evaluative framework along with
echocardiography in the assessment of patients with suspected CES.
565
151
Prognostic Value of a Qualitative MRI Scoring System for Neurologic
Outcome of Comatose Survivors After Cardiac Arrest.
Sofie Jansen, Dept of Neurology and Neurological Sciences, Stanford Stroke Ctr, Stanford
Univ Med Ctr, Stanford, CA; Nancy J Fischbein, Michael V Krasnokutsky, Dept of Radiology,
Stanford Univ Med Ctr, Stanford, CA; Michael Mlynash, Irina Eyngorn, Christine A Wijman;
Dept of Neurology and Neurological Sciences, Stanford Stroke Ctr, Stanford Univ Med Ctr,
Stanford, CA
Background Identification of comatose survivors after cardiac arrest with an unfavorable
neurologic outcome remains challenging, especially in those who do not meet conventional
prognostic criteria for poor outcome. Methods In this AHA funded study, 68 (85%) of 80
prospectively enrolled comatose survivors of cardiac arrest underwent brain MRI at a median
of 90 hours (range 2–718 hours) after the arrest. Five brain regions (cortical grey and white
matter, deep grey nuclei, hippocampus, brainstem and cerebellum) were assigned 1– 4 points
based on the severity of signal abnormalities on FLAIR and diffusion-weighted MRI (DWI) by 2
independent and blinded raters. Outcome was assessed at 3 months as favorable (Glasgow
Outcome Scale (GOS) 3–5) and unfavorable (GOS 1–2). Gold standard non-survivors met any
of the following conventional prognostic criteria: absent pupillary reflexes at ⬎⫽ 24 hours,
myoclonus status epilepticus, absent SSEPs or motor response absent or extensor at 72 hours
in the absence of sedating medications. Sensitivity and specificity of the MRI scoring system
were estimated using ROC analysis. Results Eighty-seven MRIs of 67 patients with a mean age
of 56⫾15 years and mean arrest duration of 22⫾12 minutes were included. Thirty-four MRIs
were in patients with a favorable neurological outcome and 53 in patients with an unfavorable
neurological outcome. Of these, 28 scans were in patients with gold standard unfavorable
outcome. The mean summation score of the 2 raters of the cortical grey and white matter on
both DWI and FLAIR sequences best predicted unfavorable neurologic outcome with an overall
specificity of 100% (95% CI 90 –100%) and a sensitivity of 86% (95% CI 67–96%). Inter-rater
agreement of this ‘cortex score’ was excellent (ICC⫽ 0.905). The optimal time window to
predict unfavorable outcome appeared to be ⬎ 24 hours, as 3 patients with unfavorable
neurological outcome who underwent MRI ⬍ 24 hours had minimal cortical abnormalities.
Sensitivity of the ‘cortex score’ in ‘gold standard’ patients ⬎ 24 hours was 92% (95% CI
75–99%). Applying the cortex score cutoff to ‘non-gold standard’ non-survivors identified an
additional 8 patients (32%) with unfavorable outcome resulting in an overall sensitivity of 60%
(95% CI 47–74%). Conclusion A qualitative MR scoring system involving the cortical grey and
white matter appears to accurately identify comatose post-cardiac arrest patients with an
unfavorable neurological outcome after 24 hours and may be particularly useful in patients who
do not meet conventional prognostic criteria for poor outcome.
152
CT Angiography Source Images Predict Functional Outcome In Basilar
Artery Occlusion: The Posterior Circulation Acute Stroke Prognosis Early CT
Score.
Volker Puetz, Univ of Calgary, Calgary, Canada; P.N. Sylaja, Ananthapuri Hosps and Rsch
Institute, Trivandrum, India; Michael D. Hill, Shelagh B. Coutts, Univ of Calgary, Calgary,
Canada; Imanuel Dzialowski, Pia Mueller, Ulf Becker, Technical Univ Dresden, Dresden,
Germany; Philip A. Barber, Mayank Goyal, Pranshu Sharma, Univ of Calgary, Calgary,
Canada; Georg Gahn, Ruediger von Kummer, Technical Univ Dresden, Dresden, Germany;
Andrew M. Demchuk; Univ of Calgary, Calgary, Canada
Introduction: Quantification of early ischemic changes (EIC) on non-contrast CT (NCCT) or CT
angiography (CTA) source images (CTA-SI) may predict functional outcome and treatment
response in patients with posterior circulation stroke. We tested the validity and reliability of a
novel CT score, the posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS).
Methods: Pc-ASPECTS allots the posterior circulation 10 points. One point each is subtracted
for EIC in left or right: thalamus, cerebellum or PCA territory, respectively and two points each
for EIC in any part of the midbrain or pons. We retrospectively studied 2 different patient
populations: 1) patients with clinically suspected vertebrobasilar ischemia; 2) patients with
basilar artery occlusion (BAO). In both groups, patients had CTA done within 24 hours from
symptom onset. We independently applied pc-ASPECTS to baseline NCCT, CTA-SI and
follow-up image by 3-reader consensus. For BAO, we defined TIMI 2 or 3 flow on acutely
performed angiogram as recanalization. Assuming follow-up image as the gold standard we
calculated sensitivity for early ischemic changes. We analyzed the prognostic value of the
pc-ASPECTS score for independent (modified Rankin Scale [mRS] score 0 –2), favourable (mRS
0 –3) and fatal outcome. Results: Of 130 patients with clinically suspected vertebrobasilar
ischemia, final diagnosis was posterior circulation stroke in 72% (94), TIA in 8% (10) and
nonischemic in 20% (26). Sensitivity for any ischemic change was improved with CTA-SI
compared to NCCT (65% [CI95 57%–73%] vs. 46% [CI95 37%–55%], respectively). Inter-rater
reliability for pc-ASPECTS on CTA-SI was moderate (ICC 0.72; lower CI95 0.54). The CTA-SI
pc-ASPECTS score but not the NCCT pc-ASPECTS score predicted independent functional
outcome in this population (ORs 1.58; p⫽0.005 vs. 1.22; p⫽0.42 per point pc-ASPECTS score
increase, respectively). Of 46 patients with BAO, 52% (12/23) with a CTA-SI pc-ASPECTS score
⬎8 but only 4% (1/23) with a score ⬍8 had a favourable functional outcome (risk ratio [RR]
12.1; CI95 1.7– 84.9). Similarly, patients with a CTA-SI pc-ASPECTS score ⬍8 were more likely
to die (RR 2.5; CI95 1.2–5.3). Of 23 patients with basilar artery recanalization, 75% (9/12) with
a CTA-SI pc-ASPECTS score ⬎8 but only 9% (1/11) with a score ⬍8 had a favourable
functional outcome (RR 8.3; CI95 1.2–55.0). Conclusion: Compared with NCCT, CTA-SI provide
added information for patients with supected vertebrobasilar ischemia. In basilar artery
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Vol 39, No 2
February 2008
occlusion, extensive hypocontrastation indicated by a CTA-SI pc-ASPECTS score ⬍8 identifies
patients unlikely to have a favourable functional outcome despite early recanalization.
153
Cervicocepharic Arterial Dissections in Japan: Analysis of 454 patients in
the Spontaneous Cervicocephalic Arterial Dissections Study I (SCADS-I).
Kazuo Minematsu, Hideki Matsuoka, Junji Kasuya, National Cardiovascular Cntr, Suita,
Osaka, Japan; SCADS-I collaborators
Objectives: Recent studies have suggested that clinical features of spontaneous cervicocepharic arterial dissections (SCADs) in Japan are different from those in Western countries. The aim
of the present study is to confirm this suggestion. Methods: This is a retrospective multicenter
registration study with 82 hospitals all over Japan. We collected and analyzed the clinical data
of patients with SCADs who were admitted to registration hospitals between April 2003 and
March 2006. The diagnosis of SCADs was made principally based on findings of angiographic
studies. Results: A total of 454 patients (320 men) with SCADs were enrolled. Age ranged from
13 to 88 (54 in median) years old, including 179 patients (39%) of ⱕ50 years. Cerebral arterial
lesions were examined with conventional angiography in 383 patients (84%), magnetic
resonance angiography in 288 (63%), or computed tomographic angiography in 95 (21%). The
dissections were identified in intracranial arteries for 419 patients (92%), and in the
vertebrobasilar arteries (VA) for 374 patients (82%). Only 11 patients (2.4%) had the
extracranial internal carotid artery (ICA) dissections. The most common site of SCADs was the
intracranial VAs (288 patients, 63%), followed by the anterior cerebral artery (8%), posterior
inferior cerebellar artery (6%), basilar artery (5%), and others. Stroke occurred in 389 patients
(86%); 234 ischemic, 126 hemorrhagic, and 29 both. Headache developed at the day of or
several days before the stroke onset in 291 (75%). Patient’s family had a history of SCADs in
9 patients (2%), of cerebral aneurysms in 18 (4%), and of aortic dissections in 4 (1%). As
vascular risk factors, hypertension was present in 226 patients (50%), hypercholesterolemia in
73 (16%), impaired glucose tolerance in 45 (10%), and smoking habit in 157 (35%). These
factors were more common in patients developing ischemic stroke than in those with
hemorrhagic one. Patients with ischemic stroke were treated with antiplatelets agents in 166
patients (71%) or with anticoaglants in 122 (52%) at least for several weeks after stroke onset.
As compared to patients with hemorrhagic stroke, ischemic stroke patients had symptom
progression or early stroke recurrence within the first 7 days less frequently (19% vs. 9%,
p⬍0.0001), and obtained more often favorable outcome at discharge (modified Rankin scale
0 –1, 67% vs. 51%, p⬍0.005). Conclusion: We confirmed that SCADs occurred mainly in
intracranial arteries, especially at VA in Japanese patients; being contrast to their predominant
occurrence in extracranial ICA in Western countries. Ischemic stroke with SCADs was more
common and associated with better outcome as compared to hemorrhagic one.
154
Emergent Echocardiography Is Associated With A High Rate Of Detection
Of Mobile Aortic Arch Thrombi In Acute Ischemic Stroke.
Estevo Santamarina, M Teresa Gonzalez-Alujas, Andrea Pacchioni, Marc Ribo, Marta
Rubiera, Olga Maisterra, Raquel Delgado-Mederos, Pilar Delgado, Jose Alvarez Sabin, Carlos
A Molina; Hosp Vall Hebron, Barcelona, Spain
AIM: Fast-track emergent echocardiography within the first few hours of stroke onset may increase
the accuracy in the detection of fresh thrombi into the cardiac cavities or the aortic arch. We
conducted a case-control study aimed to evaluate the yield of second harmonic transthoracic
echocardiography (SHTTE) within the first hours of acute ischemic stroke. METHODS: We study
consecutive non-lacunar ischemic stroke patients evaluated between November 2006 and April
2007. It included patients with a known cardioembolic source (atrial fribrillation, ischemic
cardiopathy, valve prothesis and dilated miocardiopathy) and patients with an undetermined origin.
Emergent SHTTE was performed during the first hours (⬍24h) of admission (early SHTTE group)
These data were compared with age- and sex- matched historical controls (delayed SHTTE group)
who underwent SHTTE as part of the standard diagnostic work-up (⬎24h) RESULTS: A total of 350
patients underwent SHTTE. One-hundred and sixty-five patients were evaluated in the early SHTTE
and 185 patients in the delayed SHTTE group. Mean time from stroke onset to SHTTE evaluation was
14⫾9 hours and 1076⫾168 hours in the early and delayed SHTTE, respectively. Among patients
with stroke of undetermined origin, detection of a cardioembolic source of emboli was significantly
higher in patients who underwent early (n⫽52;48%) compared to those who received delayed
(n⫽16;23%) SHTTE (p⫽0.001). Main findings included severe aortic atheromatosis 24(22.2%) vs.
3(3.5%), akynesia/hypokynesia 15(14%) vs. 9(11%), PFO 8(7.4%) vs. 8(9.5%), valvulpathy 6(5.6%)
vs. 2(2.4%) and dilated miocardiopathy 3(2.8%) vs. 1(1.2%). The greater diagnostic accuracy of
early compared to delayed SHTTE was mainly due to a higher detection of aortic arch atheroma with
mobile thrombus. Early (⬍24h) SHTTE evaluation increased in 7-fold the likelihood of detection of
a mobile thrombus in the aortic arch as compared with delayed (⬎24h) SHTTE exam (22.2% vs.
3.2%; p⫽0.001). CONCLUSION: The yield of SHTTE is markedly increased when performed during
the first hours of acute stroke. Early SHTTE provides a higher detection of a cardioembolic source
of emboli, mainly mobile thrombi engrafted in an aortic atheroma. These findings have an important
impact on therapeutic decisions.
155
The Balance Between The Expression Of Cd36 And Abca1 Favors Lipid
Accumulation In Ulcerated Carotid Plaques.
Pia M Isoviita, Krista Nuotio, Riitta Turunen, Jani Saksi, Petra Ijäs, Biomedicum Helsinki,
Helsinki, Finland; Petri Kovanen, Wihuri Rsch Institute, Helsinki, Finland; Markku Kaste,
Perttu J Lindsberg; Dept of Neurology, Helsinki, Finland
BACKGROUND The development of a lipid core is a key event in the progression of an
atherosclerotic plaque to a vulnerable one that causes thromboembolic strokes. CD36 is an
important scavenger receptor that accumulates lipids within macrophages, whereas ABCA1
protein counteracts this effect by removing lipids from cells. Based on DNA microarray, we
previously found that the genes encoding CD36 and ABCA1 were overexpressed in symptomatic carotid plaques (CPs) compared to asymptomatic CPs. Here we evaluated their role in CP
destabilization by studying the localization of lipid within CPs, the expression of CD36 mRNA,
as well as CD36 and ABCA1 protein expressions in ulcerated and non-ulcerated CPs and their
colocalization with intraplaque red blood cell (RBC) extravasation. METHODS 92 high-grade
(⬎70%) CPs obtained from carotid endarterectomy were stained with the Oil-red-O method to
visualize lipids. A subgroup of asymptomatic and stroke-causing CPs (n⫽44) were used in
further analyses. The relative expression of CD36 mRNA was measured by quantitative
real-time RT-PCR. Adjacent sections of CP specimens were immunostained against CD36 and
ABCA1, and analysed microscopically in detail and correlated topographically with the presence
of extravasated RBCs. RESULTS There were more extracellular lipid deposits in the ulcerated
CPs as compared to non-ulcerated CPs (P⫽0.038). The amount of CD36 mRNA associated with
CD36 protein expression (rs⫽0.551, P⫽0.001). In ulcerated CPs, the expression of both CD36
mRNA (P⫽0.010) and protein (P⬍0.001) were increased as compared to non-ulcerated CPs.
Moreover, there was more expression of CD36 than ABCA1 protein (P⬍0.001) in ulcerated CPs,
while the opposite was true in non-ulcerated CPs. CD36 and ABCA1 proteins co-localized with
each other (P⬍0.001), and with the presence of extravasated RBCs (P⫽0.007 and P⬍0.01
respectively). CONCLUSIONS Our results suggest that the balance between lipid influx (CD36)
and efflux (ABCA1) favor lipid accumulation in macrophages in ulcerated CPs, contributing to
the growth of lipid core and consequent plaque destabilization. Furthermore, co-localization of
CD36 and ABCA1 proteins with RBCs suggests that intraplaque hemorrhages may contribute
to the lipid load of CPs, and may induce the expression of lipid scavenger receptors.
156
C-reactive Protein Exerts Potent Angiogenic Effects On Vascular Endothelial
Cells.
Jerzy Krupinski, Marta M Turu, Hosp Universitari de Bellvitge,, Barcelona, Spain; Sabine
Matou, Manchester Metropolitan Univ, Manchester, United Kingdom; Cristina Rodriguez,
Jose Martinez-Gonzalez, Lina Badimon, CSIC-ICCC, Barcelona, Spain; Ana Luque, Hosp
Universitari de Bellvitge,, Barcelona, Spain; Mark Slevin; Manchester Metropolitan Univ,
Manchester, United Kingdom
Introduction: Formation of neovessels in the developing atherosclerotic plaques is thought to
contribute significantly to intra-plaque haemorrhage and instability resulting in thrombosis.
C-reactive protein (CRP) is an acute phase reactant whose expression is increased in both the tissue
and circulation of patients with inflammatory disease, in particular, in reactive plaque regions.
Although CRP is known to induce a pro-inflammatory phenotype on endothelial cells (EC) for
instance, by inducing expression of adhesion molecules, a direct role on modulation of angiogenesis
has not been identified. Hypothesis: Our hypothesis was that CRP exerts a potent pro-angiogeneic
effects on vascular endothelial cells. Methods: Angiogenic effects i.e. proliferation, migration and
tube formation of purified endotoxin-free CRP was studied in vascular EC (Bovine aortic EC {BAEC}
and human coronary artery EC {HCAEC}). Furthermore, using a specifically targeted TaqMan gene
microarrays we studied CRP-induction of pro-angiogenic genes. Results: Addition of CRP induced
a significant increase in proliferation, migration and tube-like structure formation in vitro and
stimulated blood vessel formation in the chick chorioallantoic membrane assay. We identified
CRP-induction of several key pro-angiogenic genes: vascular EC growth factor (VEGF) receptor
(KDR), NOTCH (1, 3), platelet-derived growth factor (PDGF␤[[Unsupported Character - ]]
and cysteine-rich angiogenic inducer 61 (CYR61). Western blotting showed increased expression of
phosphorylated early response kinase (ERK) 1/2, a key protein involved in EC mitogenesis, in CRP
treated cells. Conclusions: This data suggests an important role for CRP in direct stimulation of
angiogenesis and therefore may be an important mediator of neovessel formation in the intima of
vulnerable plaques.
157
Early Blood Brain Barrier Disruption Is Associated With Plasma Matrix
Metalloproteinase-9 Concentration In Acute Stroke Patients.
Taura L Barr, National Institutes of Neurological Disorders and Stroke, National Institute of
Nursing Rsch, National Institutes of Health, Bethesda, MD; Lawrence L Latour, Kyung-Yul
Lee, Timothy J Schaewe, Marie Luby, George Chang, Ziad El-Zammar, Shaista Alam,
National Institutes of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD; Chelsea S Kidwell, Georgetown Univ, Washington, DC; Steven Warach,
National Institutes of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD; for the NIH Natural History of Stroke Investigators
Background: Matrix metalloproteinases (MMP’s) may play a critical role in blood brain barrier
(BBB) disruption and ischemia/reperfusion injury following ischemic stroke. Hyperintense Acute
Reperfusion injuRy Marker (HARM) is a novel magnetic resonance imaging (MRI) marker of BBB
disruption characterized by gadolinium enhancement of cerebrospinal fluid on fluid attenuated
inversion recovery (FLAIR) images. HARM has been associated with reperfusion, hemorrhagic
transformation, and poor clinical outcome in acute stroke patients. We hypothesized that
plasma concentration of MMP-9 would be associated with HARM. Methods: This is a
prospective study of acute stroke referrals enrolled in a natural history research protocol
between May 2006 and June 2007. Patients underwent gadolinium-enhanced MRI on
presentation and approximately 24 hours later. The presence of severe HARM on post-contrast
FLAIR images was assessed by blinded expert readers. Lesion volume was measured on acute
diffusion weighted imaging (DWI). Blood samples were obtained during the initial evaluation.
MMP-9 concentration was measured by ELISA. A logistic regression model tested for predictors
of severe HARM on acute and follow-up scans using MMP-9 concentration and covariates with
known or suspected associations with HARM. Results: Sixty-eight patients were enrolled.
Diagnoses were acute ischemic cerebrovascular syndrome (n⫽52), intracerebral hemorrhage
(n⫽7) and stroke mimic (n⫽9). Thirteen patients were treated with tPA. Mean (SD) time from
symptom onset to acute imaging was 9.6 h (10.9); to acute blood draw (MMP-9 sampling)
16.2 h (27.6); to follow-up imaging 33.0 h (11.4) in 43 patients. Severe HARM was present on
post-contrast scans in 13% of the patients acutely and in 41% on the follow-up scan. Severe
HARM on acute scan was associated with MMP-9 concentration (p⫽0.023) and time to acute
MMP-9 sampling (p⫽0.006). Severe HARM on follow-up scan was associated with MMP-9
concentration (p⫽0.030), time to acute MMP-9 sampling (p⫽0.038), age (p⫽0.007), and tPA
treatment (p⫽0.017). In both models, higher MMP-9 concentrations were associated with the
presence of severe HARM. Conclusions: Plasma MMP-9 concentration was found to be an
independent predictor of HARM on acute and follow-up scans, supporting the hypothesis that
HARM reflects early blood brain barrier disruption. If the association between plasma MMP-9
concentration and HARM is confirmed in future studies, HARM may be useful as an imaging
marker to evaluate MMP-9 inhibition in ischemic stroke and other pathologies associated with
blood brain barrier disruption.
158
Regional Differences In CO2 Vasoreactivity After Stroke Using CASL MRI.
Peng Zhao, David Alsop, Magdy Selim, Beth Israel Deaconess Med Cntr, Harvard Med Sch,
Boston, MA; Amir Abduljalil, The Ohio State Univ, Columbus, OH; Peter Novak, Univ of
Massachusetts, Boston, MA; Lewis Lipsitz, Kun Hu, Sarah LaRose, Vera Novak; Beth Israel
Deaconess Med Cntr, Harvard Med Sch, Boston, MA
Redistribution of perfusion to ischemic areas with increased metabolic demands is essential for
neuronal recovery after ischemic stroke. We aimed to investigate the regional differences in
CO2 vasoreactivity (CO2VR) and their relationships to chronic infarct volume, persistent infarct
hyperintensities (PIHs) and clinical outcomes. We studied 27 subjects with chronic large vessel
infarcts in the middle cerebral artery (MCA) territory (age 65.4⫾8.9 yrs) and 43 controls
(68.4⫾5.8 yrs), matched for age, sex and history of hypertension. MRI with FLAIR, MP-RAGE,
and continuous arterial spin labeling (CASL) perfusion images were acquired with a GE 3-Tesla
scanner. We measured cerebral blood flow in regions surrounding the infarct and adjacent
vascular territories using CASL during baseline, hypocapnic and hypercapnic conditions, and
assessed its relationship to the infarct volume and NIHSS of neurologic impairment. Image
segmentation and registration were used to quantify CO2VR in major anatomical lobes and
vascular territories. Data were analyzed using repeated measures MANOVA adjusted for age,
gender and brain volume. The CO2VR was lower in the stroke group than control across several
anatomical regions (p⬍0.0001) (Fig 1) and vascular territories (p⬍0.0001) bilaterally. The
CO2VR was significantly lower in insular cortex than other regions (Fig 1). There were regional
differences in CO2VR between stroke and non-stroke sides (p⫽0.0004). In MCA territory,
perfusion during hypercapnia was reduced on the stroke side compared to the non-stroke side
(p⫽0.03) and to the control group (p⫽0.01). In the stroke group, the CO2VR in the MCA was
negatively associated with PIHs volume (p⬍0.0001), infarct volume (p⬍0.0001) and the
systolic BP increase from hyperventilation to CO2 breathing (p⬍0.0002). The same relationship
was found for CO2VR in the entire anatomical lobe and peri-infarct regions. Lower CO2VR was
associated with higher NIHSS (p⬍0.003). Impairment of CO2VR after stroke extends into
567
various brain regions and vascular territories distant from the infarct site. Neurological status,
assessed by NIHSS, correlates with CO2VR. Regional differences in CO2VR may play an
important role in recovery from ischemic stroke. These results may be of therapeutic
significance to improve the outcome of stroke patients.
159
Granulocyte-Macrophage Colony-Stimulating Factor Treatment after
Common Carotid Artery Occlusion Enhances Leptomeningeal Collateral
Growth and Reduces Infarct Size after Focal Cerebral Ischemia.
Kenichi Todo, Kazuo Kitagawa, Tsutomu Sasaki, Emi Omura-Matsuoka, Yasukazu Terasaki,
Naoki Oyama, Yoshiki Yagita, Masatsugu Hori; Osaka Univ, Osaka, Japan
Background and purpose: We have reported that chronic reduction of cerebral perfusion
induced by unilateral common carotid artery (CCA) occlusion resulted in attenuation in infarct
size after ipsilateral permanent middle cerebral artery (MCA) occlusion. These results
suggested that chronic unilateral CCA occlusion in mice may induce collateral growth at distal
leptomengeal anastomosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has
been found to accelerate the collateral growth (arteriogenesis) at the circle of Willis in rat.
However, the effect of GM-CSF on leptomeningeal collateral growth has not been established.
In this study, we examined the effect of GM-CSF treatment after CCA occlusion on
leptomeningeal collateral growth and infarct size after permanent MCA occlusion. Methods:
Adult mice were assigned to unilateral CCA occlusion or sham operation and followed by
alternate-day regimen with GM-CSF (20 ␮g/kg) or saline injection. After the CCA operation,
latex perfusion was performed to visualize the leptomeningeal vessels. In another set of mice,
after the CCA operation, permanent ipsilateral MCA occlusion was performed and the infarct
volume was measured. Results: The diameter of leptomeningeal collateral vessels 14 days
after CCA occlusion was larger than that without CCA occlusion (31.0 ⫾ 9.4 ␮m, n⫽4, 64
vessels vs. 25.6 ⫾ 4.5 ␮m, n⫽4, 64 vessels, P⬍0.01) whereas the diameter 7 days after CCA
occlusion (25.9 ⫾ 7.7 ␮m, n⫽4, 65 vessels) did not enlarge. However, with GM-CSF
treatment, 7 days after CCA occlusion, the diameter was larger than that without GM-CSF
treatment (32.0 ⫾ 8.8 ␮m, n⫽8, 127 vessels vs. 25.9 ⫾ 8.1 ␮m, n⫽8, 126 vessels, p⬍0.01).
The infarct volume due to MCA occlusion 14 days after CCA occlusion was smaller than that
without CCA occlusion (25.5 ⫾ 7.8 mm3, n⫽6, vs. 50.5 ⫾ 12.8 mm3, n⫽6, P⬍0.01)
whereas, 7 days after CCA occlusion, that did not diminish (46.7 ⫾ 13.1 mm3, n⫽6). However,
with GM-CSF treatment, 7 days after CCA occlusion, the infarct volume due to MCA occlusion
was reduced (35.4 ⫾ 12.2 mm3, n⫽9 vs. 48.0 ⫾ 14.8 mm3, n⫽9, P⬍0.05). Conclusion: We
could reveal for the first time that, after CCA occlusion in mice, GM-CSF treatment enhanced
the leptomeningeal colalteral growth and reduced the infarct volume after MCA occlusion.
160
Interference with Peroxisome Proliferator-activated Receptor Gamma
Signaling Causes Cerebral Vascular Hypertrophy and Remodeling.
Gary L Baumbach, Carmen M Halabi, Andreas M Beyer, Curt D Sigmund, Frank M Faraci;
Univ of Iowa, Iowa City, IA
The transcription factor peroxisome proliferator activated receptor-␥ (PPAR␥) exerts antiinflammatory and anti-oxidant effects and is expressed in endothelium and vascular muscle.
Its role in regulating vascular growth, however, remains undefined. To test the hypothesis that
PPAR␥ plays a protective role in the cerebral vasculature, we studied cerebral arterioles in two
groups of genetically altered mice: 1) heterozygous knockin mice expressing the P465L
dominant negative mutation in PPAR␥ (L/⫹)(equivalent to the human P467L mutation), and 2)
transgenic mice expressing the human P467L PPAR␥ mutation under the control of the smooth
muscle myosin heavy chain promoter to restrict expression to smooth muscle (SM-P467L).
Unanesthetized systemic arterial pressure was measured using a carotid indwelling catheter in
L/⫹ (n⫽15) and non-transgenic wild-type littermates (⫹/⫹, n⫽19) and radiotelemetry in
SM-P467L (n⫽7) and ⫹/⫹ (n⫽6). Whereas systolic pressure was slightly elevated in both
groups of mice with altered PPAR␥ signaling (L/⫹: 147⫾3 vs. 140⫾2 mmHg in ⫹/⫹,
p⬍0.05; SM-P467L: 128⫾2 vs. 121⫾2 mmHg in ⫹/⫹, p⬍0.05), diastolic pressure was not
significantly (p⬎0.05) altered in either L/⫹ (125⫾2 vs. 122⫾2 mmHg in ⫹/⫹) or SM-P467L
(92⫾3 vs. 89⫾2 mmHg in ⫹/⫹). External diameter (ED) of maximally dilated cerebral
arterioles was reduced and cross-sectional area of the arteriolar wall (CSA, measured
histologically) was increased in both L/⫹ (ED ⫽ 54⫾2 vs. 64⫾2 ␮m in ⫹/⫹, p⬍0.05; CSA ⫽
473⫾21 vs. 378⫾18 ␮m2 in ⫹/⫹, p⬍0.05) and SM-P467L (ED ⫽ 52⫾3 vs. 61⫾3 ␮m in
⫹/⫹, p⬍0.05; CSA ⫽ 549⫾27 vs. 365⫾22 ␮m2 in ⫹/⫹, p⬍0.05) mice. Thus, interference
with PPAR␥ signaling, whether induced systemically or restricted in a cell-specific manner to
vascular muscle, produced cerebral arteriolar remodeling and hypertrophy. These findings
indicate that PPAR␥ normally has profound effects in the cerebral circulation and provide the
first direct evidence that PPAR␥ plays a critical role in regulating vascular structure in any
vascular bed. Furthermore, cerebral vascular remodeling and hypertrophy induced by altered
signaling of PPAR␥ may impact regulation of cerebral blood flow and/or predispose to greater
levels of brain injury during ischemia.
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Vol 39, No 2
February 2008
161
Genome Wide Association Study of Intracranial Aneurysms in the Finnish
Population.
arrays enabled the detection of very small CNVs that account for disease states as well as
genome-wide association studies. Observed CNVs unique to patient group and loci that show
association with the disease can contribute to our understanding of IA pathogenesis.
Kaya Bilguvar, Yasar Bayri, Michael DiLuna, Fatih Bayrakli, Christopher E Mason, Mohamad
Bydon, Yale Univ Sch of Medicine, New Haven, CT; Mika Niemela, Aki Laakso, Juha
Hernesniemi, Helsinki Univ Sch of Medicine, Helsinki, Finland; Juha E Jaaskelainen, Univ of
Kuipio, Kuipio, Finland; Aarno Palotie, Helsinki Univ Sch of Medicine, Helsinki, Finland;
Jaakko Rinne, Univ of Kuopio, Kuopio, Finland; Matthew W State, Murat Gunel; Yale Univ
Sch of Medicine, New Haven, CT
162
Cortical Stimulation for Upper-Extremity Hemiparesis from Ischemic Stroke:
Everest Study Primary Endpoint Results
Objectives: Previously published parametric and nonparametric linkage studies have established
multiple genetic loci that may contribute to the formation of intracranial aneurysms (IAs). While there
have been several reports of loci associated with IAs, including 1p34.3–36.13, 2p13, 7q22.1,
11q25, 14q22, and 19q13.3, no causative gene has been found to date. High throughput genotyping
arrays have made large scale association studies feasible for common diseases such as rheumatoid
arthritis, coronary artery disease (Nature, June 2007). We sought to employ a genome-wide
association study for intracranial aneurysms using the Finnish population. Finland was established
by a relatively small number of settlers followed by small waves of immigration, creating a genetic
bottleneck effect. This gives the advantage of decreased population stratification, which is a
common cause of false positive results in large association studies. Additionally, Finland has a high
rate of subarachnoid hemorrhage (incidence of 19.7/100,000 person - years compared to a global
average of 9/100,000 person - years). A genome-wide association study of IAs in the Finnish
population has the potential to contribute significantly to our understanding of IAs and their
pathogenesis. Methods: We have performed classical parametric linkage analysis as well as
genome-wide association study. Illumina Human CNV 370-Duo chips will be used to genotype 500
familial index cases, 500 sporadic cases and 1,000 controls from Finland. These chips utilize
318,000 tagged single-nucleotide polymorphisms (SNPs) and 52,167 copy number variation (CNV)
markers. Genotyping data derived from these arrays will be used for whole-genome association
studies as well as copy number variation analysis. Results: Our and other groups‘ previous
parametric and non-parametric linkage analysis demonstrated linkage to multiple loci, showing
strong evidence for genetic heterogeneity for IAs. Thus far, we have genotyped 250 index cases and
200 controls out of the Finnish cohort. Our preliminary results indicate the presence of many
chromosomal regions showing CNVs. Some of these CNVs overlap with previously reported CNVs.
Other novel regions that tend to cluster in the patient group need to be further analyzed in
comparison with the control group. Preliminary association study results also show evidence of
association of novel loci with IAs. The completion of genotyping of patient and control groups will
provide statistically significant p values. Conclusions: The advent of very high density genotyping
Robert M. Levy, Northwestern Univ, Chicago, IL; Randall R. Benson, Wayne State Univ,
Detroit, MI; Carolee J. Winstein, Univ of Southern Calif, Los Angeles, CA; Everest Study
Investigators
Objectives: To determine if subthreshold epidural motor cortex stimulation (CS) is 1) safe and
2) improves hand/arm motor function of hemiparetic chronic stroke patients. Methods:
Subjects at least 4 months post ischemic stroke with an Upper Extremity Fugl-Meyer (UEFM)
score between 28 and 50 points were enrolled into a 21 center prospective, randomized,
single-blind, longitudinal study assessing cortical stimulation (using an investigational device)
for enhancing hand/arm motor function. Subjects were randomized into an investigational
group or control group. Subjects in both groups were given equal amounts of focused
rehabilitation therapy during a 6-week treatment phase. Investigational subjects were
implanted with an epidural electrode over the hand/arm area of motor strip of the ipsilesional
hemisphere (targeted by fMRI) and were given subthreshold electrical stimulation concurrently
with rehabilitation therapy. Primary outcome measures compared the UEFM, which provides an
index of subjects’ neurological and motor function, and the Arm Motor Ability Test (AMAT), a
measure of activities of daily living, obtained at 4-weeks post rehabilitation to values obtained
during baseline. Clinically meaningful improvement was defined as a change of at least 4.5
points in UEFM and 0.21 points in AMAT. CS therapy would be classed as effective if the
percentage of investigational subjects achieving clinically meaningful improvements in the
combined endpoint of the UEFM and AMAT is 20 percentage points greater than the combined
data for control subjects. Findings: A total of 104 investigational subjects and 60 control
subjects were randomized. There have been no serious device related complications. The
4-week primary endpoint data collection has been completed. Due to the requirement that
investigators remain blinded to the results throughout the 24-week study secondary endpoint,
unblinded analysis of the primary endpoint data cannot be performed until January, 2008. The
primary endpoint data will be analyzed and presented. Conclusions: The primary endpoint
results of this prospective, randomized, single-blinded 164-subject study on the safety and
efficacy of subthreshold epidural motor cortex stimulation in hemiparetic stroke patients will be
presented and discussed.
2008 ISC Poster Presentations
569
International Stroke Conference Poster Presentations
Diagnosis
P1
MRI-Based Diagnostic Evaluation has Substantial Impact on Final Stroke
Diagnosis.
Monisha A Kumar, Dennis M Campbell, Stanford Univ, Palo Alto, CA; Hema L Vangala,
Regional Med Cntr, San Jose, CA; Irina Eyngorn, Jean Marc Olivot, Anne Sophie Beraud,
Amit Belgude, Maarten G Lansberg, Ingela Schnittger, Christine A Wijman, Stanford Univ,
Palo Alto, CA; David C Tong, California Pacific Med Cntr, San Francisco, CA; Michael
Mlynash, Michael Moseley, Gregory W Albers; Stanford Univ, Palo Alto, CA
Background and Purpose - Identification of stroke etiology currently relies on clinical evaluation
supported by a multitude of diagnostic tests. However, the diagnostic yield of these tests is
unclear. We sought to determine how often an MRI-based diagnostic algorithm altered the final
diagnosis in a large consecutive series of unselected patients presenting with signs and
symptoms of stroke. Methods - In this prospective NIH funded study, 273 consecutive patients
admitted to the Stanford Stroke Service underwent CT, MRI, intracranial and cervical MRA and
echocardiography, in this pre-specified order. All patients over the age of 18 years, within 48
hours of symptom onset, and able to comply with MRI and echocardiography were included in
the study. TOAST classification was determined by a stroke neurologist both after review of the
initial history/physical and CT, and on hospital discharge, after review of all diagnostic studies.
Results - Correspondence between the initial and final TOAST classification is shown in the
Table below. Only 53.1% of the patients had the same TOAST classification on discharge as
they did after the initial (CT-based) diagnostic evaluation. Of the remaining 128 patients, MRI
findings led to a change in the diagnosis in 36.7% of the patients, MRA led to a change in
diagnosis in 18.8%, and echocardiography led to a change in diagnosis in 16.4% of the
patients. The overall prevalence of large artery atherosclerosis was correctly estimated;
however, the initial diagnosis was accurate only 46% of the time. The initial diagnosis was
correct in only 17/46 patients (37.0%) discharged with a final diagnosis of cardioembolism;
many were initially diagnosed as having large artery atherosclerosis or small vessel disease.
Though the initial diagnosis of small vessel disease had high sensitivity (92.3%), the positive
predictive value was poor (58.4%). Conclusions - The positive predictive value of the initial
CT-based stroke assessment is poor, even among fellowship-trained vascular neurologists. An
MRI-based diagnostic evaluation led to a change in final diagnosis in about half of the patients
in this consecutive series.
COMPARISON OF TOAST STROKE CLASSIFICATION BEFORE AND AFTER MRI-BASED
DIAGNOSTIC ALGORITHM.
FINAL
INITIAL
DIAGNOSIS
(N)
Large Artery
Atherosclerosis
(65)
Cardioembolic
(29)
Small Vessel
Disease (101)
Other Determined
(8)
Stroke,
Undetermined
(41)
Not Stroke (11)
Uncertain (18)
Total ⫽ 273
Patients
as embolic (artery-to artery or cardiac), small vessel, or undetermined. Cervical MRA was
considered positive if there was a ⬎50% stenosis (NASCET criteria) ipsilateral to a
symptomatic hemisphere. The ‘diagnostic utility’ of TEE was determined based on whether the
TEE findings led to a change in the final diagnosis. Results - MRI, MRA and TEE were obtained
in 154 patients. A DWI pattern suggestive of acute artery-to-artery or cardiac embolism
occurred in (55.8%). MRI evidence of a small vessel (lacunar) lesion was present in 29.9% and
in 14.3% the MRI was negative or non-specific. Among patients with an MRI pattern suggestive
of artery-to-artery or cardiac embolism, the diagnostic yield of TEE was 15.1% vs. 6.5% for the
small vessel group and 4.5% for the undetermined group (p⫽0.04). Among patients with the
combination of an embolic pattern on MRI and a negative cervical MRA, the diagnostic yield
of TEE was 17.8% in the embolic group, 6.8% in the small vessel disease group and 4.5% in
the undetermined group (Figure). Conclusions - The diagnostic utility of TEE varies substantially
based on MRI/MRA patterns. Diagnostic utility is highest in patients with an embolic MRI pattern
and a negative cervical MRA. An MRI-based diagnostic approach allows the clinician to
selectively obtain TEE examinations in patients who are most likely to benefit.
DIAGNOSIS
Positive
Large
Predictive
Artery
Small
Other
Stroke,
Not
Value
Atherosclerosis Cardioembolic Vessel Determined Undetermined Stroke Uncertain
(%)
31
11
2
1
18
1
2
47.7
3
17
1
0
5
3
0
58.6
9
8
60
0
18
2
5
58.4
0
0
1
5
0
1
1
62.5
6
8
0
2
18
3
3
43.9
1
3
51
0
1
46
0
1
65
0
0
9
5
1
64
5
3
18
0
9
20
45.5
50.0
P2
MRI/MRA Patterns Predict the Diagnostic Utility of Transesophageal
Echocardiography in Patients with Acute Stroke.
Monisha A Kumar, Stanford Univ, Palo Alto, CA; Hema L Vangala, Regional Med Cntr, San
Jose, CA; Dennis M Campbell, Irina Eyngorn, Amit Belgude, Jean Marc Olivot, Anne Sophie
Beraud, Maarten G Lansberg, Ingela Schnittger, Christine A Wijman, Stanford Univ, Palo
Alto, CA; David C Tong, California Pacific Med Cntr, San Francisco, CA; Michael Mlynash,
Michael Moseley, Gregory W Albers; Stanford Univ, Palo Alto, CA
Background and Purpose - Transesophageal Echocardiography (TEE) is a valuable tool for the
evaluation of ischemic stroke patients, but its diagnostic yield is much debated. We sought to
determine whether magnetic resonance imaging (MRI) can be used to predict which subgroups
of patients presenting with signs or symptoms of acute ischemic stroke are most likely to have
clinically relevant findings on TEE. Methods - In this prospective NIH-sponsored study,
consecutive patients admitted to the Stanford Stroke Service underwent CT, MRI, cervical MRA
and TEE, in this pre-specified order. After acquisition of the MRI, DWI patterns were classified
P3
Multimodal CT in Acute Ischemic Stroke: Predictive Value for Early Infarct
Extension.
Kristian Barlinn, Imanuel Dzialowski, Jasmin Renger, Andrei Khomenko, Dept. Neurology,
Univ of Dresden, Dresden, Germany; Olaf Wunderlich, Dept. Neuroradiology, Univ of
Dresden, Dresden, Germany; Georg Gahn, Dept. Neurology, Univ of Dresden, Dresden,
Germany; Rüdiger von Kummer; Dept. Neuroradiology, Univ of Dresden, Dresden, Germany
Background: In acute ischemic stroke, specificity of non-contrast CT (NCCT) for ischemic
damage at baseline is high, but sensitivity is not optimal. We sought to determine whether
multimodal CT might improve prediction of early infarct extension. Methods: We prospectively
studied anterior circulation ischemic stroke patients presenting within 12 hrs of symptom onset
and with a National Institute of Health Stroke Scale (NIHSS) score ⬎ 2. We examined all
patients with cranial NCCT, CT angiography and CT perfusion imaging and generated parameter
maps of TTP, CBV and CBF. Patients could be treated with IV, IA, or combined IV/IA thrombolysis
according to current guidelines. We applied the Alberta Stroke Program Early CT Score
(ASPECTS) to all NCCT, CTA-source images (CTA-SI) scans and CTP parameter maps. We
scored hypoattenuation (NCCT), diminished contrast enhancement (CTA-SI) and qualitative
reduction in CBF and CBV and prolonged TTP as abnormal. We calculated sensitivity, specificity,
positive predictive value (PPV) and negative predictive value (NPV), using 24 hr NCCT or MRI
diffusion- weighted images as reference. We determined predictive values for any (ASPECTS ⬍
10) and for extensive (ASPECTS ⱕ 7) ischemic lesions for all and for thrombolysed and
non-thrombolysed patients separately. Results: We studied 33 patients (mean age 70.2 ⫾
13.0 yrs, 46 % male, 17/33 (52%) thrombolysed, time-to-presentation 171 ⫾ 137 min, median
NIHSS score 7, NCCT-ASPECTS 9 (range 2–10)). In this unselected population, predictive values
for any and extensive ischemic lesions did not differ among the different CT-modalities. In
thrombolysed patients, sensitivity of NCCT and CTA-SI for any ischemic lesion was significantly
higher compared to non-thrombolysed patients (predictive values are presented in table 1 and
2), but we did not find differences in prediction of extensive ischemic lesions. Among
non-thrombolysed patients, sensitivity for CBV trended to be the best predictor for both any and
extensive lesion (57% and 100%). Among thrombolysed patients, predictive values did not
differ. Conclusions: In our study, multimodal CT does not seem to significantly improve
prediction of early infarct extension using ASPECTS. Sensitivity of NCCT and CTA-SI seems to
be excellent in thrombolysed but poor in non-thrombolysed patients.
570
Stroke
Vol 39, No 2
February 2008
TABLE 1. THROMBOLYSIS (Nⴝ17; ASPECTS<10)
NCCT
Sensitivity
Specificity
PPV
NPV
CTA-SI
TTP
CBF
CBV
82(0.59–0.93) 88(0.64–0.97) 76(0.53–0.90) 76(0.53–0.90) 71(0.45–0.88)
/
/
/
/
/
100(0.78–1.0) 100(0.78–1.0) 100(0.77–1.0) 100(0.77–1.0) 100(0.72–1.0)
0(0–0.56)
0(0–0.66)
0(0–0.49)
0(0–0.49)
0(0–0.49)
TABLE 2. NON-THROMBOLYSIS (Nⴝ16; ASPECTS<10)
NCCT
Sensitivity
Specificity
PPV
NPV
CTA-SI
TTP
CBF
CBV
21(0.08–0.48) 29(0.13–0.55) 54(0.29–0.77) 57(0.33–0.79) 57(0.45–0.88)
100(0.34–1.0) 100(0.34–1.0) 100(0.34–1.0) 100(0.34–1.0) 100(0.34–1.0)
100(0.44–1.0) 100(0.51–1.0) 100(0.65–1.0) 100(0.68–1.0) 100(0.68–1.0)
15(0.04–0.42) 17(0.05–0.45) 25(0.07–0.59) 25(0.07–0.59) 25(0.07–0.59)
rated as mild-moderate in 51.6% (49/95), severe in 8.4% (8/95), and as none in 40% (38/95) of
patients on immediate post-contrast FLAIR. There was a trend between time from onset to detection
and HARM, median of 4.84 hrs for mild-moderate and 8.64 hrs for severe, (p⫽0.084). Delayed
enhancement on first follow-up FLAIR, rated as mild in 44.3% (42/95) and severe in 41.1% (39/95)
of patients, was significantly associated with HARM on acute exam, (p⫽0.036). Acute imaging was
performed prior to t-PA in 22 patients and HARM was rated as mild-moderate in 45.5% (10/22),
severe in 4.5% (1/22), and as none in 50% (11/22). Median time between stroke onset to detection
of any HARM was 1.38 hrs in t-PA treated patients. On follow-up, HARM was rated as mild-moderate
in 31.8% (7/22), severe in 59.1% (13/22), and as none in 9.1% (2/22). Treatment with t-PA was
associated with HARM on follow-up MRI (p⫽0.035) but not HARM on the pre-treatment scan
(p⫽0.60). . Conclusions: It is possible to detect HARM on immediate post-contrast FLAIR imaging
performed during the acute exam and prior to treatment with t-PA. The ability to detect BBB
disruption prior to thrombolytic therapy and the high prevalence of HARM following treatment may
aid in the development of new therapies to protect the barrier and minimize further injury.
Values are presented as % (95% CI).
P4
Neuroanatomic Representation of NIHSS Sub-items Employing Acute
Diffusion Imaging: Developing a Predictive Atlas of Clinical Outcome.
Chelsea S Kidwell, Georgetown Univ, Washington, DC; Kyle W Singleton, Section on Stroke
Diagnostics and Therapeutics, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD; Timothy J Schaewe, UCLA, Los Angeles, CA;
Marie Luby, Steven Warach, Section on Stroke Diagnostics and Therapeutics, National
Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD;
Jeffry Alger, UCLA, Los Angeles, CA; for the NIH Natural History of Stroke Investigators
Background: To date, predictive models employing acute imaging data have been focused on
prediction of final infarct volume. However, the clinical utility of predictive models would be greatly
enhanced if these models were able to predict not only infarct volume and anatomical location, but
also acute and long-term clinical outcome. This information could then be used to guide treatment
decisions. Methods: As part of a global project aimed at creating a large scale stroke-specific
predictive brain atlas, we correlated acute DWI lesion location with the presence of individual
sub-item scores from the NIHSS. Inclusion criteria were: acute ischemic stroke; brain MRI (including
DWI) performed within 24 hours of symptom onset; and baseline NIHSS score available. Acute DWI
images from all subjects were aligned to a common neuroanatomic coordinate system. Chi square
images were calculated on a voxel-by-voxel basis. Results: A total of 163 patients met inclusion
criteria. Mean age was 70, range 21–97. Baseline NIHSS was median 4, mean 6, range 0 –27. The
figure shows representative axial slices from the atlas. The images show color-coded chi square
values, using a false discovery rate of 5%, for anatomic regions in which there was a significant
correlation between symptom presence and DWI hyperintensity. Item 5b (motor arm) is shown on
the top row, illustrating that the voxels significant for this subitem correspond anatomically to the
corticospinal tract. The bottom row shows slices from item 9 (language), now with the significant
regions corresponding to primary language areas. Conclusions: This is the first voxel-based stroke
atlas correlating NIHSS sub-items employing DWI data. The maps illustrate the neuroanatomic
representation of the NIHSS in standardized space. The ultimate goal is to build an atlas that uses
acute diffusion and perfusion MR imaging to predict long-term outcome for two scenarios: untreated
vs. treated with recanalization therapy. This information may then be used to influence treatment
decisions.
P5
Blood Brain Barrier Disruption in Acute Stroke Prior to Therapy is Evident
on Immediate Post-Contrast FLAIR MRI.
Lawrence L Latour, NINDS, Bethesda, MD; Chelsea S Kidwell, Georgetown Univ,
Washington, DC; Kyung-Yul Lee, NINDS, Bethesda, MD; Timothy J Schaewe, UCLA, Los
Angeles, CA; Jose G Merino, Steven Warach, NINDS, Bethesda, MD; for the NIH Natural
History of Stroke Investigators
Introduction: Hyperintense Acute Reperfusion injuRy Marker (HARM) is a novel magnetic resonance
imaging (MRI) marker of early blood brain barrier (BBB) disruption. HARM has previously been
reported as appearing on follow-up imaging but not on the acute scan immediately after
administration of contrast agent. We hypothesized that it is possible to detect HARM on the acute
scan within 5 min of first contrast injection. . Methods: 95 patients with ischemic stroke (17 month
period) presenting within 24 hrs of symptom onset, having pre- and post-contrast FLAIR on acute
MRI, and FLAIR on first follow-up occurring within 48 hrs, were included. Two expert readers
evaluated FLAIR images for evidence of HARM, blinded to identifiers, order of exam, and pre vs post
contrast imaging. HARM was graded as none, mild-moderate, and severe. Chi-square statistics
were used to test associations between HARM on acute and follow-up imaging. . Results: HARM was
P6
Early Clinical Improvement From Complete Recanalization Predicted By
Extent And Degree Of CTA Source Image Abnormality.
Nikolai Steffenhagen, Volker Puetz, Michael Hill, Univ of Calgary, Calgary, Canada; Imanuel
Dzialowski, Univ of Dresden, Dresden, Germany; Christine O’Reilly, Mayank Goyal, Andrew
Demchuk; Univ of Calgary, Calgary, Canada
Background: Mismatch on perfusion CT or MRI is thought to identify patients with benefit from
thrombolysis. CT angiography (CTA) source images (CTASI) may indicate irreversibly infarcted
tissue and the presence of an intracranial occlusion on CTA may indicate perfusion status.
Hypothesis: We sought to determine if CTA can identify patients with middle cerebral artery
(MCA) occlusion who will respond to early recanalization. Methods: We retrospectively studied
patients with CTA for acute ischemic stroke. We only selected patients with MCA mainstem
(M1) occlusion on CTA who had complete recanalization (defined as TIMI 3 flow) on digital
subtraction angiography within 8 hours from onset. We independently applied an expanded
Acute Stroke Prognosis Early CT Score (e-ASPECTS) to areas with hypoattenuation on CTA-SI
in a 3-readers consensus setting. e-ASPECTS separately rates grey and white matter for 5
cortical ASPECTS regions (M1, M3, M4, M5, M6) thus adding 5 points to conventional ASPECTS.
One point each is given for normal, 0.5 points for decreased and 0 points for absent
contrastation. An e-ASPECTS value⫽15 indicates a normal scan, e-ASPECTS⫽0 indicates
complete MCA stroke. For analysis, we categorized patients into 3 CTA-SI e-ASPECTS groups
where 15 is best and 0 is worst: ⬎⫽12; ⬎⫽9 to ⬍12; ⬍9. Primary outcome was early clinical
improvement defined as 10-point improvement in NIHSS score or NIHSS score ⱕ2 at 24 hours.
Secondary outcomes were median 24-hours NIHSS improvement and percentage independent
functional outcome (modified Rankin Scale [mRS] score ⱕ2) at 3 months. Results: From a CTA
database with 985 patients, 129 (13%) had M1 occlusion. 25 of these had complete early
recanalization on DSA. Results for categorized CTA-SI e-ASPECTS groups are given in the table.
With higher CTA-SI e-ASPECTS values, patients were more likely to have early clinical
improvement with early recanalization. Also, median improvement in 24-hours NIHSS score
was higher in patients with high compared to patients with low CTA-SI e-ASPECTS scores
(p⫽0.23). Patients with a CTA-SI e-ASPECTS score ⬍9 were unlikely to have early clinical
improvement with MCA recanalization. This trend translated into higher percentage functional
independence at 3 months (p⫽0.35). Given small numbers in the this highly selected
population, none of these findings reached statistical significance. Conclusion: Simple CTA with
CTA-SI indicating irreversibly infarcted tissue and MCA occlusion indicating perfusion
impairment may identify patients likely to respond to recanalizing therapy.
e-ASPECTS on
CTA-SI (n)
⬎⫽12 (9)
9–11 (10)
⬍9 (6)
Baseline
NIHSS
(median, [iqr])
15
15
20
NIHSS improvement ⬎⫽10
points or NIHSS ⱕ2 at
24hrs
(14to18)
(11to20)
(18to22)
56%
50%
0%
24hrs NIHSS
improvement
(median, [iqr])
8.0
6.5
-1.0
3 month
mRS of 0 2
(1 to10)
(-1to11)
(-3to 4)
56%
50%
17%
Outcome by CTA-SI e-ASPECTS category.
P7
Cardiac Multidetector Computed Tomography Accurately Detects Embolic
Sources In Acute Ischemic Stroke Patients.
Sang-Bae Ko, Yong Chai Ko, Jung-Hyun Park, Hee-Joon Bae; SNU Bundang Hosp,
Seong-nam, Republic of Korea
Background: Screening the embolic sources is an important process in acute stroke patient
evaluation. Transesophageal echocardiography (TEE), which is superior to transthoracic
echocardiography (TTE), is very sensitive in detecting intracardiac thrombi (ICT) and atheromatous plaque (AP) in the ascending aorta (AsA) and aortic arch (AA). However, due to blind
spot at the distal part of AsA, only limited evaluation is possible using TEE. With good image
resolution and no blind spot, cardiac multidetector computed tomography (MDCT) can be used
as an alternative tool to TEE in detecting ICT and AP in the AsA and AA. Methods: One hundred
and seventy four consecutive patients with acute ischemic stroke and transient ischemic attack
(TIA) were included in this study. Because lacunar infarction is unlikely to be related with ICT,
forty patients were excluded, and a total of 134 patients underwent TTE, TEE, and cardiac
MDCT scans. We compared the diagnostic yield of TEE in detecting ICT and AP with that of
cardiac MDCT. Results: Demographic data of study population as follows, (Male, 55.2% with
mean age, 66.1 ⫹/- 12.9). 1) ICT detection. TEE showed possible cardiac embolic sources in
23 patients (23/134, 16.5%), and which were mitral stenosis, mitral valve prolapse, patent
foramen ovale, dilated cardiomyopathy, congestive heart failure, and spontaneous echo
contrast. ICT was seen in only one patient using TEE. Cardiac MDCT showed embolic sources
in 27 patients, and ICT was seen in 5 patients, and average size of ICT was 5.2 mm X 3.2 mm.
One patient only showed ICT with TEE, not with MDCT. Excluding 63 patients with a stroke
mechanism of large artery disease (LAD), TEE and cardiac MDCT detected ICT with a probability
of 1.4% (1/71) and 7.0% (5/71), respectively. 2) AP detection. Complex AP, composed of
thickness of ⱖ4 mm, ulceration, pedunculation, or mobile elements, was seen on TEE in 3
patients. Cardiac MDCT showed high risk AP (low Hounsefield index with ulceration) in 10
patients. Excluding patients with cardioembolism and LAD, TEE and MDCT showed another
possible embolic source at AsA and AA with a probability of 6.3% (3/48) and 22.7% (10/44).
Conclusion: Cardiac MDCT identified more patients with ICT and AP than TEE. Combined with
TEE, Cardiac MDCT can provide more accurate information regarding embolic sources in acute
ischemic stroke patient.
P8
The Neurocardiovascular CT Protocol: A Comprehensive Analysis of Stroke
Etiology and Ischemic Penumbra Using 64-slice Multi-Detector CT in
Patients with Acute Ischemic Stroke.
Raul G Nogueira, Ricardo Cury, Stuart Pomerantz, Joshua A Hirsch, Ferdinando S Buonanno,
Lee H Schwamm, Suhny Abbara, Ramon G Gonzalez, Michael H Lev; Massachusetts
General Hosp, Boston, MA
571
scores showed similar patterns, but with less significance. Discussion: Use of VLSM produced
anatomically specific results demonstrating a subcortical area leading into the CST appears to
be critical for motor performance after a stroke. This area may represent an important
integration site for the main motor fibers from surrounding cortex. It might also represent the
joining of parallel redundant tracts that when damaged, would inhibit plasticity that would
otherwise occur. Acknowledgements: This study was funded by the investigational study
sponsor, Northstar Neuroscience, Inc. Figure: The critical anatomic region determined by VLSM
analysis (blue) was used as a seed for DTI tractography (red/yellow). The crosshairs are
centered over M1.
Background and Significance: The underlying cardiac-cervico-cranial vascular lesion determines
the optimal treatment and the clinical outcomes in acute stroke patients. The use of transthoracic
echocardiography is limited by its poor evaluation of the left atrium (LA), in particular the LA
appendage (LAA). The use of transesophageal echocardiography is limited by its degree of
invasiveness, required expertise, costs, and time-consumption. We have developed a new CT
protocol that provides detailed anatomic information about the heart and aortic arch as well as the
cervical and cranial vessels in addition to tissue perfusion data while using limited amounts of
contrast material and time. Methods: Fifteen acute stroke patients were examined by 64-slice
MDCT. Scan protocol included: (1) Non-contrast Head; (2) First Perfusion slab; (3) CTA Head and
Neck; (4) Cardiac Group; (5) Cardiac Delay; (6) Second Perfusion slab; (7) Post Processing MIPS and
CTP data. Results: The image quality of the cervico-cranial CTA (Figs. 1 & 2) and CT perfusion (Fig.
3) was similar to our previous protocol. In all cases, there was adequate evaluation of the aortic arch
and the heart (Fig. 4). No cases of poor opacification of the LAA were seen, presumably due to the
addition of the delayed cardiac phase. This is of essential importance since in previous studies the
specificity of MDCT for the detection of LAA thrombus was limited by its inability to distinguish blood
stasis or low-velocity blood flow (e.g. TEE spontaneous echo contrast) from thrombus. The total
imaging acquisition time was less than 3 minutes. The total amount of injected contrast was 150
mL. Conclusion: Advanced imaging employing 64-slice MDCT scanning allows for optimal
anatomic imaging of the heart, aortic arch, and cervico-cranial vasculature while providing
functional data about tissue perfusion. This protocol may diminish the overall costs and time spent
on the investigation of stroke etiology. In comparison to our standard acute stroke protocol, this is
accomplished by using only an extra 15 mL of iodine contrast and minimal additional scanning time.
P9
Identification Of Critical Areas For Motor Function Recovery In Chronic
Stroke Subjects Using Voxel-based Lesion-symptom Mapping.
Ryan Lo, Darren Gitelman, Robert Levy, Northwestern Univ, Chicago, IL; Justin Hulvershorn,
Northstar Neuroscience, Seattle, WA; Todd Parrish; Northwestern Univ, Chicago, IL
Introduction: Previous stroke studies using fMRI or lesion-based methods to predict residual
motor function have been limited in defining critical anatomic structures. This study uses a new
method of analysis, voxel-based lesion symptom mapping (VLSM) to overcome the limitations
of previous studies. Methods: Forty-two stroke subjects with moderate to moderately severe
motor impairment (AMFM ⬎28, AMAT ⬎ 1.25) participating in an investigational study were
imaged using a 3T Siemens TIM Trio magnet. High resolution 1 mm isotropic 3D T1 weighted
volumetric images were collected. All subjects’ motor performance was assessed by three
different behavioral measures (AMFM, AMAT, Box & Block). All T1 volume images were
normalized using SPM5 to a symmetric template using SPM5 and oriented so that lesions
appeared in the left hemisphere. The lesioned areas were identified using both the T1 image
and the non-diffusion T2 weighted scans obtained during DTI acquisition. The 3D lesion maps
were entered into the VLSM analysis. Areas showing significant correlations with performance
measures (AMFM, AMAT and Box & Block) were identified using the false discovery rate
corrected at p ⱕ 0.05. Results: The area most correlated with decreased AMAT scores was the
junction of the corona radiata leading into the corticospinal tract (CST). AMFM and Box & Block
P10
A 30-Day Cardiac Event Monitor Belt for Recording Paroxysmal Atrial
Fibrillation After a Cerebral Ischemic Event: The EMBRACE Pilot Study.
Melanie Spring, Dept of Medicine, Univ of Toronto, Toronto, Canada; Paul Dorian, Div of
Cardiology, St. Michael’s Hosp, Univ of Toronto, Toronto, Canada; Beth Fry, Brian Buck,
Demetrios J Sahlas, Julia Hopyan, Regional Stroke Cntr, Sunnybrook Health Sciences Cntr,
Univ of Toronto, Toronto, Canada; Victoria Korley, Div of Cardiology, St. Michael’s Hosp,
Univ of Toronto, Toronto, Canada; Sandra E Black, David J Gladstone; Regional Stroke Cntr,
Sunnybrook Health Sciences Cntr, Univ of Toronto, Toronto, Canada
Background - Atrial fibrillation (AF) is a major preventable cause of stroke. Improved methods
for detecting AF are needed, as it is frequently paroxysmal and asymptomatic, and routine
Holter monitoring (24 –72 hours) detects AF in only 5% of patients after stroke/TIA. Few studies
have investigated extended duration ambulatory monitoring after stroke/TIA. This study
evaluates the yield of 30-day monitoring. We hypothesize that some cases of “cryptogenic”
stroke result from cardioembolism due to (undiagnosed) paroxysmal AF. Methods - This
prospective observational study employs a soft, lightweight elastic belt (Accuheart Electrode
Belt, Advanced Bioelectric Inc.), a new technology using high resistance non-adhesive
electrodes without the need for pregelled adhesive skin contact electrodes. The belt is attached
to a programmable, event-triggered device (Braemar Inc., ER910AF) that records episodes of
572
Stroke
Vol 39, No 2
February 2008
asymptomatic AF by automated detection of R-R variability after 30 beats. It can detect up to
6 events of 5 min. each (memory storage capacity 30 min.). Patients are recruited from an
outpatient stroke clinic in Toronto. Inclusion criteria are a recent (⬍6 months) ischemic stroke
or TIA of undetermined etiology (TOAST criteria) diagnosed by a stroke neurologist after
complete etiological work-up (12-lead ECG, 24 or 48 hour Holter, echocardiography, brain MRI,
vascular imaging with MR or CT angiography, bloodwork). Exclusions are any previous
documentation of AF by history, ECG, telemetry, or Holter. The monitor is worn for 30 days or
until 6 events are recorded. Data are transmitted transtelephonically for central reading by the
study cardiologist. Main outcomes are the proportion of patients for whom the study monitor
records one or more episodes of: (1) AF ⬎30 seconds; (2) non-sustained (⬎ 3 beats) irregular
atrial tachyarrhythmia ⬍30 seconds (including brief runs of AF); or (3) atrial flutter; and the
proportion who are anticoagulated based on the monitor results. Results - The study monitor
identified new AF in 3/15 (20%) of patients with cryptogenic stroke/TIA enrolled to date. Patient
1 (age 79) had a 3-minute episode of AF; patient 2 (age 65) had a 30-beat run of AF; patient
3 (age 89) had 14 brief episodes of irregular tachycardia. None had left atrial enlargement. All
were anticoagulated based on the results. Study recruitment is ongoing. Conclusions - These
preliminary results suggest that a simple intervention of extended duration ambulatory cardiac
monitoring is feasible, improves the detection of occult AF, and results in more patients being
anticoagulated for secondary stroke prevention. If confirmed in a larger sample, these findings
may have implications for clinical practice.
P11
Telemedicine Evaluation For Acute Stroke Treatment Is Faster And
Achieves Better Protocol Adherence Than Phone Consultation.
Syed F Zaidi, Ridwan Lin, Lori Massaro, Vivek Reddy, Maxim Hammer, Lawrence R
Wechsler, Ken Uchino; Univ of Pittsburgh Med Ctr, Pittsburgh, PA
Background: Two-way video telemedicine and telephone consultations between community
hospitals and stroke centers are increasingly used to provide more optimal acute stroke care.
We sought to compare their efficiency, diagnostic accuracy, and intravenous tissue plasminogen activator (IV tPA) protocol adherence. Methods: We performed a retrospective chart
review of consecutive patients receiving IV tPA through telemedicine (TM) consultations at three
community hospitals between March 2006 and June 2007. Comparisons were made to
consecutive patients who received IV tPA at community hospitals following telephone (TP)
consultations and randomly selected patients at the university stroke center (SC) who received
IV tPA from January 2002 to October 2005. From chart review, we extracted the door-to-CT and
door-to-tPA treatment times, IV-tPA protocol violations, and the final discharge diagnoses.
Comparisons were made with Mann-Whitney U test for numerical and Fisher’s exact test for
categorical variables. Results: Thirty-three patients evaluated using telemedicine consultation
were compared to 128 patients with telephone consultation and 50 patients evaluated at the
stroke center. The door-to-TPA time was shorter in the TM group when compared to the TP
group (median 70 vs 89 minutes, p⬍0.001). The door-to-CT time was also shorter in the TM
group compared to the TP group (median 16 vs 25 minutes, p⬍0.001). The rate of IV-tPA
protocol deviations was significantly lower in the TM and SC groups compared to the TP group
(6.1%, 6.0% and 37.5%, p⬍0.001 for comparison to TP group). We also noted a trend toward
fewer rates of eventual stroke misdiagnoses in the TM group when compared to the TP group,
(3% vs 6%, p⫽0.68). When compared with the SC group, the TM group also had a significantly
shorter time to the CT scan (median 16 vs 23 mins, p⫽0.016), but the overall door to tPA time
was not significantly different (70 vs 77 mins, p⫽0.25). Conclusion: Diagnosing acute stroke
for IV-TPA therapy is faster, more accurate, and has fewer protocol violations compared to
phone consultations.Telemedicine treatment might be as efficient as on-site treatment at
stroke center.
P12
Transesophageal Echocardiography Findings Change Secondary Prevention
Strategies in Stroke Patients.
Guido Falcone, Josefina H Prebble, Dario Colombero, Juan P Guerchi, Candelaria Leiguarda,
Sebastian F Ameriso; FLENI, Buenos Aires, Argentina
Transesophageal echocardiography (TEE) was recently introduced in clinical practice for the
evaluation of the heart and aortic arch. This diagnostic modality is routinely recommended for
young stroke patients and for those with suspected embolic infarcts. Aortic arch atheromas and
patent foramen ovale (PFO) with or without atrial septum aneurysm (ASA), among other
conditions are often associated with cerebrovascular disease and are best demonstrated by
TEE. However, data are limited regarding the role of routine use of TEE in non selected stroke
patients. In clinical practice, antiplatelet agents are frequently replaced by anticoagulation in
subjects with mural left auricular/ventricular thrombi, complex aortic arch plaques, or PFO with
atrial septum aneurysm in subjects without vascular risk factors. We assessed the hypothesis
that TEE findings can modify therapeutic strategies in a substantial number of patients and
should be routinely employed in patients with stroke. We prospectively performed TEE in every
patient admitted with diagnosis of recent ischemic stroke or TIA. We excluded patients with
contraindications for anticoagulation, those who should receive anticoagulation despite TEE
findings (i.e., atrial fibrillation, valve disease, prothrombotic conditions), and those who did not
tolerate the procedure. The incidence of complex aortic arch atheromas was high but the
incidence of PFO with and without associated ASA was lower than previously reported. Five
percent of the patients had PFO without vascular risk factors. TEE detected a condition that
supported a change of initial secondary prevention measures in 65 subjects (21.5%). In
conclusion, TEE contributes to the implementation of secondary prevention strategies in a
substantial number of non selected stroke patients. These findings support a recommendation
for routine use of this modality in the diagnostic work-up of subjects with ischemic
cerebrovascular disease.
PATIENT DATA AND TEE FINDINGS
n
303
Females/males (%)
Age (mean ⫾SEM,years)
Comorbid conditions (%)
28/72
62.8⫾0.8
Hypertension
Hypercholesterolemia
Smoking
Diabetes
Coronary artery
disease
Prior stroke/TIA
Neoplasia
Migraine
64
47
38
14
16
PFO
PFO⫹ASA
Complex aortic
arch plaques
Mural left
cavity thrombus
10
4
16
Patients without vascular
risk factors (%)
TEE Findings (%)
22
6
4
17
3
P13
The Influence Of Ischemic Stroke Subtype On Infarct Expansion, Penumbral
Fate And Reperfusion.
Jane F Prosser, Louise Allport, Ken Butcher, Mark Parsons, Patricia Desmond, Brian Tress,
Stephen M Davis; Royal Melbourne Hosp, Melbourne, Australia
Background: Tissue outcome in acute ischemic stroke is imperfectly predicted by the extent
of PWI-DWI mismatch. Other physiologic characteristics may also influence the eventual extent
of infarction by altering tissue susceptibility to ischemia. Cardioembolic ischemic strokes are
more likely to be fatal and are associated with greater degrees of initial neurologic impairment.
Embolus size/site of vessel occlusion, relative cerebral hypoperfusion related to cardiac failure,
haematologic or endothelial abnormalities and increased susceptibility to reperfusion injury
have been suggested to explain this. The potential of stroke etiology to influence infarct
evolution has not been rigorously studied. Aims: We hypothesised that acute stroke associated
with a cardioembolic source would be associated with greater infarct expansion, increased
percentage mismatch lost (PML) and greater percentage reperfusion compared to strokes of
other types. Methods: Ninety eight patients with acute ischemic stroke and a non-lacunar
clinical syndrome were included. MRI was performed within 24 hours of symptom onset, on day
3–5 and day 90 from stroke onset. Fifty five patients had a region of DWI-Tmax⫹2 mismatch
that was greater than 20% of the initial DWI volume. We examined the effects of stroke subtype
(SSS-TOAST classification determined independently by two raters blinded to quantitative
imaging data), presence of atrial fibrillation or other potential cardioembolic source, presence
of ipsilateral large artery stenosis⬎50%, acute blood glucose, acute hematocrit, age, history
of diabetes mellitus and use of tPA on infarct growth, penumbral outcome (percentage
mismatch lost) and reperfusion. Results: SSS-TOAST classifications were as follows:
cardioembolism 57, large artery atherosclerosis 14, undetermined 25 (including 6 large artery
and cardioembolism combined, and 8 undetermined unclassified) and other determined causes
2. Independent predictors of subacute infarct expansion included acute blood glucose(P⫽0.009), ipsilateral large artery stenosis ⬎50%(P⫽0.013), and mismatch volume(P⫽0.028). The only independent predictor of percentage mismatch lost was increasing
blood glucose (P⫽0.002). Cardioembolic stroke was positively associated with reperfusion
(P⫽0.013), while increasing blood glucose was negatively associated with reperfusion
(P⫽0.041). Conclusions: Ipsilateral large artery stenosis is independently associated with
increased subacute infarct expansion, but stroke subtype does not influence penumbral fate.
Cardioembolism is associated with greater reperfusion; this adds weight to suspicions that
cardioembolic stroke could be associated with reperfusion injury. Acute blood glucose remains
strongly associated with adverse MRI outcomes.
P14
In-vivo Optical Imaging of Cerebral Blood Perfusion During Focal Ischemia
in Mice.
Sawan Hurst, Wenjie Huang, Wenri Zhang, Nabil J Alkayed, Andras Gruber, Ruikang K
Wang; Oregon Health & Science Univ, Portland, OR
Introduction: We have developed a new optical micro-angiography (OMAG) imaging technique
that is capable of resolving 3D distribution of dynamic blood perfusion at a capillary level
resolution within microcirculatory beds in vivo. The imaging contrast of blood perfusion is based
on endogenous light scattering from moving blood cells within vessels, thus no exogenous
contrast agents are necessary. The purpose of this study is to validate this method and assess
its potential application in the studies of cerebrovascular perfusion during and after induced
stroke in mouse models in vivo. Methods: We used an OMAG imaging system operated at 1300
nm wavelength that delivered a 3D spatial resolution of 10 microns for this study. Temporal
resolutions for 2D and 3D imaging were 0.1s and 50s, respectively. Cortical blood perfusion
under normal and induced stroke conditions was monitored using OMAG through the intact
cranium of mice. Results from OMAG imaging under baseline conditions were correlated with
cerebral blood flow rates measured in the same regions using [14C]iodoantipyribe (IAP)
autoradiography. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO)
using the intraluminal filament technique, and OMAG imaging was used to obtain 3D dynamic
perfusion images before, during and after MCAO for up to 24 hours. Results: OMAG imaging
provided real-time volumetric measurements of blood perfusion in 2 mm depth down to the
capillary level through the intact skull without the need for dye injection, contrast agents, or
surgical craniotomy. Detailed 3D superficial vascular architecture images obtained by OMAG
had an excellent agreement with that from direct photographing of blood vessels on the surface
of the cerebral cortex. Quantitative assessment of blood flow rates using OMAG imaging was
within 20% of CBF rates measured in the same region postmortem using IAP autoradiography.
Repeated OMAG imaging captured progressive cessation of cortical perfusion during MCAO in
the ipsilateral hemisphere and revealed significant progressive changes in the perfusion pattern
of the contralateral hemisphere. Following filament withdrawal, blood perfusion resumed in
some but not all blood vessels even after 24r hrs. Conclusions: OMAG provides a novel
dynamic image of cortical perfusion in real time and allows for repeated, non-invasive
assessment of blood flow rates in all patent vessels without the need for injecting dyes or
contrast agents.
P15
Withdrawn
573
P16
Therapeutic Impact of Cardiac MRI in Patients with Ischemic Stroke.
Richard A Bernstein, James Conners, John J Sheehan, George Lin, Karin Dill, Reed A
Omary, Mark J Alberts, James C Carr; Northwestern Univ, Chicago, IL
Introduction: Cardiac MRI (cMRI) identifies clinically relevant cardiac findings in stroke patients
that may not be visible by transesophageal (TEE) or transthoracic (TTE) echocardiogram. Prior
work from our group has described the diagnostic impact of cMRI (1). In a cohort of stroke
patients who underwent echocardiography, cardiac MRI identified intracardiac thrombi in 10%
of patients. In 75% of these patients, echocardiograms were either normal or ambiguous. We
now describe the effect on therapy of the detection of intracardiac thrombus by cMRI in patients
with ischemic stroke. Methods We reviewed the records of patients with ischemic stroke who
underwent cMRI between October 2005 and October 2006. cMRI was ordered by a vascular
neurologist (RAB or MJA) during in-patient evaluation; all patients had TTE, TEE, or both, prior
to cMRI. Echocardiograms and cMRI were read with clinical information available. We identified
changes in presumed stroke mechanism (using TOAST criteria) and anti-thrombotic therapy by
review of the medical records. Results Our cohort of 93 patients has been described previously
(1); 52% were male, and the mean age was 65 years (range 18 –92). TTE was performed in
89%, TEE in 41%, and both studies were performed in 32%. cMRI identified intracardiac
thrombus in 9/93 patients (9.7%); all 9 patients had echocardiography performed prior to cMRI.
In 5 out of these 9 patients the echocardiograms showed no thrombus; 3 out of these 5 had
TTE and TEE performed prior to cMRI. Secondary preventive therapy changed from antiplatelet
agents to anticoagulants (warfarin or heparin) in 4 out of 9 (44%) patients; the other 5 out of
9 were already prescribed anticoagulants for a presumed, but unproven, cardioembolic source.
Presumed stroke mechanism changed in 3/9 patients (33%), in all cases from “unknown” to
“cardioembolic”. Conclusion Cardiac MRI identified intracardiac thrombi in a significant
percentage of patients with cryptogenic strokes. This led to a change in secondary preventive
therapy for almost half of these patients. CMRI should be considered as part of the evaluation
for patients with cryptogenic stroke. (1) Evaluation of patients with suspected cardioembolic
stroke using Cardiovascular MRI - A comparative study with echocardiography. JJ Sheehan, AR
Hitchell, RA Bernstein, K Dill, RA Omary, JC Carr. SIR, Seattle, Journal of Vascular and
Interventional Radiology February 2007 (Suppl.)
P17
Diagnosis Of Vertebral Artery Dissection At CTA With A Normal Luminal
Diameter-Are we Missing Cases?
Cheemun Lum, Ravi Mohan, The Ottawa Hosp, Ottawa, Canada; Sridhar Panugpath,
NIMHANS, Bangalore, India; Marlise Santos, Mukul Sharma, Michael Schlossmacher,
Santanu Chakraborty; The Ottawa Hosp, Ottawa, Canada
Introduction: CTA for suspected dissections has complemented or even replaced catheter
angiography and may be the only imaging study performed. We present a series of acute
vertebral artery dissection (VAD) where there is normal vertebral artery (VA) luminal diameter
and characteristic thickening of the wall of the vertebral artery (VA) along its suboccipital
course(V3). We coin this the “suboccipital rind-sign” (SORS). Subsequent MRI’s demonstrated
the intramural hematoma or the imaging findings resolved at CTA follow-up. Knowledge of the
SORS may aid in detection of VAD in cases where the lumen is normal or minimally reduced
in caliber. Materials & Methods: We reviewed our prospectively collected database of patients
demonstrating the SORS. The clinical presentation and imaging findings were identified. We
subdivided the V3 portion of the VA into 5 segments. The luminal diameter at each segment
was compared to the overall corresponding vessel diameter. A comparison between the
arteries demonstrating the SORS and 50 normal patients was performed. Results: Between
November 2005 and July 2006 (9 mos.), there were 6 patients with the SORS identified. Two
of 6 had bilateral rind signs accounting for a total of 8 abnormal arteries. Of these 8 arteries,
in only 1, was there significant narrowing of the artery noted prospectively. 4/8 arteries had
normal appearing lumens, 3/8 had subtle areas of narrowing that were only noted in retrospect
after identifiying the rind sign. There was no evidence of luminal tapering in both dissected and
normal vessels. The average wall thickness of the dissection group was 2.96 mm greater for
the control group. This difference was significant by a separate variances t test, t(19.6) ⫽ 6.44,
p ⬍ .001. A 95% confidence interval for the difference between means was 2.6 mm to 3.32
mm. Conclusion: We describe a previously undescribed characteristic imaging sign of VAD in
the V3 portion where the imaging plane is parallel to the course of the VA. Our study revealed
absence of vessel tapering in the abnormal vessels emphasizing the importance of recognition
of wall thickening, the SORS. We caution using only lumen-opacifying techniques to exclude
VAD as they are limited in evaluating for mural hematoma.
574
Stroke
Vol 39, No 2
February 2008
P18
Flow Heterogeneity MRI Reveals Compensatory Changes in the
Microcirculation during Acute Ischemic Stroke.
David S Liebeskind, Jeffry R Alger, Brian H Buck, Tim Schaewe, Oh Y Bang, Sidney
Starkman, Doojin Kim, Latisha K Ali, Bruce Ovbiagele, Noriko Salamon, J P Villablanca,
Jeffrey L Saver; UCLA, Los Angeles, CA
Background: Perfusion MRI may demonstrate changes in the flow distributions of the
microcirculation as derangements of the normal flow heterogeneity (FH) within a voxel of the
ischemic brain. Such FH abnormalities have been used to predict final infarct evolution. We
used FH MRI to explore the specific microcirculatory derangements associated with collateral
perfusion in acute MCA ischemia. Methods: FH MRI measures were derived in 75 consecutive
cases of acute ischemic stroke with complete occlusion of the MCA on conventional
angiography. Separate maps were generated reflecting the width or standard deviation (FHD),
skewness (FHS), and kurtosis (FHK) of flow distributions in the microcirculation. In addition
standard perfusion MR images were obtained of CBF, CBV, MTT and CPP. Region of interest
analyses were performed to compare values of FHD, FHS, and FHK in the ischemic territory with
homologous regions of the contralateral hemisphere. Collateral circulation evident on catheter
angiography was graded with the ASITN/SIR scale. Results: Pretreatment FH MRI revealed
microcirculatory flow abnormalities in all 75 cases. FHD or the width of the flow distribution
was increased in all cases (p⬍0.001). FHS images revealed redistribution of flow within slower
routes of the microcirculation (p⬍0.001). FHK images demonstrated the predominance of
particular flow routes in all cases (p⬍0.001). Topographic features of the FH abnormalities
correlated with the degree of collateral flow noted at angiography. Conclusions: Multiparametric FH MRI reveals consistent changes in the microcirculation associated with collateral
perfusion in acute ischemic stroke due to MCA occlusion. Flow redistribution may involve
recruitment of specific preferential routes with slower flow to enhance oxygen extraction. FH
images can be rapidly generated and provide unique insights into tissue state that may help
guide management.
characteristics can guide EMS system planners in implementing stroke inventories for prehospital
use.
STROKE IDENTIFICATION PERFORMANCE
PPV
NPV
Sensitivity
Specificity
Accuracy
LAPSS
CPSS
ELAPSS
100
98.4
86.4
100
98.6
37.7
98.7
90.9
82.5
83.4
62.5
98.9
90.9
93.7
93.4
P20
Comparison of Computed Tomography Angiography to Trans-Esophageal
Echocardiography for Evaluation of Aortic Arch Disease.
Nobl Barazangi, Max Wintermark, Katy Lease, Wade Smith, S. Andrew Josephson; Univ of
California, San Francisco, CA
Aortic arch (AA) atheromas are a common source of artery-to-artery embolism, and identification of
disease in the AA is an important component of embolic stroke workup. Trans-esophageal
echocardiography (TEE) has served as the gold standard for evaluation of the AA; however, this
technique is invasive, time-consuming, and may carry a substantial morbidity in high-risk patients.
Computed tomography angiography (CTA) is used regularly to evaluate acute stroke patients upon
initial presentation to the Emergency Department (ED). This imaging modality can include
angiography of the AA, allowing for rapid, non-invasive evaluation. We sought to determine the
sensitivity and specificity of CTA for detecting AA disease compared to TEE. We performed a
retrospective review of 250 patients at a tertiary stroke center who received both a TEE and CTA
within 90 days; however, 72% of the studies were conducted within one week of each other. We
compared the presence and characteristics of AA plaques using a blinded neuroradiologist and
cardiologist. A pre-determined grading system for AA plaques in the ascending, transverse, and
descending arch was used for both modalities (Grades 1– 4). Out of the 250 patients in which the
AA could be visualized by both CTA and TEE, a total of 497 studies, with the ascending, transverse,
and descending arch each considered a separate study, were available for analysis. The sensitivity
for CTA to detect plaque as compared to TEE was 39.3% with a positive predictive value of 67.1
(59 –74), while the specificity was 77.6%, with a negative predictive value of 47.6 (42–53). If only
Grade 3 and 4 plaques were selected, the sensitivity of CTA dropped to 8.1% but the specificity
increased to 98.7%. A weighted kappa test comparing the plaque grade in CTA versus TEE was
0.0169 (95% confidence interval -0.1048 to 0.1387), reflecting a poor correlation. Based on these
results, CTA may not be a sensitive diagnostic tool for detecting AA plaques, but may be specific
for detecting high-grade plaques. Furthermore, these data may demonstrate the potential limitations
of TEE in detecting plaque in all sectors of the AA, indicating a complementary role of CTA for
improved detection of AA plaques. Further analysis of the false positive (CTA positive, TEE negative)
studies may help elucidate the role of both modalities in detecting AA disease.
P21
Biopsy Proven Isolated CNS Vasculitis, Much-Vaunted but Rarely Seen: 20
Year Retrospective Review of Brain Biopsies.
P19
The Accuracy of Prehospital Stroke Identification Instruments: Prospective
Comparison of the LAPSS, CPSS, and ELAPSS.
Parham Moftakhar, Daniel Colby, Sidney Starkman, Jeffrey L Saver, Geffen Sch of Medicine
UCLA, Los Angeles, CA; UCLA Student Stroke Team
Background: The Los Angeles Prehospital Stroke Screen (LAPSS), the Cincinnati Prehospital Stroke
Scale (CPSS), and the Expanded LAPSS (ELAPSS) are brief inventories employed by prehospital
personnel worldwide to identify stroke patients in ambulances and in the Emergency Department.
However, their relative sensitivity, specificity, positive predictive value, negative predictive value, and
overall accuracy have not been well characterized in the same study population. Methods:
Consecutive patients transported by 911 ambulances during a 7 month study period were assessed
for possible stroke. Paramedics first identified whether patients harbored neurologic complaints or
signs. The presence of any of seven neurologically-relevant complaints/signs triggered formal stroke
screening inventory assessment, and included: 1) altered level of consciousness, 2) local
neurological signs, 3) seizure, 4) syncope, 5) head pain, 6) nausea/vomiting, 7) weak/dizzy.
(Examples of non-neurologic complaints include chest pain, allergic reaction, and shortness of
breath.) Patients with neurologic complaints were evaluated with the LAPSS, CPSS, and ELAPSS.
The ELAPSS is a 9 item inventory that adds to the 8 items of the LAPSS the speech/language item
of the CPSS. Results: Among 211 consecutive, ambulance-transported patients with neurologic
complaints, mean age was 63 and 47% were female. Twenty-two patients (10.4%) had a final ED
diagnosis of acute cerebrovascular disease (ischemic stroke, intracranial hemorrhage, still
symptomatic TIA). Syncope, seizure, and toxic-metabolic encephalopathy were the most common
final non-stroke diagnoses. The accompanying table shows inventory stroke identification performance compared with final diagnoses. Conclusion: While all three standard prehospital stroke
recognition inventories show good to excellent sensitivity, the LAPSS is superior in distinguishing
stroke mimics from true strokes, yielding a higher positive predictive value. These performance
James Castle, Stanford Univ, Palo Alto, CA; Rafael Llinas, Robert Wityk; Johns Hopkins Univ,
Baltimore, MD
Background and Purpose: Biopsy of brain and meningeal are generally considered to be the gold
standard diagnostic test for CNS vasculitis short of autopsy. Sensitivity and specificity for brain and
meningeal biopsy are felt to be as high as 80% and 100% respectively. We reviewed all cases of
biopsy when CNS vasculitis was considered with the intent of evaluating which elements of the
history, physical, laboratory, and radiologic assessment were most accurate for diagnosing
vasculitis. Methods: We reviewed all cases at Johns Hopkins Hospital between 1986 and 2006 for
which a brain and/or meningeal biopsy was performed when vasculitis was considered a diagnostic
possibility. We screened the pathology database by searching for all pathology reports in which the
word “brain” and one of the words, “vasculitis”, “angiitis”, or “arteritis” were used. Using those
criteria, 41 cases were isolated and all charts were reviewed. Results: Of the 41 cases where the
CNS vasculitis diagnosis was considered and a brain biopsy was performed, not a single case of
vasculitis found on biopsy. In 7 of the 41 cases, a diagnosis was found on biopsy: 3 Alzheimer’s,
2 CJD, 1 amyloid angiopathy, 1 intravascular lymphoma. In the remaining 34 cases, the physician
diagnosed 14 patients as having biopsy negative vasculitis. Of those, 5 eventually had autopsy or
other diagnostic biopsy. All showed an alternative diagnosis: 2 atherosclerosis, 1 metastatic renal
cell carcinoma with possible hypercoaguable state, 1 CNS lymphoma, and 1 idiopathic basement
membrane disease on kidney biopsy. 25% (7/28) of the patients in this series who had a
conventional angiogram were thought to have definite vasculitis by the reviewing radiologist. Only
32% (9/28) of these patients who had conventional angiogram were felt not to have vasculitis by
the reviewing radiologist. Conclusions: Based on our retrospective series over 20 years and 41
patients, isolated CNS vasculitis was often considered but rarely proven. In fact, was never
responsible for the clinical picture in patients who went on to have CNS biopsy. Biopsy and autopsy
not-infrequently revealed other diagnosis. Angiogram frequently identified “vasculitis” which was
later not confirmed by biopsy. The authors feel that clinicians should avoid being cavalier regarding
the diagnosis of Isolated CNS Vasculitis as it is a rare disorder. In our series more common diagnosis
were found later to be the true diagnosis when CNS vasculitis was considered.
P22
Predicting Stroke Deficit From Infarct Topography.
Thanh G Phan, Jian Chen, Monash Med Cntr, Clayton VIC, Australia; Geoffrey A Donnan,
National Stroke Rsch Institute, Heidelberg, Australia; Velandai Srikanth, Amanda Wood,
David C Reutens; Monash Med Cntr, Clayton VIC, Australia
Background & Aims: Improving the ability to predict potential stroke deficit may aid the
selection of patients most likely to benefit from acute stroke therapies. Current methods, based
on ischaemic volumes or initial neurological condition do not predict neurological outcome
adequately. On the basis that there is a close relationship between anatomy and function in the
brain, we developed and validated a predictive tool for stroke outcome incorporating
information on infarct location. Methods: A prospective study of 60 patients with ischaemic
stroke (38 in the training set and 22 in the validation set), using a novel implementation of
partial least squares with penalised logistic regression (PLS-PLR), was performed. The method
yielded a predictive model relating location of infarction (on a voxel-by-voxel basis) and
neurological deficits. Results: In the validation phase, this model accurately predicted the
presence of neglect (3 errors in 22, 86% correct), aphasia (4 errors in 22, 82% correct),
right-arm motor deficit (1 error in 22, 95% correct), right-leg motor deficit (1 error in 22, 95%
correct), left-arm motor deficit (10 errors in 22, 55% correct) and left-leg motor deficit (6 errors
in 22, 73% correct). The model accurately predicted no to mild disability (Rankin ⱕ2) versus
moderate to severe disability (Rankin⬎2) in 73% (16 errors in 22). Conclusion: The model has
moderately high accuracy for predicting different neurological deficits and its severity following
stroke. This study provides proof of the concept that a model based on imaging data can be
used to predict the outcome of the individual patient following stroke.
575
9%). Age, female, AF, and NIHSS score ⬎7 on admission were significantly higher in CE than
in other stroke subtypes. The mean plasma BNP level of the CE group was significantly higher
than that of the other 3 subtypes (409.6 pg/ml for CE, 94.0 pg/ml for LVD, 37.4 pg/ml for SVD,
and 156.9 pg/ml for others, p⬍0.001). The optimal cut-off values, sensitivity, and specificity
of the plasma BNP levels to distinguish CE from other ischemic stroke subtypes were 140.0
pg/ml, 80.5% and 80.5%, respectively. Conclusions The plasma BNP level appears to be
significantly highest in CE patients among stroke subtypes. Furthermore, BNP should be a good
biological marker to differentiate cardioembolic stroke from the other ischemic stroke subtypes.
We should strongly consider cardioembolic stroke when the plasma BNP level is over 140.0
pg/ml in acute ischemic stroke patients.
P24
Integrity Of The Left Arcuate Fasciculus May Predict The Prognosis Of
Aphasia In Patients With Left Middle Cerebral Artery Infarct.
Akiko Hosomi; Dept of Neurology Graduate Sch of Med Science, Kyoto Prefectural Univ of
Medicine, Kyoto, Japan
Background and Purpose: It is often clinically difficult to assess the severity of aphasia in the
earliest stage of cerebral infarction. A method enabling objective assessment of verbal function
is needed for this purpose. We examined whether diffusion-tensor (DT) tractography is of
clinical value in assessing aphasia. Methods: Thirteen right-handed patients with left middle
cerebral artery territorial infarcts who were scanned within 2 days after stroke onset were
enrolled in this study. MR data of 10 healthy controls were also examined by DT tractography.
Based on the severity of aphasia at discharge, patients were divided into 2 groups: 6 patients
in an aphasia group and 7 in a non-aphasia group. Fractional anisotropy (FA) and number of
arcuate fasciculus fibers were evaluated. Asymmetry index was calculated for both FA and
number of fibers. Results: FA values for the arcuate fasciculus fibers significantly differed
between hemispheres in neither the patient groups nor in the controls. In the control subjects,
the mean FA value was 0.44⫾0.028 for the right AF (range, 0.39 to 0.47) and 0.44⫾0.047 for
the left AF (range, 0.35 to 0.51). There was no asymmetry in FA value (mean FA ratio,
-0.02⫾0.057). In the non-aphasia group, the measured FA values also exhibited no
asymmetry. The measured FA values of the non-aphasia group tended to be lower on the left
side, and the FA ratio was for the majority of patients slightly negative (indicating rightward
asymmetry). However, none of these differences was statistically significant. Number of
arcuate fasciculus fibers exhibited a significant leftward asymmetry in the controls and the
non-aphasia group, but not in the aphasia group. The number ratio of AF fibers was
significantly smaller (indicating rightward asymmetry) in patients with aphasia than in patients
without aphasia and controls; both of these differences were significant (P ⫽ 0.014 and 0.002,
respectively). There was no significant difference in number of AF fibers between patients
without aphasia and controls. Loss of leftward asymmetry in number of AF fibers predicted
aphasia at discharge with a sensitivity of 0.83 and specificity of 0.86. Conclusions: We found
in this study that in left MCA stroke patients, loss of leftward asymmetry of AF fibers predicted
persistent aphasia with high sensitivity and specificity. DT tractography of arcuate fasciculus
fibers may be useful for predicting the fate of vascular aphasia.
P25
Yield of Transesophageal Echocardiography in Ischemic Stroke Patients by
Age and Lesion Pattern on Diffusion-Weighted MRI.
Dennis M Campbell, Stanford Stroke Cntr, Stanford, CA; Anne-Sophia Beraud, Stanford Sch
of Medicine Dept of Cardiovascular Medicine, Stanford, CA; Michael Mlynash, Stanford
Stroke Cntr, Stanford, CA; Ingela Schnittger, Stanford Sch of Medicine Dept of
Cardiovascular Medicine, Stanford, CA; Irina Eyngorn, Monisha A Kumar, Stanford Stroke
Cntr, Stanford, CA; David C Tong, Stanford Sch of Medicine, Stanford, CA; Michael Moseley,
Stanford Sch of Medicine Dept of Radiology, Stanford, CA; Gregory W Albers, Christine A
Wijman; Stanford Stroke Cntr, Stanford, CA
P23
Plasma Brain Natriuremic Peptide Should Be A Good Biological Marker For
Cardioembolic Stroke.
Kensaku Shibazaki, Kazumi Kimura, Yasuyuki Iguchi, Yoko Okada, Takeshi Inoue; Kawasaki
Med Sch, Kurashiki Okayama, Japan
Background and Purpose Plasma brain natriuremic peptide (BNP) is used as a marker of heart
failure. In acute ischemic stroke, we hypothesized that plasma BNP level was highest in
patients with cardioembolic stroke compared with other stroke subtypes, and could be a
biological marker to differentiate cardioembolic stroke from the other ischemic stroke subtypes.
Methods Consecutive patients with acute ischemic stroke within 24 hours of onset were
prospectively enrolled. We measured plasma BNP on admission. Patients were divided into four
groups according to the TOAST classification: large-vessel disease (LVD), cardioembolism (CE),
small-vessel disease (SVD), and other stroke. We examined relation between plasma BNP level
and stroke subtypes. Results Total 200 patients (124 male; mean age, 71.4 ⫹ 12.8 years)
were enrolled into the present study. Cardioembolism (n⫽82, 41%) was the most frequent
stroke subtype, followed by other stroke (n⫽68, 34%), SVD (n⫽32, 16%), and LVD (n⫽18,
Introduction: Ischemic stroke is a major cause of death and disability, and up to 30% of these are
attributed to cardioembolism. The most common approach of detecting subtle cardiac lesions is
transesophageal echocardiography (TEE); however, due to its invasiveness, it is typically used in a
subset of ischemic stroke patients. We sought to determine the yield of TEE in a consecutive series
of unselected patients presenting with symptoms of ischemic stroke who underwent diffusion
weighted MRI (DWI). Methods: In this prospective NIH funded study, TEE and DWI were obtained in
194 consecutively admitted patients with symptoms suggestive of ischemic stroke. TEE results were
categorized into high-risk (left atrial thrombus, left atrial appendage thrombus, left ventricular
thrombus, left-sided cardiac mass, mitral valve vegetation, aortic valve vegetation, patent foramen
ovale (PFO) with an atrial septal aneurysm (ASA), and large (⬎4 mm) or mobile aortic plaque) and
moderate-risk (left atrial spontaneous echo-contrast, ASA alone, PFO alone, and moderate sized
(3– 4 mm) aortic plaque) lesions. The distribution of diffusion deficits on DWI were categorized into
the following categories: single lesion, multiple lesions in a single vascular territory, and multiple
lesions in multiple vascular territories. TEE yield was determined by age (⬎65 years vs. ⬍65 years)
and DWI pattern. Results: Overall, the yield of TEE was 21.6% for detecting a high risk lesion and
28.4% for detecting one or more moderate risk lesions, for an overall yield of 50.0%. A lesion within
the heart or aortic arch was detected more commonly in older (⬎65) vs younger (⬍65) patients
(66.1% vs 29.4%; p⫽⬍0.001). Overall, positive TEE occurred more commonly in patients with
multiple DWI lesions than in those with a single lesion identified on DWI (66.7% vs 44.6%;
p⫽0.0221). This difference remained significant when comparing patients with multiple MRI lesions
confined to a single vascular territory and positive TEE with those with single MRI lesions (p⫽0.003);
however, the difference between multiple DWI lesions scattered over multiple vascular territories
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Vol 39, No 2
February 2008
and positive TEE vs those with single MRI lesions was not significant. Conclusion: The yield for
detecting a moderate or high risk lesion on TEE in unselected ischemic stroke patients is substantial,
and is particularly high in elderly patients (age ⬎ 65 years) and in those with multiple acute DWI
lesions. How often the detection of these lesions influences final diagnosis of stroke subtype and
treatment decisions is under investigation. This study was funded by the NIH: RO1 NS34866, PI Mike
Moseley.
P27
Blood Flow Measurement In A Canine Carotid Stenosis Model Using
Quantitative Magnetic Resonance Angiography.
Mateo Calderon-Arnulphi, Sepideh Amin-Hanjani, Ali Alaraj, Meide Zhao, Univ of Illinoins,
Chicago, IL; Lauren Ostergren, VasSol, Inc, Chicago, IL; Sean Ruland, William Ashley, Xinjian
Du, Fady T Charbel; Univ of Illinoins, Chicago, IL
analysis was performed to define the threshold for infarct growth that has the highest
sensitivity and specificity for predicting clinical response. Results: Lesion growth was
significantly associated with clinical outcomes in patients with a Mismatch. Median (IQR) lesion
growth was ⫹2cc (-2, ⫹10) in Mismatch patients with favorable clinical response, vs. ⫹29cc
(⫹6, ⫹52) in Mismatch patients who did not have favorable response (p⫽0.004) independent
of age, baseline NIHSS and baseline DWI volume. There was no association between lesion
growth and clinical outcomes in the No mismatch group [⫹1cc (-3, ⫹6) vs. ⫹1cc (-1, ⫹11),
p⫽0.755]. The ROC analysis demonstrated that for Mismatch patients, lesion growth of less
than 7 cc is highly predictive of a favorable clinical response (odds ratio, 13.5; p⫽0.006,
sensitivity 82%, specificity 75%). Conclusion: There is a strong relationship between ischemic
lesion growth and clinical outcomes in patients with a perfusion/diffusion mismatch; no
relationship could be demonstrated in patients who did not have a mismatch. Infarct growth
may be a suitable surrogate outcome measure for Mismatch patients
P29
Introduction The hemodynamic effects of cerebrovascular stenosis may have implications for
stroke risk. Direct large vessel flow measurement has traditionally only been available in the
intraoperative setting with flow probes. Quantitative magnetic resonance angiography (QMRA),
however, allows non-invasive measurement of vessel flows utilizing phase contrast techniques.
To evaluate the accuracy of blood flow quantification related to progressive arterial stenosis,
we measured flows in a canine carotid artery model with QMRA in comparison to an ultrasonic
flow probe, the gold standard in direct flow measurement. Methods Hound dogs (n⫽6) were
placed under general endotracheal anesthesia, and an ultrasonic flow probe (Transonic
Systems, Inc.) implanted around the canine common carotid artery (CCA) for measurement of
mean blood flow. Arterial pressure was continuously recorded via a femoral arterial line. A
vascular tourniquet was applied around the CCA to produce varying degrees of stenosis. QMRA
was performed using NOVA software (VasSol, Inc.). CCA flows were measured simultaneously
using QMRA and the flow probe. Statistical comparisons were made using Pearson correlation
coefficient, and Bland Altman plots. Results A total of 48 paired CCA flow measurements were
performed. Stable mean arterial pressure was maintained during each paired measurement.
Using pharmacological blood pressure manipulation and progressive tourniquet stenosis, CCA
blood flows ranging between 10 to 700 ml/min were generated. The correlation coefficient
between the QMRA measurements and the flow probe was 0.99 (p⬍0.0001). The average
difference between the two techniques was 16.5 ml/min (SE ⫹/- 2.20 ml/min), and the
average proportional difference (PD) was 5.9% (SE⫹/- 0.75). PD increased at higher degrees
of stenosis and lower flow: PD⫽ 12.9% SE ⫹/- 2.17 at ⬍80ml/min compared to PD⫽ 3.38%
SE⫹/- 0.55 at flow rates ⬎350ml/min (NOVA higher than flow probe). ConclusionsCCA flow
measurement using QMRA is accurate in vivo compared to direct flow probe measurement in
a canine arterial stenosis model. QMRA is a promising modality for the evaluation of the
hemodynamic effects of cerebrovascular atherostenosis.
Etiology of Ischemic Stroke Determined Using Blood Gene Expression
Profiling.
Huichun Xu, Jeffrey P Gregg, Univ of California at Davis, Sacramento, CA; Arthur Pancioli,
Edward C Jauch, Univ of Cincinnati, Cincinnati, OH; Piero Verro, Univ of California at Davis,
Sacramento, CA; Joseph P Broderick, Univ of Cinicnnati, Cincinnati, OH; Frank R Sharp;
Univ of California at Davis, Sacramento, CA
Determining the etiology of ischemic stroke is critical for developing the most appropriate treatment
to prevent stroke recurrence. Though imaging of the carotid and heart are very specific, they are not
very sensitive for detecting cardiac and large vessel atherosclerotic causes of stroke. Recently we
and other groups demonstrated gene expression changes in blood cells following ischemic stroke
as early as 2–3hr after onset. The expression of as few as 18 genes can correctly classify most
stroke patients. We reasoned that different etiologies of stroke would be associated with different
RNA expression profiles in peripheral blood. Forty -five peripheral blood samples were taken at ⬍3,
5 and 24 hours from 15 patients who had either cardioembolic, large vessel atherosclerotic or
ischemic stroke of undetermined etiology. Sixteen peripheral blood samples were taken from
healthy controls. RNA was purified, labeled and hybridized to Affymetrix Human U133 Plus 2.0
Arrays. Seventy five genes were significantly different between cardioembolic and large vessel
atherosclerotic stroke and controls (⬎ 1.5 fold change, ANOVA with Benjamini-Hochberg false
discovery rate ⬍ 0.05, Student-Newman-Keuls post hoc test). Functional analyses show that
atherosclerotic stroke-specific genes regulate hemostasis and cytokine activities and are expressed
mainly in platelets and monocytes. In contrast, cardioembolism-specific genes are involved in the
immune response to pathogens and are expressed mainly in polymorphonuclear cells (neutrophils).
Our results suggest that blood gene expression profiling can be used to determine the etiology of
ischemic stroke. It also can offer pathological insights into the molecular mechanisms of ischemic
stroke, which will have important implications for the development of novel, etiology-specific
treatments.
P30
Perfusion Angiography: A Novel Technique for Characterization of
Perfusion in Cerebral Ischemia.
David S Liebeskind, UCLA, Los Angeles, CA; Gregory Szilagyi, Sandra E Black, Brian H
Buck; Sunnybrook Health Sciences Cntr, Univ of Toronto, Toronto, Canada
P28
Lesion Growth is Associated with Clinical Outcome in Patients with
Mismatch, but not in No Mismatch Patients.
Jean-Marc Olivot, Michael Mlynash, Dept of Neurology and Neurological Sciences and the
Stanford Stroke Cntr, Stanford Univ Med Cntr, Stanford, CA; Vincent N Thijs, Neurology,
Univ Hosps, Leuven, Leuven, Belgium; Marteen G Lansberg, Stephanie Kemp, Dept of
Neurology and Neurological Sciences and the Stanford Stroke Cntr, Stanford Univ Med Cntr,
Stanford, CA; Roland Bammer, Dept of Radiology and the Stanford Stroke Cntr, Stanford
Univ Med Cntr, Stanford, CA; Lawrence Wechsler, UPMC Stroke Institute and Dept of
Neurology., Univ of Pittsburgh, PA; Gregory W Albers; Dept of Neurology and Neurological
Sciences and the Stanford Stroke Cntr, Stanford Univ Med Cntr, Stanford, CA
Background: Most perfusion imaging modalities for acute stroke or cerebral ischemia depend
on contrast bolus tracking, yet the anatomy of specific flow routes remains obscure.
Conversely, conventional angiography is increasingly used for endovascular procedures in
acute stroke; however, standard perfusion parameters may be difficult to ascertain. We
developed a novel post-processing technique that allows for rapid determination of various
perfusion parameters from digital subtraction angiography (DSA). Methods: Angiodensitometry
of DSA data acquired in acute stroke was utilized to estimate perfusion. A standalone computer
software algorithm was developed to iteratively process temporal changes in contrast intensity,
yielding concentration-time curves based on the known arterial inflow within each pixel.
Cerebral blood volume (CBV) is calculated at each pixel by numerical integration over the entire
corresponding concentration-time curve. Cerebral blood flow (CBF) is determined by deconvolving the tissue concentration-time curve with the arterial input function (AIF) using
singular-value decomposition with a block-circulant deconvolution matrix. Subsequent generation of multiparametric perfusion maps allowed for region of interest analyses. Results:
Perfusion angiography images were processed in 20 cases of acute ischemic stroke, exhibiting
various types of occlusive lesions and degrees of collateral circulation. Perfusion maps were
Background and Purpose: Ischemic lesion growth has been proposed as a surrogate measure
of stroke outcome. It is hypothesized that patients who have less ischemic lesion growth will
have better clinical outcomes. We investigated the association between lesion growth and
clinical outcomes in the DEFUSE dataset for patients with a perfusion/diffusion mismatch
(Mismatch) as well as for No Mismatch patients. Methods: DEFUSE is an open-label,
NIH-funded, multicenter study in which acute stroke patients were treated with intravenous tPA
between 3 and 6 hours after symptom onset. A magnetic resonance imaging (MRI) scan was
obtained immediately before, 3 to 6 hours and 30 days after thrombolytic treatment. Ischemic
lesion growth was defined as the difference between the final infarct volume (measured on 30
day FLAIR) and the baseline DWI volume. Baseline MRI profiles were used to determine which
patients had a Mismatch (N⫽23) or No Mismatch (N⫽27). Favorable clinical response was
defined as ⱖ8 point improvement in the NIHSS, or a score of 0 –1 at 30 days. An ROC curve
577
generated to display cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time
(MTT) and cerebral perfusion pressure (CPP). Simultaneous visualization of anatomic structures
allowed the user to identify specific flow routes. Perfusion images were generated in frontal,
lateral, and oblique planes. Software capability included use of DSA data with variable frame
rates and spatial resolution. Validation was performed on multicenter datasets and correlation
assessed with noninvasive perfusion imaging modalities. Conclusions: Perfusion angiography
provides a novel means to rapidly assess numerous perfusion parameters at the time of
endovascular procedures. Serial changes in perfusion associated with treatment may be
evaluated with this software in a multicenter setting.
P31
Detection Of Right-to-left Shunt In Stroke Satients: Contrast-enhanced
Transesophageal Echocardiography At The Bilateral Atria, Aortic Arch, And
Descending Aorta.
Rieko Suzuki, Kazunori Toyoda, Ryoichi Otsubo, Sohei Yoshimura, Masatoshi Koga, Kuni
Konaka, Fumio Miyashita, Masahiro Yasaka, Hiroaki Naritomi, Kazuo Minematsu;
Cerebrovascular Div, Dept of Medicine, National Cardiovascular Cntr, Osaka, Japan
Objectives: Because the right-to-left shunt (RLS) is an important cause of paradoxical
embolism, it is necessary for patients with cryptogenic stroke to receive screening examinations for RLS. Although monitoring with contrast-enhanced transesophageal echocardiography
(cTEE) at the bilateral atria (BA) is commonly used for detecting RLS, the procedure has several
limitations. In particular, nonsmoke spontaneous individual contrast (NSSIC) is generated in the
atrium just after the Valsalva maneuver without contrast injection, and makes the diagnosis of
RLS difficult. To overcome the limitations, we determined the efficacy of monitoring with cTEE
at three sites: the BA, aortic arch (AA), and descending aorta (DA). Methods: Between October
2004 and July 2006, 613 patients (414 men, 68⫾12 years) with cerebrovascular diseases
underwent cTEE monitoring at the BA, AA, and DA using a real-time two-dimentional
echocardiography system equipped with a 5.0-MHz phased array omniplane transducer. In
each monitoring site, visualization of contrast much brighter than NSSIC during the respiratory
maneuver with administration of the contrast medium was considered to be positive. When the
positive finding was proven at least in two sites or when it was reproduced in one site, patients
were diagnosed as having RLS. Results: We diagnosed 92 patients (15%) as having RLS;
positive findings were obtained at all the three sites for 45 patients, at two sites for 22 patients
(9 at the BA and AA, 7 at BA and DA, and 6 at AA and DA), and at one site for 25 patients (13
at the BA, 8 at AA, and 4 at DA). RLS was not the diagnosis for 55 patients who had a positive
finding at one site without reproducibility (48 at the BA, 4 at AA, and 5 at DA). The sensitivity,
specificity, positive and negative predictive values of the positive finding at BA for the diagnosis
of RLS were 80%, 91%, 61%, and 96%, those at AA were 74%, 99%, 89%, and 96%, and
those at DA were 67%, 99%, 92%, and 95%, respectively. Conclusions: Among three
monitoring sites for cTEE, the BA had the highest sensitivity and AA and DA had almost the
perfect specificity for the diagnosis of RLS. Combined monitoring at the BA, AA, and DA may
improve the diagnostic accuracy for RLS in stroke patients.
P32
Proteomic Identification Of Potential Biomarkers For Ischemic Stroke
Subtype.
David Brea, Tomás Sobrino, Manuel Rodrı́guez-Yáñez, Iván Cristobo, Raquel
Rodrı́guez-González, Octavio Moldes, Rogelio Leira, José Castillo; Dept of Neurology, Clinical
Neuroscience Rsch Laboratory, Hosp Clı́nico Universitario, Univ of Santiago de Compostela,
Santiago de Compostela, Spain
Background. Accurate classification of ischemic stroke subtype is very important because
secondary prevention is subtype-dependent. Nowadays, despite imaging advances, 30 – 40%
strokes still remain as “undetermined stroke”. Therefore, we need molecular markers to
accurately classify ischemic stroke. In this study, we hypothesise that variations in the serum
protein expression from patients with different ischemic stroke subtype may help to find new
diagnostic biomarkers. Methods. Serum proteins from 24 patients with ischemic classified
according to TOAST criteria (12 atherothrombotic and 12 cardioembolic matched by age, sex,
serum glucose, fibrinogen levels and NIHSS socre on admission, infarct volume and modified
Rankin Scale at 3 months) were separated by two-dimensional gel electrophoresis. Resulting
patterns were compared and founded differences were identified by mass spectrometry.
Results. A comparison of protein expression patterns (analyzed with PDQuestTM 2D analysis
software) showed that four spots were found to be fourfold or more expressed in
atherothrombotic patients than in cardioembolic patients. These spots were identified as
haptoglobin ␣1 chain, serum amyloid A (two spots) and haptoglobin related protein (Figure).
Conclusions. Haptoglobin ␣1 chain, serum amyloid A and haptoglobin related protein may be
potential molecular markers of atherothrombotic ischemic stroke subtype. Figure. Gel fragment
including the different expression of spots, between atherothrombotic and cardioembolic
patients, in tridimensional view. SAA, Serum Amyloid A. HPTR, Haptoglobin Related Protein.
HPT␣1chain, Haptoglobin ␣1chain.
P33
Benign Oligemia Reflects Collateral Perfusion: MRI and Angiography of Low
Perfusion Hyperemia in Humans.
David S Liebeskind, Jeffry R Alger, Oh Y Bang, Brian H Buck, James C Norman, Sidney
Starkman, Doojin Kim, Latisha K Ali, Bruce Ovbiagele, Amytis Towfighi, Samir H Shah, Reza
Jahan, Gary R Duckwiler, Fernando Vinuela, Noriko Salamon, J P Villablanca, Jeffrey L
Saver; UCLA, Los Angeles, CA
Background: The basis of benign oligemia, or regions of the ischemic territory not at risk of
infarction, remains unknown. Characterization of the vascular pathophysiology in such regions
may provide insight regarding hemodynamic vulnerability of the adjacent ischemic penumbra
and enhance prediction models of infarct evolution. We utilized concurrent MRI and
conventional angiography in a large series of acute ischemic stroke cases to probe the basis
of benign oligemia. Methods: Data were analyzed from a consecutive series of acute MCA
ischemia cases evaluated with concurrent MRI and conventional angiography. Tmax thresholds
of 2, 4, and 6 seconds on perfusion-weighted MRI were used to delineate potential regions of
benign oligemia. Volumetric and voxel-based analysis methods were used to correlate cerebral
blood volume (CBV) and cerebral perfusion pressure (CPP) values within these regions, using
contralateral hemispheric areas to derive ratios of relative CBV and CPP. Angiographic features
were scored with the TICI scale for the degree of occlusion and the ASITN/SIR scale for extent
of collateral flow. Results: Pretreatment MRI and angiography were analyzed in 50 consecutive
cases of acute MCA occlusion. For all Tmax thresholds used to identify potential areas of benign
oligemia, marked variability in the extent of such non-penumbral regions was noted despite
complete occlusion and cessation of antegrade MCA flow (TICI 0) in all 50 cases. Hyperemia,
or increases in relative CBV values, were evident in these regions of “oligemia” in all cases
(p⬍0.001). Cerebral perfusion pressure (CPP) was mildly decreased in these areas, yet
consistently exhibited a further gradient extending deep from the cortical surface in all cases
(p⬍0.001). Although the presence of collateral flow was always evident, the correlation
between angiographic collateral grade and the area of hypoperfusion varied with the specific
Tmax thresholds employed. Conclusions: Regions of benign oligemia, or non-penumbral areas
at the periphery of the ischemic territory, are hyperemic, not oligemic. Perfusion pressure,
evident on MRI CPP maps, declines from cortex to deep regions of the ischemic territory,
corresponding to progressive slowing of retrograde leptomeningeal collateral flow on angiography. Features of collateral perfusion including an interaction between CBV and CPP, not
autoregulation, likely account for determinants of ischemic vulnerability in areas of low
perfusion hyperemia.
P34
A Pearl In Every Cowslip’s Ear: Pearls on Diffusion-Weighted MRI Predict
Large Vessel Stroke.
Lisa C Turtzo, Univ of Connecticut, Farmington, CT; Rebecca F Gottesman, Rafael H Llinas;
Johns Hopkins Bayview Med Cntr, Baltimore, MD
Background Infarct pattern on diffusion-weighted (DWI) MRI may predict stroke etiology. The
“string of pearls” pattern has been described as a result of large artery disease, but evidence
is lacking to confirm this relationship. Other similar patterns have not been investigated. In this
retrospective study, we investigated whether or not “pearls” (DWI-bright lesions) on MRI were
predictors of intracranial and/or extracranial arterial stenosis. Methods We reviewed all stroke
and TIA admissions to an academic hospital over a 2-year period (495 subjects), excluding
patients without DWI, with hemorrhagic strokes, or with non-vascular disease. Two vascular
neurologists reviewed patients’ records to classify probable stroke etiology by modified TOAST
criteria. Another investigator, blinded to clinical information, reviewed DWI and ADC images
from patients’ MRIs. “String of pearls” was classified as 3 or more pearls in a line found
unilaterally in the anterior circulation. “Scattered pearls” were defined as 3 or more pearls
distributed such that no single line could connect them, also found unilaterally in the anterior
circulation. Results After review of exclusion criteria, 370 patients were included in this study,
averaging 66.8 years in age. “String of pearls” or “scattered pearls” were found on the MRIs
of 6 and 30 patients, respectively. 56% of patients with either “pearls” sign were classified as
TOAST 1 or 2, but this classification was only found in 33% of subjects with any other DWI
pattern (p⫽0.009). Cases with scattered pearls, in particular, were found to have a TOAST 1
or 2 etiology 53% of the time (versus 33% without this pattern) (p⫽0.027). Four of 6 cases with
string of pearls had this mechanism, versus 34% of other cases (p⫽0.187). If either “pearl”
sign was seen on MRI, a patient was 2.65 (95% CI 1.32, 5.32) times as likely to have either
intracranial or extracranial large vessel stenosis. Conclusion Having either “string of pearls”
or “scattered pearls” was associated with an independently determined mechanism of
intracranial or extracranial large vessel stenosis. If either type of “pearls” is seen on MRI, these
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Vol 39, No 2
February 2008
data would suggest that a thorough workup of the intracranial and extracranial vasculature be
pursued.
P35
P37
Frontal Bone Window Improves Success Rate of Transcranial Color-Coded
Ultrasonography in Visualizing Anterior Cerebral Artery in Japanese Stroke
Patients.
Higher ABCD2 Score Predicts Patients Most Likely to Have True TIA.
Sohei Yoshimura, Masatoshi Koga, Kazunori Toyoda, Boo-Han Hyun, Kazuyuki Nagatsuka,
Hiroaki Naritomi, Kazuo Minematsu; National Cardiovascular Cntr, Osaka, Japan
S. Andrew Josephson, Univ of California San Francisco, San Francisco, CA; Stephen Sidney,
Kaiser-Permanente Northern California, Oakland, CA; Allan L Bernstein, Kaiser-Permanente,
Santa Rosa, CA; Trinh N Pham, S. Claiborne Johnston; Univ of California San Francisco, San
Francisco, CA
Objectives: Proper bone windows for transcranial color-coded ultrasonography (TCCS) are
essential to detect intracranial vascular lesions not only for the diagnosis, but also for
hyperacute sonothrombolytic therapy. Because Japanese patients do not frequently have the
adequate temporal bone window (TBW), the success rate for identification of basal cerebral
arteries via TBW, in particular that of the anterior cerebral artery (ACA), is not high enough for
the clinical use. Additional examinations via the frontal bone windows (FBW) may overcome the
limitations. We hypothesized that the success rate in visualizing the basal cerebral arteries may
be improved by the combination of TBW and FBW. Methods: We studied 100 consecutive stroke
patients (age, 69⫾12 or 32 to 93; 72 men) who were admitted to our hospital from June to
August in 2007. The success rates of visualizing the ACA (A1/A2), M1 segment of the middle
cerebral artery (MCA), and the posterior cerebral artery (PCA) through TBW and FBW were
evaluated using a unit (Sonos 5500; Philips Medical Systems, Japan, Tokyo) with a 1.0 –3.0
MHz sector scan. FBW consists of a lateral FBW, which is located above the lateral aspect of
the eyebrow, and a paramedian FBW, which was slightly lateral of the midline of the forehead.
Ultrasound contrast-enhancing agents were not used in this study. Results: Success rates in
visualizing the MCA (37.0%) and PCA (23.0%) through FBW were inferior to those through TBW
(56.0%; p⬍0.001, 56.0%; p⬍0.001, respectively). The combination of observation via the both
windows slightly increased the detection rate of MCA to 63.5% (p⫽0.126) and that of PCA to
62.5% (p⫽0.186). ACA was similarly detected via FBW (42.0%; 50.7% in men, 19.6% in
women) and TBW (38.5%; 47.9% in men, 14.3% in women) (p⫽0.475). It was notable that
20.5% of the ACA was detected only via FBW. The combination significantly increased the
detection rate of the ACA to 59.0% (69.4% in men, 32.1% in women) as compared to the
examination only via TBW (p⬍0.001). Conclusions: Examination of TCCS via FBW in addition
to TBW improved the success rate in visualizing the ACA. The compensatory technique appears
to be useful for patients having the inadequate TBW.
Background: Some patients diagnosed with TIA in the Emergency Department (ED) may
actually have alternative diagnoses such as seizure, migraine, or other non-vascular spells. The
ABCD2 method has been shown to predict subsequent risk of stroke in patients with TIA
diagnosed by emergency physicians, but perhaps high ABCD2 scores simply separate those
patients with true TIA from those with alternative diagnoses. We investigated this hypothesis
in a cohort of patients with TIA identified in the ED whose charts were reviewed by an expert
neurologist. Methods: All patients diagnosed by emergency physicians with TIA in 16 hospitals
in the Kaiser-Permanente Medical Care Plan over a 1-year period ending February 1998 (prior
to publication of prediction rules) were included (n⫽1707). An expert neurologist blinded to
outcome reviewed the charts of 713 of these patients and determined if the spell was likely to
represent a true TIA. Subsequent strokes within 90 days were identified in the cohort. ABCD2
scores were calculated for all patients and two-sided Cochran-Armitage Trend tests were used
to assess subsequent risk of stroke. Results: Of the 713 patients reviewed by the expert
neurologist, 642 (90%) were judged to likely have experienced a true TIA. Ninety-day stroke
risk was 24% in the group judged to have experienced a true TIA, and 1.4% in the group judged
to not have a true TIA. ABCD2 scores were higher in those judged to have a true TIA compared
with those who were not (p⫽0.0001). In the group judged to have a true TIA, 90-day stroke
risk increased as ABCD2 score increased (p⬍0.0001); there was no relationship between
ABCD2 score and stroke risk in those judged unlikely to have had a TIA (p⫽0.73). Conclusions:
In this cohort of patients with TIA, higher ABCD2 score was associated with patients thought to
have true TIA on review by an expert neurologist. Risk of subsequent stroke was quite low in
patients judged to likely have not experienced a true TIA. Higher ABCD2 scores still remained
predictive of 90-day stroke rate in the group of patients judged to have a true TIA by an expert
neurologist. The predictive power of the ABCD2 model is therefore partially explained by
identification of those patients likely to have experienced a true TIA, an important aspect of the
score when used by non-neurologists.
P38
Clinical Features Of Patients With Acute Ischemic Stroke Who Had
Hyperintense Lesions In The Aortic Arch Plaque On T1-weighted Magnetic
Resonance Imaging.
Hiroyuki Kawano, Chiaki Yokota, Naoaki Yamada, Kazunori Toyoda, Kazuo Minematsu;
National Cardiovascular Cntr, Suita, Japan
P36
Real-Time 3D Contrast-Enhanced Transcranial Ultrasound.
Daniel T Laskowitz, Heather A Nicoletto, Duke Univ Med Cntr, Durham, NC; Nikolas M
Ivancevich, Gianmarco Pinton, Stephen W Smith, Duke Univ BioMed Engineering, Durham,
NC; Monica Scism, Ellen Bennett; Duke Univ Med Cntr, Durham, NC
Background and Purpose: Contrast enhanced transcranial color-coded duplex sonography
(CE-TCCD) and reconstructed 3-dimensional TCCD have shown advantages over traditional
TCCD in assessing a variety of cerebrovascular diseases. We tested the feasibility of real-time
3D (RT3D) CE-TCCD in a baseline study of 17 healthy adults Methods: Per an IRB approved
protocol, we used the Volumetrics (VMI) 3D ultrasound scanner with a 2.5 MHz matrix array to
obtain 3D scans from the temporal and sub-occipital acoustic windows of healthy volunteers
given the FDA approved dosage (10 ␮L/kg) of Definity echo contrast agent. The VMI scanner
generates a real-time, 65° 3D pyramidal scan displaying three orthogonal planes, spectral and
3D color flow Doppler. Two observers later reviewed the data, identifying cerebral vessels. In
addition, we used adaptive imaging to estimate and correct the skull-aberration in the temporal
acoustic window, to increase image quality. Color Doppler volumes were then acquired preand post- correction for comparison. Results: In Figure 1, we demonstrate simultaneous axial
(A) and coronal (B) scans of a typical subject. In A, we show the circle of Willis. In B, we see
the length of the M1 and M2 segments of both middle cerebral arteries. In 82% of subjects,
we identified the ipsilateral Circle of Willis, and in 65% we imaged the entire Circle of Willis.
Figure 1C shows a coronal scan of the vertebral arteries (VA) merging into the basilar artery
(BA) in a typical subject. In the sub-occipital approach, we imaged the entire vertebrobasilar
circulation in 22% of subjects. In 50% we imaged the basilar artery. For proof of principle, with
the corrected data we visualized an A1 segment that was not present in the uncorrected data.
Conclusions: In this study, we present a novel transcranial technique which allows real-time,
three dimensional visualization of the Circle of Willis and proximal vasculature. RT3D CE-TCCD
increases ease of use compared to 2D imaging; precise and accurate positioning and aiming
of the transducer is not necessary to image the vessels, as a whole 3D volume of data is
acquired. We also believe that skull-aberration correction will help increase the image quality
of RT3D CE-TCCD.
Objective: Atherothrombotic diseases in the aortic arch as well as in the carotid artery is known
to be a strong and independent risk factor of ischemic stroke. MRI can identify the plaque
instability by characterizing plaque components. In the case of the carotid artery, a lipid-rich
necrotic core with intraplaque hemorrhage displays a hyperintense signal on T1-weighted MRI
(T1WI). Hyperintense lesions in the aortic arch on T1WI may indicate a high risk for future
cerebrovascular events. We aimed to clarify the clinical features and transesophageal
echocardiography (TEE) findings of acute ischemic strokes with hyperintensity in the aortic arch
on T1WI. Methods: Of 345 consecutive patients who were admitted within 7 days after the
onset of ischemic stroke between May 2006 and May 2007, 61 patients with either ⬎50% area
stenosis of the carotid artery or a plaque ⬎4.0mm of thickness in the aortic arch detected by
TEE were enrolled. All patients underwent plaque imaging studies using 3-dimensional
inversion-recovery-based T1WI (alternatively known as magnetization- prepared rapid acquisition with gradient-echo or MPRAGE) in the aortic arch. A high signal plaque on MPRAGE was
defined as a plaque with the intensity of ⬎200% as compared to that of adjacent muscular
tissues. All the patients were followed up until 3 months after the onset. The end-points were
cerebrovascular events including ischemic stroke and carotid endarterectomy. Results:
Thirty-five patients (57%) had high signals of atheroma in the aortic arch on MPRAGE. Eighteen
patients (30%) had cerebrovascular events within 3 months after the onset. Current/former
smoking habit was more common in patients with high signals of atheroma on MPRAGE than
without (74% vs. 42%, p⫽0.011). Male (83% vs. 62%, p⫽0.061) and larger plaques in the
aortic arch (5.6⫾1.7 vs. 4.9⫾1.5 mm, p⫽0.072) tended to be observed more frequently in
patients with hyperintensity in the aortic arch on MPRAGE. The optimal cut-off score of the
thickness in the aortic arch atheroma for high signals on MPRAGE was ⬎4.5mm (sensitivity,
76%; specificity, 62%). Adjusted for age, gender and smoking habit, high signals on MPRAGE
were associated with larger plaques (⬎4.5mm) in the aortic arch (odds ratio 5.20, 95%CI
1.39 –19.53), but not associated with future cerebrovascular events within 3 months after the
index stroke. Conclusion: Larger plaques in the aortic arch, in particular ⬎4.5mm thickness,
were associated with high signals in the aortic arch on MPRAGE in patients with acute ischemic
stroke.
P39
Unilateral versus Bilateral Monitoring for Quantitation of Right-to-Left
Shunt by Power M-Mode Transcranial Doppler.
Jill T Jesurum, Cindy J Fuller, Swedish Med Cntr, Seattle, WA; Mark A Moehring, Merrill P
Spencer; Spencer Technologies, Seattle, WA
Background: Though technically challenging, bilateral monitoring is the clinically accepted
standard for performing transcranial Doppler (TCD) examination despite published guidelines
that recommend monitoring at least one temporal bone window to detect right-to-left
circulatory shunt (RLS). Insonation of both temporal bone windows may be difficult or
impossible in some patients, particularly in elderly females. Systematic comparisons of
unilateral and bilateral monitoring are limited; therefore, the purpose of this study was to
compare unilateral vs. bilateral monitoring by power M-mode TCD (pmTCD) for quantifying RLS.
Methods: Recorded Doppler data from 89 patients referred for transcatheter closure of patent
foramen ovale were re-analyzed for embolic track (ET) counts observed from left and right
temporal bone windows. Patients were excluded for carotid artery stenosis ⬎70%. Unilateral
ET counts were obtained by multiplying each side by two; bilateral ET counts were obtained by
summing left- and right-sided ET. Gender and age group subanalyses and inter-rater reliability
were performed. Results: The sample consisted of 47 males (53%) and 42 females; 47 (53%)
were aged ⬍ 55 years and 42 were aged ⱖ 55 years. Most patients had minimal internal
carotid artery (ICA) stenosis, defined as ⬍15% using carotid duplex ultrasound. All patients had
adequate bilateral temporal bone windows. ET counts were similar between left and right
windows; therefore, the left window was randomly selected for comparison with bilateral
windows. No significant differences were found between unilateral (left multiplied by 2) and
bilateral ET counts at rest (mean ⫾ SD: left 107 ⫾ 122 vs. bilateral 112 ⫾ 124; p ⫽ 0.054)
or following strain (left 211 ⫾ 140 vs. bilateral 214 ⫾ 141, p⫽ 0.164). No differences were
found within genders or younger patients for left versus right ET counts. For the group aged ⱖ
55 years, the right side yielded greater ET counts (12% ⫾ 13%; 95% CI, -3% to 28%) than
the left side at rest only (Z ⫽ -2.577, p ⫽ 0.010). Inter-rater reliability of ET counts was
satisfactory (r ⫽ 0.903). Conclusions: This is the first study to show that, compared to bilateral
monitoring, unilateral monitoring of ET counts by pmTCD is sufficient to detect and quantify
RLS. This will allow design of more portable and user-friendly equipment to screen for presence
of RLS using a single temporal bone window.
P40
Persistence of the Diffusion-Perfusion Mismatch up to 24 Hours:
Dependence upon Proximal Arterial Occlusion.
William A Copen, Elizabeth R Barak, Lee H Schwamm, Leila Reza-Gharai, Shahmir
Kamalian, Ona Wu, R. G Gonzalez, Pamela W Schaefer; Massachusetts General Hosp,
Boston, MA
579
Diagnosis II
P41
Anatomic Localization of the Hand Motor Area in Chronic Stroke Affected
Brains is as Accurate as Functional MRI.
Todd Parrish, Robert Levy, Lora Cope, Dan Krainak, Northwestern Univ, Chicago, IL; Justin
Hulvershorn; Northstar Neuroscience, Seattle, WA
Introduction: Neurosurgical procedures frequently require accurate localization of the precentral
gyrus. Yousry (1997) proposed an anatomic technique for locating the precentral gyrus. We
determined whether this approach is valid in stroke patients, whose brain injury and resulting
neuroplasticity may alter these critical functional/anatomic relationships. Methods: Using the
Yousry method, three independent observers located the hand motor area in 46 chronic stroke
patients enrolled in a stroke motor recovery investigational trial with an implanted cortical
stimulation device (n⫽92 hemispheres; right lesion⫽26, left lesion⫽20). fMRI localized the
affected hand in 43 subjects and the non-affected in 14. The fMRI coordinates were the center
of mass located in the precentral gyrus. The functional location was compared with the
anatomically derived localizations, see figure. Results: The mean Euclidian error between
observers was 6.5 mm and 6.2 mm on the stroke and normal hemispheres, respectively. The
mean distance between fMRI hand motor localization and anatomic localization was 9.3 mm
and 8.2 mm on the stroke and normal hemispheres, respectively. Conclusions: The Euclidian
error between the functional and anatomic localization was less than 10 mm, even in the
infarcted brain, which is on the order of the typical error in fMRI localization. The acquisition
resolution of fMRI is ⬃4mm; processing decreases resolution to 6 – 8mm. Thus, the variability
of anatomic localization between trained observers and the difference between fMRI location
of motor areas and the anatomically derived localization are essentially equivalent in chronic
stroke patients. References: Yousry TA, et.a l. Localization of the motor hand area to a knob
on the precentral gyrus: A new landmark. Brain 1997; 120: 141–157. Acknowledgements: This
study was funded by Northstar Neuroscience, Inc., the manufacturer of the implanted
stimulation device system. Figure: Results from a single patient with a large infarct. The
individual localization of motor cortex is well clustered and the functional imaging result is just
anterior to the anatomic localization.
Background: Ongoing research is investigating the efficacy of intravenous thrombolysis up to
9h after stroke onset in patients with diffusion-perfusion mismatch seen on MRI. In order to
assess the potential impact of future studies that might involve thrombolysis even later than 9h,
we studied the prevalence of persistent mismatch up to 24 hours after onset, and assessed the
relationship of persistent mismatch to the existence of proximal arterial occlusion. Methods:
110 patients underwent diffusion- (DWI) and perfusion-weighted (PWI) MRI, as well as vascular
imaging (MR or CT angiography) within 24 hours after they were last seen at neurologic
baseline. 86 patients were scanned before (“pre9h”) and 24 patients after (“post9h”) the 9h
threshold. 71 had intracranial proximal arterial occlusions (PAO), defined as ICA, M1, M2, A1,
or A2 occlusion, and 29 (NPAO) did not. DWI and mean transit time (MTT) lesion volumes were
measured, and mismatch size was computed as a percentage of the size of the MTT lesion.
Results: 75/86 (87%) of pre9h and 17/24 (71%) of post9h patients had at least a 20%
mismatch. Among NPAO patients, the percent mismatch was smaller in post9h than in pre9h
patients (p⫽0.02, 2-tailed t-test), with a significant negative correlation between percent
mismatch and time as a continuous variable (r⫽-0.37, p⫽0.02). However, among PAO
patients, there was no significant correlation between percent mismatch and time (r⫽0.14,
p⫽.24), and no significant difference in mean percent mismatch between pre9h and post9h
patients (p⫽0.28). The mean percent mismatch at different times is shown below. Conclusion:
Most of our patients scanned within 24 hours demonstrated a substantial diffusion-perfusion
mismatch. Among patients without proximal arterial occlusion, percent mismatch decreased as
a function of the time since the patient was last seen without symptoms. However, no such
time-related decrease was seen among patients with proximal arterial occlusive lesions that
may be accessible to intra-arterial intervention. This apparent persistent penumbra may reflect
prolonged collateral support of larger regions of at-risk tissue. Further study is warranted.
P42
Combined Perfusion and Diffusion MR Imaging Can Improve Diagnostic
Yield in Hemispheric TIA.
Michael Mlynash, Dept of Neurology and Neurological Sciences, Stanford Stroke Cntr,
Stanford Univ Med Cntr, Stanford, CA; David C Tong, California Pacific Med Cntr,
Comprehensive Stroke Care Cntr and Cntr for Stroke Rsch, San Francisco, CA; Maarten G
Lansberg, Jean-Marc Olivot, Irina Eyngorn, Stephanie Kemp, Dept of Neurology and
Neurological Sciences, Stanford Stroke Cntr, Stanford Univ Med Cntr, Stanford, CA; Michael
E Moseley, Dept of Radiology, Lucas Magnetic Resonance Spectroscopy and Imaging Cntr,
Stanford Univ Med Cntr, Stanford, CA; Gregory W Albers; Dept of Neurology and
Neurological Sciences, Stanford Stroke Cntr, Stanford Univ Med Cntr, Stanford, CA
Objective Transient ischemic attacks are strong predictors of future stroke. However, current
diagnostic criteria for TIA are not sensitive and specific. Acute diffusion weighted imaging (DWI)
lesions can be detected in about one third of TIA patients. The yield of MR perfusion imaging
(PWI) for detecting ischemic lesions in TIA patients has not been established. Methods In this
prospective NIH-funded study, DWI and PWI images were performed within 48 hours of
symptom onset in 43 consecutive patients admitted with suspected hemispheric TIAs
(symptom duration less than 24 hours). Mean transit time perfusion maps (PWI) and DWI
580
Stroke
Vol 39, No 2
February 2008
images were assessed for the presence and location of lesions by two independent raters,
blinded to clinical features. MRA scans were assessed for the presence of an arterial lesion in
the ICA or intracranial vessels by a third reader. Correspondence of the lesions with the
suspected clinical localization and baseline characteristics was assessed. Clinical features
predictive of a positive PWI lesion were determined in a multivariate logistic regression model.
Results PWI and DWI lesions were detected in 33% and 35% patients respectively. An isolated
PWI lesion was present in 16%, and both a DWI and a PWI lesion were present in 16%. The
combined yield for identification of either a PWI and/or a DWI lesion was 51%. Correspondence
with the clinically suspected hemisphere was 93% for DWI and 86% for PWI lesions. Both of
the patients who had PWI lesions in a clinically silent hemisphere also had acute DWI lesions
in the same region. Both raters agreed on the existence and location of PWI lesions in 81% of
the patients (Kappa⫽0.58). Inter-rater agreement regarding the presence and location of DWI
lesions occurred in 98% of the cases (Kappa⫽0.95). Fourteen percent of the patients had an
MRA lesion in the symptomatic hemisphere or ipsilateral ICA; ipsilateral MRA lesions were
present in 36% of the patients with a PWI lesion and 20% of the cases with DWI lesions.
Obtaining the MRI scan within 12 hours of symptom resolution and multiple symptomatic
episodes were the only clinical features predictive of a positive PWI lesion. There was no
statistically significant association of symptom type or duration with presence of a perfusion
abnormality. Conclusion DWI in combination with early PWI can detect cerebral ischemic
lesions in approximately half of all patients who present with a suspected hemispheric TIA. MR
imaging has the potential to substantially improve the accuracy of TIA diagnosis.
P43
Sodium MRI Intensity Evolves Over Time in Human Acute Ischemic Stroke.
Muhammad S Hussain, Robert W Stobbe, Yusuf A Bhagat, Derek Emery, Kenneth S
Butcher, Dulka Manawadu, Nasir Rizvi, Perkash Maheshwari, Ashfaq Shuaib, Christian
Beaulieu; Univ of Alberta, Edmonton, Canada
Background: The time of onset of ischemic stroke is a critical determinant for acute therapy.
Presently, there are no imaging methods that determine the time of stroke onset within the
acute time frame (⬍7 days). Although correlations between relative signal intensity within the
ischemic lesion and time of onset have been demonstrated with sodium magnetic resonance
imaging (MRI) in animal models, this correlation has not been demonstrated in acute human
stroke. The purpose of this study is to determine whether relative signal intensity measured
within the ischemic lesion on sodium MRI evolves with time following stroke onset in humans.
Methods: Fifteen patients (58 ⫾ 16 years) with clearly defined time of onset were scanned
between 4 - 61 hours post symptom onset. Several patients were scanned more than once,
yielding 24 time points. A standard stroke imaging protocol was acquired at 1.5 Tesla (T),
followed by sodium MRI at 4.7T, where whole brain sodium images were acquired in 10
minutes. Relative signal intensity within each lesion was measured with respect to the
contralateral side. Results: Representative sodium MRI images from one patient at two
different time points are shown (figure). The sodium image quality was sufficient to elucidate
each lesion (lesion volume range 1.7 - 93 mL), and the total imaging protocol was tolerated
well by all patients. Relative signal intensity (mean ⫾ 95% CI) measured within the lesion on
sodium MRI was increased 5 ⫾ 3 % by 4 - 7 hours (n ⫽ 5), 37 ⫾ 9 % by 13 - 29 hours (n ⫽
10), and 61 ⫾ 12 % by 36 - 61 hours (n ⫽ 9) (p ⬍ 0.01). Conclusion: Good quality sodium
MRI images were acquired from acute stroke patients at 4.7T. The relative signal intensity
within the ischemic lesions measured on these images evolved with time following stroke
onset. For this reason, sodium MRI may be a useful imaging tool in acutely determining time
of onset in ischemic stroke patients.
from the extracorporeal circulation circuit, and hypoperfusion of brain. Acute ischemic stroke
and cerebral air embolism can be detected on diffusion-weighted imaging (DWI) and
T2*-weighted gradient-echo imaging (GRE), respectively. Objectives: In this study, we
evaluated the frequency and pattern of air emboli on GRE and acute ischemic stroke on DWI.
Moreover, we investigated the factors associated with new lesions on DWI and GRE. Methods:
We conducted a prospective study of patients who underwent cardiac valve replacement
surgery. We checked baseline characteristics (demographic features, stroke risk factors,
National Institutes of Health Stroke Scale (NIHSS) scores, and modified Rankin Scale (mRS)
scores), operative factors (atheroma detected on ascending aorta, duration of operation,
postoperative atrial fibrillation), and MRI (including DWI, GRE, and MR angiography) before
surgery. Three days after operation, we followed up NIHSS, mRS, DWI and GRE. At 3 months
after operation, we scored mRS again. We defined any new lesions on DWI as ischemic stroke,
and any new low signal lesions on GRE as air emboli. We analyzed the relationship between
new lesions on MRI and baseline characteristics, operative factors, and preoperative imaging
characteristics. Results: Among 44 consecutive patients who were screened, 40 patients were
enrolled and 19 completed all preoperative and postoperative tests. Among 19 patients, 10
patients (52.6%) developed 20 air emboli on postoperative GRE, and 1 patient (5.3%) showed
new infarct on postoperative DWI. There were no significant factors associated with
development of air embolism. Two patients developed new clinical events after surgery. One
patient developed generalized seizure accompanied by confusion and mild facial palsy several
hours after surgery. MRI performed 2 days after surgery showed large ischemic cortical lesions
on DWI in right middle cerebral artery territory and 8 air emboli lesions on GRE scattered in
bilateral supratentorial and infratentorial areas. The other patient developed transient irritability
and confusion after surgery. Postoperative DWI did not show any new lesion, but GRE revealed
four air emboli in supratentorial and infratentorial areas. Conclusions: Air emboli documented
on GRE were more frequent than new ischemic lesions on DWI after cardiac valve replacement
surgery. Further studies are needed to reveal the clinical significance of these findings.
P45
Complications of Modern Diagnostic Cerebral Angiography in an Academic
Medical Center.
Johanna T Fifi, Philip M Meyers, Sean D Lavine, Virgnia Cox, Lynn Silverberg, Sundeep
Mangla, John Pile-Spellman; Columbia Univ, New York, NY
Background: Catheter-based cerebral angiography has steadily improved over the past several
decades. Simultaneously, non-invasive imaging of the cerebral vasculature, predominantly
using CT and MR, has increased in accuracy and now supplants catheter-based angiography
in many circumstances. Catheter-based angiography is now most commonly used for
treatment planning, either endovascular or open surgical procedures. To remain a viable
diagnostic modality, catheter-based angiography must not represent a significant source of
patient morbidity. We report the complication rate of catheter-based cerebral angiography
performed by neurointerventional specialists at a major academic medical center. Methods:
From July 2001 through June 2007, 3417 catheter-based cerebral arteriograms were
performed at a large academic institution. Data were prospectively acquired over a 6 year
period according to institutional policy and NYPORT criteria. Data collected included patient
age, sex, indication for procedure, operator, and nature of symptomatic or asymptomatic
adverse event, including need for treatment. Results: Among 3417 diagnostic cerebral
angiograms performed over this 6 year period, there were 11 (0.32%) clinical complications.
One (0.03%) patient had MRI detected stroke with no apparent clinical deterioration. Iatrogenic
dissections of 5 (0.15%) arteries occurred with one patient requiring immediate stent
placement due to angiographic flow impairment. No patient developed neurological symptoms.
Non-neurological complications occurred in 5 (0.15%) patients who suffered puncture site
related complications: 1 femoral abscess in the setting of repeat angiography through a groin
hematoma and use of a arterial closure device, 2 occlusions of the femoral artery with leg
ischemia requiring surgical revascularization also associated with groin closure devices, 1
dissection with pseudoaneurysm formation requiring percutaneous thrombin injection, and 1
retroperitoneal hemorrhage requiring transfusion. There were no deaths. Conclusions: Modern
catheter-based cerebral angiography performed by experienced neurointerventionalists is
associated with a very low complication rate of 0.32% even in a highly complex, frequently
symptomatic patient population. Non-neurological complications were associated with the use
of arterial closure devices.
P46
CT Perfusion Estimation of Penumbra During Acute MCA Strokes in
Patients Receiving Thrombolytic Treatment: Does the Perfusion Package
Matter?
David Clopton, Ansaar T Rai, Jeffrey S Carpenter; West Virginia Univ, Morgantown, WV
P44
Cerebral Air Embolism and Acute Ischemic Stroke Detected on MRI after
Cardiac Valve Replacement Surgery.
Sang-Beom Jeon, Jae Won Lee, Kyoung-Sun Kim, Cheol Hyun Chung, Hyun Song, Suk Jung
Choo, Eun-Kyung Kim, Dong-Wha Kang; Asan Med Cntr, Seoul, Republic of Korea
Background: Stroke is major neurologic complication after cardiac valve replacement surgery.
The etiology of postoperative stroke has been suggested as the macroembolization from the
heart or ascending aorta (including air emboli, atheromatous debris, and fat), the microemboli
Objective: To compare standard CT perfusion parameters in acute middle cerebral artery
strokes as determined by two perfusion analysis packages and to assess the clinical relevance
of the estimations of penumbra size. Methods: CT perfusion imaging was performed on 17
patients with documented M1 or M2 MCA occlusions prior to thrombolytic therapy. All strokes
were confirmed by follow-up imaging. Infarct core was defined for the purposes of this
comparison as the zone of perceptible CBV decrease within a region of CBF decrease as noted
on color maps (rainbow type) with dynamic range of 0 to 10 for CBV (ml/100g) and 0 to 100
for CBF (ml/100g/min). Free hand regions of interest were drawn about the region of CBV and
CBF decrease compared to the contralateral side. The average of the parametric indices of CBF
and CBV were recorded within these regions. The percentage of penumbra remaining was then
determined by 1 - (CBVarea / CBFarea) * 100. These steps were performed retrospectively using
GE CT Perfusion 2 software (ver. 2.6.6i) and Vital Images’ Vitrea 4.0 CT Perfusion. Results:
There are significant differences (p ⬍ 2 x 10 -6) between the mean value of CBV within the
infarct core as determined by the GE Perfusion 2 software (0.80 ⫹/- 0.30) and the Vital
Perfusion software (1.8 ⫹/- 0.5). The mirrored values in the non-ischemic hemisphere are
significantly different (p ⫽ 0.016) with GE value of 2.3 ⫹/- 0.9 and Vital value of 3.6 ⫹/- 1.5.
The ratio of CBVcore / CBVmirror differed as well (p ⫽ 0.001). With respect to estimated residual
penumbra, the Pearson Coefficient is 0.77 indicating a strong linear correlation between the
software. The Vital software uniformly estimates the penumbra to be greater than that
estimated by GE Perfusion 2. Conclusions: The two analysis packages differ significantly in their
quantitative characterization of the infarct core. Yet when the parametric maps of CBV and CBF
are compared and the penumbra estimated, there is a strong linear correlation between the two
packages. Of the 17 cases perhaps one patient’s treatment may have differed between the two
packages (GE⫽15, Vital⫽84) if basing treatment decisions on physiologic parameters alone
assuming thrombolytic treatment for patients with at least 1/3 of the abnormally perfused area
estimated as penumbra. Does it matter? It depends.
581
in the general population, effective prevention and treatment of PFO-related stroke requires
refining and developing clinical criteria for accurate diagnosis and risk assessment. In this
prospective cohort population study, we investigate the association of gender and age with
respect to PFO-related strokes. Methods: From 346 consecutive patients who presented to the
Cardio-Neurology Clinic specializing in PFO assessment at Massachusetts General Hospital
between July 2005 and July 2007, 102 young patients (age 21–55) were determined to have
PFO-related strokes. In this group of patients with PFO-related strokes, 96% had positive
imaging findings of strokes correlating to the clinical assessment and 100% were determined
by 2 vascular neurologists to have had a PFO-related stroke. In this group, 52% were women,
equally distributed with respect to age. Men and women had similar baseline risk factors such
as hypertension (HTN), diabetes (DM), hyperlipidemia (HL), smoking and alcohol intake (p⫽NS).
However, women were more likely than men to have a history of migraine (54% vs. 20%
p⬍0.00001), positive pelvic venous abnormalities (20% vs. 8.3% p⬍0.05), and higher ESR at
presentation (p⬍0.005), while men had higher percentages of precipitating a stroke with
Valsalva maneuvers, such as weight lifting (24% vs. 5% p⬍0.01). When the entire group was
dichotomized using the median age into younger (21– 45) vs. older (46 –55) age groups,
conventional stroke risk factors (HTN, DM, HL, sedentary lifestyle) increased with age; however,
the incidence of migraine and of obesity remained similar in both age groups (p⫽NS).
Conclusions: In patients whose strokes are attributable to PFO, women were more likely than
men to have migraines, higher ESR, and pelvic venous findings on imaging. While older patients
predictably had more conventional risk factors, age did not change the incidence of migraine
or obesity in this cohort. These findings suggest that while the modification of certain risk
factors (e.g. obesity) is “ageless,” an individualized evaluation and stroke prevention strategy
is needed with respect to gender, as the pathophysiology of PFO-related stroke may differ
between men and women. Further studies in a larger cohort are underway to confirm these
findings.
P49
Dwi-mri Study In Patients With Mild Ischemic Stroke.
P47
Stroke Mechanisms Of Intracranial Artery Dissection.
Hideki Okatsu, Hideki Matsuoka, Kazunori Toyoda, Junji Kasuya, Hiroaki Naritomi, Kazuo
Minematsu; National Cardiovascular Cntr, Suita. Osaka, Japan
Objectives: Previous studies indicated that carotid artery dissections produce ischemic stroke
mainly by an embolic mechanism, because of a high incidence of microembolic signals on
ultrasound in the middle cerebral artery (MCA) distal to the dissection and of the frequent
localization of infarcts in the cortex rather than in watershed areas. In Japanese patients,
dissections occur more commonly in intracranial arteries than in the extracranial carotid
arteries. However, the stroke mechanisms of intracranial artery dissections have not fully been
elucidated. The objective of this study was to investigate stroke mechanisms of intracranial
artery dissections. Methods: Of 1874 patients who were admitted to our hospital within two
weeks after the onset of ischemic stroke between 2001 and 2007, 34 patients were diagnosed
as having intracranial artery dissections as a cause of ischemic stroke. Diagnosis of the
dissection was principally made based on findings of the digital subtraction angiography.
Infarcted lesions were assessed using MRI scans including diffusion weighted imaging (DWI),
unless contraindicated, with regard to the anatomical localization (involving the cortex or not),
multiplicity, and topographical relationship of the infarcts with the dissections (if the infarct lay
close to or remote from the dissected artery). Results: The dissections were identified in the
intracranial vertebral artery (VA) for 10 patients, posterior inferior cerebellar artery (PICA) for 3,
basilar artery (BA) for 5 (3 patients had VA dissections simultaneously), posterior cerebral artery
(PCA) for 5, MCA (M1) for 4, and anterior cerebral artery (ACA) for 7. The patients having PCA
dissections were younger than the others (30.8⫾6.6vs.54.2⫾2.8 years, p⫽0.003), and did not
have traditional risk factors including hypertension, diabetes mellitus, and dyslipidemia.
Cortical infarcts were more common in patients with supratentorial artery dissections (PCA,
MCA, ACA, 16 patients, 100%) than in those with infratentorial artery dissections (VA, PICA, BA,
7 patients, 39%, p⬍0.001). Infarcts were multiple in 8 patients (50%) with supratentorial
dissections and in 6 (33%, p⫽0.324) with infratentorial dissections. Infarcts were remote from
the dissected artery in 11 patients (69%) with supratentorial dissections and in 8 (44%,
p⫽0.154) with infratentorial ones. Conclusions: Stroke mechanisms of intracranial artery
dissections may vary among the dissected arteries. As compared to infratentorial artery
dissections, infarcts with supratentorial dissections are more suggestive of embolic mechanisms.
P48
Gender and Age Associated Clinical Characteristics of Young Patients with
Patent Foramen Ovale (PFO) Related Strokes.
MingMing Ning, Igor F Palacios, Ignacio Inglessis, Mary Ellen McNamara, Mary Lievens,
Zareh N Demirjian, Ignacio Cruz-Gonzalez, Massachusetts General Hosp/Harvard Med Sch,
Boston, MA; David McMullin, New York Univ, New York, NY; Pablo Rengifo, Ferdinando S
Buonanno; Massachusetts General Hosp/Harvard Med Sch, Boston, MA
Strokes related to patent foramen ovale (PFO) have been reported to be the etiology for up to
40% of cryptogenic strokes in the young. However, given the high baseline prevalence of PFO
Angel Ois, Elisa Cuadrado-Godia, Jordi Jimenez-Conde, Claustra Pont, Gracia Cucurella,
Meritxell Gomis, Xavier Perich, Alberto Solano, Jaume Roquer; Hosp del mar, Barcelona,
Spain
Background The presence of acute ischemic lesion in the diffusion-weighted-imaging (DWI)
has been related with a high risk of recurrence in patients with transient ischemic attack. The
aim of our study was to determine if the presence of multiple acute lesions in patients with mild
stroke are associated with aetiology, vascular risk factors, recurrence rate and outcome at six
months. Patients and methods Prospective cohort of patients admitted to stroke unit with first
ischemic stroke of mild severity (NIHSS 1–7). The DWI-MRI study was performed during
hospitalization by a trained radiologist blind for patient’s data. Stroke severity was measured
using NIHSS. Poor outcome was defined as moderate-severe disability or death (modify Rankin
Scale (mRS) ⬎2) at six months. The relationship between radiological data stroke severity,
vascular risk factors, aetiology, recurrence rate and outcome was analyzed using logistic
regression model with 95% CI. Results The final cohort was 218 patients. NIHSS median
(q1-q3) 3 (2–5), mean age (SD) 69.9 (12.8). The DWI study showed multiple acute lesions in
64 patients (29.4%). Presence of multiple lesions was independently associated with
cardioembolic stroke (adjusted OR⫽12.81; 95%CI 2.96 –55.52), large-vessel disease (adjusted
OR⫽8.41; 95%CI 2.80 –25.22), and previous TIA (adjusted OR⫽4.00; 95%CI 1.53–10.51).
Stroke recurrence was found in 29 patients (16 patients 55.2% with multiple lesions) whereas
49 patients (22.5%) had poor outcome. The presence of multiple lesions in DWI independently
predicted stroke recurrence [adjusted OR⫽2.49; 95%CI (1.04 –5.97)] but not poor outcome
[adjusted OR⫽1.49; 95%CI (0.72–3.07)]. Conclusion Multiple acute ischemic strokes in DWI
are found in a considerable rate of patients with mild stroke. The presence of multiple acute
lesions can help to identify stroke aetiology and also patients with a higher recurrence risk.
P50
Diagnostic Accuracy of Transcranial Color Flow Imaging against Magnetic
Resonance Angiography in Japanese Patients with Ischemic Stroke.
Hidetaka Mitsumura, Kiyoharu Inoue, Dept of Neurology, Jikei Univ, Tokyo, Japan; Hiroshi
Furuhata; ME Lab, Jikei Univ, Tokyo, Japan
Background and Purpose; In order to increase availability of transcranial color flow imaging
(TC-CFI) for ischemic stroke, we aimed to evalate the diagnostic accuracy of TC-CFI compared
with magnetic resonance angiography (MRA) in Japanese patients with ischemic stroke.
Methods; We examined TC-CFI for one hundred fifty one cases of Japanese patients with
ischemic stroke (⬍14 days from onset) from bilateral temporal bone window without
echo-contrast agents, and evaluated the rate of recordable CFI focused on middle cerebral
artery (MCA; M1 and M2) and posterior cerebral artery (PCA; P1 or P2). We assigned the
recordable conditions to three categories (A; all arteries were recordable, B; some arteries were
recordable, C; non - recordable), and then analyzed the proportion of category in each age
group (20 – 49, 50 –59, 60 – 69, 70 –79, and over 80y.o.) and gendor group separately. In only
patients of group A, the findings of TC-CFI were compared with those of MRA. The accuracy
was calculated by a paired statistical analysis. Results; The 151 patients (104 man and 47
female, mean age 68.6⫾12.9 y.o.) were separated to 75 cases (49.7%) in group A, 41 cases
(27.1%) in group and 35 cases (23.2%) in group. The proportion of group C was significantly
higher in females than in males (p⬍0.0001), and increased with age gradually. Particularly, the
detectability of the group over 80 y.o. was significantly lower than the other groups. In 71
patients of group A who underwent MRA, the diagnosis of TC-CFI was adequately same enough
582
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Vol 39, No 2
February 2008
to those of MRA with the accuracy of 90.7% (sensitivity; 86.7% and specificity; 91.6%).
Conclusion; TC-CFI has the same diagnostic ability as MRA in patients with ischemic stroke,
who have sufficient bilateral echo windows. However, it is necessary to improve the
detectability of TC-CFI in Japanese patients with poor echo windows.
P51
Cardiovascular MRI in Detection and Measurement of Aortic Atheroma in
Stroke/TIA Patients.
Souvik Sen, Jennifer W Simmons, David Y Huang, Susan E Wilson, James Barnwell, William
B Hyslop, Alan L Hinderliter; Univ of North Carolina, Chapel Hill, NC
Background: Aortic atheroma (AA; ⱖ4 mm) is an independent risk factor for new and recurrent
stroke. AA ulceration and mobility are associated with an increased risk for brain embolism.
Transesophageal echocardiography (TEE) is the gold standard for detection and measurement
of AA in stroke/TIA patients. Cardiovascular MRI (cMRI) could be an alternative, non-invasive
imaging modality for stroke/TIA patients. Objective: To assess the accuracy and correlation of
AA detected and measured by cMRI versus TEE in patients with recent stroke/TIA. Methods:
Stroke/TIA patients undergoing TEE as a part of their stroke workup consented to a
protocol-mandated cMRI performed on a 1.5 T magnet. The protocol included an axial
non-breathhold EKG-gated dual-echo spin echo MRI of the thoracic aorta (TR/TE1/TE2⫽900/
29/69) and a contrast-enhanced breathhold 3D gradient-echo image of the thorax (flip/TR/TE⫽
12/4.0/1.71). AA was assessed using spin-echo and 3D images. Maximum plaque thickness,
ulceration (ⱖ2 mm) and mobility were assessed in the proximal (ascending and proximal arch)
and distal (distal arch and descending) segments of thoracic aorta, by a cardiologist (TEE) and
a radiologist (cMRI), blinded to one another’s readings. Results: Twenty-two stroke/TIA
patients (mean age 68 years, 55% males) had TEE and cMRI assessment for AA. There was
good correlation bewteen cMRI and TEE in measurement of plaque thickness in the proximal
segments (R⫽0.93, p⬍0.0001) and the distal segments (R⫽0.81, p⬍0.0001) of the AA. cMRI
had a high degree of accuracy in detecting measurable AA (ⱖ1 mm) in the proximal segments
(sensitivity 90%, specificity 100%), as well as the distal segments (sensitivity 67% , specificity
100%). cMRI also had a high degree of accuracy in detecting significant AA (ⱖ4 mm) in
proximal segments (sensitivity 71%, specificity 93%), as well as distal segments (sensitivity
71%, specificity 100%). However, cMRI was able to identify proximal AA ulceration in 89% and
in 64% in the distal segments (Figure). AA mobility was not assessed by MRI using this
protocol. Conclusions: The study shows a high degree of accuracy and correlation of AA
detected and measured by cMRI as compared to TEE in patients with recent stroke/TIA. cMRI
has limitations in detection of AA ulceration, and protocols assessing AA mobility need to be
developed.
P52
Evaluation of the Vertebral Artery Using Transoral Carotid Ultrasonography.
Rieko Suzuki, Ryoichi Otsubo, Kazunori Toyoda, Hiroyuki Kawano, Sohei Yoshimura, Kayoko
Kawase, Masatoshi Koga, Kazuyuki Nagatsuka, Hiroaki Naritomi, Kazuo Minematsu;
Cerebrovascular Div, Dept of Medicine, National Cardiovascular Cntr, Suita, Japan
Objectives: The transoral carotid ultrasonography (TOCU) is used to demonstrate the distal
internal carotid artery which conventional ultrasonography cannot examine. It has not been
clarified whether TOCU can also evaluate the distal vertebral artery (VA). The goal of this study
was to solve this question. Methods: The study subjects consisted of 45 patients (64⫾13 years
in age, 40 men) with cerebrovascular disease. The VA was visualized using conventional
angiography in 29 patients, magnetic resonance angiography in 43, and computed tomographic
angiography in 17. TOCU examinations were performed with a color Doppler flow imaging
system equipped with the 6-MHz convex array transducers, originally designed for transrectal
use. A probe was inserted transorally, touching the tip to the pharyngeal posterolateral wall. We
then attempted to detect the VA and measure its diameter and flow velocities using principal
images obtained by TOCU. The results were compared with those by conventional ultrasonography using the Student’s t-test and linear-regression analysis. Results: In all 90 VAs, 13
vessels were ineligible for the analysis because of occlusion or stenosis on the angiographic
studies. Four VAs could not be examined because of gag reflex. Although TOCU identified the
remaining 73 VAs, 6 VAs were excluded from the flow velocity analysis because of improper
angles of insonation. On TOCU, VAs were visualized at a depth of 23.9⫾5.9mm from the
pharyngeal wall as a vertical linear vessel between almost two transverse processes of the
cervical spine, mainly at the height of the C2 level. The diameter was 3.7⫾1.1mm on TOCU
and 3.9⫾0.7mm on conventional US. The peak systolic (Vmax), mean (Vm), and end-diastolic
flow velocities (Vmin) of the VAs were significantly higher on TOCU than on the conventional US
(61.5⫾29.3 vs. 46.8⫾16.9 cm/s, 34.0⫾15.9 vs. 26.0⫾10.6, 21.1⫾11.7 vs. 15.3⫾7.9,
respectively, all p⬍0.001). Between the two US techniques, the correlation coefficients of
Vmax, Vm and Vmin were 0.91, 0.92 and 0.90, respectively (all p⬍0.001). Conclusions: TOCU
can visualize the distal VA mainly at the height of the C2 level. The flow velocities were
significantly higher on TOCU than on the conventional US, but their correlations were excellent.
TOCU may be useful for the evaluation of morphology and flow dynamics of the distal
extracranial VA.
P53
Diameter of The Basilar Artery May Be Associated With Neurological
Deteriorarion in Acute Pontine Infarction.
Junya Aoki, Yasuyuki Iguchi, Takeshi Inoue, Kensaku Shibazaki, Shinji Yamashita, Kazumi
Kimura; Kawasaki Med Sch, Kurashiki, Japan
Purpose: 20% of patients with acute pontine infaction, especially branch atheromatous disease
(BAD), have neurological deterioration at acute phase of stroke. However, it has still unknown
about predictors for neurological deterioration in pontine infarction. The aim of present study
is to investigate the predictive factors associated with neurological deterioration in pontine
infarction. Methods: We consecutively enrolled patients with acute pontine infarction without
BA occlusion. We performed diffusion weighted magnetic resonance imaging (DWI) twice, on
admission and after 7days of onset and measured the ischemic volume. Magnetic resonance
angiography was also examined to identify to measure a diameter of internal carotid artery (ICA)
and basilar artery (BA), and BA diameter/ ICA diameter (BA/ICA ratio) were calculated in each
patient. When ischemic lesion extended to third ventricle, we diagnosed one as BAD. We
defined neurological deterioration as worsening of NIHSS score 2 points or more for one week.
All patients were classified based on the presence of neurological deterioration during first 7
day of onset into two groups, deteriorated group (D group) and no deteriorated group (ND
group). Clinical characteristics were compared between two groups. Results: 65 patients (age;
71.0 ⫾ 9.9 years, men; 46) were enrolled into the present study. BAD was found in 32 (49.2%)
of 65 on initial DWI and 38 (58.4%) of 65 on follow up DWI. Neurological deterioration occurred
11 (16.9%) in 65 patients. Initial infarct volume was 0.44 ⫾ 0.19cm3 in D group and 0.32 ⫾
0.35cm3 in ND group, respectively (p⫽0.016). In follow-up DWI study, 10 (90.9%) of 11
patients in D group comprised BAD and 29 (53.7%) of 54 patients in ND group had BAD
(p⫽0.016). BA/IC ratio was 0.76 ⫾ 0.13 in D group and 0.66 ⫾ 0.17 in ND group (p⫽0.014).
Optimal cut-off infarct volume on initial DWI and BA/IC ratio to differentiate D from ND group
was 0.37cm3 (sensitivity of 74%and specificity of 73%) and 0.72 (sensitivity of 76% and
specificity of 73%), respectively. Multivariate regression analysis demonstrated that initial
infarct volume of 0.37cm3 or more (OR 7.78, 95%CI 1.10 –54.78, p⫽0.039) and BA/IC ratio of
0.72 or more (OR 7.98, 95%CI 1.46 – 43.67, p⫽0.017) were independent factors associated
with neurological deterioration. Conclusion: Diameter of the basilar artery may be associated
with neurological deterioration in acute pontine infarction.
P54
Can CT Angiography of Great Vessels and Cervical Carotids Predict
Micro-Embolic Signals on Transcranial Doppler?
Firosh Khan, Youngbin Choi, Univ of Calgary, Calgary, Canada; Maher Saqqur, Univ of
Alberta, Edmonton, Canada; Ali Al-Khathaami, Pranshu Sharma, Eileen Stewart, Caroline
Stephenson, Andrew M Demchuk; Univ of Calgary, Calgary, Canada
Purpose: Significance of atheromatous disease of great vessels as a potential source of
cerebral embolism varies. Though CT Angiography (CTA) delineates structural details,
Transcranial Doppler (TCD) provides direct information regarding cerebral embolization. We
aimed to define the variables in CTA of great vessels predicting micro-embolic signals (MES)
in TCD. Methods: We analyzed 1hour TCD emboli-detection monitoring studies of patients with
anterior circulation cerebral ischemia in a prospectively maintained CTA database, and
correlated MES with great vessel and cervical carotid CTA features. Standard Power M-mode
Doppler apparatus with head frame (Spencer Tech, Inc; PMD100 mol/L) was used and bilateral
middle cerebral arteries insonated at 55– 65mm depth. Studies from May’02-Dec’06 were
reanalyzed jointly by two neurosonologists to count MES in PMD and/or spectrogram. CTAs of
aortic arch, great vessels and cervical carotids were done on a 66-slice multi-row-detector CT
scanner. Images were analyzed jointly by a stroke-neurologist and a neuroradiologist, to note
size/shape/surface/density/calcification of plaques, degree of internal carotid artery (ICA)
stenosis and presence of intra-luminal thrombus. MES positivity and count were correlated with
CTA features using univariate analysis, and variables found significant tested in a multivariate
model. Results: There were 243 emboli-monitoring studies on 198 subjects (151 males; mean
age 66.2 years, range 16 –94), done at median of 19 hrs (IQR 12 hrs-4 days) after ischemic
event and one day (IQR 0 –3 days) after CTA. Fifty two studies in 45 patients detected MES
(median 3 MES/study, range 1– 87). Univariate analysis showed plaque-length/thickness,
stenosis degree and intraluminal thrombus in ICA as the CTA features predicting MES. None of
the features of common carotid arteries, brachiocephalic artery or aortic arch was significantly
related. On multiple-logistic-regression analysis, intra-luminal thrombus [RR 5.4 (CI951.8 –
15.8), p⫽.002] and ICA stenosis remained significant. Ipsilateral 50 –70% and 70 –90% ICA
stenoses had odds of 3.6 (CI951.5– 8.7, p⫽.004) and 9.3 (CI953.7–23.3, p⬍.01) respectively for
MES, whereas 30 –50% stenosis (p⫽.42) and total occlusion (p⫽.65) had no predictive value.
When number of MES was analyzed as dependent variable in stepwise multiple-linearregression, each 1mm increase in ICA plaque-width raised MES count by 0.8 (p⫽.004), while
presence of intraluminal thrombus increased the count by 4.5 (p⫽.007). Conclusions: Out of
various quantitative and qualitative characteristics of aortic arch, great vessels and cervical
carotids in CT Angiography, only intraluminal thrombus in ICA and moderate to severe degrees
of ICA stenosis predict TCD-emboli in anterior circulation cerebral ischemia. Intraluminal
thrombus and ICA plaque-width are principal determinants of quantity of emboli.
P55
Plasma Brain Natriuretic Peptide as a Predictor For Appearance of Atrial
Fibrillation in Stroke Patients With Sinus Rhythm on Admission.
Yoko Okada, Kensaku Shibazaki, Kenichirou Sakai, Junya Aoki, Yuka Terasawa, Kazuto
Kobayashi, Shinji Yamashita, Masao Watanabe, Junnichi Uemura, Noriko Matsumoto,
Takeshi Inoue, Yasuyuki Iguchi, Kazumi Kimura; Kurashiki, Okayama, Japan
Background Atrial Fibrillation (AF) is a major risk factor for ischemic stroke. Acute stroke
patients with sinus rhythm on admission sometimes have appearance of AF after admission.
Patients with AF have been reported to have high level of plasma brain natriuretic peptide
(BNP). Therefore, we made a hypothesis that high BNP on admission indicated that stroke
patients with sinus rhythm on admission had appearance of AF after admission. The aim of the
study was to investigate the hypothesis. Methods Between March 2006 and May 2007,
consecutive patients with acute ischemic stroke and TIA with sinus rhythm on admission within
24hours of onset were prospectively enrolled. We measured plasma BNP on admission. All
patients routinely underwent electrocardiography (ECG) on admission and 24-hour Holter ECG
within 7 days after admission. Patients with AF on admission, coronary heart disease,
dialysis-dependent chronic renal failure, and mechanical prosthetic valve were excluded from
the study because plasma BNP increases in such patients. We divided patients into two groups;
AF group had appearance of AF after admission, and Non-AF group had no appearance of AF.
Results 173 patients (54 female; mean age, 71⫾12 years) were enrolled into the study. AF
was observed in 19 patients (AF group). Age (77 years vs. 70 years, p⫽0.01), female (56% vs.
28% p⫽0.04), NIHSS score on admission (mean 8.5 vs. 4.3, p⫽0.01), modified Rankin Scale
on discharge (mean 3.1 vs. 1.8, p⫽0.01), and D-dimer (mean 1.5 vs. 1.4, p⫽ 0.02), were
higher in AF group than non-AF group. Mean plasma BNP levels were significantly higher in AF
group than non-AF group (306.4 pg/ml vs. 65.6 pg/ml, p⬍0.01). The cut-off value, sensitivity,
and specificity of BNP levels to distinguish the AF from the non-AF group were 80 pg/ml,
77.8%, and 76.7%, respectively. Multivariate regression analysis demonstrated that plasma
BNP over 80 pg/ml was an only independent factor associated with detection of AF (odds ratio
6.7, 95% CI; 1.86 to 24.1, p⫽0.01) Conclusion Plasma Brain Natriuretic Peptide can predict
an appearance of AF in acute stroke patients with sinus rhythm on admission.
583
non-H group did not have. We studied clinical characteristics including the presence of
microbleeds between 2 groups. Results ; Hemorrhagic infarction was observed in 111 (30.0%)
patients (31 patients in symptomatic and 80 in asymptomatic) on follow up T2* weighted
imaging. Microbleeds was more frequently seen in non-H group than H-group (60.2% vs.
45.1%; p⫽0.007). The significant differences between two groups were observed following
factors; (hyperlipiemia; 20.4% for H group vs 33.5% for Non-H group, p⫽0.013, age;
75.7⫾12.0 vs 71.3⫾12.9, p⫽0.002, atrial fibrillation (AF); 52.0% vs 26.9%, p⬍ 0.0001,
NIHSS on admission; 11.7⫾7.8 vs 6.1⫾6.6, p⬍ 0.0001). There were no differences in
following factors; gender, smoking, hypertension, diabetes mellitus, diastolic and systolic blood
pressure. Multivariate analysis demonstrated that NIHSS score of 10 or more on admission (OR
2.7, 95%CI 1.5 to 4.8, p⫽0.0006) and AF (OR 1.9, 95%CI 1.1–3.4, p⫽0.02) were independent
factors associated with hemorrhagic infarction. However, microbleeds were a negative
independent factor associated with hemorrhagic infarction (OR 0.5, 95%CI 0.3 to 0.9, p⫽0.02).
Conclusions ; Microbleeds on MRI T2* imaging on admission could not predict hemorrhage
infarction in acute ischemic stroke.
P57
Robustness of Prognostic Models to Interrater Variability in Delineating
Final Infarct Lesion.
Lars R Ribe, Kim Mouridsen, Anders Neumann, Niels Hjort, Kristjana Jonsdottir, Leif
Østergaard; Cntr of Functionally Integrative Neuroscience, Dept of Neuroradiology, Aarhus
Univ Hosp, Aarhus, Denmark
Introduction: Perfusion and diffusion MR images are often used in acute stroke to assess
salvable tissue. Recently, multiparametric statistical models have been introduced, assessing
probability maps of tissue outcome at a voxel level by integrating acute perfusion, diffusion and
structural images, based on acute and expert classified follow-up (FU) images from previous
patients. The success of predictive algorithms, however, depends on correct delineation of FU
in the training data and performance may therefore be influenced by interrater variability. Here
we compare the influence of both FU modality (T2 and FLAIR) as well as interrater variability
on the predictive performance of the common GLM algorithm. Materials and methods: Data
from 14 patients with acute stroke was included. Nine experienced neuroradiologists manually
outlined final infarct regions on 3-month follow-up FLAIR and T2 images, respectively. Two
algorithms were trained for each observer by using either T2 or FLAIR as FU resulting in a total
of 2x9 algorithms. Infarct predictions calculated by an algorithm was compared voxel-wise to
the FU outcome outlined by each rater, yielding 9 validations per algorithm. Predictive
performance was measured using (a) area under the ROC curve (AUC) and (b) statistical
accuracy (SA). Results: Predictive performance on FLAIR (AUC⫽0.82⫾0.01, SA⫽0.74⫾0.02)
was significantly higher than T2 (AUC⫽0.81⫾0.02, p⬍0.01, SA⫽0.73⫾0.02, p⬍0.01). Using
FLAIR as FU performance was also less influenced by interrater variability (AUC range:
0.79 – 0.85 (FLAIR) and 0.74 – 0.85 (T2)). The lower, right corner of the figure demonstrates
AUC performance for all pairs of raters when trained on FLAIR. To visually assess the effect of
differences in AUC, the top row of the figure shows an example of probability maps for two
observers (number 2 and 3). The FU FLAIR image is shown in the lower, left corner. Conclusion:
To maximize performance and robustness of predictive algorithms, FLAIR images should be
used for delineating end infarcts. Although some variations in performance are detected for
different raters, these are likely too subtle to be appreciated visually in probability maps.
P56
Microbleeds on MRI T2* Weighted Imaging Cannot Predict Hemorrhagic
Infarction in Acute Ischemic Stroke.
Kenichirou Sakai, Kazuto Kobayashi, Noriko Matsumoto, Kensaku Shibazaki, Takeshi Inoue,
Yasuyuki Iguchi, Kazumi Kimura; Kawasaki Med Sch, Kurashiki, Japan
Background and purpose ; 5–10 % of acute ischemic stroke patients have hemorrhagic
infarction. Recently, hemorrhagic lesions including hemorrhagic infarction and microbleeds can
be clearly detected by MRI T2* weighted imaging. The aim of this study is to investigate
whether microbleeds on MRI T2* weighted imaging on admission could predict hemorrhagic
infarction at acute phase of ischemic stroke. Methods ; 370 patients with acute ischemic
stroke excepting lacuna stroke within 48 hours of onset were enrolled. We performed twice MRI
studies including T2* weighted imaging for all patients on admission and 7th day. Patients were
classified into 2 groups, H group had hemorrhagic infarction including asymptomatic and
symptomatic (neurological deterioration as worsening of NIHSS score 2 points or more) and
584
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Vol 39, No 2
February 2008
P58
Abc/2 Estimation Technique Is Not An Accurate Measurement Of Acute
Ischemic Stroke Volume With Diffusion Weighted Imaging.
Salvador Pedraza, Josep Puig, Gerard Blasco, Carla Guergue, Jaume Astarloa, Idi. Hosp Dr
Josep Trueta, Girona, Spain; Maria Garcia, Hosp Dr Josep Trueta, Girona, Spain; Sebastian
Remollo, Ana Quiles, Eva Gomez, Mar Castellanos, Idi. Hosp Dr Josep Trueta, Girona, Spain;
Joaquin Serena; Hosp Dr Josep Trueta, Girona, Spain
Introduction Measurement of infarct volume have been used as a surrogate or auxiliary
outcome method in clinical stroke trials. Planimetric method is considered the gold standard
technique to measure the infarct volume. However, this method is slow and difficult to apply
in the acute setting. On the other hand, ABC/2 is an easier and faster method but to our
knowledge, there have not been reported comparative studies about the concordance between
both methods. Objective The aims of this study were to compare the level of concordance
between the ABC/2 method and the planimetric method in the measurement of infarct volume
in DWI sequences. Methods. Infarcts volumes measurements were calculated using DWI
images by three independent observers. Each observer performed their analysis blinded to the
relevant patient clinical information. The volume measurements were performed in the MR
workstation. Observers used two methods to measure infarcts volumes: ABC/2 technique and
planimetric method. In both methods, all volumes were calculated three times, and the mean
value was taken as definitive. Results We studied Ninety-one patients (mean age, 71.7 years;
range, 40 to 89 years). Five patients were excluded because the movement artifacts. Eighty-six
stroke patients (mean age, 67,9; range, 40 to 89 years) were enrolled in the study.The patients
were studied in the first 12 hours the first 12 hours after the stroke onset (mean, 2.8 hours;
range, 0.25 to 9.8 hours) in a period of 3 years. Eighty-six infarct volume of MCA territory were
calculated: 52 were located in superficial territory (60.5%), 19 were deep (22.1%), and 15
affected both territories (17.4%). The ABC/2 technique overestimated the infarct volume by
median false increase of 8.8 cm3 [2.9, 32.4], an increase over the gold standard value of 182%
[148.03, 294.74]. The intraclass correlation coefficient between measurements by ABC
technique and planimetric analysis were 0.636, 0.717, 0.722 between different observers.
Scatterplots show the ratios between ABC/2 and planimetric measurements with values from
2 to 2.3. In each method the Interrater reliability was excellent with an intraclass correlation
of 0.991 and 0.984 for a ABC/2 technique and planimetric method, respectively. Conclusion Our
findings indicate that the abc/2 method overestimates the real volume of the infarction. A faster
and more reliable volumetric method is needed to allow the measurement of infarct volume in
the acute setting.
P59
30-Day Event Monitors in Detecting Atrial Fibrillation in Cryptogenic
Stroke.
P60
MRI Use in TIA Patients: Variations by Joint Commission Stroke Center
Certification Status and Implications for a Revised Tissue-Based Definition
of TIA.
Andrew W Asimos, Carolinas Med Cntr, Charlotte, NC; Wayne D Rosamond, Kathryn M
Rose, Annie Green Howard, Carol V Murphy, Univ of North Carolina, Chapel Hill, NC; Charles
H Tegeler, Wake Forest Univ Sch of Medicine, Winston-Salem, NC; Sylvia W Coleman; North
Carolina Dept of Health and Human Services, Raleigh, NC
Background: A tissue based definition of TIA, which includes no evidence of acute infarction,
has been proposed, implying that an MRI is necessary for an accurate diagnosis. Data are
lacking for the proportion of TIA patients receiving an MRI across hospital settings. Thus, we
examined the proportion of presumed TIA cases receiving an MRI and variations by Joint
Commission Primary Stroke Center (JCPSC) certification status. Methods: Between January
2005 and July 2007, the North Carolina Collaborative Stroke Registry (NCCSR), a CDC-funded
Paul Coverdell National Acute Stroke Registry, tracked MRI use in 3,350 presumptive TIA
patients from 39 NC hospitals with access to MRI. We used logistic regression to compare MRI
use in patients treated at JCPSCs (n⫽10) and non-JCPSCs (n⫽29). Covariates included age,
gender, and hospital type (teaching vs. non-teaching, based on criteria established by the CDC).
Due to an interaction between JCPSC and teaching status (p ⬍ 0.0001), analyses were
stratified by teaching status. Results: Of patients with a presumed admitting diagnosis of TIA,
64% (n⫽2,149) underwent an MRI during their hospitalization. Patients at JCPSCs were more
likely to receive an MRI than were those at non-JCPSCs (72% vs. 55%, p⬍0.0001). At teaching
hospitals, MRI use did not vary between JCPSCs and non-JCPSCs (OR ⫽ 0.89, 95% CI ⫽
0.69 –1.15). In contrast, in non-teaching hospitals, patients treated at JCPSCs were more likely
to undergo an MRI than those treated at non-JCPSCs (OR ⫽2.74, 95% CI 2.22–3.40). Final
discharge diagnoses, based on ICD-9 discharge codes, included TIA for 48%, ischemic stroke
for 25%, and other for 27% of patients admitted with a presumptive diagnosis of TIA. Of
patients discharged with a diagnosis of TIA, 61% received an MRI during their admission, while
72% of patients with a final diagnosis of ischemic stroke had an MRI performed. Conclusions:
This experience, including a broad range of hospitals in North Carolina with access to MRI,
found that over one-third of admitted presumptive TIA patients did not have an MRI during their
hospitalization. At non-teaching hospitals, MRIs were more likely to be performed at JCPSCs
than non JCPSCs. This suggests that changing to a tissue based definition of TIA would be
significantly undermined by lack of MRI performance, especially at non-JCPSC, non-teaching
hospitals.
P61
Comparison of Regional Perfusion Parameters Derived from Two Perfusion
Packages on “Stroke Protocol” Patients without Cerebrovascular Disease
or Subsequent Stroke.
David Clopton, Ansaar Rai, Jeffrey S Carpenter; West Virginia Univ, Morgantown, WV
Lucas Elijovich, S. Andrew Josephson, Gordon L Fung, Wade Smith; UCSF, San Francisco,
CA
Introduction: A large proportion of cryptogenic stroke may be due to atrial fibrillation. Thirty-day
cardiac event monitors may increase the detection rate of atrial fibrillation compared with
standard investigations such as EKG, inpatient cardiac telemetry, and short-term Holter
monitoring. Methods: We conducted a retrospective study of all patients admitted to a tertiary
stroke center or seen in clinic from June 2006 to March 2007 who were diagnosed with a
cryptogenic stroke or TIA. Cryptogenic stroke was defined by the attending Neurologist if a
thorough workup failed to identify an etiology for a large-vessel stroke. All patients underwent
standard investigation for stroke etiology including EKG, 48 hours of inpatient cardiac telemetry,
cervical and intracranial vascular imaging, and echocardiogram. In all included patients, there
were no pre-exisiting indications for anticoagulation. Two models of 30-day event monitors
were used, the AFIB Dual Alert (West Palm Beach, Florida) and LifeStar AF Express 3X (Buffalo
Grove, Illinois) that are programmed to automatically detect R-R interval irregularities that may
represent malignant arrhythmias. A cardiologist reviewed the study record at the time of each
event transmission and upon completion of the 30-day study period. Results: Twenty-six
patients were referred for 30-day event monitor, and twenty (76%) completed the study.
Inpatients were monitored on cardiac telemetry for an average of 54 hours (range 24 –96)
without any episodes of atrial fibrillation. Nineteen of the patients (95%) had an echocardiogram, and five (26%) patients had severe left atrial enlargement. Only one of the 5 patients with
severe left atrial enlargement was found to have atrial fibrillation. Five patients (25%) had
clinically significant findings on their event monitors. Four (20%) had newly diagnosed atrial
fibrillation, and one additional patient had three asymptomatic episodes of ST segment
depression associated with tachycardia. Two out of the five patients with clinically significant
findings were evaluated as outpatients and both had atrial fibrillation discovered on long-term
monitoring Conclusion: Thirty-day event monitors identified a larger proportion of atrial
fibrillation in patients with cryptogenic stroke than would be expected with standard
investigations. Further prospective studies of extended event monitors in the setting of
cryptogenic stroke are warranted.
Objective: To demonstrate the significant territorial differences in perfusion parameters derived
from perfusion CT and the differences in values generated by two existing perfusion packages.
Methods: Standard CT Perfusion of the brain and CT angiographic imaging of the head and neck
was performed on 734 patients between 5/1/05 and 5/30/07. No stroke was identified on in
360 of these patients. Exclusions from analysis were made for prior stroke, presence of any
detectable arterial stenoses by CTA, excessive motion, inadequate bolus arrival curve or lack
of MR or CT follow-up within 30 days. A single operator reprocessed the raw perfusion data
on both Vital Images’ Vitrea 4.0 CT Perfusion and GE CT Perfusion 2 software selecting region
of interests encompassing both gray and white matter within the ACA, MCA, and PCA bilaterally
and of the basal ganglia region on the 80 remaining patients. The same arterial input and
venous output source were selected on the level best depicting all vascular territories being
evaluated. Regions of interest were evaluated on this level only. Conclusion: All perfusion
values generated are significantly different (two tailed student t-test p values less than 0.05)
between the two packages with the exception of CBV values in the ACA, BG, and PCA territories.
The differences can be due to a number of sources including differences in motion correction,
vascular pixel elimination and numerical method differences in calculation of CBV and MTT.
These differences may have clinical significance when upgrading or switching packages if
treatment decisions are based upon absolute values of these perfusion parameters. Both
perfusion packages indicate prolonged mean transit times within the PCA distribution
compared with the ACA and MCA values (p value ⬍ 1 x 10-15) with increased variance within
this region as well. This may lead to unnecessary concern and further testing of the
vertebrobasilar system unless recognized as a “normal” finding of the CT perfusion technique.
RESULTS
MTT (s)
ACA
BG
MCA
PCA
CBF (ml/100gm/min)
CBV ml/100gm
Vital
GE V2
Vital
GE V2
Vital
GE V2
4.0⫹/-0.7
3.4⫹/-0.6
3.8⫹/-0.7
4.8⫹/-1.1
3.4⫹/-0.7
3.0⫹/-0.6
3.4⫹/-0.8
4.4⫹/-1.2
45⫹/-15
50⫹/-17
54⫹/-18
38⫹/-17
57⫹/-27
60⫹/-27
83⫹/-40
58⫹/-37
2.7⫹/-0.9
2.6⫹/-0.9
3.1⫹/-0.9
2.8⫹/-1.2
2.5⫹/-1.0
2.5⫹/-1.0
3.5⫹/-1.4
3.1⫹/-1.6
P62
Utility of CT Angiography and MR Angiography in Evalution of Vertebral
Artery Origin Stenosis.
Mouhammad A Jumaa, Alexandra Popescu, Nirav A Vora, Ajith Thomas, Vivek Reddy, Syed
F Zaidi, Ridwan Lin, Maxim D Hammer, Lawrence R Wechsler, Tudor G Jovin, Michael B
Horowitz, Jawad Tsay, Ken Uchino; Univ of Pittsburgh Med Cntr Stroke Institute, Pittsburgh,
PA
Background: Atherosclerotic disease of the V1 Segment of the vertebral artery is reported to
be found in 20% of patients with posterior circulation stroke. Our goal was to determine the
sensitivity and specificity of CT angiography (CTA) and MR angiography (MRA) in detecting
stenosis of the vertebral artery origin compared to Digital Subtraction Angiography (DSA) as the
standard. Methods: With IRB approval, we reviewed medical records of patients evaluated in
our center for vertebral artery origin stenosis between 2003 and 2007. Patients were included
if they had a noninvasive study (CTA or MRA) and a DSA within a three months period. Data
extracted from MRA, CTA and DSA reports included whether the vertebral artery origins were
imaged and appropriately visualized and the degree of stenosis (none, ⬍ 50%, ⬎50%, or
occlusion). All MRAs and CTAs were independently reviewed by a second Neuro-radiologist
blinded to the first interpretation. Interrater agreement was calculated between observers.
Sensitivity and specificity were calculated with DSA as the standard for determination of
stenosis with thresholds of 50% and 0%. Proportions were compared by Fisher’s exact test.
Results: Forty-eight subjects with 23 CTA and 38 MRA studies were included. There were 92
interpretable vertebral arteries on DSA, since 4 right vertebral arteries could not be visualized.
Only 15% (7/46) of arteries evaluated by CTA were deemed as not interpretable, whereas 45%
(34/75) were not interpretable on MRA (p⬍0.001 by Fisher’s exact test). Interrater agreement
of interpretability was moderate for CTA with kappa of 0.43, whereas that for MRA was fair at
0.39. Sensitivity and specificity for ⱖ50% stenosis by CTA was 61.9% and 77.8%. Sensitivity
and specificity for ⱖ50% stenosis by MRA was 55.0% and 85.7%. Interrater agreement for
ⱖ50% stenosis was fair at kappa of 0.26 for CTA and 0.32 for MRA readings. Conclusions:
MRA and CTA have comparable sensitivity and specificity, but CTA has a higher rate of
interpretable studies. Further studies are needed to validate our data. The low interrater
agreement indicates a need for development of standardization for measurement of vertebral
artery origin stenosis.
CTA vs. DSA
Threshold for stenosis
Number of arteries
examined
Sensitivity % (95% CI)
Specificity %
(95% CI)
⫹Predictive
Value
-Predictive Value
ⱖ50%
MRA vs. DSA
⬎0%
ⱖ50%
⬎0%
46
46
75
75
61.9%
(40.9–79.3)
77.8%
(54.8–91.0)
0.765
91.3%
(73.2–97.6)
56.3%
(33.2–76.9)
0.750
55.0%
(34.2–74.2)
85.7%
(65.4–95.0)
0.786
90.9%
(72.3–97.5)
47.4%
(27.4–68.3)
0.667
0.636
0.818
0.667
0.818
P63
Hyperdense Basilar Artery Sign on Unenhanced CT Predicts Thrombus and
Outcome in Acute Posterior Circulation Stroke.
Gregory V Goldmakher, Erica C Camargo, Karen L Furie, Wade S Smith, Gordon J Harris,
Maggie J Chou, Massachusetts General Hosp, Boston, MA; Trese Biagini, Univ of California,
San Francisco, San Francisco, CA; Luca Roccatagliata, Elkan F Halpern, Massachusetts
General Hosp, Boston, MA; William P Dillon, Univ of California, San Francisco, San
Francisco, CA; R Gilberto Gonzalez, Aneesh B Singhal, Walter J Koroshetz, Michael H Lev;
BACKGROUND: In acute stroke patients, the dense MCA sign on unenhanced CT is a specific
but insensitive indicator of acute thrombosis. It has been suggested that the dense basilar
artery (DBA) sign may have utility in detecting thrombosis and predicting recanalization after
thrombolysis. However, it is not known how specific and sensitive this sign is for outcome
prediction in suspected posterior circulation stroke. Methods: We reviewed unenhanced CT
scans obtained within 24 hours of symptom onset in 95 consecutive patients with suspected
posterior circulation stroke. Three blinded neuroimagers rated presence of DBA sign on a
5-point level of certainty scale (1 ⫽ definitely absent; 5 ⫽ definitely present). ROC curve
analysis was performed, with concurrent CTA as the reference standard. NIHSS score at
discharge was used to measure short-term outcome, and 6-month modified Rankin score
(mRS) was used to measure long-term outcome (poor outcome defined as mRS⬎2). Univariate
analysis assessed the correlation of the following variables with short and long-term outcome:
DBA, age, sex, time from onset to imaging, admission NIHSS, history of stroke/TIA, atrial
fibrillation, CAD, HTN, DM, hypercholesterolemia, tobacco use, and thrombolysis. Variables
associated with outcomes at p⬍0.1 on univariate analysis were included in multivariate
regression models. RESULTS: Using a level of certainty cutoff score of 4 or higher (probable,
definite), DBA sign had 71% sensitivity, 98% specificity, 94% accuracy, 83% PPV, and 95%
NPV for basilar artery occlusion. In univariate analysis, factors significantly associated with
short-term outcome were: admission NIHSS (p⬍0.001, R⫽0.77), DBA (p⫽0.01), and DM
(p⫽0.02), with thrombolysis showing a trend (p⫽0.053). Factors significantly associated with
poor long-term outcome were age (p⫽0.02), admission NIHSS (p⫽0.007), DBA (OR⫽5.6,
95%CI 1.1–29.3; p⫽0.02), and history of stroke/TIA (p⫽0.007). In multivariate analysis, the
585
only independent predictors of short-term outcome were admission NIHSS (p⬍0.001) and DBA
(p⫽0.03). Significant independent predictors of poor long-term outcome were age (p⫽0.02),
admission NIHSS (p⫽0.005), history of stroke/TIA (p⫽0.02), and DBA (p⫽0.04). CONCLUSION:
In patients with a high pretest probability of posterior circulation stroke, the presence of a DBA
sign on unenhanced CT is a specific and accurate predictor of basilar artery thrombosis, and
an independent predictor of short and long-term clinical outcome.
P64
CT Perfusion Cerebral Blood Volume Can Be Used to Predict Anatomic
Collaterals in Acute Stroke Patients Receiving Endovascular Therapy.
Nirav Vora, Ridwan Lin, Ajith Thomas, Syed Zaidi, Vivek Reddy, Univ of Pittsburgh,
Pittsburgh, PA; Ken Uchino, Univ of Pittsburgh, Pittsburgh, MI; Maxim Hammer, Lawrence
Wechsler, Michael Horowitz, Tudor Jovin; Univ of Pittsburgh, Pittsburgh, PA
Background: Our aim was to correlate CT perfusion, hemispheric mean cerebral blood volume
(CBV) and mean transit time (MTT) values to the presence of collaterals in acute stroke patients
treated with endovascular therapy. Methods: We retrospectively reviewed patients who
underwent endovascular therapy for anterior circulation stroke and received a pre-treatment CT
perfusion. Hemispheric mean CBV and MTT values were obtained using a software which
calculates average values within selected regions of interest (ROI). ROI were drawn in both
middle cerebral artery (MCA) distributions for both CBV and MTT maps. Additionally, a ratio was
generated using hemispheric mean CBV ipsilateral to the stroke divided by the hemispheric
mean CBV contralaterally. Angiographic collaterals during intervention were graded based on
late angiographic filming of the symptomatic hemisphere. A score of 1 to 5 was ascribed to the
collaterals as follows: a score of 1 if collaterals reconstituted any part of the MCA M1 segment,
2 for any reconstitution of the MCA M2 segments, 3 for any reconstitution of the MCA M3
segments, 4 for any reconstitution of the MCA M4 segments, 5 for absent collaterals.
Correlation techniques were performed to determine the relationship of hemispheric mean CBV,
hemispheric mean CBV ratio, and hemispheric mean MTT to the presence of collaterals.
Results: A total of 31 patients were identified with mean age 63⫾13 years and mean NIHSS
16⫾4. Two patients had an internal carotid artery (ICA) origin occlusion; 8 had an ICA terminus
occlusion; 9 had a middle cerebral artery (MCA) M1 segment occlusion; 3 had a MCA M2
segment occlusion, and 9 had a tandem occlusion of the ICA origin and intracranial circulation.
Both hemispheric mean CBV and hemispheric mean CBV ratio showed a significant correlation
to the presence of collaterals (r ⫽ -0.60, z⫽3.17 and r ⫽ -0.63, z⫽3.33, respectively for an
␣⫽0.05). Hemispheric mean MTT statistically did not correlate with the presence of collaterals
(r ⫽ -0.18, z⫽0.95 for an ␣⫽0.05). Conclusion: CBV, and not MTT, may be a tool for
predicting the presence of anatomical collaterals in acute stroke. Further correlation with stroke
outcome is needed to determine if this tool can be used to tailor endovascular strategies prior
to treatment.
P65
Arterial Input Choice in CTP Map Construction with Acute MCA Thrombus:
Does Side Matter? - Not If Delay Correction Software Is Used Proximal to
the Occlusion.
Rafael M Ferreira, Gregory Goldmakher, Shahmir Kamalian, Pamela W Schaefer, R Gilberto
Gonzalez, Michael H Lev; Massachusetts General Hosp, Boston, MA
PURPOSE: Using software from two vendors for CT perfusion (CTP) map construction in acute
stroke patients, we examined how CBV, CBF, and MTT values vary with the placement of the
arterial input function (AIF) region-of-interest (ROI) relative to an arterial occlusion. METHODS:
A neuroradiologist constructed CTP maps for 14 acute stroke patients using deconvolutionbased software from two vendors (A: CT Perfusion 4, GE Healthcare; B: Brain Perfusion, Philips
Medical Systems). All cases had unilateral proximal MCA clot confirmed by CTA and infarct core
confirmed by MR-DWI. CTP maps were generated with the AIF ROI in 4 positions relative to the
MCA clot (AIF1 - proximal ipsilateral; AIF2 - distal ipsilateral; AIF3 - proximal contralateral; AIF4
distal contralateral). Other technical parameters were held constant. For each map, CBV, CBF
and MTT values were sampled in the infarct core, healthy gray matter and healthy white matter.
RESULTS: Using software A, mean CBF and CBV at the infarct core remained ⬍12
mL/100g/min and ⬍2 mL/100g, respectively, for AIF1, 3, and 4. For AIF2, mean CBF and CBV
values were 17.3 mL/100g/min and 2.85 mL/100g, respectively. Using software B, mean CBF
and CBV at the infarct core remained ⬍12 mL/100g/min and ⬍1.8 mL/100 g, respectively, for
AIF1, 3, and 4. For AIF2, mean CBF and CBV values were 19.4 mL/100g/min and 2.5 mL/100g,
respectively. For both packages, a significant difference was observed between the CBF and
MTT values at the infarct core obtained with AIF2 and those obtained with AIF1, 3, and 4
(p⬍0.05). Using AIF2 led to higher mean CBF (software A: ⫹7 mL/min/100g; software B:
⫹11.3 mL/min/100g) and lower mean MTT (software A: -1.5s; software B: -2.5s). Mean CBV
showed a trend towards increase (p⫽0.083) with AIF2 for all tissues sampled (software A:
⫹1.01 mL/100g; software B: ⫹1.32 mL/100g). With AIF2, 43% of cases showed visible
differences in the CTP maps, most notably for MTT; time-density curves (TDCs) showed visually
depressed peak enhancement. These effects were qualitatively less pronounced with software
A. CONCLUSION: For accurate quantitative CTP map construction, laterality of AIF ROI
placement is less important than avoiding placement distal to an MCA occlusion. TDCs suggest
that decreased AIF peak enhancement distal to a clot may lead to overestimation of CBV and
CBF, and underestimation of MTT. This pitfall is less severe with delay-corrected deconvolution
software.
586
Stroke
Vol 39, No 2
February 2008
P66
MR Regional Perfusion Values in Hyperacute Ischemic Stroke Treated by
Intra-Arterial Thrombolysis are Influenced by Recanalization and Time to
Recanalization.
Luis A Verduzco, Albert J Yoo, Kit Mui, Michael H Lev, Joshua A Hirsch, Ramon G Gonzalez,
Pamela W Schaefer; Massachusetts General Hosp, Boston, MA
Purpose: In the setting of hyperacute ischemic stroke, DWI-PWI mismatch identifies hypoperfused but potentially salvageable brain parenchyma, the ischemic penumbra. We sought to
determine regional cerebral blood flow (CBF) values in penumbral tissue that progressed to
infarction versus tissue that recovered in hyperacute stroke patients who underwent
intra-arterial thrombolysis (IAT). Furthermore, we sought to determine the effect of recanalization status and time to recanalization on these values. Methods: 14 patients with acute MCA
and/or ICA terminus occlusion underwent DWI/PWI before IAT followed by post-thrombolysis
imaging to ascertain infarct extension. CBF values were obtained from the pre-treatment
perfusion scans in three regions: (1) infarct core (abnormal on admission DWI and CBF); (2)
penumbra that infarcted (normal on admission DWI, abnormal on admission CBF, abnormal on
follow-up); (3) penumbra that survived (normal on admission DWI, abnormal on admission CBF,
normal on follow-up). CBF ratios (rCBF) were determined for these regions by dividing by CBF
values in mirror-image regions of interest in the non-ischemic hemisphere. Results: In the
entire group, mean rCBF values for regions 1–3 were 0.35⫾0.15, 0.53⫾0.16, and 0.61⫾0.17,
respectively (p⬍0.0001). Mean rCBF values for region 2 in recanalizers (RC) versus
non-recanalizers (NRC) were 0.48⫾0.16 and 0.56⫾0.15 (p⬍0.03), respectively. Mean rCBF
values for region 2 in patients with recanalization within 3 hours of imaging versus after 3 hours
of imaging were 0.40⫾0.12 and 0.67⫾0.06, respectively (p⬍0.0001). Conclusion: In
penumbral tissue that goes on to infarct, mean rCBF values are lower in the setting of RC. Early
time to RC also resulted in lower mean rCBF values for this region. These findings support the
time dependence of CBF thresholds in the ischemic penumbra.
P67
Assessment Of Large Vessel Cerebral Blood Flow In Healthy Subjects Using
Quantitative Magnetic Resonance Angiography.
Table of Contents
䡠Arteries Arteries
TVA
TCF
TCBF
Mean ⫾ 1.96 SD ml/min (95% CI of Lower and Upper bound)
18 – 40
41– 60
ⱖ61
197⫾88(⫾15)
1014⫾211(⫾53)
731⫾210(⫾36)
190⫾77(⫾14)
950⫾265(⫾48)
698⫾195(⫾35)
173⫾78(⫾19)
925⫾309(⫾76)
641⫾198(⫾49)
P68
The Assessment of Lesion Volumes in TIA and Minor Stroke Patients.
Cynthia R Campos, Young B Choi, Firosh Khan, Dept of Clinical Neurosciences, Foothills
Med Cntr, Univ of Calgary, Calgary, Canada; Jayme Kosior, Dept of Electrical and Computer
Engineering, Univ of Calgary, Calgary, Calgary, Canada; Michael D Hill, Andrew M Demchuk,
Shelagh B Coutts; Dept of Clinical Neurosciences, Foothills Med Cntr, Univ of Calgary,
Calgary, Canada
Background and Purpose: The risk of disability following TIA or minor stroke is high. Clinical
trials are needed for acute treatment options in these patients and reducing the sample size
required may improve feasibility. Lesions volumes measurements in disabling stroke have been
used in some clinical trials; however the usefulness of this method in TIA or minor stroke
patients who generally have smaller lesion volumes is unknown. We sought to see how feasible
measuring lesion volumes in TIA and minor stroke patients was and also to assess in what
proportion of patients the presenting lesion had disappeared at 30 days and in how many had
the initial lesion grown. Methods: Patients with TIA or minor stroke were examined within 12
hours by a stroke neurologist and had a brain MRI within 24 hours of symptom onset and at
30 days. Patients with acute lesions on DWI had the volumes of their lesions measured both
on the baseline DWI and on the follow-up FLAIR MRI. When more than one lesion was present,
the total volume of the lesions was considered. Volumes of the follow-up FLAIR lesion were
compared to the baseline DWI lesion to define lesion growth (increase⬎2mL). Volumes were
measured by commercially available software using computer-assisted volumetric analysis.
The intrarater reliability for measurement of these lesions was calculated. Results: From 180
patients enrolled, 80 patients had at least one acute lesion on the baseline DWI. The mean
volume of the baseline lesion was 2.73mL (range: 0.1–32.95mL). On the follow-up MRI, in
14(17.5%) patients the initial lesion disappeared; in 5(6.2%) the volume decreased; in
14(17.5%) the volume increased, and in 47(58.8%) no change in volume occurred. The
intraclass correlation was excellent; ICC⫽0.99, suggesting that although these lesions are
small, lesion volume measurements are reproducible. Conclusions: Lesion volume measurements are feasible in minor stroke and TIA patients. Although others have previously reported
in TIA and minor stroke patients that the presenting lesions persist, we have found that in a
high proportion (17.5%) of these patients the initial lesion disappears by 30 days. We also found
a high proportion of patients in whom the lesion increased in volume from baseline. Further
studies are required to assess whether this can be used as a surrogate marker for therapeutic
trials in TIA and minor stroke.
Xinjian Du, Sepideh Amin-Hanjani, Meide Zhao, Sean Ruland, Weihua Gao, Craig Beam,
Fady Charbel; UIC, Chicago, IL
BACKGROUND AND PURPOSE: Blood flow rate in major cerebral arteries can be measured
non-invasively with quantitative magnetic resonance angiography (QMRA). However, normal
values have not been previously determined. METHODS: QMRA was performed in 255
subjects18 to 80 years old and free of known disease (124 women, mean age 47⫾15; 131
men, mean age 46⫾16.). Cerebral blood flows were measured in 6 cervical and 9 intracranial
arteries in each volunteer. Normal range for each major cerebral artery was established based
on sample mean ⫾ 1.96SD, 95%CI for lower and upper bound was also obtained. The mean
flow rate of basilar artery (BA) and internal carotid arteries (ICA) was calculated after excluding
volunteers with absent first segment of anterior cerebral artery (ACA0, existing fetal posterior
cerebral artery (PCA), or posterior communicating artery (PCOM ⱖ 30ml/min. Because
anatomic asymmetry in the ACAs and vertebral arteries (VA) is common, we calculated total
ACAs (TACA) and total VAs (TVA). We also examined ranges for total cranial flow (TCF),
calculated from the sum of both common carotid arteries (CCA) and TVA, and for total cerebral
blood flow (TCBF), calculated from the sum of 2 ICAs and 2 VAs. RESULTS: See table1. Table
1. The Range of Blood Flow Rate for Major Cerebral Arteries in Different Age Groups
CONCLUSIONS: Non-invasive large vessel cerebral blood flow rates can be determined using
QMRA. This is a promising tool for assessing the hemodynamic effects of cerebrovascular
disease.
Table of Contents
䡠Arteries Arteries
BA
LICA
RICA
LMCA
RMCA
LPCA
RPCA
TACA
LCCA
RCCA
Mean ⫾ 1.96 SD ml/min (95% CI of Lower and Upper bound)
18 – 40
166⫾54(⫾11)
274⫾87(⫾18)
262⫾95(⫾20)
169⫾68(⫾11)
158⫾62(⫾10)
74⫾33(⫾6)
71⫾32(⫾5)
186⫾75(⫾13)
417⫾140(⫾23)
406⫾157(⫾27)
41– 60
150⫾61(⫾13)
250⫾89(⫾26)
241⫾101(⫾20)
157⫾52(⫾9)
144⫾52(⫾9)
69⫹25(⫾4)
64⫾26(⫾4)
171⫾65(⫾11)
378⫾124(⫾21)
382⫾137(⫾24)
ⱖ61
129⫾40(⫾12)
231⫾95(⫾26)
220⫾201(⫾28)
141⫾48(⫾12)
130⫾51(⫾12)
61⫾22(⫾5)
58⫾22(⫾5)
156⫾58(⫾15)
371⫾154(⫾37)
381⫾169(⫾40)
P69
Ophthalmic Artery High Flow As The Risk Indicator For The Intracranial
Hemorrhage In Moyamoya Disease.
Shoichiro Kawaguchi, Dept of Neurosurgery, Nara Prefectural Nara Hosp, Nara, Japan;
Toshisuke Sakaki, Dept of Neurosurgery, Nara Med Univ, Kashihara, Japan; Masami
Imanishi, Dept of Emergency and Critical Care, Nara Prefectural Nara Hosp, Nara, Japan;
Yasunori Sasaoka, Dept of Neurosurgery, Nara Prefectural Nara Hosp, Nara, Japan; Takeshi
Matsuyama, Dept of Emergency and Critical Care, Nara Prefectural Nara Hosp, Nara, Japan;
Toshikazu Takeshima, Dept of Neurosurgery, Nara Prefectural Nara Hosp, Nara, Japan;
Misato Nobayashi; Dept of Emergency and Critical care, Nara Prefectural Nara Hosp, Nara,
Japan
Introduction: In this paper, the authors analyzed the relationship between the clinical symptoms
and the findings of the ophthalmic artery (OA) flow in moyamoya disease. Hypothesis: The
authors hypothesized that the OA high flow is the risk indicator for the intracranial hemorrhage
in moyamoya disease. Methods: The 43 patients (mean age: 36 years) with moyamoya disease
were evaluated. Their clinical symptoms were following; an intracranial hemorrhage in 11
patients, an ischemic event in 28 patients and asymptomatic in 4 patients. OA flow was
examined using the OA color Doppler flow imaging (CDFI) revealing the peak systolic flow
velocity (Vs), time-averaged maximum flow velocity (TAMX) and pulsatility index (PI)of both side
OA. Results: 1) The average Vs was 0.47 m/sec, the average TAMX was 0.30 m/sec. These
values were significantly (p⬍0.05) high compared to the normal controls. The average PI was
1.14, which was significantly low compared to the controls. 2) The CDFI findings of the eleven
OAs same side to the intracranial hemorrhage showed the significantly (p⬍0.05) high Vs
(mean: 0.60 m/sec), high TAMX (mean: 0.39m/sec), and low PI (mean: 0.86) compared to the
CDFI findings of the other 75 OAs same side to the ischemic or asymptomatic side. 3) During
the follow-up period (mean period: 3.0 years), an intracranial hemorrhage was seen in 2
patients showing the high Vs, TAMX, and low PI. Conclusion: The OA high flow, such as high
Vs, high TAMX and low PI, was the significant risk indicator for intracranial hemorrhage in
moyamoya disease including the follow-up period.
P70
Small Cortical Lesions Visible on Acute DWI are not Visible on 90 day
FLAIR.
Karima Benameur, Jose Merino, NINDS-NIH, Bethesda, MD; Chelsea S Kidwell, Georgetown
Univ, Washington, DC; Steven Warach, Lawrence Latour; NINDS-NIH, Bethesda, MD
BACKGROUND: Improved diffusion weighted imaging with increased signal-to-noise and
resolution results in improve acute lesion conspicuity and an unexpected prevalence of cortical
lesions. Lesion seen on high resolution DWI that are not seen on conventional DWI are typically
punctuate. The purpose of this study is to determine the fate of such small acute lesion on 90
day follow up FLAIR and T1 imaging. . METHODS: This was a retrospective study of acute stroke
patients seen by the NIH stroke team at Suburban hospital between September 2004 and
March 2007. Inclusion criteria were; a discharge diagnosis of ischemic stroke, an imaging
study within 24 hours of symptom onset including high resolution diffusion weighted imaging
(DWI) and FLAIR, a 90 day follow up study including FLAIR and T1 sequences. Ischemic lesions
were defined as hyper-intense lesions on DWI, and were verified for their acuity by comparing
acute and 90 day FLAIR. Lesions present on both sequences were excluded from the study.
Lesion location and volume were recorded on acute DWI. Acute DWI images were co-registered
to their corresponding 90 day FLAIR and T1 respectively, lesions were then compared between
DWI, 90 day FLAIR, and 90 day T1. . RESULTS: A total of 30 patients were included in the study
with a total lesion number of 88 lesions. Categorization of lesions per location on DWI identified
67 (76%) as cortical, 15 (16%) as sub-cortical, 3 (3%) as cortico-subcortical, and 2 (2%) as
cerebellar. Follow up of acute DWI lesions on 90 day FLAIR identified 53 (61%) lesions as
visible, 34 (39%) as non visible, and 1 (1%) as non readable. A break down per lesion location
on 90 day FLAIR identified 32 (45 %) of cortical lesions as non visible as opposed to 4 (25 %)
of sub-cortical. Follow up of acute DWI lesions on 90 day T1 identified 38 (43 %) of overall
lesions as non visible, 35 (40 %) of lesions as hypo-intense, and 15 (17 %) of lesions as
hyper-intense. As many as 83% of non visible lesions on 90 day T1 were cortical on acute DWI,
as opposed to 11% of sub-cortical lesions. A break down per lesion location on 90 day T1
identified 32 (48%) of cortical lesions as non-visible, as opposed to 4 (25%) of sub-cortical
lesions. . CONCLUSIONS: Almost half the lesions were not visible on 90 day FLAIR. A
preponderance for cortical lesions to disappear was observed, with a few cases clear cortical
gray matter atrophy on T1 imaging. Small cortical ischemic lesions evident acutely, but not
apparent on chronic FLAIR imaging may contribute to diffuse cortical atrophy.
P71
Intracranial Aneurysm Formation As An Indirect Consequence Of Traumatic
Brain Injury.
Jefferson T Miley, Adnan I Qureshi; Zeenat Qureshi Stroke Rsch Cntr Univ of Minnesota,
Minneapolis, MN
Background: Projectile injury and skull and vertebral fractures result in direct aneurismal
injuries to the carotid and vertebral arteries. Recently, it has been observed that vessels can
suffer changes due to indirect effect trauma. We report the occurrence of intracranial
aneurysms in patients with traumatic brain injury without direct vessel injury. Methods We
reviewed all the cerebral angiograms performed in patients with traumatic brain injury at a level
I trauma center from January 2006 to July 2007. Vessel injuries are classified as grade I and
grade II lesions show less than 25% and greater than 25% luminal narrowing, respectively;
grade III pseudoaneurysms; grade IV thrombosis; grade V transections with extravasation.
Results A total of 73 cerebral angiograms where performed for the indication of possible
vascular injury. In 26 patients a vascular injury was identified as tabulated below. In 22
patients, direct vascular injuries where confirmed by cerebral angiogram. Indirect vascular
injury was found in four patients (4 with carotid grade III). These injuries or aneurysms where
found in the intracranial segment of the internal carotid (2 supraclinoid, one cavernous and one
paraophthalmic) without evidence of a fracture at the exact level of the injury. Two patients
where treated with coil embolization, one required further embolization 2 days later due to
incomplete endovascular treatment. Another patient had a cerebral angiogram following coil
embolization for a vertebral artery occlusion and no change in the morphology of the ICA
aneurysm was found. The last patient died as a consequence of severe head trauma.
Conclusion: We report the occurrence of intracranial aneurysm as indirect consequence of
traumatic brain injury. A low threshold should be maintained to detect these aneurysms in
patients with traumatic brain injury.
Carotid
Vertebral
Grade I
Grade II
Grade III
Grade IV
Grade IV
Fistula
3
5
1
0
5
0
2
7
1
0
2
0
P72
Is Routine CT Scanning Indicated After Neuroendovascular Embolization?
Mateo Calderon-Arnulphi, Ali Alaraj, Sepideh Amin-Hanjani, Adam Wallace, Goro Osawa,
Soma Sinha Roy, Rajeev Deveshwar, Qasim Bashir, Pawan Singh, Fady T Charbel, Victor
Aletich; Univ of Illinoins, Chicago, IL
INTRODUCTION Endovascular neurosurgical embolization procedures carry a potential risk for
intracranial injury. A post-procedural brain CT scan is indicated when patients have
complications during the intervention, or new neurological findings emerge after the procedure.
587
However, the value of routine brain CT scan in patients without peri-procedural complications
and no immediate new neurological findings after the intervention is not clear. We sought to
assess the need for routine brain CT scan after endovascular neurosurgical procedures in these
patients. METHOD Consecutive neuroendovascular embolization procedures performed in the
department of Neurosurgery, University of Illinois at Chicago during the period of January 2000
to June 2007 were retrospectively reviewed. Diagnosis, neurological status, and CT finding
were noted before and after the procedures. Inclusion criteria: Patients included in the review
had normal neurological exams and brain CT scans negative for acute injury. The endovascular
procedure was uncomplicated and post procedure neurologic exam was unchanged from
baseline. Exclusion criteria: Patients presenting with pre-existing neurological deficit, positive
brain CT prior to the intervention, complications during the procedure, or new neurological
findings after the procedure. Results A total of 1157 neuroendovascular embolization
procedures performed on 880 patients (655 aneurysms, 191 arterio-venous malformations and
34 meningiomas) were reviewed. 580 procedures met the exclusion criteria of the study. For
the 577 procedures that met inclusion criteria, 337 had post procedural CT scans. The
corresponding brain CT scans post intervention in this subgroup revealed no instances of
hemorrhage or new ischemic injury. Conclusions In selected patients with no signs of bleeding
in preoperative brain CT scan, no complications during the embolization procedure and no new
neurological findings after embolization, there appears to be no value for routine brain CT scan.
P73
Ultrasound Velocity Criteria For Vertebral Origin Stenosis.
Sebastian Koch, Amir Murtaza, Hannah Park, Jose G Romano, Alejandro Forteza; Univ
Miami, Miami, FL
Background: The vertebral artery origin (VAo) is commonly affected by atherosclerosis and
may be a cause of cerebral embolism. Although this segment is easily insonated by ultrasound,
diagnostic criteria for vertebral origin stenosis are not well established. We undertook the
present study to compare different ultrasound criteria for diagnosis of vertebral artery stenosis.
Methods: We retrospectively reviewed catheter cerebral angiograms and extracranial Duplex
ultrasounds in patients undergoing both procedures at a community based teaching hospital.
Data collected included the degree of angiographic vertebral artery origin stenosis, peak
systolic velocities (PSV) and end diastolic (EDV) flow velocities at the VAo, the proximal vertebral
pre-foraminal (V1) segment and intra-foraminal (V2) segment. Angiographic stenosis of ⬎ 50%
was confirmed with electronic calipers, utilizing the diameter ratio between VAo and V1. A
receiver operator characteristic curve (ROC) was computed for the following diagnostic criteria
for VAo stenosis: PSV Vo, PSV ratio VAo/V1 and PSV ratio of VAo/V2. Results: A total of 218
patients met inclusion criteria allowing analysis of 386 vertebral arteries. Angiographic
vertebral artery stenosis ⬎ 50% was found in 36 (9 %) vessels of which 31 were insonated
by ultrasound. The mean vessel stenosis was 71 ⫾ 15 %. Mean VAo PSV was 175 ⫾ 109
cm/sec in patients with VAo stenosis vs. 64 ⫾ 28 cm/sec in patients with ⬍50% stenosis (p⬍
0.0001). The ROC area under the curve for PSV VAo was 0.82 (CI: 0.72, 0.92), 0.77 (CI: 0.66,
0.87) for PSV VAo/V2 and 0.73 (CI 0.62, 0.84) for PSV VAo/V1. A threshold PSV of 78 cm/sec
resulted in a sensitivity of 80% and specificity of 72% for diagnosing ⬎ 50% VAo stenosis.
Conclusion: PSV has the highest diagnostic accuracy among the criteria tested and is useful
in identifying vertebral artery origin stenosis. Threshold velocity values for the diagnosis of VAo
stenosis will need to be tailored towards the individual needs of ultrasound laboratories and
respective patient population.
P74
MR-Based Algorithms Combining DWI-PWI More Accurately Predicts Tissue
Outcome Than DWI or PWI Individually in a Large Patient Cohort.
Ona Wu, Hakan Ay, E. M Arsava, Thomas Benner, Christopher Melinosky, Vicky J Tiglias,
Athinoula A Martinos Cntr for BioMed Imaging, MGH, Charlestown, MA; Christian A Holt,
Dept of Neurology, Massachusetts General Hosp, Boston, MA; Kiran Garimella, Meiyun
Wang, Mingwang Zhu, Athinoula A Martinos Cntr for BioMed Imaging, MGH, Charlestown,
MA; William A Copen, Pamela W Schaefer, R. G Gonzalez, Dept of Radiology,
Massachusetts General Hosp, Boston, MA; Walter J Koroshetz, Aneesh B Singhal, Dept of
Neurology, Massachusetts General Hosp, Boston, MA; A. G Sorensen; Athinoula A Martinos
Cntr for BioMed Imaging, MGH, Charlestown, MA
Background: Previous studies have shown that MRI-based algorithms combining acute
DWI-PWI can accurately predict tissue outcome in acute stroke patients. However, these
studies have been performed in relatively small patient data sets (⬍ 20 patients). This study
investigates the applicability of these models to a large cohort. Methods: DWI-PWI from
patients admitted between 1994 –2007 who were not given thrombolytic or catheter-based
therapy or enrolled in clinical trials and who received acute MRI⬍12 h from stroke onset and
follow-up imaging (F/u) ⬎⫽5 d were analyzed (n⫽120). Combinations of apparent diffusion
coefficient (ADC), T2 (T2WI) and DWI (DWI), CBF, CBV, MTT and Tmax (time of peak of
deconvolved residue function) were used as covariates in a generalized linear model (GLM)
where the output is infarction risk on a voxel-wise basis. Coefficients were calculated using
bootstrapping and jackknifing. Receiver operating characteristic curves were generated. Area
under these curves (AUC) were calculated and compared (repeated measures ANOVA followed
by Student Newman Keuls (SNK) test). Subset analysis among SSS-TOAST subtypes was
performed (ANOVA followed by SNK test). The predicted lesion volumes (PLV) using a threshold
588
Stroke
Vol 39, No 2
February 2008
of 50% for classifying infarcted tissue were correlated with the measured lesion volumes (MLV)
on F/u and acute NIH stroke scale scores (NIHSSS). Results: Median NIHSSS was 6,
interquartile range (IQR) 3–11. Onset time to MRI was 6.0⫾2.9 h. Age was 65⫾16 y, and 67%
male. Distribution of SSS-TOAST subtypes were cardio-aortic embolism (CE: 41%), large artery
atherosclerosis (LAA: 26%), small artery occlusion (SAO: 5%), other (12%) and unknown (17%).
F/u lesion volume (MLV) had a median of 14 cm3, IQR⫽3– 49 cm3. AUC of the model combining
all 7 imaging parameters (ALL model) (0.85⫾0.13) was significantly higher (P⬍0.01) than
models using individually T2 (0.47⫾0.12), ADC (0.74⫾0.13), DWI (0.80⫾0.15), CBF
(0.69⫾0.14), CBV (0.59⫾0.13), MTT (0.67⫾0.15), or Tmax (0.70⫾0.15), a combination of
T2⫹ADC⫹DWI (0.80⫾0.15), and a combination of CBF⫹CBV⫹MTT⫹Tmax (0.75⫾0.15). The
ALL model PLV was significantly correlated with the MLV (R⫽0.79, P⬍0.001) and acute
NIHSSS (R⫽0.61, P⬍.001). Subset analysis showed that the AUC for SAO (0.67⫾0.29) was
significantly smaller (P⬍0.04) than for CE (0.87⫾0.11), LAA (0.84⫾0.11), Other (0.80⫾0.15)
or Unknown (0.89⫾0.10). No correlation between MLV and AUC was found. Conclusion:
Predictive algorithms combining multiparametric MRI maps on a voxel-wise basis can more
accurately predict tissue outcome than only DWI or PWI parametric maps. The high accuracy
of these models in a large patient cohort suggest that these algorithms can be used to predict
natural infarct risk in different stroke subtypes and therefore assist in the development of
treatment strategies on an individual patient basis.
P75
Hemorrhage Detection, Both Acute and Chronic, is Comparable on 1.5 vs
3.0 Tesla Magnet Strength.
Amie W Hsia, Lynn Huang, Washington Hosp Cntr, Washington, DC; Brittany R Copenhaver,
Georgetown Univ, Washington, DC; Timothy J Schaewe, UCLA, Los Angeles, CA; Chelsea S
Kidwell, Georgetown Univ, Washington, DC; for the NIH Natural History of Stroke
Investigators
Background: MRI gradient echo (GRE) imaging has been shown to accurately detect both acute
and chronic hemorrhage, including cerebral microbleeds. However, the detection rate of
hemorrhage by field strength has not been systematically studied. We sought to determine if
the two most commonly available field strengths (1.5T and 3.0T) are comparable in the
detection of both acute and chronic hemorrhage. Methods: We performed a retrospective
analysis of consecutive patients admitted to a single stroke center for evaluation of acute
ischemic stroke or intracerebral hemorrhage from October 2004 to April 2007. GRE sequences
were designed to have equivalent susceptibility weighting. Only patients who underwent MRI
with GRE on both a 1.5T and 3.0T scanner were eligible. Images were resliced to 4 –7 mm to
minimize slice thickness as a confounding factor. The number and location of acute and chronic
hemorrhages were determined by two experienced independent readers, a neuroradiologist
and a stroke neurologist, blinded to clinical and MRI field strength information. Results:
Thirty-one patients met inclusion criteria. Mean age was 60 years. Primary diagnosis was
ischemic stroke in 27 (87%) patients, and ICH in 2 (6%) patients. Median interval between
scans was 3 days with the 1.5T MRI performed first in 81% of cases. The number of
microbleeds ranged from 0 to 30 with 35% of cases having 1 or more microbleeds on 1.5T
versus 32% on 3.0T (p⫽1.0). Inter-observer reliability was high (Cohen’s kappa ⫽ 0.86). There
was no significant difference between the number of microbleeds detected on 1.5T compared
to 3.0T MRI (pⱕ0.9 and pⱕ0.8, respectively for the 2 readers). In 10 cases the number of
microbleeds was discrepant (range of discrepancies 1– 4) between the scanners. In half, more
microbleeds were seen on 3.0T and in the other half more on 1.5T. Acute hemorrhages were
detected equally for patients undergoing both scans within 7 days of onset. There was no
significant difference in detection rate of chronic hematomas (p⫽1.0 for the both readers).
Conclusions: This study demonstrates that, using standard GRE sequences, there is no
difference in the detection rate of hemorrhage, including microbleeds, on MRI at 1.5T vs 3.0T
magnet strength. This finding has important implications for both clinical diagnostic assessment and for multi-center studies. Our findings support the validity of combining data from
different scanner strengths in studies that involve cross-sectional or longitudinal microbleed
quantification.
P76
Endothelial Progenitor Cells and Leukoaraiosis.
Glen Jickling, Muhammad S Hussain, Richard Camicioli, James Scozzafava, Ashfaq Shuaib;
Univ of Alberta, Edmonton, Canada
Introduction Endothelial progenitor cells (EPC) are proposed to be markers of endothelial
function and cardiovascular risk. When vascular endothelium is damage, EPCs are mobilized by
cytokines and vascular endothelial growth factor. Patients with atherosclerotic vascular
disease, including cerebrovascular disease, have significantly lower numbers of EPC. White
Matter Changes (WMC) can be seen on CT scan and correlates pathologically with vascular
disease. Here we show that the number of EPC correlate with severity of WMC on CT scan.
Methods Twenty-five patients experiencing a transient ischemic attack or ischemic stroke were
recruited for analysis. EPC were measured using immunolabelling according to the methods
previously described. Severity of WMC was assessed on CT using the Age-Related White Matter
Changes rating scale previously described. Briefly, two raters independently scored 25 CT
scans obtained at the time of cerebrovascular event for severity of infratentorial and
supratentorial WMC. Interrater reliability was evaluated by using k statistics. Results EPC were
found to decrease significantly with increasing severity of WMC (R2 ⬎0.97, P⬍0.05).
Compared to patients without WMC (mean 12.0, SD 4.8), the number of EPC were 83.3% in
those with mild WMC (mean 10.0, SD 7.8), 52.5% in moderate WMC (mean 6.3, SD 3.1), and
17.5% in severe WMC (mean 2.1, SD 0.9). Discussion Compared to patients without evidence
of WMC on CT scan, EPC levels were significantly lower with increasing severity of WMC. These
preliminary results support the association of EPC with cerebrovascular disease, and the use
of EPCs as a surrogate marker for vascular dysfunction in cerebrovascular disease.
P77
Parenchymal Enhancement on T1-weighted MRI Predicts Subsequent
Hemorrhagic Transformation in Acute Ischemic Stroke.
Kyung-Yul Lee, Lawrence L Latour, Jose G Merino, Steven Warach, NINDS, Bethesda, MD;
for the NIH Natural History of Stroke Investigators
Background and purpose: Parenchymal enhancement (PE) on T1-weighted MRI may be
evidence of blood-brain barrier breakdown and it reflects risk of hemorrhagic transformation.
In addition to conventional T1-weighted image, T1-weighted MRA source image can also detect
PE. We assessed the incidence of early PE on T1-weighted images and Hyperintense Acute
reperfusion injuRy Marker (HARM) on fluid attenuated inversion recovery (FLAIR) images and
their association with subsequent hemorrhagic transformation (HT) in acute ischemic stroke.
Methods: Consecutive patients with ischemic stroke with MRI examination performed within
24 hours after onset were enrolled. Immediate PE was evaluated on T1-weighted post
gadolinium images acquired within several minutes after gadolinium injection. The first follow
up T1-weighted MRA source images and FLAIR images performed within one day after initial
gadolinium injection were used to look for PE and HARM, and gradient echo image or CT which
performed at anytime within 10 days after stroke to look for hemorrhagic transformation.
Results: Immediate PE on T1-weighted post gadolinium images was found in 11 out of 59
patients (18.6%). HT was present in 5 out of 11 patients with immediate PE and 7 out of 47
without it (OR, 4.76; 95% CI, 1.13–19.96; p⫽0.039). PE on follow up was found in 36 out of
80 (45%). HT was present in 19 of the 36 patients with PE on follow up, but only 6 out of 44
without it (OR, 7.08; 95% CI, 2.4 –20.87; p⬍0.001). PE on follow up was seen before HT in 12
patients, and simultaneously or later in 5 and 2. PE on follow up was significantly correlated
with higher initial NIHSS score, non-lacunar infarction and shorter time from gadolinium use to
follow up MRI. HARM was found in 61 out of 82 patients and most of patients with PE on follow
up also showed HARM. HT occurred in 21 out of 60 patients with HARM and 3 out of 21 without
HARM (OR, 3.23; 95% CI, 0.85–12.25; p⫽0.098). Using a composite variable of PE on follow
up or severe grade HARM, the association with HT was stronger (OR, 10.35; 95% CI,
2.76 –38.75; p⬍0.001). Conclusions: We found PE more frequently in the first follow up
T1-weighted MRA source images than in the immediate T1-weighted post gadolinium images.
PE on follow up is better than any other single factor in predicting HT and addition of severe
grade HARM to PE can increase its power to predict HT. In conclusion, early PE on MRA source
image can be used as surrogate imaging marker to predict subsequent HT in acute ischemic
stroke.
P78
Neural Network Model for Prediction of Final Infarct Volume in Treated
versus Untreated Stroke Patients.
Marie Luby, Jennifer L Jothen, José G Merino, Julie L Bykowski, National Institutes of
Health, Bethesda, MD; Peter D Schellinger, Neurologische Klinik, Erlangen, Germany; Steven
Warach, National Institutes of Health, Bethesda, MD; for the NIH Natural History of Stroke
Investigators
Background and Purpose: The purpose of this study was to predict final infarct volume in
patients treated with IV tPA therapy with a neural network model that combines both clinical
and imaging variables and to demonstrate the model’s specificity by applying it to untreated
patients. Methods: The model was designed using the generalized regression neural network
(GRNN) in Matlab™ (v6.5). The model was trained using the baseline predictors of sex, age,
National Institutes of Health Stroke Scale (NIHSS), stroke onset time to MRI scan time and
corresponding values for follow-up modified Rankin Score (mRS), follow-up NIHSS, baseline
lesion volume on diffusion weighted MRI, baseline hypoperfusion volume (on MTT map),
follow-up reperfusion (reduction of MTT volume by at least 30%), and final infarct volume on
FLAIR MRI. The model was trained with data from patients (N⫽99) that presented with stroke
symptoms within 3 hours of onset and underwent acute MRI scans prior to treatment with IV
rt-PA therapy. The model was tested with baseline predictors from 13 different patients in order
to predict final infarct volume. In order to assess the model’s specificity for predicting outcome
in tPA-treated patients, the model was used to predict final infarct volume in 30 untreated
stroke patients from the same hospital. Results: The medians and Wilcoxon signed-ranks test
were calculated to compare the predicted versus actual values (SPSS for Windows v14.0). The
final infarct volume predicted by the treated model (median⫽26.68 cc) did not significantly
differ from the actual measured volume for the tPA-treated patients (median⫽21.16 cc,
Z⫽-.734, p⫽.463). In the sample of untreated patients, the final infarct volume predicted by
the tPA-treated model (median⫽2.07 cc) was different from the actual measured volume
(median⫽14.23 cc, Z⫽-3.075, p⫽.002), indicating that the model was specific for tPAtreatment. Conclusions: The neural network prediction model demonstrated promising results
for prediction of final infarct volume in tPA-treated patients and in distinguishing tPA-treated
from untreated patients.
589
In-hospital mortality and the proportion of patients discharged home remained stable over time
(both p⬎.30). Conclusions: In this nine-year cohort, current physicians are treating strokes of
greater severity, with fewer deviations from accepted treatment protocols, compared to earlier
time periods. Onset-to-ED arrival and arrival-to-treatment times have not improved over time,
suggesting additional work is needed in identifying treatment barriers and potential solutions.
Additional attention to meeting post-treatment (inpatient) treatment guidelines appears
warranted as well.
P79
Lower Presenting Systolic Blood Pressure Is Associated With
Cardioembolic Subtype In Ischemic Stroke.
William J Meurer, Lynda Lisabeth, Brisa N Sánchez, Melinda Smith, Jennifer J Majersik,
Devin Brown, Univ Of Michigan, Ann Arbor, MI; Ken Uchino, Univ of Pittsburgh, Pittsburgh,
PA; Lewis B Morgenstern; Univ Of Michigan, Ann Arbor, MI
Introduction: Readily identifying ischemic stroke subtype is crucial for providing directed
secondary stroke prophylaxis. We used data from a population-based stroke surveillance study
to test the association between presenting systolic blood pressure (SBP) and the ischemic
stroke subtype based on TOAST criteria. We hypothesized that clinicians could use low
presenting SBP to predict cardioembolic (CE) stroke. Methods: Active and passive surveillance
were used to identify all ischemic strokes in patients ⬎44 years in Nueces County, Texas as
part of the Brain Attack Surveillance In Corpus Christi (BASIC) study. Ischemic strokes identified
between January 2000-December 2002 were validated by board-certified neurologists using
source documentation. Cases were classified into subtype categories according to a published,
modified version of the TOAST criteria: large-artery atherosclerosis, CE, lacunar non-lacunar
stroke of unknown etiology, stroke of other determined etiology and stroke of undetermined
etiology. Multinomial logistic regression was used to examine the association between stroke
subtype and first documented SBP in the medical record. Gender, ethnicity, NIHSS, age, and
history of hypertension and coronary artery disease (CAD) were examined as potential
confounders or additional predictors of stroke subtype. Results There were 402 cases
identified with completed ischemic stroke. Subtype could not be determined in 22% and 1.5%
had a stroke of other determined etiology, leaving 308 cases for analysis. Presenting SBP was
associated with stroke subtype (P⫽0.007) in an unadjusted model. The association was also
significant (p⫽0.01) in the final model adjusted for age and history of CAD (see table). A 10
year increase in age increased the odds of CE subtype by 56% (OR⫽ 1.56, 95% CI: 1.13–2.16).
Conclusions SBP at ischemic stroke presentation is associated with stroke subtype. Lower
initial SBP is associated with the CE subtype. Suspicion of CE stroke should be increased in
those presenting with lower SBP.
RESULTS OF MULTINOMIAL LOGISTIC MODEL OF INITIAL SBP AND SUBTYPE ADJUSTED
FOR AGE AND CAD HISTORY. OR IS FOR 10 MM HG DECREASE IN SBP.
Subtype
OR
CE
Non Lacunar
Large Artery
Small Vessel
1.20
1.12
1.04
1.00
P81
CT Angiography And CT Perfusion Before IV tPA For Acute Ischemic Stroke
Within The Window: Are We Delaying tPA Therapy Unnecessarily?
Anitha Abraham, Sheryl Martin-Schild, Andrew D Barreto, Hen Hallevi, Miriam Morales,
James Grotta, Sean Savitz; Univ of Texas, Houston, TX
CTA and CTP before IV t-PA for AIS within the window: Are we delaying t-PA therapy
unnecessarily? Background: A noncontrast head CT is the only required neuroimaging test prior
to t-PA therapy within the 3 hour window for acute ischemic stroke. Many stroke centers are
using rapid CT angiography (CTA) and CT perfusion (CTP). At our institution, these studies are
used routinely to evaluate extra- and intracranial large arteries and to provide an approximation
of the penumbra in patients presenting beyond 3 hours or with an unknown onset time. In some
patients presenting within 3 hours, these studies are performed prior to t-PA administration. We
sought to determine if pre-lytic advanced neuroimaging with CTP and/or CTA delays
administration of IV t-PA for patients presenting within three hours of stroke onset. Methods:
From our prospective stroke registry over the past 3.5 years, we identified 277 patients treated
in our emergency department with IV tPA within 3 hours of onset. Of these patients, 13 had CTA
alone and 12 had both CTA and CTP prior to IV t-PA. We compared onset to needle time and
door to needle time among these three groups. Results: The door-to-needle times and
onset-to-needle times were not significantly different in patients that had CTA or both CTA and
CTP prior to t-PA. There was no difference in baseline NIHSS among patients that had these
studies compared with those that only had a noncontrast CT (p⫽0.19). There were no
significant differences in discharge disposition (p⫽0.67) or mRS scores (p⫽0.74). Discussion:
Rapid CTA and CTP provide potentially useful information regarding tissue salvagability. In our
population, IV t-PA treatment was not delayed in patients that had CTA and CTP studies. This
result may be explained in part by a protocol we implemented to obtain rapid serum creatinine
within 10 minutes of patient arrival to the ED. Further investigations are necessary to determine
whether the results of CTA and CTP have meaningful impact on treatment decisions for patients
presenting with ischemic stroke in the 3 hour time window.
Noncontrast
CT only N⫽252
CTA
alone
N⫽13
CTA
and
CTP
N⫽12
p-value
129⫾ 34
65⫾23‡†
134⫾ 30
71⫾23‡
131⫾ 39
77⫾14†
0.78, ANOVA
0.136,ANOVA
95%CI
1.07
1.01
0.92
Referent
1.35
1.25
1.18
Onset to needle time, min, mean ⫾ SD
Door to needle time, min, mean ⫾ SD
‡p⫽0.235 †p⫽0.911
P82
Partial Recanalization after Intraarterial Thrombolysis: Angiographic
Consequences and Clinical Outcome.
Acute Management
P80
Gyeong- Moon Kim, Oh Young Bang, Chin-Sang Chung, Kwang Ho Lee; Samsung Med Cntr,
Sungkyunkwan Univ Sch of Medicine, Seoul, Republic of Korea
Objectives: Tissue-type Plasminogen Activator (tPA) was first introduced over a decade ago.
The goal of the present analysis was to examine whether there have been improvements in the
frequency of protocol deviations, speed of treatment, hemorrhage rates, or outcomes over time.
Methods: Time series analysis of 273 stroke patients treated with tPA from 1/1/1996 to
1/1/2005 (55% male, mean age ⫽ 68) from four hospitals in southeastern MI. Treatment years
were stratified into three groups (pre-specified): early (1996 –1998, n⫽62); middle (1999 –
2001, n⫽120) and recent (2002–2004, n⫽91). Descriptive statistics, chi square test and
two-sample t-tests were use to examine differences in the variables of interest over time.
Results: Patient age, gender proportion, premorbid disability (mRS), and onset-to-ED arrival
time remained consistent over time (all p⬎.05). The stroke severity (NIHSS) of tPA-treated
patients increased from a median of 11 in the early group to 14 in the recent group (p⬍.01).
The number of patients with one or more tPA protocol deviations declined significantly (p⬍.01)
over time - from 58% in the early group to 33% in the recent group. The improvement was due
primarily to reductions in protocol deviations prior to treatment (p⬍.01) as compared to those
occurring after treatment (p⫽.38). The mean time from ED arrival to tPA bolus was 100, 93 and
93 minutes in the early, middle and recent groups, respectively. This change was not
significant (p⬎.09). The rate of symptomatic intracranial hemorrhage (sICH) did not improve
over time (11%, 8% and 9% for early, middle and recent groups respectively; p⫽.66).
Background and Purpose: Recanalization is strongly associated with improved functional outcomes
and reduced mortality in acute ischemic stroke. For further understanding of the angiographic and
clinical consequences of acute ischemic stroke after intraarterial (IA) thrombolysis, we investigated
the follow-up MR angiography and functional outcomes with respect to the degree of immediate
recanalization status. Methods: We studied 32 consecutive patients with angiographically proven
middle cerebral artery (MCA) or internal carotid artery (ICA) occlusion. IA thrombolytic therapy was
administered within 3 to 6 hours of onset of symptoms using mechanical thrombolysis alone or in
combination with minimal dosage of recombinant tissue plasminogen activator (20mg⬎) or
urokinase (300,000 U⬎) given intra-arterially. Angiographic reperfusion was classified according to
thrombolysis in myocardial infarction (TIMI) grades. Serial MR angiography (MRA) and perfusionweighted imaging (PWI) at 1, 7, and 90 days, the NIH Stroke Scale (NIHSS) score, 3-month modified
Rankin Scale (mRS) were evaluated and compared among complete recanalization (CR, TIMI flow
3), partial recanalization (PR, TIMI flow 1–2), and no recanalization (NR, TIMI flow 0) groups. Results:
Mean scores of baseline NIHSS were not different among 3 groups. Any recanalization after IA
thrombolysis was observed in 78% of patients (CR: 41%; PR: 37%). Restenosis or occlusion of
corresponding vessel on 7-day MRA was found in 2 of 13 patients (15%) with CR and 2 of 12
patients with PR (17%) compared with the initial TIMI grades after IA therapy. Further improvement
of TIMI grade was observed in 25% of PR group on 90-day MRA. Baseline improvement of 1 and
7 day NIHSS scores were not statistically different between CR and PR group. NR was associated
with poor functional outcome (mRS 0 –2: 13%, P⫽0.03), but no statistical difference was found
between CR and PR group (mRS 0 –2: 66% vs 64%). CR group showed early significant
improvement of PWI deficits measured by the PWI lesion volume after immediate IA thrombolysis
Use of Tissue-type Plasminogen Activator: Have We Improved?
Angela F Caveney, William J Meurer, Zhenzhen Xu, Shirley Frederiksen, Ann B Holden,
Robert Silbergleit, Phillip A Scott; Univ of Michigan, Ann Arbor, MI
590
Stroke
Vol 39, No 2
February 2008
(p⫽0.027), whereas PR group showed less but persistent improvement of perfusion deficits
compared to NR group through 1 week after symptom onset (CR vs NR, p⫽0.002; PR vs NR,
p⫽0.003). Conclusions: These data suggest that partial recanalization may not be associated with
poor angiographic and clinical outcomes after IA thrombolysis. The relatively fair clinical outcome
may be associated with delayed but persistent improvement of perfusion deficits during acute
period.
P83
Safety of Thrombolytics in Patients with Malignancy and Acute Ischemic
Stroke.
Shihab Masrur, MD, Abdul R Abdullah, Eric E Smith, Renzo Hidalgo, Ahmed El-Ghandour,
Guy Rordorf, Lee H Schwamm; Massachusetts General Hosp, Boston, MA
Background: Little is known about the risk of thrombolytic therapy in patients with malignancy, as
these patients have been excluded from most clinical trials. We reviewed our single center
experience of thrombolytic therapy for safety in patients with acute ischemic stroke (AIS) and
malignancy. Methods: Consecutive AIS patients admitted from 1/03 to 12/06 (n⫽2148) were
retrospectively analyzed to identify those treated with thrombolysis. Patient data were abstracted per
the Get With The Guidelines Stroke definitions, or from medical records, by a trained abstractor.
Malignancy was identified based on past history or work-up during the index AIS admission. Logistic
regression with backward elimination was used to identify independent predictors of in-hospital
mortality controlling for age, NIHSS and malignancy. Results: 308 cases of AIS with thrombolytic
therapy were identified: 210 (68%) received IV tPA only, 41 (13%) IV tPA ⫹ intra-arterial therapy
(IAT), and 57 (18%) IAT only. There were 44/308 (14%) with malignancy (breast, 21%; lung, 18%;
colon, 16%; hematologic, 9%; prostate, 9%; skin, 9%; others, 18%); active malignancy was present
in 15/44. In-hospital mortality occurred in 16/44 with malignancy (table 1) including 7/15 with active
malignancy. Worsening medical condition contributed to 5/7 deaths among those with active
malignancy and 1/9 deaths among those with inactive malignancy (p⫽0.03). Active malignancy, but
not inactive malignancy, was independently associated with in-hospital mortality when controlling
for other predictors (table 2). Symptomatic intracranial hemorrhage (ICH) did not account for the
excess mortality in active malignancy (2/15 vs. 17/293, p⫽0.24). Discussion: Active malignancy,
but not history of malignancy, is associated with increased in-hospital mortality following
thrombolysis for AIS. Nevertheless we cannot exclude a beneficial effect of thrombolysis in this
group despite the high mortality. The mortality in active malignancy is mostly attributed to medical
comorbidities, and not ICH. These data suggest that IV and IA thrombolysis can be safely given to
patients with active or inactive malignancy that have acceptable medical comorbidities and
performance status.
Patient
Characteristic
Age (mean ⫹ SD)
Gender (% female)
NIHSS initial (mean)
CAD/MI (%)
Diabetes (%)
Hypertension (%)
Atrial Fibrillation (%)
Dyslipidemia (%)
Prior Stroke/TIA (%)
Smoking (%)
Warfarin Use (%)
PT ⬎ 15 (%)
Platelet count
IV t PA only (%)
Serious systemic hemorrhage (%)
Symptomatic ICH (%)
Any ICH on imaging (%)
Ambulatory at discharge (%)
Mortality (%)
Mortality
Age
NIHSS
HTN
Smoking
Active Malignancy
Inactive Malignancy
Malignancy
(Active or Inactive)
(N⫽44)
No malignancy
(N⫽264)
P value
75.1⫹10.4
52.2
15.8⫹7.4
36.4
14.3
70.5
29.6
18.1
18.2
36.4
9.1
15.9
241,300
72.7
2.3
11.4
29.5
47.7
36.4
69.6⫹14.9
50.8
14.6⫹6.8
23.5
18.9
65.5
26.5
15.9
14.4
31.8
5.3
14.5
253,000
67.4
2.3
5.3
28.8
62.1
19.7
0.02
0.85
0.49
0.07
0.2
0.52
0.67
0.71
0.51
0.55
0.32
0.80
0.001
0.48
1.0
0.12
1.0
0.07
0.01
Adjusted Odds Ratio
95%CI
P value
1.01
1.20
2.74
0.39
4.26
1.86
0.98–1.03
1.13–1.27
1.20–6.23
0.19–0.82
1.20–15.09
0.66–5.26
0.59
⬍0.001
0.02
0.01
0.03
0.24
P84
The Usefulness Of Algorithm Of Dysphagia For Management Of Acute
Stroke Patients.
Boo-Han Hyun, Kayoko Kawase, Shoichiro Satoh, Kuni Konaka, Hiroaki Naritomi; National
Cardiovascular Cntr, Suita, Osaka, Japan
Background: Dysphagia is an important manifestation of acute stroke which is often connected
with poor prognosis. We produced original algorithm of dysphagia for managing acute stroke
patients and studied its usefulness in a retrospective manner. Methods: The algorithm was as
follows. Stage1 is the initial step in which patients swallow 5 ml water 3 times. Patients
clearing Stage 1 move to Stage 2 and swallow 30 ml water. Patients clearing Stage 2 go to
Stage 3 and try Repetitive Saliva Swallowing Test. Patients who can not clear Stage 1 move
to Stage 4 and swallow a teaspoon of jelly. On the basis of such algorithm, the type of food
to be given is determined, such as normal, hard pasting, soft pasting, or tube feeding. The
algorithm was applied to all acute stroke patients within 3 days after admission. To clarify the
usefulness of algorithm, the time to start food intake and the prevalence of infection or
gastrointestinal symptoms were compared between two groups of patients admitted within 3
days after onset, such as Group A admitted between September 2002 and March 2003 without
using algorithm (n⫽94, 70⫾12 years) and Group B admitted between September 2005 and
March 2006 with using algorithm (n⫽121: 70⫾12 years). Patients going to Stage 4 and the
remainders were classified to high-risk and low-risk patients, respectively. The comparison
was made also between these two groups. Results: Baseline characteristics including risk
factor, stroke subtype, and NIHSS score on admission were the same in Groups A and B. The
mean time to start food intake or tube feeding were significantly shorter in Group B than in
Group A (1.6⫾2.2 vs 4.0⫾6.6 days, p⫽0.007). The prevalence of pneumonia was lower in
Group B than in Group A (19.2% vs 9.1%, p⫽0.03). The prevalence of gastrointestinal
symptoms was significantly lower in Group B than in Group A (24.5% vs 13.2%, p⫽0.03).
High-risk patients had higher prevalence of pneumonia or gastrointestinal symptoms than
low-risk patients (37.5% vs 4.3% and 25% vs 0%, respectively, p⫽0.045). Conclusions: The
use of algorithm shortens the time to start food intake safely and detects high-risk patients
consequently reducing complications. The algorithm is considered useful for management of
acute stroke.
P85
Acute Stroke CT Perfusion Imaging Profiles Predict Outcomes Of Early
Intravenous Thrombolytic Therapy.
Brian H Buck, David J Gladstone, Gabriella Mallia, Sandra E Black, Demetrios J Sahlas,
Julia Hopyan, Jacqueline Pettersen, Sean P Symons, Richard I Aviv; Regional Stroke Cntr,
Sunnybrook Health Sciences Cntr, Univ of Toronto, Toronto, Canada
Background: Multimodal MRI has been used to identify subgroups of stroke patients most likely
to benefit from IV-tPA therapy in the 3– 6 hour window. In the 0 –3 hour time window, imaging
markers that predict outcome following IV-tPA therapy are less well defined. On CT imaging,
the extent of early ischemic change at best has a modest relationship to prognosis. In this
study, we present preliminary results from an ongoing prospective cohort study to determine
if CT perfusion (CTP) imaging can improve the prediction of prognosis in IV-tPA treated patients
in the 0 –3 hour window. Methods: Consecutive anterior circulation ischemic stroke patients
treated with IV-tPA within 3 hours of onset and imaged with multimodal CT prior to therapy
were identified in a prospectively maintained database at a regional stroke centre in Toronto.
CTP studies consisted of 8 slices covering 20 mm, processed with CT Perfusion 3 software (GE
Healthcare) to generate CBF, CBV and MTT maps. Volumetric analysis was performed using a
semiautomatic threshold technique. Decreased CBV was used to define infarct core and
penumbra was defined by the region of increased MTT. Mismatch was calculated as:
100*(MTT-CBV)/CBV. Patients with no perfusion lesion or lesion volumes of less than 10 ml
were excluded. Patients were categorized into three groups based on the DEFUSE criteria:
target mismatch (⬎ 20% mismatch and lesion volumes less than 100 mL), matched (less than
20% mismatch) and malignant mismatch (mismatch and lesion volume ⬎ 100 mL). Primary
outcome was modified Rankin score (mRS) at 3 months. Results: Thirty-six patients met study
inclusion/exclusion criteria, mean age was 68.7 and median (IQR) NIHSS was 18 (13–21). The
numbers of patients with matched, target, and malignant lesions were respectively: 6 (16.7%),
15 (41.7%), and 15 (41.7%). 83.3% of patients with malignant mismatch had ASPECT scores
⬍8, compared to 50% in the target mismatch and 40% in the matched group. The proportion
of good outcomes (mRS ⬍2) at 90 days in the target (26.7%) and malignant mismatch groups
(35.7%) did not differ. There was, however, a significant difference in poor outcomes (mRS
4 – 6) between patients with mismatch compared to those matched lesions. All patients (6/6)
in the matched group had poor outcomes at 90 days, which was significantly greater than the
proportion of poor outcomes in the target (53.3%) and malignant groups (57.7%) (p⫽0.032).
Worse outcomes occurred despite the matched group having smaller baseline MTT volumes
than the mismatch group (64.1 mL vs 107.8 mL; p⫽0.007) and similar initial median NIHSS
scores (18 vs 19). Conclusions: This study showed that in the 0 –3 hour time window, perfusion
CT identifies a subgroup of patients without significant mismatch who do not appear to benefit
from IV-tPA therapy. These results, if validated in a larger sample, suggest that perfusion CT
may enhance patient selection for early thrombolytic therapy.
P86
Breaking Traditional Study Time Barriers: A Descriptive Review of
Demographic Variables and Unique Early Observations Seen in a
Prehospital Stroke Study.
Anna Yanes, Theresa Haley, Brenda Pierce, Miranda Gordon, Bogdan Filip, Mike Lee, Minja
Cho, Sidney Starkman, Jeffrey Saver, UCLA, Los Angeles, CA; on behalf of FAST MAG
investigators and staff
Background Many neuroprotective drugs have proven beneficial in the lab but later failed to
demonstrate similar effects in phase III trials with 4 –12 hour time windows. FAST MAG (Field
Administration of Stroke Therapy - Magnesium) is the first neuroprotective trial to treat subjects
in hyperacute time windows similar to the preclinical models. FAST-MAG is a multi-center,
double blind, placebo controlled, Phase III clinical trial designed to determine if fieldadministered intravenous magnesium sulfate, given within two hours of stroke symptom onset,
improves patients’ functional outcomes. Methods The study has now enrolled more than
one-fourth of the planned 1298 patients, permitting delineation of the features of a prehospital
trial population.. Results Among the first 382 enrollments, the average interval from last known
well time to start of study drug 44 minutes and 73% have had study drug initiated within the
first hour after onset. The mean age is 69 and 39% are female. The median NIHSS on ED arrival
is 8. Final diagnoses are ischemic stroke in 58%, TIA in 12%, intracerebral hemorrhage in 26%
and other in 4%. Unique study aspects will be discussed, such as early conversation by cell
phone with an enrolling stroke physician-investigator, multiple confirmations of symptom onset
time, and multi-tiered feedback to the paramedics. Conclusion Successes, pitfalls and pearls
of wisdom gained from early enrollments of such a novel study will be offered and may prove
beneficial for any researcher and coordinator wishing to incorporate a similar study design.
P87
Safety and Early Outcomes of Thrombolysis in Patients Who Wake-up with
Stroke.
Andrew D Barreto, Sheryl Martin-Schild, Hen Hallevi, Miriam M Morales, M. Rick Sline,
Nicole R Gonzales, Kachi Illoh, James C Grotta, Sean I Savitz; Univ of Texas-Houston,
Houston, TX
Background: Approximately 25% of ischemic stroke patients awaken with their deficits. The
last-seen-normal (LSN) time is defined as the time the patient went to sleep which usually
places these patients outside the window for thrombolysis. Purpose: The purpose of this study
was to describe our center’s experience with off-label, compassionate thrombolysis for
wake-up stroke (WUS) patients. We sought to determine the safety and rates of early outcomes
in WUS patients treated with a compassionate protocol consisting of intravenous (IV) and/or
intra-arterial thrombolysis (IAT). Methods: Our prospective stroke database was utilized to
identify three cohorts of ischemic stroke patients: a) WUS patients treated with compassionate
thrombolysis, b) WUS patients not treated with thrombolysis, and c) 0 –3 hour IV tPA treated
patients. Outcome measures were symptomatic intracerebral hemorrhage (sICH), favorable
outcome (discharge modified Rankin score, mRS 0 –2) and mortality. Statistical analysis was
performed using ␹2, Fisher’s Exact and t-Tests. Outcome measures were controlled for
baseline NIHSS, age, early ischemic changes on CT scan and admission glucose using
multivariate logistic regression. Results: Thirty-five WUS patients treated with thrombolysis
were identified. Sixty percent (21/35) of the treated WUS patients underwent IV thrombolysis
alone while 29% (10/35) were given only IAT. Four patients received both IV and IAT (11%).
Nine of the 35 had mismatch on penumbral imaging, however presence of mismatch was not
associated with better outcomes compared with non-contrast CT alone (P⫽0.47). Treated WUS
were compared to 175 standard-of-care (0 –3 hour) IV-tPA patients. There were no significant
differences in rates of sICH or favorable outcome after controlling for baseline NIHSS, age,
glucose, and presence of early ischemic changes (Figure). A second comparison controlling for
the same baseline variables between treated WUS and 26 non-thrombolysed WUS patients
revealed similar safety profile and functional outcomes. Conclusion: Thrombolysis may be safe
in wake-up stroke patients. Our center’s experience supports considering compassionate
thrombolysis for these patients, but a prospective, randomized trial is needed to validate these
results.
591
consecutive patients who underwent intra-arterial thrombolysis using tPA within 6 hours
following stroke symptom onset. TPA was delivered at 1mg per minute in all cases, and never
exceeded 100 mg tPA. The three methods included: 1) continuous infusion of tPA following
microcatheter placement within the offending thrombus; 2) microcatheter infusion within the
offending thrombus with “microwire clot maceration” and 3) microcatheter placement within
the offending thrombus with periodic gentle microcatheter contrast injections and microcatheter repositioning to insure that tPA surrounded the thrombus during delivery throughout the
treatment. The latter method results in more homogenous distribution of the thrombolytic agent
within the thrombus. Arteriograms were reviewed to assess reperfusion on the basis of the
modified thrombolysis in myocardial ischemia score (Mori score)1. Logistic regression analysis
for Mori score was performed. Predictors tested included the following factors previously
shown to be associated with higher recanalisation rates: time to treatment, site of occlusion
(distal vs. proximal), presence of slow antegrade flow around the clot (SAF) and microcatheter
technique. All factors with p⬍.10 were entered into the final model as predictors of clinical
outcome using backward selection. Any hemorrhage associated with an increase in National
Institutes of Health Stroke Scale score of 4 or more was considered symptomatic. Results:
Statistically significant predictors for reperfusion on logistic regression analysis (whole model
test: p⬍0.0001; r2⫽ 0.26) included: SAF (p⫽0.0008) and method of recanalisation
(p⬍0.0001). Good reperfusion rates (Mori 2 or 3 scores) were present in 80% of patients with
SAF (p⫽0.0094; Pearson). Good reperfusion rates were found in 31%, 32% and 78% of cases
with methods 1, 2 and 3 described above respectively (p⬍0.0001; Pearson); symptomatic
hemorrhage rates with methods 1,2 and 3 were 7.1%, 10.7% and 7.3% respectively (p⫽0.867;
Pearson). Conclusion: A more homogenous distribution of tPA throughout the offending
thrombus via microcatheter repositioning results in higher reperfusion rates in acute stroke.
Reference: 1) Arnold M, Nedeltchev K, Remonda L et al. Recanalisation of middle cerebral
artery occlusion after intra-arterial thrombolysis: different recanalisation grading systems and
clinical functional outcome. J Neurol Neurosurg Psychiatry. 2005; 76:1373– 6.
P89
Mediators Of Symptomatic Penumbral Recruitment In Patients With Acute
Ischemic Stroke.
Mar Castellanos, Hosp Universitari Dr. Josep Trueta, Girona, Spain; Natalia Pérez de la
Ossa, Hosp Univ Germans Trias i Pujol, Badalona, Spain; Salvador Pedraza, MRI Unit-IDI.
Radiology Service, Girona, Spain; Manuel Rodrı́guez-Yáñez, Hosp. Clı́nico Univ. Santiago de
Compostela, Santiago de Compostela, Spain; Joaquı́n Serena, Yolanda Silva, Hosp
Universitari Dr. Josep Trueta, Girona, Spain; José Castillo, Hosp. Clı́nico Univ Santiago de
Compostela, Santiago de Compostela, Spain; Antoni Dávalos; Hosp. Univ. Germans Trias i
Pujol, Badalona, Spain
Background and purpose: Although ischemic lesion enlargement is often associated with
early neurological deterioration (END), the recruitment of the penumbral tissue does not always
cause neurological worsening. In this study we aimed to investigate those factors that might
be associated with the symptomatic penumbral recruitment (SPR) in patients with acute
ischemic stroke. Methods: From a total of 200 patients with an acute hemispheric infarction
within the first 12 hours of evolution, 104 who had significant (ⱖ20%) perfusion-diffusion
mismatch (PDM) on admission and significant DWI lesion volume enlargement (ⱖ20%)
between admission and 72 h were studied. NIHSS score was evaluated at the same intervals,
and END was defined as an increase ⱖ 4 points between the two examinations. The ultimate
infarct volume was calculated on FLAIR-MRI at day 30. SPR was considered when the
significant DWI lesion enlargement was accompanied by END. For a secondary analysis of the
effect of molecular factors, glutamate, interleukin-6, tumor necrosis factor-␣, matrix
metalloproteinase-9, and cellular fibronectin levels were determined in blood samples obtained
on admission. Results: SPR occurred in 18 patients (17.3%) and was associated with a higher
frequency of diabetes history, lower NIHSS score on admission, higher mean systolic blood
pressure (SBP) levels at 48 h of evolution, cortical location of the lesion and higher levels of
glutamate. No differences were found regarding PWI, DWI, PDM and FLAIR lesion volumes at
any time. After adjustment for potential clinical and radiological confounders lower NIHSS score
on admission (OR 0.78; 95% CI, 0.62 to 0.99; p⫽0.041) and high SBP at 48h (OR 1.07; 95%
CI, 1.01 to 1.02; p⫽0.024) independently predicted SPR. However, after the inclusion of
molecular mediators in the model, only glutamate levels remained independently associated
with SPR (OR 1.01; 95% CI, 1.00 to 1.03; p⫽0.046) Conclusions: Among clinical, radiological
and biochemical mediators, only glutamate levels are associated with SPR which suggest that
excitotoxicity mediates symptomatic penumbral recruitment in patients with acute ischemic
stroke.
P90
Real-Time Validation of Thrombolysis in Brain Ischemia (TIBI) Flow Grading
of Recanalization during Intra-Arterial Rescue for Acute Ischemic Stroke.
P88
Does The Method For Intra-arterial TPA Delivery Affect Reperfusion Rate?
Gregory Christoforidis, Yousef Mohammad, Marinos Kontzialis, Louis Caragine, Andrew
Slivka; Ohio State Univ, Columbus, OH
Purpose: Three methods for intra-arterial delivery of tissue plasminogen activator (tPA) for
acute stroke were compared to determine whether reperfusion rates differ. More homogenous
distribution of tPA throughout the offending thrombus via microcatheter repositioning was
hypothesized to result in higher reperfusion rates. Methods: This study reviewed prospectively
collected clinical information, arteriograms and CT scans following treatment, from 82
Georgios Tsivgoulis, Comprehensive Stroke Cntr, Univ of Alabama Hosp, Birmingham, AL;
Marc Ribo, Dept of Neurology, Hosp Universitari Vall d’Hebron, Universitat Autonoma de
Barcelona, Barcelona, Spain; Mark R Harrigan, Dept of Neurosurgery, Univ of Alabama
Hosp, Birmingham, AL; Agniezska A Ardelt, David Brenner, Alice Robinson, Comprehensive
Stroke Cntr, Univ of Alabama Hosp, Birmingham, AL; Carlos A Molina, Dept of Neurology,
Hosp Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain,
Birmingham, AL; Joseph A Horton, Div of Neuroradiology, Dept of Radiology, Univ of
Alabama Hosp, Birmingham, AL; Andrei V Alexandrov; Comprehensive Stroke Cntr, Univ of
Alabama Hosp, Birmingham, AL
Background&Purpose: Recanalization is strongly associated with improved functional outcomes and reduced mortality in acute ischemic stroke (IS). It is considered a marker of
592
Stroke
Vol 39, No 2
February 2008
therapeutic activity in early phase trials of thrombolytic treatment for IS. Transcranial Doppler
(TCD) is a bedside, non-invasive tool for the real-time monitoring of the residual flow at the site
of occlusion. However, validation of ultrasonographic criteria for recanalization with contrast
angiography is limited. We aimed to determine the diagnostic accuracy of TCD detection of
recanalization in real time during intra-arterial rescue in acute IS. Subjects&Methods:
Consecutive acute IS patients with proximal intracranial occlusions underwent intra-arterial
rescue procedures (IA) including mechanical thrombectomy (MT) with simultaneous real-time
TCD-monitoring. Residual flow signals at the site of occlusion were monitored at a constant
angle of trans-temporal insonation during IA using a standard head-frame. Recanalization was
assessed simultaneously by angiography and ultrasound using TIMI (Thrombolysis in Myocardial Infarction) and TIBI (Thrombolysis in Brain Ischemia) criteria respectively. Independent
readers blinded to angiographic findings performed real-time validation of TIBI flow grades.
Results: We evaluated time-linked real-time DSA-TCD images from 42 diagnostic DSA runs
during 10 IA procedures in consecutive acute IS patients. The mean age was 57⫾24 years;
there were 4 men and 6 women; median NIHSS was 18, range 6 –28. Four patients had
M1-MCA, 1 M2-MCA, 3 TICA, and 2 distal BA occlusions. IA procedures included rt-PA (n⫽3),
MT (n⫽2), and combination of rt-PA and MT (n⫽5). IA procedures started at median time from
symptom onset of 180min, range 75– 620min. Compared to angiography, TCD had the
following accuracy parameters for detection of complete recanalization (TIBI IV-V vs TIMI III flow
grades): sensitivity 91% (95% CI 74%–100%), specificity 97% (91%–100%), PPV 91%
(74%–100%), NPV 97% (91%–100%), and overall accuracy 95% (89%–100%). In two cases,
TCD-monitoring showed flow changes consistent with re-occlusion and collateralization that
were helpful to interventionalists in decision-making during the IA procedures. Conclusions:
TCD assessment of recanalization yields excellent agreement with invasive contrast angiography in real-time and provides additional hemodynamic data. The usefulness of TCDmonitoring during IA procedures in acute IS is promising and should be further investigated.
after stroke, and proxy vs. pt responder. Results: To date, “waiver” data exist for 124 pts
(median age 69 yrs, range 38 –93; 22% black/78% white; 48% female; 39% with ⬎12th grade
education; median initial NIHSS of 4, range 0 –25; median mRS of 3 at 30 days post-stroke;
20% by proxy); 6 did not answer the waiver questions, and 118 interviews remain to be done
in 2007. See Figure for responses from the cohort. The only predictor of a positive response
was pt sex: men were more likely to agree to blood samples (OR 2.7, 95% CI 1.1– 6.8, p⫽0.03)
and invasive procedures (OR 2.32, CI 1.01–5.3, p ⫽0.047). Conclusions: Nearly half of the
interviewed stroke pts were unsure or had a negative opinion regarding acute stroke research
involving medical treatments or invasive strategies without express consent from self or family,
even though this cohort had already consented for research. Pt sex as an independent predictor
of willingness to participate in waiver of consent studies will be further explored and presented
within the full cohort.
P91
Modified ABCD And ABCD2 Scores Appear Safe For TIA Triage.
James Castle, Connie Wolford, Gregory Albers; Stanford Univ, Palo Alto, CA
Background and Purpose: There is existing uncertainty about the appropriateness of using an
outpatient rather than inpatient setting to evaluate TIA patients. The purpose of this study was
to assess if the use of a modification of the ABCD and ABCD2 models for triage of acute TIA
patients would result in a low rate of early stroke (⬍ 2–3%) in patients referred to an outpatient
TIA clinic. Methods: In July 2006 the Stanford Stroke Center began using a modification of the
“ABCD score” for TIA patient triage: acute TIA patients with 0 –3 points or 4 points and a
favorable stroke risk factor profile were referred to rapid outpatient evaluation (TIA Clinic) rather
than inpatient hospital admission. On February 20, 2007, after evidence of an improved stroke
risk model was published, a modification of the ABCD2 score was adopted: ‘low-risk” patients
with a TIA score of 0 –3 points were referred to TIA clinic as were “moderate-risk” patients with
a score of 4 –5 points and unremarkable vascular imaging performed in the Emergency
Department (no evidence of large artery stenosis (ⱖ50%), clot, or unstable plaque on CT
angiography). All other TIA patients are admitted for inpatient observation and evaluation. We
prospectively followed all patients referred from the Emergency Department to the TIA Clinic at
Stanford University from July, 2006 to July, 2007 to assess the seven day stroke rate. Seven
day stroke data were available for 66/68 patients (2 of the patients were lost to follow-up).
Results: Of the 66 patients referred from the emergency room to the TIA clinic for whom
follow-up data are avialbe, only one had a stroke within one week of their referral. This patient
had been triaged using the initial modified ABCD score criteria, and would have been admitted
using the new modified ABCD2 criteria, as a significant stenosis with clot was observed on
cerebrovascular imaging of his carotid artery. Our overall stroke rate at one week in the
referred population was 1.54% (95% confidence interval of 0.1% to 7.6%). Conclusions: Our
data indicates that a modification of the ABCD2 and ABCD scores can likely be used to safely
triage acute TIA patients to an outpatient evaluation. Future studies with larger sample sizes
will provide greater clarification of the risk of early stroke in these patinets.
P92
Stroke Patient Perspective Regarding Waiver of Consent and Acute Stroke
Research.
Dawn Kleindorfer, Kathleen Alwell, Christopher J Lindsell, Charles J Moomaw, Matthew L
Flaherty, Daniel Woo, Jane Eilerman, Pooja Khatri, Opeolu Adeoye, Christopher W Nichols,
Simona Ferioli, Joseph P Broderick, Brett M Kissela; Univ of Cincinnati, Cincinnati, OH
Introduction: “Waiver of consent” is a rigorous procedure regulated by the FDA that requires
community assent but allows enrollment without patient (pt) or family consent. Recently,
several acute stroke trials have explored the use of waiver of consent to improve enrollment.
We obtained ischemic stroke survivors’ opinions regarding hypothetical enrollment into a
clinical trial at the time of their stroke without personal or proxy consent. Methods: During
2005, 502 ischemic stroke pts (or their proxy) were prospectively interviewed. At two years
post-stroke, 82 had died, 76 were lost to follow-up, and 96 refused follow-up, leaving 248 pts.
Pts were asked to think back to the time of their stroke and indicate whether they would have
wished to be enrolled in an acute stroke research study before individual or proxy consent could
be obtained, understanding that consent would be sought as soon as possible thereafter. Using
a modified Likert scale (Figure), they rated how agreeable they would have been to acute stroke
research with different levels of invasiveness. Predictors of a positive opinion regarding the
hypothetical research were analyzed using logistic regression. Variables included in the model
were age, race, sex, education, initial NIHSS, modified Rankin (mRS) prior to stroke and 30 days
P93
Evidence of Clustered Recruitment in Randomized Clinical Trials Pertaining
to Cerebrovascular Diseases.
Jill M Novitzke, Adnan I Qureshi; Zeenat Qureshi Stroke Rsch Cntr Univ of minnesota,
Minneapolis, MN
Introduction: As a coordinating center for a number of clinical trials, we observed that
recruitment varies considerably among participating sites in multi-center trials, potentially
impacting overall performance and even outcome of the trial. Our objective was to report
recruitment patterns in randomized clinical trials pertaining to cerebrovascular diseases. This
information could be utilized for optimal site selection; thus promoting time management and
fiscal responsibility. Hypothesis: We assessed the hypothesis that a minority percentage of
clinical sites complete the majority of recruiting in clinical trials pertaining to cerebrovascular
diseases. Methods: We analyzed data from randomized clinical trials that provided the number
of subjects recruited at participating sites. We determined the number of sites that recruit 10%
or greater, 5–9%, 1– 4%, and less than 1% of the total number of subjects recruited. Patterns
were compared between trials performed predominantly in United States or abroad. Results:
We analyzed a total of 7 randomized trials. Of these, 257 participating centers recruited a total
of 6432 subjects. Two trials were conducted in the United States and five were conducted
abroad. The results are tabulated below: Conclusions: The analysis suggests that nearly half
of the participating sites recruit less than 1% of the subjects in clinical trials, highlighting the
importance of more rigorous methods to screen, select, and monitor clinical sites. Inference
could be made that sites enrolling the majority of subjects are better equipped clinically and
have the necessary infrastructure to conduct trials. These data could ultimately be used as a
basis to create budget models that are predictive of a center’s recruiting ability, leading to
appropriate fund allocation. In conclusion, the pursuit of further data regarding site-specific
recruitment performance may translate into a meaningful resource to assist investigators in
trial planning and execution, as well as provide guidance to aspiring centers regarding
successful trial management.
Proportion of subjects recruited
⬍1%
1–4%
5–9%
ⱖ10%
Number of centers
120
83
36
18
P94
Transcranial Duplex 24 Hour-monitoring of Acute MCA Occlusions after i.v.
t-PA Administration: Prognostic Impact of Time-point and Degree of
Arterial Recanalization.
Laura Dorado, Juan F Arenillas, Natalia Pérez de la Ossa, Mónica Millán, Cristina Guerrero,
Domingo Escudero, Elena López-Cancio, Ana C Ricciardi, Patricio Sandoval, Antoni Dávalos;
Neurosciences Dep. Germans Trias i Pujol Universitary Hosp, Barcelona, Spain
Background and purpose. Early (⬍300 min) & complete arterial recanalization has been
shown to be independently associated with favourable clinical outcomes in acute ischemic
stroke patients treated with i.v. t-PA. It remains unclear whether recanalization is still beneficial
when occurring at later time points or in a partial manner. We aimed to evaluate the prognostic
impact of the degree and time-point of arterial recanalization during the first 24 hours after t-PA
administration, in patients with acute middle cerebral artery (MCA) occlusions. Methods. We
prospectively studied consecutive ischemic stroke patients treated with i.v. tPA following
SITS-MOST criteria, who showed MCA occlusions on pre-bolus transcranial Duplex (TCCD)
examinations. TCCD recordings were obtained 1, 2, 6, 12 and 24 hours after t-PA treatment.
Thrombolysis in Brain Ischemia criteria were used to define complete, partial or absent MCA
recanalization at each time point. Early neurological improvement (ENI) was defined as a
decrease in ⱖ4 points in the NIHSS score during the first 24 hours. A modified Rankin scale
score ⱕ2 at day 90 was considered indicative of good long-term clinical outcome. Results. A
total of 61 patients were included. Median baseline NIHSS score was 13 (interquartile range
9 –18). ENI was observed in 32 (53%) patients. Complete, but not partial, recanalization at any
time-point was independently associated with ENI in adjusted logistic regression models. The
probability of ENI was maximal for ⬍1h complete recanalization (OR 14.7, 95% CI [1.9 –109.2],
p⫽0.009) and gradually decreased with later time-points. Thirty-five (57%) patients showed
good long-term outcome. Both partial and complete MCA recanalizations achieved at any
time-point during the first 12 hours after t-PA bolus were independently associated with good
outcome. Odds ratios for favourable outcome attending time frame of any degree of MCA
recanalization were 33.7 [2.2–520] for ⬍1h, 12.9 [1.1–182] for 1– 6 h, and 3.1 [0.3–35] for
6 –24h, using the absence of recanalization at 24 hours as the reference category. Conclusion.
Any degree of MCA recanalization observed during the first 12h following t-PA administration
predicted good long-term outcome. In contrast, only complete recanalization was associated
with early neurological improvement.
P95
Combined Therapy of IV t-PA with Caffeinol in Acute Ischemic Stroke.
593
prevalence of CIN in those who had a CTA/CTP upon initial evaluation. We hypothesized that
the use of contrast for CTA/CTP prior to the availability of renal function tests is safe in code
stroke patients. Methods: We retrospectively analyzed our prospectively collected database.
We identified all patients seen in our ED as code stroke, presenting within 9 hours of
neurological symptom onset. We collected the clinical data that was available at the time of the
code stroke activation and until discharge including: demographics, comorbidites and
laboratory results. A baseline Cr level ⬎ 2.0 was considered to be the upper cut-off for
administration of contrast. An increase in the Cr of ⬎25% within 72 hours of contrast
administration was defined as CIN. We used simple descriptive statistics to report our findings.
Results: We identified 131 consecutive code stroke patients from December 2006-June 2007.
Mean age was 67.8 (⫹/-17.5) years and 79 (62%) were women. A total of 68 (52%) underwent
a CTA of the head and neck and 28 received a CTP in addition to the CTA, prior to availability
of BUN/Cr. The mean age of these patients was 71.1 (⫹/- 12.9); 59% were women. Of these
patients, only 1 patient (1.5%) had a baseline Cr greater than 2, when the laboratory results
became available. This patient was known to have end-stage renal disease on dialysis. There
were follow up Cr results, obtained within 72 hours, available for 66 of the 68 patients who
received contrast. Two (3%) had an increase in the Cr of greater than 25%. Among the
remaining 63 code stroke patients who did not receive contrast, 4 (6.3%) had a baseline Cr
greater than 2. Three of these 4 patients (75%) had a known history of renal disease. A
GFR⬍60, indicating moderate kidney disease, was present in 34% of our code stroke patients,
and was not linked with the development of CIN. A total of 78 patients (59%) had a discharge
diagnosis of TIA, infarct or hemorrhage. Conclusion: In this population of code stroke patients,
3.8% would not have received contrast based on a Cr level ⬎ 2 upon initial evaluation.
However, 80% of these patients had a known history of renal disease and would have been
excluded from consideration for CTA/CTP for this reason alone. Our findings suggest that the
use of contrast agents in code stroke patients prior to availability of renal function tests appears
safe in patients who do not have a known history of renal disease.
Sheryl Martin-Schild, Miriam M Morales, Andrew D Barreto, Hen Hallevi, Jarek Aronowski,
Sean I Savitz, James C Grotta; UT Houston Health Science Cntr, Houston, TX
Background: Two different rodent models of transient ischemic stroke in separate laboratories
have shown that caffeinol reduces cortical damage and enhances neurological recovery. When
tested in conjunction with tPA, caffeinol maintained its efficacy and did not increase
hemorrhagic conversion. In this phase 1 study, we tested the dosing, safety, and short term
outcome of caffeinol as an adjunctive therapy to IV t-PA in acute stroke patients. Methods:
Patients 18 years of age and older who presented with a clinical syndrome compatible with
ischemic stroke and clinical signs localizing to the cortex were treated with IV t-PA within 3 hrs
and caffeinol within 6hrs from symptom onset. Patients were given a 2hr infusion of caffeinol.
The dose of caffeine was 8mg/kg or 9mg/kg and the dose of ethanol varied from 0.3g/kg to
0.4g/kg. Our control group was retrospectively collected from our prospective database and
consisted of IV t-PA patients treated from 2004 –2007 in our emergency department within 3
hrs of symptom onset who would have met the inclusion criteria for the caffeinol study.
Results: Ten patients received t-PA and caffeinol while 90 patients received t-PA alone. There
were no significant differences in age or onset to treatment time. Patients treated with tPA
alone had significantly lower baseline glucose levels and a trend towards lower median
baseline NIHSS scores compared with patients treated with tPA and caffeinol. The caffeinol
group had a non-significant shorter time to t-PA treatment and none had early ischemic
changes. There was no difference in the rates of hemorrhagic transformation. A significantly
higher percentage of patients achieved a mRS 0 –1 at hospital discharge in the caffeinol group
(p⬍.05). Discussion: This study suggests that t-PA followed by caffeinol is safe and may lead
to a better outcome in acute stroke patients compared with historical controls. A randomized
trial testing the efficacy of caffeinol/t-PA compared with standard t-PA treatment alone has
been designed.
Age
Male
Baseline NIHSS (median)
Glucose
Early ischemic changes
Time from onset to tPA
Time from onset to caffeinol
sICH
mRS 0–1 at discharge
Caffeinol plasma level
Ethanol plasma level
tPA ⫹ caffeinol n ⫽ 10
tPA alone n ⫽ 90
60⫹19 [26,90]
3 (30%)
18 [7, 24]
178⫹86 [89,333]
0
113.44⫹32.10 [80,170]
195.80⫹61.51 [125,325]
1 (10%)
6 (60%)
8.5 ⫹/- 2.1
26.2 ⫹/- 18.6
67⫹15 [26,90]
46 (50%)
13 [7,25]
141⫹51 [83,341 ]
14 (16%)
131.51⫹29.10 [47,196]
0.211
0.176
0.128
0.046
0.265
0.287
3 (3%)
23 (26%)
0.348
0.032
p value
P96
Reducing The Delay In t-PA Use: Is It Necessary To Await The Results Of
Renal Function Tests Before CT Perfusion And Angiography In “Code
Stroke” Patients?
Manu Mehdiratta, Gottfried Schlaug, Sandeep Kumar, Louis R Caplan, David Searls, Adnan
Safdar, Magdy Selim; Beth Israel Deaconess Med Cntr, Boston, MA
Background: CT Angiography (CTA) and Perfusion CT (CTP) are becoming increasingly utilized
in the diagnosis and management of patients with suspected acute ischemic stroke. There is
a risk of contrast induced nephropathy (CIN) with these studies. Awaiting the results of serum
creatinine (Cr) and glomerular filtration rate (GFR) can delay these studies and the initiation of
thrombolysis. We aimed to determine the percentage of patients presenting as “code stroke”
who would be excluded from these studies based on their laboratory results; and the
P97
Safety And Efficacy Of Ultrasound-enhanced Thrombolysis: A Meta-analysis
Of Randomized And Non-randomized Studies.
Georgios Tsivgoulis, Comprehensive Stroke Cntr, Univ of Alabama at Birmingham Hosp,
Birmingham, AL; Carlos A Molina, Dept of Neurology, Hosp Universitari Vall d’Hebron,
Universitat Autonoma de Barcelona, Barcelona, Spain; Jürgen Eggers, Neurology, Asklepios
Hosp North, Hamburg, Germany; Fabienne Perren, Dept of Neurology, Neurosonology Unit,
HUG, Univ Hosp and Med Sch of Geneva, Geneva, Switzerland; Marta Rubiera, Dept of
Neurology, Hosp Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona,
Spain; Vincent Larrue, Service de Neurologie Vasculaire, Université de Toulouse III, France,
Toulouse, France; Andrei V Alexandrov; Comprehensive Stroke Cntr, Univ of Alabama Hosp,
Birmingham, AL
Background&Purpose: Ultrasound-enhanced thrombolysis (UET) is a promising new approach
to facilitate reperfusion therapies for acute ischemic stroke. So far, three different ultrasound
technologies were used to increase the thrombolytic activity of tPA including transcranial
Doppler (TCD), transcranial color-coded duplex (TCCD) and low-frequency ultrasound (LFUS).
We performed a meta-analysis to evaluate the safety and efficacy of UET compared to the
current standard of care (iv-tPA). Subject&Methods: Through Medline search, we identified
and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia.
Principal investigators were contacted if data not available through peer-reviewed publication
was needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were
compared between tPA, tPA⫹TCD⫾microspheres (␮S), tPA⫹TCCD⫾␮S, and tPA⫹LFUS.
Results: A total of 6 randomized (224 patients) and 3 non-randomized (192 patients) studies
were identified. The rates of sICH in randomized studies were as follows: TCD 3.8% [95%CI:
0%–11.2%], TCCD 11.1% [0%–28.9%], LFUS 35.7% [16.2%– 61.4%] and TPA alone 2.9%
[0%– 8.4%], Table. Complete recanalization rates were higher in patients receiving combination of TCD with TPA 37.2% (26.5%– 47.9%), compared with patients treated with TPA alone
17.2% (9.5%–24.9%) both in randomized and combined trials. Additional data including
non-randomized studies are shown in the Table. Conclusions: The present safety and
signal-of-efficacy data should be taken into account in the design of randomized controlled
trials evaluating ultrasound-enhanced thrombolysis. Table. Recanalization and sICH rates in
randomized and non-randomized studies of ultrasound-enhanced thrombolysis.
Variable
Randomized
studies
Number of
patients
sICH
(95%CI)*
Recanalization
(complete)
Randomized
and
nonrandomized
studies
Number
of
patients
tPA
tPA⫹TCD⫾␮S
tPA⫹TCCD⫾␮S
tPA⫹LFUS
105
78
27
14
2.9%
(0%–8.4%)
3.8%
(0%–11.2%)
11.1%
(0%–28.9%)**
17.2%
(9.5%–24.9%)
37.2% ¶
(26.5%–47.9%)
26.9% ¶¶
(9.9%–44.0%)
35.7%
(16.2%–
61.4%)***
Not
available
141
208
53
14
594
Stroke
Variable
sICH
(95%CI)*
Complete
Recanalization
(95%CI)
Vol 39, No 2
February 2008
tPA
tPA⫹TCD⫾␮S
tPA⫹TCCD⫾␮S
tPA⫹LFUS
3.5% (0%–8.3%)
3.8% (0%–7.5%)
18.8%
(12.0%–25.5%)
40.9%
(34.2%–47.6%)§
9.7%
(0%–20.7%)#
42.3%
(28.9%–55.7%)§§
35.7%
(16.2%–61.4%)##
Not available
*Adjusted Wald **p⫽0.175 vs. TCD (Fisher’s exact test), p⫽0.100 vs. tPA (Fisher’s exact test) ***p⫽0.002 vs. TCD
(Fisher’s exact test), p⬍0.001 vs. tPA (Fisher’s exact test) ¶ p⫽0.003 vs. tPA (␹2-test) ¶¶ p⫽0.267 vs. tPA (␹2-test)
# p⫽0.147 vs. TCD (Fisher’s exact test), p⫽0.140 vs. tPA (Fisher’s exact test) ## p⬍0.001 vs. TCD (Fisher’s exact test),
p⬍0.001 vs. tPA (Fisher’s exact test) §p⬍0.001 vs. tPA §§p⫽0.001 vs. tPA
P98
Uric Acid Prevents The Early Increase In Endogenous Active MMP-9 Levels
In Acute Stroke Patients Receiving tPA.
Sergio Amaro, Manuel Gomez-Choco, Xabier Urra, Alvaro Cervera, Victor Obach, Stroke Unit,
Hosp Clı́nic and IDIBAPS, Barcelona, Spain; Planas AM, Pharmacology and Toxicology Dept,
Consejo Superior de Investigaciones Cientı́ficas (IIBB-CSIC) and IDIBAPS, Barcelona, Spain;
Angel Chamorro; Stroke Unit, Hosp Clı́nic and IDIBAPS, Barcelona, Spain
INTRODUCTION: In experimental ischemia Uric Acid (UA) administration is neuroprotective.
Furthermore, in human stroke the combined treatment with tPA and UA is safe and decreases
lipid peroxidation. tPA increases the plasma levels of MMP-9, an enzyme able to degrade the
blood-brain barrier and to promote hemorrhage and edema. OBJECTIVES: The aim of this study
was to evaluate the effect of the antioxidant agent UA in the temporal profile of total and
endogenous active MMP-9 levels in stroke patients receiving tPA. METHODS: Patients were part
of the Uricoictus trial, a single center, double-blind, randomized, vehicle-controlled trial of
intravenous administration of UA in 24 acute ischemic stroke patients treated with tPA
(0,9mg/kg) within 3 hours of onset. At the end of the 1-hour tPA infusion, patients were
randomized to receive an intravenous infusion lasting 90 minutes of 500 mg of UA (n⫽8), 1
gr of UA (n⫽8), or vehicle alone (n⫽8). Disability was evaluated at day 90 using the modified
Rankin Scale (mRS). The levels of total MMP-9 (tMMP-9) and of endogenous active MMP-9
(eaMMP-9) were assessed in serum samples at baseline (T0), at the end of UA/vehicle infusion
(T1), and at 48 hours (T2). RESULTS: The tPA treatment was initiated within mean (SD) 133 (35)
minutes of onset and UA/vehicle treatment within 212 (42) minutes. Patients who had good
clinical outcome at day 90 (mRS of 0 or 1) had lower baseline eaMMP-9 levels (18.3⫾8.2
ng/ml vs 27.5⫾9.4 ng/ml; p 0.028, t-test) and lower T1 eaMMP-9 levels (18.1⫾10.5 ng/ml vs
27.7⫾8.3 ng/ml; p 0.022, t-test). Baseline tMMP-9 and eaMMP-9 levels were not different
between treatment groups. In the whole population tMMP-9 levels increased in the hyperacute
phase with a peak observed at T1 (183.1⫾117.5 ng/ml at T1 vs 145.6⫾97.3 at T0; p 0.016,
paired t-test). At T1 those patients allocated to vehicle showed an increment in the eaMMP-9
levels, while those allocated to the low dose or to the high dose of UA showed a decrement
(⫹19.3% ⫾19.4 for vehicle group, -10.2% ⫾14.8 for 500 mg UA group, and -2.5% ⫾ 21.5
for 1000 mg UA group; p 0.013, ANOVA). CONCLUSIONS: UA administration immediately after
tPA prevents the hyperacute increase in eaMMP-9 levels observed in acute stroke patients
receiving tPA. In tPA treated patients, high acute levels of eaMMP-9 are related to bad clinical
outcome. These findings support the role of oxidative stress in in-vivo regulation of MMP-9 and
the potential clinical utility of combined treatment with tPA and antioxidants in acute stroke.
findings. The Houston outcome analysis showed that HB, EB and WAR were independently
predictive of a favorable outcome (p⫽0.004) while ASA treatment predicted a poor outcome
(p⫽0.003). Conclusions: Anticoagulation of CES patients can be safely started with warfarin
within the first days after CES. Bridging with a full-dose of either heparin or enoxaparin does
not reduce stroke recurrence and may increase the risk of systemic and intracerebral
hemorrhage.
P100
Feasibility and Safety of Very Mild Hypothermia Therapy Using Oral
Non-steroidal Anti-inflammatory Drugs in Acute Embolic Stroke: A
Case-Control Study.
Hiroshi Moriwaki, Kotaro Miyashita, Kazuyuki Nagatsuka, Kuni Konaka, Buhan Hyon, Hiroaki
Naritomi; National Cardiovascular Cntr, Suita, Japan
BACKGROUND and PURPOSE: Acute stroke is commonly accompanied by fever, which is an
important aggravating factor of clinical outcome. Antipyretic pharmacological intervention using
acetaminophen was proposed to be an alternative therapy of moderate hypothermia, which
requires general anesthesia. However, the effect of acetaminophen administered as suppositories 6 times daily in acute ischemic stroke has been still controversial. We propose the new
concept of more feasible therapy using oral administration of loxoprofen-Na, a novel
non-steroidal anti-inflammatory drugs (NSAID) with powerful antipyretic and anti-inflammatory
actions accompanied by minimal gastro-intestinal complications, in acute ischemic stroke.
METHODS: We prospectively included 20 patients (Group A: 13 males, mean age 72.2 yrs) with
cardiogenic embolism of ICA or MCA trunk admitted from 3 to 12 hours after stroke. They were
treated with very mild hypothermia therapy using oral NSAID (powdered loxoprofen-Na 60 mg,
administered via a stomach-tube 3 times daily for 7 days) and ice-cooling. Historical cohort of
similar 60 patients without hypothermia therapy matched for age, and time from stroke onset
to admission were evaluated as a control (Group B). Patients with thrombolytic therapy were
excluded. Axillary temperature was recorded every 6 hours. Sequential CT examinations were
performed at days 1, 2, 4 and 7. Stroke severity was quantified with the National Institutes of
Health Stroke Scale (NIHSS), and functional outcome was assessed with the modified Rankin
Scale (m-RS) and the Barthel Index (BI) at 3 months. RESULTS: Baseline NIHSS scores,
occluded site of major arteries, and body temperature on admission were the same in the two
groups. Body temperature from days 2 to 7 was significantly lower in Group A than in Group
B (36.4⫹/-0.4 degrees vs. 37.1⫹/-0.6 degrees, p⬍0.05) without noticeable side effects.
Ischemic lesions on CT were more distinctly demarcated from the surrounding normal area in
Group A. Maximum midline shift on CT was significantly smaller in Group A than in Group B
(3.7⫹/-2.9 mm vs. 8.2⫹/-6.4 mm, p⬍0.01), and the frequency of massive hemorrhagic
transformation was somewhat smaller in Group A (15% vs. 33%). Reduction of NIHSS score at
day 30 as compared with the baseline was significantly larger in Group A than in Group B (8.4
vs. 4.9, p⬍0.05). There were no significant differences in the m-RS at 3 months, however the
percentage of patients with good function (BI⬎/⫽ 75 at 3 months) was significantly higher in
Group A than in Group B (35% vs. 13%, p⬍0.05). CONCLUSION: Very mild hypothermia
therapy using oral NSAID and ice-cooling may be useful for the treatment of acute stroke,
because of its feasibility, safety and capability to reduce the extent of brain edema.
P99
Starting Warfarin After Cardioembolic Stroke: To Bridge or Not To Bridge?
P101
The Use of a Portable CT Scanner is Associated with a 58% Reduction in
Request-to-Scan Times for Neuro CT Imaging in the Emergency Room of a
280-Bed Community Hospital.
Hen Hallevi, Univ of Texas Houston, Houston, TX; Karen C Albright, Dept of Neuroscience,
Univ of California, San Diego, San Diego, CA; Sheryl Martin-Schild, Andrew D Barreto, Sean
I Savitz, Miguel A Escobar, Nicole R Gonzales, Elizabeth A Noser, Kachi Illoh, James C
Grotta, Univ of Texas Houston, Houston, TX; The VISTA Investigators
David B Weinreb, North Shore Med Cntr/Salem Hosp, Salem, MA; Lee H Schwamm;
Background: Cardioembolic Stroke (CES) comprises 20% of all ischemic strokes and may carry
a higher risk of hemorrhagic transformation. While guidelines do not support acute anticoagulation of CES patients, uncertainty exists regarding the best timing and method of initiating
long-term anticoagulation. Methods: We conducted a retrospective review of all patients
admitted to our stroke center with CES not treated with tPA. Data was abstracted regarding
type of anticoagulation or antiplatelet and adverse events. Clinical outcome was determined
using the modified Rankin scale (mRS). Poor outcome was defined as mRS 4 to 6. Patients
were grouped into the following treatments treatment: No treatment, aspirin only (ASA), aspirin
followed by warfarin (WAR), IV heparin in the acute phase followed by warfarin (heparin
bridging- HB), and full-dose enoxaparin combined with warfarin (enoxaparin bridging- EB). The
study endpoints were hemorrhagic transformation (HT), systemic bleeding, stroke progression,
mortality and the rate of poor outcome on discharge. Pooled data from the Virtual International
Stroke Trials Archive (VISTA) project of 402 CES patients that served as control in acute stroke
treatment trials was used to validate our adverse events distribution. Results: Two hundred and
four patients met inclusion criteria. Recurrent stroke occurred in 2 patients (one in the ASA
group and 1 in WAR). Progressive stroke was the most frequent serious adverse event seen in
11 patients (5.4%). Anticoagulation was associated with a reduced rate of stroke progression
(1/108 in anticoagulated patients vs 10/96 in patients treated with aspirin or no-treatment;
p⬍0.001). HT occurred in a bimodal distribution- an early (day 0 –3 from stroke onset)
non-symptomatic HT, and a late (9 –22 days) symptomatic HT. All 3 cases of symptomatic HT
cases were in the EB group (10% of the EB group, p⫽0.003 comparing EB and non-EB
patients). Systemic bleeding occurred in 2(1%) of patients - all in the HB group (4.5% of the
HB group, p⫽0.043 comparing HB to non-HB patients). The VISTA cohort replicated these
Background: Our Emergency Department (ED), residing in a 280-bed community hospital,
ordered more than one thousand head CT scans within the last year. Many of these patients
had presented with signs of acute stroke and rapid neuroimaging is necessary before
anti-coagulation or thrombolytic therapy can be initiated. The NIH and American Stroke
Association recommend that CT imaging of acute stroke patients be performed with 25 minutes
of the patient’s arrival. To facilitate rapid neuroimaging, many large tertiary care centers have
installed fixed CT scanners in the ED, although it may be more cost-effective for community
hospitals to purchase a portable head/neck CT. We performed a prospective study to determine
whether the use of a portable CT scanner reduces request-to-scan times for ED patients.
Methods: A portable head/neck CT scanner was purchased for the ED (CereTom® CT,
NeuroLogica Corporation, Danvers, MA). The system is a mobile, high-resolution 8-slice CT
scanner equipped to perform non-enhanced CT, CT angiography and CT perfusion studies.
Request-to-scan times were recorded on all patients requiring neuroimaging for any clinical
indication, including acute stroke and trauma. Request-to-scan times are reported as
mean⫾standard deviation for the months prior to and following the introduction of the portable
scanner. The data was analyzed using a two sample student’s t-test. Results: The use of the
portable CT scanner was associated with a 58% reduction in mean request-to-scan times for
neuroimaging of ED patients (P ⬍ 0.001, n⫽530). The mean request-to-scan time was
39⫾5.1 minutes (n⫽127) for the month prior to the use of the portable scanner;
request-to-scan times for the four consecutive months for which the portable scanner was
used were 17⫾2.7 minutes (n⫽121, P ⬍ 0.001), 13⫾1.9 minutes (n⫽92, P ⬍ 0.001)
and19⫾1.8 minutes (n⫽120, P ⬍ 0.001) and 13⫾1.3 minutes (n⫽69, P ⬍ 0.001). Image
quality was determined to be equivalent to the conventional CT scanner by the interpreting
radiologists. Conclusion: A portable head/scanner CT scanner may be a cost-effective
approach to reduce time to rapid neuroimaging of patients with acute neurological injury (e.g.,
suspected stroke, trauma, infection) in the community hospital setting.
P102
Safety of Thrombolysis in Stroke Mimics.
Georgios Tsivgoulis, Stroke Program, Barrow Neurological Institute, Phoenix, AZ and UAB
Comprehensive Stroke Cntr, Birmingham, AL; Steven Hoover, James L Frey, Annabelle Y
Lao, Vijay K Sharma, Wei Liu, Murray Flaster, Stroke Program, Barrow Neurological
Institute, Phoenix, AZ; Anne W Alexandrov, College of Nursing, Arisona State Univ, Phoenix,
AZ and UAB Sch of Nursing, Birmingham, AL; Marc Malkoff, Stroke Program, Barrow
Neurological Institute, Phoenix, AZ; Andrei V Alexandrov; Comprehensive Stroke Cntr, Univ of
Alabama at Birmingham Hosp, Birmingham, AL
Background&Purpose: Efforts to increase the availability of intravenous thrombolysis and to
shorten the time for delivery of iv-TPA carry the potential for TPA administration in stroke
mimics. Limited data exist regarding the use of thrombolysis in patients erroneously diagnosed
as having ischemic stroke (IS) in emergency department (ED). We aimed to determine safety
of thrombolysis in stroke mimics and to describe outcomes in these patients.
Subjects&Methods: A retrospective cohort design was used to analyze stroke registry data
from consecutive IS admissions treated with iv-TPA according to standard indications from
January 2002 to December 2005. The National Institutes of Health Stroke Scale (NIHSS) scores
on admission, the presence of previous and modified Rankin Scores (mRS) at discharge were
documented as standard of care. Ischemic lesions on brain MRI (routinely performed as part
of diagnostic work-up 24 –72 hrs from symptom onset) were documented from radiology
reports. Decision for administration of thrombolytic treatment was based on baseline brain
CT-scan in all cases. Initial stroke diagnosis in ED was compared to the final hospital discharge
diagnosis. The diagnosis of stroke mimics was based on the absence of ischemic lesions on
DWI sequences in addition to the final diagnosis. Symptomatic intracerebral hemorrhage (sICH)
was defined as brain imaging evidence of ICH with clinical worsening by NIHSS score increase
of ⱖ4 points. Results: A total of 381 IS patients (216 men; mean age 66⫾14years) received
intravenous thrombolysis. Misdiagnosis of IS was documented in 31 cases (8%, 95%CI:
5.4%–10.9%). Conversion disorder (35%) and complicated migraine (19%) were the most
common final diagnoses in stroke mimics treated with TPA. Stroke mimics were younger (mean
age 56⫾12 years) and had milder stroke severity (median baseline NIHSS: 5 points,
interquartile range 5 points) compared to those with confirmed acute IS (mean age 67⫾14
years; NIHSS 10 points, IQR 8 points; p⬍0.001). No sICH occurred in stroke mimics (0%,
Adjusted Wald 95% CI: 0%–9.6%). All stroke mimics were functionally independent at hospital
discharge (mRS: 0 –1). The length of hospitalization was shorter in stroke mimics (median 3
days, IQR 2 days) compared to confirmed acute IS patients (median 5 days, IQR 4 days;
p⬍0.001). Conclusions: Our data indicate that symptomatic hemorrhagic complications did
not occur in stroke mimics treated with iv-TPA at our center. Since the number of cases is
limited, definitive conclusions regarding safety of thrombolysis cannot be drawn with statistical
confidence. Stroke mimics also had a shorter length of hospital stay and they were functionally
independent at hospital discharge.
P103
Periprocedureal Sedation During Intervention for Acute Stroke.
Christopher W Nichols, Pooja Khatri, Univ of Cincinnati, Cincinnati, OH; Sharon Yeatts, Med
Univ of South Carolina, Charleston, SC; Janice Carrozzella, Judith Spilker, Thomas Tomsick,
Joseph P Broderick, Univ of Cincinnati, Cincinnati, OH; The IMS II Investigators
Background: In order to safely perform acute intra-arterial (IA) revascularization procedures,
use of sedative medications and paralytics is often necessary. In our experience, the clinical
indication and level of sedation can vary greatly, ranging from protocol mandated paralysis of
all IA cases to no routine sedation. We sought to identify patient characteristics that would
correlate with the need for deeper sedation, and to explore whether levels of sedation relate
to patient outcomes. Methods: We studied 75 of 81 patients in the Interventional Management
of Stroke (IMS) II Study who had anterior circulation strokes and underwent angiography and/or
intervention. We defined “mild sedation” as that which did not affect the patient’s exam, and
“heavy sedation” as that which did affect the exam by clinical judgment. We tested for factors
potentially associated with four levels of sedation (Table 1), and examined whether dichotomized sedation (no/mild sedation versus heavy sedation/pharmacological paralysis) correlated
with 90-day modified Rankin Score (mRS) 0 –2 or death. Results: Among the baseline and
treatment factors listed in the Table 1, only baseline NIHSS was significantly associated with
level of sedation (p⫽0.01). Sedation (p⫽0.02), baseline NIHSS (p⫽0.03) and baseline systolic
blood pressure (p⫽0.04) were associated with death in univariate analysis. Using stepwise
logistic regression, only level of sedation was associated with death (p⫽0.02; OR 5.0, 95% CI
1.34, 18.7). Sedation (p⫽0.003), baseline NIHSS (p⫽0.08), baseline aphasia (p⫽0.11),
baseline glucose (p⫽0.12), female sex (p⫽0.004), and duration of procedure (p⫽0.13) were
associated with poor outcome in univariate analysis. Stepwise regression showed only sedation
(p⫽0.002; OR 7.0, 95% CI 2.0, 24.5) and female gender (p⫽0.004; OR 5.5, 95% CI 1.7, 17.2)
to be associated with poor clinical outcome. Conclusion: In our analysis, higher baseline NIHSS
correlated with use of deeper sedation during or prior to angiography and/or intervention. The
clinical indication for the level of sedation confounds the analysis, since higher levels of
sedation mark more severe disease. In this small sample, patients not receiving sedation fared
better. Further examination of the indications for procedural sedation or paralysis and their
effect on outcome is warranted. Table 1. Characteristics and outcomes of patients in each
sedation category
Number
Age
Baseline NIHSS
Male Gender
Non-White
Atrial Fibrillation
Aphasia Present
Left Hemisphere
Involved
Baseline Glucose
Baseline SBP
Onset to IV
treatment (min)
Received IA
treatment
Onset to IA
treatment (min)
Duration of
procedure (min)
Death
mRS 0–2
595
No Sedation
Mild
Sedation
Heavy
Sedation
Pharmacological
Paralysis
All Groups
p-value
40
64.6
17.30
26 (65%)
7 (17.5%)
11 (27.5%)
19 (47.5%)
20 (50%)
9
63.56
19.44
4 (44.4%)
2 (22.2%)
2 (25%)
6 (66.6%)
6 (66.6%)
9
64.00
21.00
3 (33.3%)
1 (11.1%)
2 (22.2%)
6 (66.6%)
8 (88.8%)
17
62.82
21.24
11 (64.7%)
5 (29.4%)
3 (17.6%)
11 (64.7%)
11 (64.7%)
75
64.00
18.89
44 (58.6%)
15 (20%)
18 (24.3%)
44 (58.7%)
45 (60%)
0.98
0.03
0.26
0.68
0.95
0.11
0.17
120.1
⫾ 42.6
143.8
⫾ 22.6
141.6
⫾ 33.5
25 (62.5%)
116.1
⫾ 19.4
150.1
⫾ 10.4
127.67
⫾ 38.3
8 (88.8%)
169.0
⫾ 104
143.67
⫾ 20.9
139.11
⫾ 28.4
8 (88.8%)
125.24
⫾ 38.8
147.41
⫾ 21.0
139.00
⫾ 25.5
12 (70.5%)
126.63
⫾ 52.5
145.36
⫾ 20.7
139.05
⫾ 31.6
53 (70.6%)
231.6
⫾ 55.3
111.2
⫾ 59.3
3 (7.5%)
4 (8.2%)
24 (60%)
30(61.2%)
234.63
⫾ 55
119.89
⫾ 65.9
1 (11.1%)
236.8
⫾ 57.7
136.80
⫾ 65.7
6 (35.2%)
234.3
⫾ 51.9
123.09
⫾ 60.5
238.5
⫾ 35.4
150.89
⫾ 44.4
2 (22.2%)
8 (30.8%)
6 (66.6%) 2 (22.2%)
6 (23.1%)
0.68
0.83
0.75
0.31
0.99
0.26
12 (16%)
4 (23.5%)
36 (48%)
P104
Microcatheter-Guided Intra-Clot Administration of Microbubbles During
External Continuous 2-MHz Ultrasound Insonation Safely Enhances
Thrombolysis in Acute Stroke.
Marc Ribo, Carlos Molina, Marta Rubiera, Beatriz Alvarez, José Alvarez-Sabin, Manel Matas;
Hosp Vall d’Hebron, Barcelona, Spain
AIM Microbubbles (MBs) and ultrasound have shown to enhance the thrombolytic effect of
systemic tPA. We sought to evaluate the safety and efficacy on middle cerebral artery (MCA)
recanalization of local microcatheter-guided intra-clot administration of MBs during intraarterial (IA) thrombolysis and external continuous 2-MHz pulsed-wave transcranial Doppler
(TCD) monitoring. METHODS. Nine patients with acute stroke due to proximal MCA occlusion
were treated with IA tPA (repeated 4 mg doses up to 20 mg or recanalization) and IA galactose
based MBs (up to 3 doses of 1 ml (400 mg/dl)). MBs and tPA were infused through a
microcatheter directly intra-clot. TCD flow monitoring during the procedure allowed continuous
insonation at clot location. Retrieving devices were not used. Recanalization was angiographically assessed according to the TICI reperfusion score and compared to simultaneous online
TCD data. In all cases IA procedures were stopped at 6 hours after symptoms onset.
Recanalization was re-assessed with TCD at 12 hours after symptoms onset. Hemorrhagic
transformation was assessed at 24 hours according to NINDS criteria. In-hospital neurological
status was assessed with the NIHSS score. At three months patients were considered
independent if mRS was ⱕ2. RESULTS Of the nine included patients (mean age 72 years) 7
received standard iv. tPA treatment (0.9 mg/kg) prior to the IA rescue procedure. Median pre-IA
procedure NIHSS score was 20. Median time to IA procedure initiation was: 175 minutes. The
mean IA administered doses were: tPA 10 mg, MBs 3 ml. TCD monitoring allowed direct
visualization of massive MBs arrival during every dose administration In 7 patients (78%)
recanalization was confirmed at the end of MBs infusion: complete-TICI 3: 2 patients (22%),
partial-TICI 2: 5 patients (56%). A perfect correlation was observed between TICI and TCD
scores. According to TCD, at 12 hours recanalization rate was still 78%, however complete
recanalization increased to 56%. One patient (11%) experienced a symptomatic intracranial
hemorrhage accounting for the only death in the series. Median NIHSS evolution was: 12
(inter-quartile range 6 –19) at 24 hours and 10 (range 6 –14) at discharge. At three months 44%
of patients were independent. CONCLUSION Ultrasound-activated intraclot-delivered MBs in
combination with tPA may be a safe strategy to enhance the thrombolytic effect and increase
recanalization rates. Ongoing study: presented data will include all future treated patients.
P105
Lack Of Association Between Cholesterol Levels And Risk Of Hemorrhagic
Transformation After Intravenous Rtpa.
Manuel Gomez-Choco, Victor Obach, Xabier Urra, Sergio Amaro, Alvaro Cervera, Martha
Vargas, Angel Chamorro; Hosp Clinic, Barcelona, Spain
Introduction: Low total cholesterol levels have been associated to hemorrhagic stroke and
recently low LDL cholesterol (LDL-c) has been associated to hemorrhagic transformation after
thrombolysis. Methods: We prospectively collected the demographic, clinical and radiological
data of consecutive patients treated with IV-rtPA within 3 h from symptoms onset at our
institution from July 2001 to June 2007. The aim of our study was to asses if there was a
relationship between the cholesterol levels and the risk of hemorrhagic transformation after
IV-rtPA in our population.Only patients whose cholesterol levels were determined within 48 h
from stroke were included in the study. Results: One hundred and twelve out of 192 patients
were analyzed (mean age 70.86 SD 12.78, 68 men and 45 women). There were a total of 11
hemorrhagic infarctions and 6 parenchymal hemorrhages. There were not differences in the
596
Stroke
Vol 39, No 2
February 2008
levels of either total cholesterol or LDL-c between patients with or without hemorrhagic
trnasformation (195.29 SD 43.85 vs. 197.45 SD 45.55, p⫽ 0.857 and 127.94 SD 59.94 vs.
123.49 SD 38.52, p⫽0.771). Both total cholesterol and LDL-c levels were also similar among
patients with either IH, PH or no bleeding (127.09 SD 66.78 vs. 129.50 SD 50.74 vs. 123.49
SD 38.52; p⫽ 0.918 and 187.45 SD 45.42 vs. 209.66 SD 40.55 vs 197.45 SD 45.55; p⫽
0.618, respectively). In the multivariate analysis, neither total cholesterol nor LDL-c adjusted for
age, glucose, arterial pressure, NIHSS, smoking, early ischemic changes and time to treatment,
were associated to hemorrhagic transformation(OR 0.996, IC 95% 0.982–1.011, p⫽ 0.657 and
OR 1.003, IC 95% 0.988 –1.019, p⫽ 0.669, respectively). Conclusions: We have not found any
relationship between either total cholesterol or LDL-c levels and hemorrhagic transformation
after IV-rtPA in our population. Preexistent hypocholesterolemia should not play a role in the
treatment decision of stroke patients until more data are available.
P106
The HAT Score: A simple Grading Scale for Predicting Hemorrhage After
Thrombolysis.
Min Lou, The 2nd Affiliated Hosp of Zhejiang Univ, Hangzhou, China; Adnan Safdar,
Sandeep Kumar, Gottfried Schlaug, Louis Caplan, Manu Mehdiratta, David Searls, Magdy H
Selim; Beth Israel Deaconess Med Ctr, Boston, MA
Background and Purpose: Intracerebral hemorrhage (ICH) is the most feared complication of
thrombolytic therapy for acute ischemic stroke (AIS). We aimed to develop a simple grading
scale that can be used at the bedside during the hyperacute phase to predict the risk of ICH
after treatment with intravenous t-PA. Methods: We identified key factors associated with
increased risk for ICH after t-PA in AIS from published literature. We allotted point(s) to each
predictor based on its prognostic value, and constructed a 5-point scale, based on the weight
of 4 easily-obtainable pre-treatment factors to predict the risk of hemorrhage after t-PA “HAT
Score”. We evaluated the predictive ability of this model in 2 independent cohorts of patients;
the t-PA treated group in the NINDS study, and consecutive patients treated with IV t-PA at our
institution, according to ASA/AHA guidelines. The prognostic ability of the model was evaluated
with c-statistics. Results: The HAT score comprised the sum of individual points assigned as
follows: pre-treatment NIHSS score ⱕ 15 (⫽0 points), 15 - ⱕ 20 (⫽1), and ⬎ 20 (⫽2); history
of diabetes and/or baseline blood glucose ⬎ 200 mg/dl (yes ⫽1; no ⫽0); and the presence
of visible hypodensity on initial head CT scan (no ⫽0; ⬍ 1/3 of middle cerebral artery territory
⫽1; and ⱖ 1/3 of MCA territory ⫽2). We evaluated 302 patients in the NINDS trial (age:
68⫾11; 57% women), after excluding 10 with incomplete data elements, and 98 local patients
(age: 71⫾17; 51% women). The percentage of patients who developed any ICH after t-PA rose
with higher scores in both cohorts. Collectively, the rate of any symptomatic ICH was 2% (0
point), 5% (1 point), 10% (2 points), 15% (3 points), and 44% (ⱖ 4 points). The predictive
capability of the model, c statistic, was 0.72 (95% CI 0.65– 0.79; p⬍0.0001) for all
hemorrhages; 0.74 (0.63– 0.84; p⬍0.0001) for any symptomatic hemorrhages; and
0.79(0.70 – 0.88; p⬍0.0001) for symptomatic fatal hemorrhages. Similar results were obtained
when each of the two cohorts was analyzed separately. Including other variables, such as age,
smoking, or concurrent use of antithrombotics, did not improve the model’s predictive ability.
Conclusions: The HAT score is a practical, quick, and easy-to-perform scale that allows
reasonable risk stratification of ICH after IV t-PA, and could improve standardization of t-PA use
in patients with AIS. The prognostic value of this scale needs to be prospectively confirmed in
a larger cohort of patients.
P107
Lack Of Association Between Neurology Consultation Prior To
Administration Of Intravenous Thrombolytics And Prevalence Of Protocol
Deviations.
William J Meurer, Angela F Caveney, Lingling Zhang, Robert Silbergleit, Phillip A Scott; Univ
Of Michigan, Ann Arbor, MI
Introduction: It is common practice for emergency physicians to consult a neurologist prior to
administering tPA in acute ischemic stroke. It is unclear whether this prevents protocol
deviations from published guidelines. We assessed the hypothesis that consultation with
neurology would be associated with fewer protocol deviations. Methods: Retrospective
analysis of 273 consecutive tPA-treated acute stroke patients at 4 hospitals from 1996 through
2004 was performed. The primary outcome studied was presence of a protocol deviation,
including pre and post-treatment. Multivariate binary logistic regression was then used to
determine the odds ratios for protocol deviation without consultation compared to patients with
consultation. Results: TThere were 119 patients with protocol deviations (52 in ED, 48
inpatient, 19 both.) Patients receiving a consult had protocol deviation rate of 44.4%, whereas
those without a consultation had a rate of 40.9% (p ⫽ .614 by chi-square.) The door to drug
time was similar with and without consultation (94 and 98 minutes, respectively.) In the
adjusted model (see table), the association between obtaining a neurology consultation and
protocol deviation did not achieve statistical significance, after controlling for covariates.
Treating hospital, history of prior stroke and history of atrial fibrillation were significant
predictors and were included in the final model. Stroke severity and patient demographic
factors such as age, gender, and race were not significant predictors. Conclusions:
Neurological consultation was not found to be associated with decreased protocol deviations
in this cohort. The sample size for a clinical trial able to detect the observed 3.5% difference
in protocol deviations would require 3134 patients per group, assuming 80% power. This
approaches U.S. estimates for the total number of tPA-treated stroke patients annually. A
registry or a very large observational study would be the optimal study design to demonstrate
such a difference, if present.
Method of Consult
Neurology
Thrombolytic Expert
Either/Both
Adjusted Odds Ratio For
Deviation
1.06
0.62
1.25
95% CI
P
(0.55,2.06)
(0.66,2.01)
(0.58,2.68)
0.86
0.62
0.57
P108
Intracranial Volume Adaptation and Complications after Decompressive
Hemicraniectomy with Durotomy.
Axel J Rosengart, Charity Cordero-Tumangday, Jeffery I Frank, Bahk Yamini, Fernando D
Goldenberg; The Univ of Chicago Med Cntr, Chicago, IL
Decompressive hemicraniectomy with durotomy (DHwD) is increasingly utilized in patients with
expanding, space-occupying hemispheric lesions neuromedically intractable intracranial hypertension, often as a life-saving procedure. However, there is limited information available
delineating the intracranial volume changes and operative complications post DHwD. We report
a prospective case series of 28 DHwD patients with the following diagnoses: 12 (43%) ischemic
stroke, 9 (32%) subarachnoid hemorrhage (SAH), 2 (7%) intracerebral hemorrhage, 5 (18%)
non-vascular. Intracranial volume changes on pre- and postoperative head CT were quantified
in 15 cases using ANALYZE software. All pre- and postoperative CT images and complications
thought to be directly related to the DHwD procedure were evaluated by 2 independent
neurointensivists. Mean age of 48 years; 57% females; 57% Non-Caucasian, 43% Caucasian.
Hemicraniectomy was performed within an average of 2.6 hours from onset of the clinical
herniation syndrome. Mean pre-operative intradural volume was 1353cc which increased to a
mean of 1506 cc post-operatively (11%). Postoperative subgaleal volume increased by 10%,
while the intraventricular CSF space expanded by 25%. Pre-operative ICP monitoring was
available in 57% (n⫽16) of cases with mean ICP of 40 mmHg (range 16 –90 mmHg).
Post-operative ICP monitor was utilized in 82% (n⫽23) with mean ICP values of 16 mmHg
(range 8 - 30). The average ICP reduction post-operatively was 25 mmHg. Pre-operative mean
anteroseptal shift was 10 mm (range 4 - 19), while the mean pre-operative pineal shift was 5
mm (range 0 - 12). Mean reduction was 6 mm and 3 mm, for anteroseptal and pineal midline
shift, respectively. Complications included: a) nonsurgical ipsilateral intraparenchymal hemorrhages 4/28 (14%) b) subdural hematoma requiring surgical evacuation (3/28, 11%) c)
hydrocephalus 7/28 (25%) d) wound breakdown in 4/28 (14%) e) CSF drainage-related
infection in 3/28 (11%). Decompressive hemicraniectomy with durotomy reverses the brain
herniation syndrome from acutely expanding hemispheric vascular lesions as demonstrated by
ICP normalization and detailed intracranial morphometric analyses. However, DHwD may be
associated with clinical complications including subdural and intraparenchymal hemorrhages,
hydrocephalus, wound breakdown, and infections.
P109
SPECTRM - Stroke Patients Eligible for Clinical Trials - a Regression
Model.
Alexis M Taylor, Amanda B Castle, NIH, NINDS, Section on Stroke Diagnostics and
Therapeutics, Bethesda, MD; Amie W Hsia, Washington Hosp Cntr, Washington, DC; Jose G
Merino, NIH, NINDS, Section on Stroke Diagnostics and Therapeutics, Bethesda, MD;
Chelsea S Kidwell, Georgetown Univ, Washington, DC; Steven Warach, NIH, NINDS, Section
on Stroke Diagnostics and Therapeutics, Bethesda, MD; for the NIH Natural History of
Stroke Investigators
Objective: To develop a model for estimating the proportion of stroke patients eligible for
clinical trials based on the three most influential variables: age, National Institutes of Health
Stroke Scale (NIHSS), and onset to triage time (OTT). Methods: This study was a retrospective
review of all patients with confirmed acute ischemic cerebrovascular syndromes referred to the
stroke team over a 70 month period at two hospitals. Patients were excluded if missing any of
the required data points. Onset to treatment time window was assumed to be one hour later
than the onset to triage time, which was recorded for each patient. The cumulative proportion
of patients over the range of values was plotted for each of the three variables and fit to a
regression curve. The regression equations thus generated were used to calculate the
proportion of strokes satisfying a given range of trial eligibility criteria (e.g., NIHSS 6 –30).
Assuming the correlations among these factors are negligible, the product of the predicted
proportions for each of the 3 eligibility criteria is taken as the overall estimate of the proportion
of stroke patients meeting these trial eligibility criteria. Results: The model was developed from
one half of the total sample of 1323 cases, and confirmed using the second half of the data.
Age was fit by a Weibull function, onset to triage time by a third order logarithmic function, and
NIHSS by a first order logarithmic function (See figure). When applying this model to a clinical
trial, for example the MR RESCUE trial, with inclusion criteria of age 18 – 85, NIHSS 6 –30, and
onset to triage time (OTT) 2–7 hours, the probability of patients meeting each of these criteria
would be 81 %, 37%, and 27% respectively. The final probability of patients meeting all three
criteria is 8.1%. Conclusions: We have demonstrated a simple approach to estimating the
proportion of a stroke center’s population that may be eligible for a specific clinical trial based
on age, NIHSS, and onset to triage time. Differing demographics across stroke centers and
geographies may yield different regression equation parameters, but the approach should be
applicable to all stroke centers and additional eligibility criteria. This approach may be valuable
for clinical trial planning.
P110
Application Of The “Practical” Continual Reassessment Method (CRM) To
Two Phase I Dose-finding Studies Of Neuroprotection In Ischemic Stroke.
Scott W Miller, Sharon D Yeatts, Med Univ South Carolina, Charleston, SC; Adnan I Qureshi,
Univ of Minnesota, Minneapolis, MN; Steven R Messe, Univ of Pennsylvania, Philadelphia,
PA; Yuko Y Palesch; Med Univ South Carolina, Charleston, SC
Background - There are no FDA-approved neuroprotective medications for ischemic stroke.
However, given the public health implications of an effective neuroprotective agent, it is likely
that a large pool of potential agents will continue to be developed and investigated. As a result,
methods for improving the efficiency and safety of Phase I dose-finding and safety studies are
desirable. The “practical” continual reassessment method (pCRM) is a non-Bayesian approach
to dose-finding. It has several modifications to improve safety over the original CRM model,
while still retaining statistical advantages over more traditional algorithms, e.g. the commonly
used “3⫹3” design. Unlike the “3⫹3” design, the pCRM allows for a continuous dosing range
rather than requiring pre-specification of a limited number of arbitrary doses. We evaluated the
operating characteristics of the pCRM for Phase I dose-finding studies in the setting of two
planned erythropoiesis neuroprotection studies. Methods - We conducted simulation studies
using a SAS macro to examine the behavior of the pCRM for these two treatments across a
wide range of possible MTDs/MEDs. For the first agent, we modeled a traditional doseresponse curve to identify the maximum tolerated dose (MTD). For the second agent, we used
an efficacy response to find the minimally effective dose (MED) worthy of further study. We
examined the average sample size required, the average dose recommended, the number of
patients exposed to subtherapeutic doses, and the effect of model mis-specification. Results
- Based on approximately 1000 simulated datasets per setting examined, the pCRM is efficient,
in that it requires a median of 39 subjects (95% CI 25– 45) to reliably estimate the MTD/MED.
Few subjects (18%) are treated at sub-therapeutic doses (doses significantly below the
MTD/MED), and the majority of these are due to the requirement to start at the lowest dose;
excluding these decreases this to only 5%. Less than 3% of the subjects were treated in the
upper 10th percentile of the doses under consideration, and none were exposed to doses
beyond the pre-specified maximum acceptable dose. 57% of the simulations recommended a
dose within 10% of the true dose, and 90% within 20%. Conclusions - Our simulations highlight
several of the advantages of the pCRM. The sample size needed for this approach is in a
feasible range for a Phase I trial, patient exposure to non-efficacious or toxic doses is
minimized, and the model appears to be robust to mis-specification of the underlying
dose-response curve. Finally, the pCRM demonstrated excellent accuracy in determining the
correct dose established by the simulation. We recommend that this model be considered more
routinely for Phase I dose-finding neuroprotectant trials for stroke.
P111
Is Mechanical Clot Removal a Cost-Effective Treatment for Acute Stroke?
Mai N Nguyen-Huynh, S Claiborne Johnston; UCSF, San Francisco, CA
Background Several mechanical clot-retrieval devices have been tested as therapies for acute
ischemic stroke and one of these was recently approved by the FDA for the removal of clots
causing ischemic strokes. While reported rates of recanalization with mechanical therapies
have been promising and would be expected to improve outcomes, it is not known whether the
upfront costs and risks would make this option cost effective. We sought to examine whether
mechanical clot removal is a cost-effective treatment for acute stroke compared to best
medical therapy, using recanalization as an intermediate to derive expected outcomes.
Methods We performed a cost-utility analysis of patients with acute stroke due to large
intracranial artery occlusion presenting beyond the 3-hour window for intravenous tPA. We
compared mechanical clot removal to best medical therapy for secondary stroke prevention.
This analysis was done with a societal perspective. Model inputs for the mechanical clot
removal arm were derived from raw data from Multi MERCI trial as well as a recent
meta-analysis [Stroke 2007;38:967–73], and included rate of recanalization with the device,
rates of intracerebral hemorrhage (ICH) for successes and failures, and functional outcomes, as
well as costs of the procedure and hospitalization. For the best medical therapy arm, we used
597
rates of spontaneous recanalization [Stroke 2007;38:967–73], intracerebral hemorrhage (ICH),
and functional outcomes [JAMA 1999; 282:2003–2011] based on current literature. Discounted
QALYs were determined for 65-year-old patients with acute stroke, with 3-month functional
outcomes categorized by modified Rankin scores (mRS) of 0 –2, 3–5, and 6. Interventions with
cost-effectiveness ratios ⬍$50,000/QALY are generally considered cost-effective. Results For
the base case, we modeled a rate of recanalization was 84% for mechanical clot removal with
a 6.2% rate of symptomatic ICH. For best medical therapy, we modeled a spontaneous
recanalization rate of 24% with a 2% rate of symptomatic ICH. With these inputs mechanical
clot removal was associated with a $26,000 net saving and a gain of a 0.21 QALYs for each
use, thus dominating medical therapy. In sensitivity analysis, results were highly dependent on
the rates of recanalization, symptomatic ICH, and 3-month functional outcomes. Conclusions
Based on the published literature, mechanical clot removal in qualified patients presenting with
acute stroke who are beyond the 3-hours window appears to be cost-effective compared to
best medical therapy. However, results of this analysis are based on a number of assumptions
and are sensitive to estimated variables.
P112
Barriers to the Emergency Use of Thrombolysis for Acute Ischemic Stroke:
the INcreasing Stroke Treatment through INteractive Behavioral Change
Tactics (INSTINCT) Trial.
William J Meurer, Jennifer J Majersik, Shirley M Frederiksen, Lingling Zhang, Annette
Sandretto, Phillip A Scott; Univ Of Michigan, Ann Arbor, MI
Introduction: Numerous internal and external barriers exist which inhibit adherence to
guidelines recommending tPA delivery in acute stroke. We used qualitative methods to describe
and prioritize barriers to the delivery of tPA. Methods: The INSTINCT trial is a multi-center,
randomized, controlled study to evaluate a barrier assessment and interactive educational
intervention designed to increase appropriate tPA use in stroke. Hospitals were randomly
selected from the population of eligible Michigan acute care hospitals and matched into 12
pairs. The intervention sites, randomly assigned within the pairs, underwent qualitative barrier
assessment. Focus groups were conducted by trained leaders with representatives from each
intervention site using a professionally developed discussion guide. Six groups, of 4 – 6
individuals each, ran concurrently and had verbatim transcriptions made. A prespecified
taxonomy was employed to characterize barriers to clinical guideline adherence. Two
investigators independently coded the transcripts into themes using a grounded theory
approach. Participant responses were coded into 9 main themes: 6 internal barriers
(motivation, self-efficacy, outcome expectancy, and lack of awareness, agreement, or
familiarity with guidelines) and 3 external barriers (environmental factors such as slow
specialist response, patient/family factors such as delayed arrival times, and guideline factors
such as contradictory guidelines). A single paragraph (the coding unit) could be assigned 0 –9
themes. Results: There were 30 participants: 10 emergency physicians (EPs), 15 nurses, 3
neurologists, 1 hospitalist, and 1 pharmacist. A total of 605 responses were coded into the 9
themes. The agreement between the coders was 82.1%. Environmental and patient factors
were the most frequently cited barriers (37.1% and 16.7% of total coded responses
respectively). Other important barriers included familiarity with (13.0%) and motivation to
adhere to (10.4%) the guidelines, self-efficacy (the feeling that one could not perform the
guideline) (9.7%), and outcome expectancy (the belief that performing the guideline would not
lead to the desired outcome) (8.0%). Lack of awareness of the existence of acute stroke
guidelines, presence of conflicting guidelines, and lack of agreement with the guidelines were
not important barriers (each ⬍5%). Nurses were somewhat more likely to cite lack of
familiarity as a barrier (17.3% vs. 8.8%) and less likely to cite lack of agreement (1.4% vs.
5.1%) when compared to EPs. Conclusions: Acute stroke stakeholders perceive environmental
and patient factors as the primary barriers to adherence with acute stroke guidelines. Detailed
knowledge of these barriers is crucial to designing effective educational interventions to
improve guideline adherence.
P113
Serum Magnesium And Early Stroke Severity: Influence On Stroke
Syndromes.
Paolo Milia, Stroke Unit, Univ of Perugia, Perugia, Italy; Ken Lees, Stroke Unit, Glasgow,
United Kingdom; Katiuscia Nardi, Neurology, Perugia, Italy; Maurizio Paciaroni, Michele
Venti, Valeria Caso, Sergio Biagini, Giancarlo Agnelli; Stroke Unit, Univ of Perugia, Perugia,
Italy
Background: Magnesium revealed to be benefit in animal models of stroke and recently the
IMAGES trial revealed significant benefit of intravenous magnesium in patients with non cortical
stroke particularly in lacunars clinical syndromes (LACS) Purpose and methods: We aimed to
test whether serum magnesium collected at admission on acute stroke patients can play a role
on early neurological clinical pattern and if there is a difference between the various clinical
syndromes and/or subtypes of stroke We studied patients consecutively admitted to our Stroke
Units. Serum Magnesium was collected at admission: values were divided in four subgroups
(Mg⬍1.6, Mg 1.7, Mg 1.8 –1.9, Mg ⬎ 2). Severity of stroke was assessed according to NIHSS,
respectively at admission (NIHSS0) and after 72 hours (NIHSS72). Outcome was valuated using
mRS. Results: One thousand consecutive acute stroke patients were studied (832 Ischaemics,
mean age 75⫾11, 168 Haemorrhagics mean age 73⫾13). Among the overall patients the
mean NIHSS score difference between the four Mg groups showed a worst clinical pattern in
patient with Mg⬍1.6 at NIHSS0 ( 10⫾7 p 0.01). Focusing on ischemic stroke the same results
was obtained for Mg⬍1.6 group at NIHSS0 (10⫾7 p0.02) showing also a less probability to be
598
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Vol 39, No 2
February 2008
alive at 72 hours (p 0.02). There were no differences in hemorrhagic strokes. The stroke
syndromes had similar frequencies among the four subgroups although LACS showed a worst
clinical pattern at NIHSS72 (6⫾5, p0.01) within the Mg⬍1.6 group. After binomial logistic
regression analysis Lacs group showed a more probability of bad outcome (mRS⬎2) having a
Mg 1.7 at admission (p 0.03 CI 1.07–7.3). Conclusions: Low serum magnesium at admission
seems to be related with bad clinical presentation in ischaemic stroke patients rather than
haemorrhagics. Particularly LACS syndrome seems to be more sensible to low serum
magnesium, thus justifying the recent results of clinical trials and underlying the opportunity of
MG treatment in LACS.
P114
Mechanical Approaches Combined with Intraarterial Pharmacological
Therapy are Superior to Either Intervention Alone in Revascularization of
Acute Carotid Terminus Occlusion.
Ridwan Lin, Nirav Vora, Sayed Zaidi, Ajith Thomas, Michael Horowitz, Univ of Pittsburgh
Med Ctr, Pittsburgh, PA; Rishi Gupta, Michigan State Univ, East Lansing, MI; Susan Kim,
Maxim Hammer, Ken Uchino, Lawrence R. Wechsler, Tudor Jovin; Univ of Pittsburgh Med
Ctr, Pittsburgh, PA
Background and Purpose: Acute stroke caused by occlusion of the internal carotid artery
terminus (TICA) carries a poor prognosis. Intraarterial (IA) pharmacologic thrombolysis is
associated with low recanalization rates. We sought to determine whether adjunctive
mechanical revascularization achieves better vessel recanalization and functional outcome in
acute TICA occlusions. Methods: We retrospectively reviewed 59 consecutive interventional
cases of acute stroke due to TICA lesions treated at our center between October 1998 and July
2007 and collected clinical, CT, angiographic and followup outcome data. Mechanical
approaches (MERCI retrieval, angioplasty, stent) with or without adjunctive IA pharmacological
therapy were compared to intraarterial thrombolysis alone (urokinase (UK) or tissue plasminogen activator (TPA)). Some patients in both groups also received intravenous thrombolysis.
Univariate and multivariate analyses were performed to determine predictor(s) of recanalization
(Thrombolysis in Myocardial Infarction (TIMI) scores of 2–3) and favorable functional outcome
at 3 months (modified Rankin score of 0 –2). Results: Lowest recanalization rates were
observed with IA-TPA/UK with or without adjunctive intravenous TPA or glycoprotein IIB-IIIA
inhibitor (3/13, 23.1%). MERCI retriever and adjunctive intraarterial TPA/UK therapy was
associated with the highest recanalization rates (8/10, 80%, p⫽0.012). Angioplasty and/or
stenting with adjunctive IA-TPA/UK achieved 54.6% recanalization (6/11,p⫽0.21). Baseline
age, admission NIH stroke score (NIHSS), Alberta Stroke Program Early CT score (ASPECTS)
score, time to intervention, and stroke etiologies were not significantly different between these
groups. In a multivariate regression analysis, MERCI retriever ⫹ IA-TPA/UK adjunct (OR⫽12.5,
CI⫽2.24 –106.2, p⫽0.01) and any mechanical thrombolysis ⫹ IA-TPA/UK adjunct (OR⫽4.71,
CI⫽1.2–21.2, p⫽0.031) independently predicted TIMI 2–3 recanalization. No statistically
significant difference was observed between the use of mechanical only (1/4), mechanical ⫹IA
(3/18), or IA only therapies (3/13) in development of type 2-parenchymal hemorrhages
(p⫽0.88). In a stepwise logistic regression model, age (OR⫽0.94, CI⫽0.88 –1.0, p⫽0.045),
admit NIHSS (OR⫽0.78, CI⫽0.61–1.0, p⫽0.05), and TIMI 2–3 recanalization (OR⫽5.6,
CI⫽0.98 –31.9), p⫽0.052) were associated with favorable functional outcome. Conclusions:
Mechanical approaches in combination with adjunctive IA pharmacological therapy are superior
to pharmacologic thrombolysis or mechanical intervention alone in revascularization of acute
TICA occlusion.
P115
Reliability of NIHSS Training and Certification in Across Multiple Venues.
Patrick Lyden, Rema Raman, Lin Liu, Karen Rapp, Univ of California, San Diego, CA; Marion
Emr, Margo Warren, John Marler; NINDS, Bethesda, MD
The AHA/ASA offers web-based training and certification for users of the NIH Stroke Scale, the
most widely used certification for participation in modern stroke clinical trials. Users may train
and certify from the web, using a DVD individually, or in group settings. We sought to measure
inter-rater reliability of the certification video across multiple venues using methodology
previously published for NIHSS reliability. We obtained scores from users who certified on the
website (n⫽7,419), individually (n⫽379), in small groups (n⫽178) and at large meetings of
trial investigators (n⫽238). Demographic data was not available for website raters, but from
the other venues we obtained responses from 795 raters: 32.5% of all responses came from
nurses, 3.9% from ED physicians, 44.2% from neurologists, and 7.7% from others. One half
(50.8%) of raters were previously NIHSS certified. Item responses were tabulated, scoring
performed as previously published, and agreement measured with unweighted Kappa
Coefficients and an intraclass correlation coefficient. We used bootstrap and jackknife methods
to estimate variances and confidence intervals since there were an unequal number of ratings
within patients. Kappas ranged from 0.15⫾0.06 (Ataxia) to 0.81⫾0.16 (LOCC questions). Of 15
items, 2 showed poor, 11 moderate, and 2 excellent agreements, based on Kappa scores. The
pattern of Kappa scores resembled those obtained in previous studies, with Ataxia, and Face
showing poorest agreement, and LOCQ and LOCC shows best agreement. The intraclass
correlation coefficient for total score was 0.85 (95% CI 0.80 - 0.90). Reliability scores were not
statistically significantly different among all venues although scores for individual use were
highest, followed by group settings, followed by website. There were no major differences in
agreement between nurses and physicians for non-web users. Kappa scores were similar by
previously certification status. These data show that NIHSS certification via the AHA/ASA
website does not differ, in terms of reliability, from certification obtained via other venues and
is a reasonable alternative to DVD certification.
P116
Characteristics of Cardioembolic Stroke in Response to Thrombolytic
Treatment.
Hyo Suk Nam, Dept of Neurology, Ajou Univ College of Medicine, Suwon, Republic of Korea;
Kyung-Yul Lee, Dept of Neurology, Yonsei Univ College of Medicine, Youngdong Severance
Hosp, Seoul, Republic of Korea; Seong Hwan Ahn, Dept of Neurology, Chosun Univ College
of Medicine, Gwangju, Republic of Korea; Sang Won Han, Dept of Neurology, Inje Univ
College of Medicine, Sanggye Paik Hosp, Seoul, Republic of Korea; Jong Yun Lee, Dept of
Neurology, National Med Cntr, Seoul, Republic of Korea; Seo Hyun Kim, Dept of Neurology,
Yonsei Univ Wonju College of Medicine, Wonju, Republic of Korea; Dong Chul Park, Dept of
Neurological sciences, Univ of Nebraska Medicine Cntr, Omaha, NE; Ji Hoe Heo; Dept of
Neurology, Yonsei Univ College of Medicine, Seoul, Republic of Korea
Objective: Although responses to thrombolytic treatment vary among individual, clinical factors
to predict the responses are not well known. A growing body of evidence suggests that stroke
patients due to cardioembolism (CE) show poor prognosis and frequent hemorrhagic
transformation. However, it is uncertain how patients with CE would respond to the
thrombolytic treatment. Methods: This study was conducted by retrospective review of case
series from a prospective stroke registry. All the consecutive patients who received the
thrombolytic treatment were investigated. Stroke due to CE were defined as the presence of
atrial fibrillation, sick sinus syndrome, mechanical valve replacement, mitral stenosis, dilated
cardiomyopathy, and congestive heart failure. The recanalization was determined based on the
Thrombolysis In Myocardial Infarction (TIMI) grading system. Results: From January 2000 to
May 2005, 166 patients received thrombolysis. Among them, 11 (6.6%) patients were excluded
due to incomplete data. Finally, data of 155 patients were analyzed for this study. The modality
of thrombolytic treatment was IV tissue-type plasminogen activator (tPA) in 73 (47%),
intraarterial (IA) urokinase in 32 (21%), combined IV tPA and IA urokinase treatment in 50
patients (32%). Eighty patients (52%) had been identified having one or more than one CE
before thrombolytic treatment. The patients with CE were older (p⫽0.007) and of female
predominance (p⫽0.003). Onset-to-treatment (159.5 vs. 137 minutes p⫽0.056), and baseline
NIHSS scores (18 vs. 14, p⫽0.074) were not different between patients with CE and those
without. Although, overall recanalization rate (TIMI 2 or 3) was not different (67% vs. 73%
p⫽0.456), complete recanalization (TIMI 3) was less often achieved in patients with CE (22%
vs. 44%, p⫽0.01). According to the modality, IV tPA was less effective for achieving complete
recanalization against CE clots (19% vs. 58%, p⫽0.013), while responses to IA urokinase
(p⫽0.961) and combined treatment (p⫽0.139) were not different between patients with CE
and those without. Hemorrhagic transformations were more common in patients with CE (44%
vs. 23%, p⫽0.005). Poor outcome (modified Rankin score ⱖ3) at 3 month were frequent (59%
vs. 37%, p⫽0.008) in patients with CE. Conclusions: The present study demonstrated that
cardioembolic stroke is predictive of incomplete recanalization, a poor response to IV tPA, poor
functional outcome, and hemorrhagic transformation.
P117
Impact of the Metabolic Syndrome on the Temporal Profile of Arterial
Recanalization after Thrombolysis for Acute Middle Cerebral Artery
Ischemic Stroke.
Juan F Arenillas, Mónica Millán, Natalia Pérez de la Ossa, Cristina Guerrero, Domingo
Escudero, Laura Dorado, Elena López-Cancio, Ana C Ricciardi, Patricio Sandoval, Antoni
Dávalos; Neurosciences Dep. Germans Trias i Pujol Universitary Hosp, Barcelona, Spain
Background and purpose: The metabolic syndrome (MetS) is a cluster of vascular risk factors
associated with a prothrombotic state and enhanced inhibition of endogenous fibrinolysis. We
aimed to evaluate the impact of MetS on the temporal profile of arterial recanalization after
systemic thrombolysis in patients with acute middle cerebral artery (MCA) ischemic stroke.
Methods: We prospectively studied 77 consecutive ischemic stroke patients showing an MCA
occlusion on prebolus transcranial Duplex (TCCD) examination, who were treated with i.v. t-PA
following SITS-MOST criteria. The MetS was diagnosed during admission following AHA/NHLBI2005 criteria. The occluded MCA was monitored by serial TCCD recordings obtained 2, 6, and
24 hours after t-PA treatment. Thrombolysis in Brain Ischemia (TIBI) criteria were used to define
complete, partial or absent MCA recanalization at each time point. Arterial recanalization was
defined as early when complete or partial recanalization occurred ⬍6h after t-PA bolus.
Results: Mean age of included patients was 67.8 ⫾ years. The MetS was diagnosed in 44
(56%) patients. Median baseline NIHSS score was 14 (interquartile range 9 –18). Patients with
the MetS showed a temporal profile of MCA recanalization characterized by a lower likelihood
of achieving complete or partial recanalization at 2h [16 MetS patients (36%) vs. 19 no-MetS
(58%)] and at 6h [22 (50%) vs. 25 (76%)] after t-PA, and by a higher frequency of absent
recanalization at 24 hours [16 (36%) vs. 2 (6%)] (p⫽0.021). The differences were more
pronounced in the same direction when considering the time profile of complete MCA
recanalization (p⫽0.0004). The MetS emerged as independently associated with a lower
probability of early MCA recanalization (OR 0.34, 95% CI [0.12– 0.98], p⫽0.046) and with a
higher odds of absent MCA recanalization at 24 h (OR 9.8, 95% CI [1.8 –53.5], p⫽0.008), in
multivariate logistic regression analyses adjusted for age, sex and baseline glycemia.
Conclusion: The temporal profile of t-PA induced MCA recanalization in patients with the MetS
appears to be characterized by a lower likelihood of early (⬍6h) MCA recanalization and by a
higher risk of persistent (⬎24h) MCA occlusion.
P118
Rescue Thrombolysis And Beyond ; Usefulness Of Intravenous Tirofiban In
Acute, Progressing Cerebral Infarction.
Jae H Sung, Seung H Yang, Jae T Hong, Byung C Son, Sang W Lee, Chun K Park; St.
Vincent’s Hosp. (Neurosurgery), Suwon, Republic of Korea
Introduction The platelet glycoprotein (GP)IIb-IIIa receptor blockers has been accepted for
coronary intervention and nowadays, they are increasingly used for thrombolysis of acute
occlusive stroke. For powerful blocking of platelet-fibrin aggregation, we applied intravenous
(IV) tirofiban to various acute progressing ischemic strokes. Material and Method From March
2006 to Feb 2007, total 18 cases of cerebral infarction were treated using intravenous tirofiban
(male 9, mean age 63.2⫾10.7). Progression of infarction was defined as any subjective or
objective neurologic deterioration despite of conventional conservative management of acute
infarction. Dosage was strictly matched with manufacturer’s recommendation (body weight
dependent loading dose for 30 min followed by maintenance dose). Categories of infarction are
as follows; acute occlusion of major cerebral arteries (Group 1, n⫽3), progressing infarction of
anterior circulation (Group 2, n⫽8) and of posterior circulation (Group 3, n⫽7). During
maintenance infusion, the blood pressure was strictly controlled under 160mmHg of systolic
pressure. Results Mean interval between admission and onset of progression in group 2 and
3 was 25.3⫾15.1 hrs. Total duration of tirofiban maintenance were 1.1⫾0.9 days in group 1,
3.9⫾1.7 days in group 2 and 5.0⫾3.3 days in group 3. Success rate of progression arrest were
33% (1/3) in group 1, 62.5% (5/8) in group 2 and 85.7% (6/7) in group 3. Most frequent side
effect was hematuria (4 cases) followed by rash (1 case). In only one case with gross
hematuria, tirofiban was used intermittently. No intracranial hemorrhagic complication
occurred. Conclusion Intravenous tirofiban therapy may be effective and promising for arrest
of various types of progressing stroke.
P119
Early Ischemic Changes May Be Associated With Symptomatic Hemorrhage
in Multi MERCI.
Helmi L Lutsep, Oregon Stroke Cntr, Oregon Health & Science Univ, Portland, OR; Tudor G
Jovin; Univ of Pittsburgh Med Cntr, Pittsburgh, PA
Objective: To investigate whether more marked early ischemic changes, measured using the
Alberta Stroke Program Early CT Score (ASPECTS), are associated with the development of
symptomatic intracerebral hemorrhage (sICH), poorer outcomes and lower frequency of
recanalization in patients treated with mechanical embolectomy in the Multi MERCI study.
Background: More significant early ischemic changes, ASPECTS ⱕ 7, have been associated
with parenchymal hemorrhages in 6 hour trials of tissue plasminogen activator and
pro-urokinase. More severe ischemia has been linked with lower likelihood of vessel
recanalization. Methods: Patients with anterior circulation strokes enrolled in Multi MERCI and
baseline ASPECTS ⱕ 7 were compared to those with ASPECTS ⬎ 7 as determined by the
investigator for development of sICH (4-point National Institutes of Health Stroke Scale (NIHSS)
change and any blood on imaging at 24 hours), good outcome (modified Rankin ⱕ 2) and post
procedural revascularization success (TIMI 2–3). The groups were compared for age, gender,
baseline NIHSS, baseline blood glucose, history of congestive heart failure, use of lytics, lesion
location, time to groin stick, procedure duration and number of passes. Results: ASPECTS ⱕ
7 was present in 24 of 147 cases (16%) and baseline characteristics did not differ from the
ASPECTS ⬎7 group. Those with ASPECTS ⱕ 7 trended toward higher overall sICH rates (17%
(4/24) versus 6.5% (8/123), p⫽0.11) and developed more symptomatic PH2s (dense
hemorrhages exceeding 30% of infarct volume) (13% versus 0.8%, p⫽0.014). Good outcomes
(29% in low ASPECTS vs. 39% high, p⫽0.49) and mortality (33% in each, p⫽1) did not differ
significantly between the 2 groups, despite a tendency toward more revascularization success
in those with higher ASPECTS (54% vs. 69%, p⫽0.16). Conclusions: More marked early
ischemic changes may be associated with sICH and perhaps less vessel recanalization while
not significantly affecting outcomes after mechanical embolectomy. Since only 16% of the
cases were reported to show these changes, however, the accuracy of the study investigator’s
assessments is uncertain. A blinded panel review of the MERCI and Multi MERCI scans is in
progress.
P120
Drip-and-Ship Thrombolytics: Is This Approach Safe to Deliver
Standard-of-Care Therapy for Acute Ischemic Stroke?
Sheryl Martin-Schild, Miriam M Morales, UT Houston Health Science Cntr, Houston, TX;
Aslam M Khaja, Univ of Illinois at Chicago, Chicago, IL; Andrew D Barreto, Hen Hallevi,
Anitha Abraham, M. Rick Sline, James C Grotta, Sean I Savitz; UT Houston Health Science
Cntr, Houston, TX
Background: Tissue plasminogen activator within 3 hrs of symptom onset remains the only
proven treatment for acute ischemic stroke (AIS), yet national rates of t-PA use among eligible
patients remain ⬍5%. Many small hospitals are reluctant to treat with t-PA unless the patients
can be rapidly transferred to stroke centers for post-lytic care. While this approach has been
shown to increase t-PA delivery, the safety and liability, remain concerns. Our stroke center
serves as a hub for emergency departments covering a radius of more than 100 miles.
Methods: From our prospective stroke registry, we identified patients over the past 3.5 years
who presented to outside hospitals (OSH) with acute stroke symptoms, were treated with t-PA
599
after consultation with our stroke team, and then transferred for further care. We compared the
baseline demographics, NIHSS, onset-to-needle and door-to-needle times, adverse events
(sICH, PH2, and neurological deterioration), and early outcomes (discharge mRS and
disposition) of drip-and-ship patients with patients treated within 3 hours of onset with IV t-PA
in our emergency department. Pearson’s Chi-Square (for categorical measures) and t-Test (for
continuous measures) explored potential differences between transfer patients and patients
treated at our stroke center. Results: We accepted 93 patients after treatment with IV t-PA at
outside hospitals. Only 67 (72%) were treated within 3 hrs of onset. When these patients
treated within 3 hrs were compared with the 319 patients treated directly at our institution over
the same period, we found no difference in age or gender, but a significantly higher proportion
of transfers were white. The baseline NIHSS was lower in patients treated at OSH (p⫽0.043).
The door-to-needle time was significantly prolonged at OSH (p⬍0.0001), but there was no
difference in adverse events. Patients treated at OSH had a trend to more favorable early
outcomes. The inclusion of patients treated beyond 3 hrs at OSH yielded a mean onset to
needle of 160 minutes, which did not affect the incidence of adverse events or good outcomes
(mRS 0 –1). Discussion: The drip-and-ship strategy for delivering standard of care for AIS has
similar safety profiles and discharge outcomes compared with patients treated at our
institution. This approach likely increases the number of treated patients which translates into
improved outcome. The trend to higher rate of good outcomes in the transfer population may
be due to lower baseline NIHSS scores.
Treated MHH ⬍3hrs from
onset N⫽319
Age, years, mean ⫾ SD
Race, % White Black
Hispanic Other
Male, %
Time from onset (or last
seen normal) to tPA
bolus, min
Door to needle time, min
NIHSS pre-tPA, mean ⫾
SD, median (range)
Adjuvant IAT rate, %
Complications, % PH2
sICH neurological
deterioration
Discharge mRS 0–2, %
Discharge mRS 0–1, %
Discharge disposition, %
Good (home or inpatient
rehab)
Treated OSH
⬍3hrs from onset
N⫽67
p-value
64.9 ⫾ 14.5
45.8 37.9 14.4 1.9
65.5 ⫾ 14.4
76.1 10.4 13.4 0
0.77
⬍0.0001
44.2
129.1
44.8
138.0
0.52
0.051
65.1 N⫽306
13 ⫾ 7 12 (0–38) N⫽312
⬍0.0001
0.043
15.4
5.7 4.4 23.7
85.2 N⫽46
11 ⫾ 6 10 (3–28)
N⫽56
7.5
4.5 6.1 18.2
41
26.5
66.3
43.9
28.5
77.0
0.06
0.50 0.38
0.21
0.195
0.404
0.066
P121
Predictors of Recanalization with Mechanical Thrombectomy for Acute
Ischemic Stroke.
Kwang Deog Jo, Gangneug Asan Hosp, Gangneung, Republic of Korea; Jeffrey L Saver,
Sidney Starkman, Doojin Kim, Latisha K Ali, Bruce Ovbiagele, Oh Young Bang, Susan Yun,
Amytis Towfighi, Samir H Shah, Paul M Vespa, Chad Miller, Satoshi Tateshima, Reza Jahan,
Fernando Vinuela, Gary R Duckwiler, David S Liebeskind; UCLA, Los Angeles, CA
Background and Purpose— Arterial recanalization significantly improves functional outcomes
and reduces mortality in patients with acute ischemic stroke. The MERCI® Retriever System
(MERCI) was recently cleared by the FDA for use in acute stroke patients based on technical
efficacy. The purpose of this study was to determine predictors of recanalizaton in acute
ischemic stroke patients treated with the MERCI device. Methods—We analyzed a prospectively maintained database of consecutive patients treated with the MERCI Retriever device for
acute ischemic stroke at a single center from May 2001 to June 2007. Demographic, clinical,
radiological and detailed angiographic features, and therapeutic variables were analyzed. We
compared these variables between patients with successful recanalization (Thrombolysis in
Cerebral [TICI] grades 2 or 3) and those with unsuccessful recanalization (TICI grades 0 or 1).
Predictors of recanalization were determined based on multivariate logistic regression model.
Results—One-hundred fourteen acute stroke patients were treated with mechanical thrombectomy using the MERCI device. Mean age was 65⫾19 years, and median baseline National
Institutes of Health Stroke Scale (NIHSS) score was 19. Recanalization was achieved in 75
(66%) patients (48 TICI 2; 27 TICI 3). On multivariate analysis, independent predictors of
recanalization were prior antiplatelets use (odds ratio [OR], 3.19 [95% CI, 1.03 to 9.85];
P⫽0.044) and good collateral flow (P⫽0.009) defined using the graded ASITN /SIR scale. Other
demographic and clinical features, including time from onset to treatment, baseline NIHSS
score, comorbidities, stroke mechanism, and vital parameters on admission, did not predict
recanalization. Laboratory results, routine CT/MRI findings, angiographic occlusion site, and
adjunctive therapeutic modalities were also not significant predictors of recanalization after
MERCI Retriever thrombectomy. Conclusions—Prior antiplatelets use and greater degree of
collateral circulation evident on pretreatment angiography are associated with successful
recanalization with mechanical thrombectomy using the MERCI Retriever device. These
observations suggest that antiplatelet and collateral enhancement therapies are worthy of study
as concomitant treatments in patients undergoing mechanical thrombectomy.
600
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February 2008
P122
Impact of Timing of Recanalization after Intra-arterial Thrombolysis on
Clinical Outcome.
Kyung-Hee Cho, Eun Kyung Kim, A-Hyun Cho, Sun U. Kwon, Deok Hee Lee, Choong Gon
Choi, Sang Joon Kim, Dae-Chul Suh, Jong S. Kim, Dong-Wha Kang; Asan Med Cntr, Seoul,
Republic of Korea
Background and Purpose: Thrombolytic therapy is based on the “recanalization hypothesis”,
i.e., that reopening of occluded vessels improves clinical outcome through reperfusion and
salvage of threatened tissues. Intra-arterial (IA) thrombolysis is considered to be effective for
treatment of acute ischemic stroke attributable to large artery occlusion. We examined the
relationship between timing of recanalization and functional outcome after IA thrombolysis.
Methods: We retrospectively reviewed 98 acute ischemic stroke patients treated with IA
urokinase (⫾ intravenous (IV) tissue plasminogen activator (tPA)) between March 2004 and
February 2007. The angiogram immediately after completion of IA thrombolysis was used for
the assessment of immediate recanalization, and follow-up CT angiography or MR angiography
within a week were used for the assessment of delayed recanalization. The patients were
excluded for the analysis: 1) if they received concomitant stent insertion (n⫽10), or 2) if they
did not undergo follow-up vascular imaging despite the lack of recanalization immediately after
IA thrombolysis (n⫽13). Patents were divided into 3 groups: immediate; delayed; and no
recanalization. Clinical outcome was evaluated using the modified Rankin Scale (mRS) at 7-day
and at 3-month after onset. Factors related to each recanalization group were also explored,
Results: Of the 75 patients, recanalization was observed in 53 (70.6%): immediate in 28
(37.3%) and delayed in 25 (33.3%). The proportion of functionally independent patients
(mRS ⱕ 2) at 7-day were 53.6% (15/28) in immediate, 28.0% (7/25) in delayed, and 22.7%
(5/22) in no recanalization group (p⫽0.047). At 3-month, it was 64.3% (18/28), 40.0% (10/25),
and 27.3% (6/22), respectively (p⫽0.027). Multivariate analysis showed that cardioembolism
(odds ratio (OR), 3.74; 95% confidence interval (CI), 1.15–12.19) and middle cerebral artery
occlusion (OR, 3.23; 95% CI, 1.04 –10.04) were independent predictors of any recanalization
(either immediate or delayed) and that IV tPA prior to IA therapy was an independent predictor
of immediate recanalization (OR, 3.91; 95% CI, 1.09 –14.00). Conclusions: Our results show
that the timing of recanalization after IA thrombolysis is significantly associated with clinical
outcome. Stroke mechanism and site of occlusion may be factors discriminating between
recanalization and non-recanalization. The fact that delayed recanalization group has similar
baseline characteristics to immediate recanalization group suggests that more efficient
thrombolytic strategies are needed in this group.
SD ⫽ standard deviation, NIHSSS ⫽ NIH Stroke Scale Score, IQR ⫽ Interquartile range, GOS ⫽ Glasgow
Outcome Scale, mRS ⫽ modified Rankin Scale *Small numbers of subjects were missing outcome data for
each measure. These subjects were assigned a negative outcome. ^Within 36 hours of study drug
administration. Each group includes both placebo and rt-PA treated patients.
P124
Hypointense Leptomeningeal Vessels on T2*-weighted Gradient Echo
Imaging in Acute Ischemic Stroke: A Correlation with Angiographic
Findings.
Sam-Yeol Ha, Sang-Hyuck Seo, Gyeong-Moon Kim, Chin-Sang Chung, Kwang-Ho Lee;
Samsung Med Cntr, Sungkyunkwan Univ Sch of Medicine, seoul, Republic of Korea
Background and purpose: T2*-weighted gradient echo (GRE) imaging is sensitive to changes
in blood oxygenation. The oxygen extraction fraction (OEF) increases when decreased perfusion
pressure cannot be compensated by increment of cerebral blood volume. Hypointense
leptomeningeal vessels (HLV) draining hypoperfused regions on GRE imaging may indicate the
presence of tissue with increased OEF and deoxyhemoglobin in the vessels. Thus, we analyzed
the correlation between HLV, angiographic findings, and clinical improvement in patients with
acute ischemic stroke who received thrombolytic therapy. Methods: From Samsung Acute
Stroke Registry 22 patients with middle cerebral artery stroke were included, who were treated
by combined intravenous and intra-arterial thrombolysis or intra-arterial thrombolysis within 6
hours of symptom onset. Brain MRI including GRE, diffusion-weighted and perfusion-weighted
imaging was performed with a 3.0-T imager just before digital subtraction angiography.
Results: The small to medium sized HLV on GRE corresponded to the veins in the zone of
delayed wash-out of capillary stain in the delayed venous phase of angiography. These veins
drained into venous sinuses through superior cerebral veins, vein of Labbe, and/or superficial/
deep middle cerebral veins. HLV on GRE imaging may mainly indicate the venous system from
small veins before draining into venous sinuses. Group I with extensive small to medium sized
HLV (n⫽7) which drained into all the superior cerebral veins, vein of Labbe, and superficial/
deep middle cerebral veins (see figures) had the initial NIHSS score from 11 to 22 (mean
16.9⫾3.4) and the group II with less extensive or no HLV (n⫽15) from 6 to 21 (mean
11.7⫾5.3). Major neurologic improvement (defined by a ⱖ8-point improvement in NIHSS score
at 24 hours) was observed in 6/7 patients in group I and 2/15 patients in group II. Conclusions:
The extensive small to medium sized HLV on GRE imaging may predict major neurologic
improvement following thrombolytic treatment in acute ischemic stroke. Figure legend: The
extensive zone of delayed wash-out of capillary stain in the delayed venous phase of
angiography and small to medium sized hypointense leptomeningeal vessels on gradient echo
imaging in a patient with acute right MCA stroke.
P123
How Important is Surrogate Consent for Stroke Research?
Matthew L Flaherty, Jane C Khoury, Dawn Kleindorfer, Joseph P Broderick; Univ Cincinnati,
Cincinnati, OH
Background: Many patients with stroke are unable to provide informed consent for research
studies because of aphasia, neglect, or reduced level of consciousness. In several states
current legal interpretations do not allow surrogate consent for research studies except when
consent is provided by a medical power of attorney or court-appointed guardian. We explored
the importance of surrogate consent in the NINDS rt-PA Stroke Trial, the study that led to the
only FDA-approved treatment for acute ischemic stroke. Methods: Utilizing the NINDS rt-PA
Stroke Trial database we determined which subjects provided their own consent and which
subjects were enrolled by surrogate consent. We compared the baseline characteristics of
these groups and their clinical outcomes in univariable and multivariable analyses. Results:
The NINDS rt-PA Stroke Trial enrolled subjects from 2/4/1991 to 10/30/1994. Of 624
participating subjects, 439 (70%) were enrolled by surrogate consent. Comparisons of subjects
providing their own consent and those enrolled by surrogate consent are provided in the table.
Subjects enrolled by surrogate consent were older, had more severe strokes, and were less
likely to make a good recovery than subjects who provided their own consent. In multivariable
modeling there was no interaction between method of consent and response to rt-PA. If the
NINDS rt-PA Stroke Trial had used the same sample size and recruited at the same rate but
excluded subjects who could not provide their own consent, it would have taken approximately
12.5 years to complete. Conclusions: The NINDS rt-PA Stroke Trial would not have been
completed in a timely fashion without the participation of subjects enrolled by surrogate
consent. Furthermore, exclusion of subjects who could not provide their own consent would
have severely limited the generalizability of trial results and may have produced misleading
estimates of treatment effects if attempts were made to generalize such results. Surrogate
consent is essential to acute stroke research.
Self Consent (%)
Subjects
Age
Time to treatment (hours)
Baseline NIHSSS
90-day NIHSSS ⱕ 1*
90-day Barthel ⱖ 95*
90-day GOS ⫽ 1*
90-day mRS score 0–1*
90-day mortality
Symptomatic intracranial hemorrhage^
185
63.4
2.0
9
76
113
106
98
14
7
(30)
439
(SD12) 68.5
(SD0.62) 1.99
(IQR6–14)17
(41.1)
93
(61.1) 165
(57.3) 131
(53.0) 116
(7.6)
104
(3.8)
15
Surrogate
Consent (%)
(70)
(SD11.3)
(SD0.61)
(IQR11–22)
(21.1)
(37.6)
(29.8)
(26.4)
(23.7)
(3.4)
p-value
⬍0.001
0.88
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
0.82
Acute Management II
P125
Short-term Clinical Outcome Following Gastro-intestinal Tube Feeding By
Immunonutrition-oriented Or Protein-oriented Food In Acute Stroke
Management:Preliminary Results.
Hiroyuki Tajiri, Takahisa Mori, Tomonori Iwata; Shonan Kamakura General Hosp, Kamakura
City, Japan
[Backgrounds/Purpose] Most of acute stroke patients who can not take food orally due to
serious neurological symptoms undertake gastro-intestinal tube feeding (GITF). However, some
of them are led to protein-energy malnutrition (PEM) state, secondary complications occur and
result in longer hospitalization and worse clinical outcome. The purpose of our prospective
study is to investigate whether or not there are any differences between costly
immunonutrition-oriented IMPACTTM and not costly protein-oriented PEMVestTM for GITF on
short-term clinical outcome. [Objects and Methods] Included were patients as follows, 1) who
were admitted to our institution from 1st January 2007 to 15th August 2007, 2) who undertook
GITF during the study period and were assigned randomly to PEMVestTM (P) and IMPACTTM (I)
group. Excluded were patients as follows, 1) who suffered from gastro-intestinal bleeding on
admission or on the second day, 2) who suffered from serious pneumonia on admission or on
the second day, and 3) who presented coma state of 3 in Glasgow coma scale on admission
or on the second day. Evaluation items were age, man(%), NIHSS score on admission, NIHSS
score on the 10th day, change of NIHSS score, albumin value (AV) on admission, AV on the 10th
day, change of AV, and in-hospitalization period. [Results] During the study period, 266 acute
stroke patients were admitted to our institution. Forty-one of them undertook GITF and were
assigned randomly to P group in 15 patients and I group in 26 patients. In P and I groups, an
average age was 78 and 76 years, man (%) was 40 and 61.5, an average NIHSS score on
admission was16.9 and 17.7, median NIHSS score on the 10th day was 16 and 15.5, median
change of NIHSS score was 0 and -0.5, an average albumin value (AV) on admission was 3.86
and 3.94, an average AV on the 10th day was 3.17 and 3.20, an average change of AV was
-0.69 and -0.74, and median in-hospitalization period was 10 and 11.5 days, respectively.
Although there were no significant differences between two groups (Student’s t test, chi square
test, and M-W test), albumin value decreased significantly in P group (p⬍0.005, Wilcoxon test)
and in I group (p⬍0.001, Wilcoxon test). [Conclusions] Although protein-oriented PEMVestTM
was not costly compared to immunonutrition-oriented IMPACTTM, it had the same effect on
short-term clinical outcome and in-hospitalization period in management of serious state of
acute stroke patients.
P126
Does Application of Radio Contrast Media Prior to Thrombolysis Impact
Thrombolytic effect in Acute Ischemic Stroke?
Imanuel Dzialowski, Univ of Dresden, Dept Neurology, Dresden, Germany; Volker Puetz,
Andrew M Demchuk, Univ of Calgary, Dept of Clinical Neurosciences, Stroke Program,
Calgary, Canada; Alastair M Buchan, Univ of Oxford, Dept. Geratology, Oxford, United
Kingdom; Michael D Hill, Univ of Calgary, Dept of Neurosciences, Stroke Program, Calgary,
Canada; for the Calgary CTA Study Group
Objectives: Experimental data suggests a negative interaction between radio contrast media
(RCM) and the fibrinolytic effect of rt-PA. We studied the hypothesis that application of RCM
prior to thrombolysis reduces the response to intravenous thrombolysis with rt-PA. Methods:
We retrospectively studied consecutive ischemic stroke patients receiving CT Angiography
(CTA) prior to IV treatment with rt-PA within 6 hrs from symptom onset and compared functional
outcome to a historical control group NOT receiving CTA before standard thrombolysis with
rt-PA: the Canadian Alteplase for Stroke Effectiveness Study (CASES). Exclusion criteria were
pre-morbid modified Rankin Scale Score (mRS) ⬎ 3 and any intra-arterial intervention. Our
primary endpoint was favourable functional outcome at 90 days defined as modified Rankin
Scale (mRS) scores 0 –2 (if not available score at discharge carried forward). We performed
logistic regression analysis including the variables age, gender, history of diabetes, baseline
NIHSS score, onset-to-treatment-time (OTT), and baseline Alberta Stroke Program Early CT
Score (ASPECTS). Results: For the CTA group, we identified 111 patients (mean age 68 ⫾ 16,
51% male, OTT 155 ⫾ 63 min, median NIHSS score 12), the control group included 1119
patients (mean age 70 ⫾ 13, 55% male, OTT 150 ⫾ 38 min, median NIHSS score 14). Apart
from a higher proportion of pre-thrombolysis anti-platelet therapy in the control group, baseline
characteristics did not differ among groups. Proportions of favourable functional outcome were
47.8% for the CTA and 49.5% for the control group (p⫽0.4). In our logistic regression model,
performance of CTA prior to thrombolysis was an independent negative predictor of favourable
functional outcome (OR 0.62, CI95 0.39 – 0.99, p⫽0.049). Adjusted probabilities for favourable
outcome were 0.48 (CI95 0.37– 0.58) and 0.51 (CI95 0.47– 0.54) for CTA and control group,
respectively. Conclusion: Our retrospective study suggests that performing a CTA prior to IV
thrombolysis with rt-PA might reduce response to thrombolysis. This effect might be caused by
a negative interaction between RCM and rt-PA. These results need to be confirmed, however,
in a prospective fashion. Further basic and clinical research is needed to study possible
interactions between CT and MR contrast media and thrombolytic agents.
P127
Clinical Research Coordinator Turnover: Impact on NIH Funded Clinical
Trials and Potential Solutions.
Edward C Jauch, Judith Spilker, Pooja Khatri, Rose Beckmann, Univ of Cincinnati,
Cincinnati, OH; Michael Hill, Univ of Calgary, Calgary, Canada; Renee Martin, Med Univ of
South Carolina, Charleston, SC; Joseph Broderick; Univ of Cincinnati, Cincinnati, OH
Introduction: With clinical trials growing in complexity and regulatory oversight, clinical
research coordinators (CRC) play an increasingly pivotal role in clinical trials; CRC described as
“the glue that holds the study together”. Recent studies illustrate a growing concern: half of
all CRC leave their positions within 3 years, at the same time the overall CRC experience level
is declining. Locally, CRC loss causes delays in study initiation and regulatory material
submission, and interruptions in recruitment. CRC loss in a multicenter study causes repeat site
initiation visits and orientation, reduced patient recruitment rates, delays in study completion,
and increased study costs. For these reasons, CRC retention is a concern in ongoing clinical
stroke trials. The Interventional Management of Stroke (IMS) III trial is a multicenter phase III
trial investigating new treatment strategies for ischemic stroke. The IMS3 study design is
complex, incorporating IV tPA administration followed by potential intra-arterial strategies, often
necessitating transfer to tertiary care centers. The high-dose human albumin therapy for
neuroprotection in acute stroke (ALIAS) trial is a phase III multicenter study, and while less
complex, faces similar CRC challenges. We investigated the impact of CRC loss on these
studies and began an investigation into ways to improve CRC retention. Methods: We reviewed
IMS3 study initiation data and personnel turnover. A similar review is underway for the ALIAS
trial. We constructed a confidential survey instrument related to CRC turnover and retention
issues. After IRB approval, the survey was sent to all CRC involved in the IMS3 study and ALIAS
trial. The survey data will be presented using descriptive statistics. Results: Funding for the
NINDS sponsored IMS3 study was awarded in 09/05 and first patient recruited in 08/06. IMS3
will utilize 50 clinical sites in the US and Canada, and will enroll 900 patients over a 5 year
period. As of 08/14/07, 32 sites have been visited and reviewed by study executive committee
members, 32 centers are authorized to receive study supplies, 27 are screening, 4 are on hold,
and an additional 21 invited to participate. Since first contact or re-contact after funding was
assured, 37 CRC, 9 principal investigators, and 7 principal interventionalists have resigned or
sought reassignment. 73 patients have been enrolled in IMS3 out of a projected 900 patients.
601
CRC survey results from the IMS3 study and ALIAS trial will be presented at the 2008 ISC.
Conclusions: Clinical research coordinator retention is a growing concern and threatens clinical
trial success. The operational and fiscal impact of CRC loss warrants efforts to improve CRC
retention and preempt their loss
P128
Routine Transthoracic Echocardiography May Be Of Limited Value In
Ischemic Stroke Patients Who Have Normal Electrocardiograms And
Normal Troponin And Brain Naturitic Peptide Levels.
Sanjay Gill, Seema Bansal, D A Shoham, John T Barron, Rima Dafer, Michael Schneck;
Loyola Univ Med Cntr, Chicago, IL
INTRODUCTION The utility of TTE in acute ischemic stroke (AIS) patients is mainly in identifying
wall motion abnormalities, low ejection fractions (EF) or valvular anomalies that may be source
markers for thrombus. Transthoracic echocardiography (TTE) is of limited utility in identifying
intracardiac thrombus yet TTE is routinely performed at most institutions following an acute
ischemic stroke (AIS); some patients may then undergo transesophageal echocardiography
(TEE) thereafter. We hypothesized that a panel consisting of normal troponin and brain naturitic
peptide serum levels along with a normal electrocardiogram (ECG) would preclude the need for
TTE in the overwhelming majority of stroke patients. METHODS One hundred and thirty eight
consecutive patients admitted with the diagnosis of AIS were grouped according to whether or
not they had normal values for troponin (ⱕ0.1 ng/ml), BNP (ⱕ100 pg/ml) as well as a normal
ECG. A normal ECG was defined as absence of the following findings: old infarcts, possible
current ischemia/MI, atrial fibrillation, atrial flutter, left bundle branch block, right bundle
branch block, second degree heart block, third degree heart block, premature ventricular
contractions, left ventricular hypertrophy, left atrial enlargement, or peaked T-waves. The
‘normal values’ (NL) group with normal BNP, troponin, and ECG was compared with the
‘abnormal values’ (ABNL) group for which there was an abnormality in at least one of the three
variables. These two groups were compared with respect to the presence of any wall motion
abnormalities, valvular defects (as defined as moderate or severe stenosis or regurgitation), or
an ejection fraction less that 50% as measured by TTE. RESULTS The average age of the
patients was 70 years with a range of 39 to 92. There were 30 patients in the NL group, and
108 patients in the ABNL group. The NL group had a significantly reduced rate of wall motion
abnormalities (3.3% vs. 28.7%, p ⫽ 0.0036) and a significantly reduced rate of any valvular
defects (6.7% vs. 23.2%, p ⫽ 0.0441) as compared with the ABNL group. Furthermore, there
were no patients in the NL group who had an EF less than 50%; however there were 24
patients in the ABNL group (0.00% vs. 22.2%, p ⫽ 0.0045) with a reduced EF. CONCLUSION
These results suggest that a normal ECG on admission coupled with normal values for BNP and
troponin in patients admitted for AIS may mitigate the need for a TTE with respect to
assessment of wall motion abnormalities, valvular defects and reduced EFs. For those AIS
patients for whom intracardiac thrombus or interatrial anomalies continue to be clinically
suspected, direct assessment with TEE can then be considered.
P129
Predictors of Outcome Following Local Intra-arterial Fibrinolysis for Central
Retinal Artery Occlusion.
Eric M Aldrich, Johns Hopkins Hosp, Baltimore, MD; Andrew W Lee, Celia S Chen, Flinders
Univ Med Cntr, Bedford Park, Australia; Rebecca F Gottesman, Johns Hopkins Hosp,
Baltimore, MD; Mona N Bahouth, Univ of Maryland Med Cntr, Baltimore, MD; Robert J
Wityk, Phillipe Gailloud, Kieran J Murphy, Neil R Miller; Johns Hopkins Hosp, Baltimore, MD
Introduction: Local intra-arterial fibrinolytic therapy (LIF) for central retinal artery occlusion
(CRAO) was developed over ten years ago, but has not become widespread. There is significant
debate in the literature regarding its efficacy, safety and practicality. Understanding what
factors are predictive of either good or bad outcomes would be of significant value in
determining which subjects should be offered this therapy. Methods: Consecutive subjects with
CRAO referred to the Johns Hopkins Hospital Stroke Service from 2001 to 2007 were reviewed.
Twenty-three subjects were identified who received LIF. Clinical characteristics including
stroke risk factors were collected as well as diagnostic test information. In addition, the
characteristics of the diagnostic cerebral angiogram and the subsequent intervention were
collected. The individuals who collected the angiographic data were blinded as to clinical
presentation and outcome. The primary outcome measure was a one line improvement in visual
acuity as tested on a Snellen chart. The secondary outcome was a three line improvement in
visual acuity. Results: Regarding clinical characteristics a prior history of hypercholesterolemia
or stroke showed a trend toward significance, predicting negatively on final visual(OR ⫽ 0.15,
p⫽0.09 for each). No predictive effect was seen from routine diagnostic tests such as EKG,
carotid ultrasound, echocardiography or brain imaging. Diagnostic cerebral angiograms
revealed no significant incidence of concurrent ipsilateral carotid stenosis. One interesting
effect was that in approximately half the subjects super-selective cannulation of the ophthalmic
artery was possible prior to LIF, whereas in the other cases the tip of the catheter could only
by positioned just adjacent to the origin of the ophthalmic artery. Despite this difference in
technique, super-selective vs. non-selective, there was no difference in the primary or
secondary outcome measures. Conclusion: A prior history of hypercholesterolemia or stroke
showed a trend toward significance as negative predictors for outcome following LIF for CRAO.
All other clinical characteristics, including visual acuity at presentation, showed no predictive
effect. However, due to small sample size the statistical power was limited. In addition, both
super-selective and non-selective cannulation of the ophthalmic artery resulted in similar
efficacy of LIF for CRAO. A prospective randomized clinical trial with a larger number of subjects
602
Stroke
Vol 39, No 2
February 2008
is needed to further investigate safety, efficacy and clinical predictors of outcome for this
treatment.
P130
Improving Acute Stroke Care in a Community Hospital Utilizing
Neurohospitalists.
Stanley N Cohen, Kyle Malone, Glenn M Fischberg, Donna Delaney, Rob Phoenix, Scott L
Selco; Sunrise Hosp and Med Cntr, Las Vegas, NV
Objectives: Administration of tPA to acute stroke patients is underutilized in community
hospitals. We studied the effect of having two stroke-fellowship trained neurohospitalists on
tPA utilization in a community hospital with no academic affiliation. Methods: Data on all stroke
admissions were collected using the ASA Get with the Guidelines worksheet. We analyzed
information gathered on all stroke admissions for 2006, the first complete year in which our
hospital had stroke protocols and order sets with 2 stroke neurologists working full time as
neurohospitalists in one hospital with 24/7 availability. Results: Of 1025 patients admitted with
a diagnosis of cerebrovascular disease during the study period, 970 (95%) were seen by the
neurohospitalists; 502 acute ischemic strokes, 225 TIAs, 141 ICHs, 63 SAHs, 39 uncertain. Of
the ischemic stroke patients, 100 (20%) received any type of lytic treatment; IV tPA (N⫽67),
IA tPA (N⫽18), IV/IA tPA (N⫽7), experimental drug (N⫽3), and IV tPA started at an outside
hospital prior to transfer (N⫽5). Mean symptom onset to arrival at the ER was 1.1 and 5.4
hours for IV and IA tPA treated patients, respectively. Mean door-to-CT time was 24 and 30
mins for IV and IA tPA patients, respectively. Mean door-to-treatment time was 74 and 225
mins for IV and IA tPA administration, respectively. Patients receiving IV tPA had a mean age
of 66 years and 54% were male. The IV tPA patients arrived by ambulance from the scene
(84%), by private transport (10%), and by hospital transfer (5%). At least 86% of eligible
patients with no exclusions received tPA. Of patients receiving IV tPA, 6 (9%) died during the
hospitalization, 1 as a complication of drug administration. Of those surviving to discharge,
41% were able to ambulate without assistance, 21% ambulated with assistance, and 33%
were unable to ambulate. Of the 402 patients not receiving thrombolysis, the most common
reasons were arrival ⬎3 hrs after onset (34%), stroke severity too mild (31%) or too severe
(11%) and active internal bleeding (16%). Conclusions: In a community hospital, creation of a
neurohospitalist service with two stroke neurologists, responsible for ER coverage 24/7 but no
outpatient services, resulted in successful administration of lytic therapy to 100 appropriate
acute ischemic stroke patients in one year.
P132
Comparison of Intravenous and Intra-arterial with tPA within 3–6 Hours
Guided by Multi-MRI: Randomised Study of 36 Patients.
Yilong Wang, Weijian Jiang, Xiaoling Liao, Bin Du, Xingquan Zhao, Kehui Dong, Jing Xue,
Peiyi Gao, Liping Liu, Yongjun Wang; Beijing Tiantan Hosp, Capital Med Univ, Beijing, China
Objective To compare the efficacy and safety of intravenous and intra-arterial with rt-PA within
3– 6 hours of acute ischemic stroke with PWI/DWI mismatch guided by multi-MRI. Methods All
acute ischemic stroke patients within 6 hours of symptom onset were recruited from 7 centers
in China between 2005 and 2006 for this prospective, clinical trial. This study is registered as
an International Standard Randomised Controlled Trial, number ISRCTN69163448. Within 3
hours, patients were treated according to NINDS criteria. After 3 to 6 hours, treatment with
randomized intravenously or intra-arterial rt-PA was performed based on multi-MRI findings.
Favorable outcome was assessed after 90 days using a dichotomized modified Rankin scale
score of 0 to 1. Intracerebral bleeding complications were assessed on follow-up MRI or
computed tomography. Data were compared with the pooled placebo and pooled tPA patients
of the ATLANTIS, ECASS, and NINDS tPA trials. Results Favorable outcome was trend to more
frequent but non-significantly in 36 patients (20.3%) be performed with randomized intravenously (n⫽18) or intra-arterial (n⫽18) rt-PA based on multi-MRI findings (50%) compared with
pooled placebo (35.9%; P⫽0.088) and pooled rt-PA patients (37.7%; P⫽0.068). Among those
patients, the rate of good outcome in MRI-selected intra-arterial rt-PA group was 55.6%, but
the intravenous group only was 44.4% (p⫽0.739). The rate of sICH in intra-arterial rt-PA group
was 3/18 (16.7%), the intravenous group was 1/18 example (5.6%), but difference showed no
significance (p⫽0.603). Patients given intravenous rt-PA were treated significantly earlier than
intra-arterial (300 minutes vs 265 minutes; p⫽0.005). The direct cost of intra-arterial
treatment was significantly more expensive than intravenous by RMB 9,000 Yuan (p⫽0.005).
Conclusions To compared with intravenous rt-PA within 3– 6 hours of acute ischemic stroke
with PWI/DWI mismatch guided by multi-MRI. The intra-arterial approach shows the trend to
more effective, but need to enlarge the sample to further study.
P133
Effectiveness of Establishing Critical Pathway and Emergency CT Room in
Thrombolytic Treatment.
Hee Young Park, Jung Han Yoon, Jun Young Choi, Ji Hye Shin, Hye Gyeong Lee, In Ok Han,
Mi Suuk Bog, Hyo Suk Nam; Dept of Neurology, Ajou Univ Sch of Medicine, Suwon,
Republic of Korea
P131
Angiographic Scales in Acute Ischemic Stroke: The MERCI/Multi MERCI
Experience.
David S Liebeskind, UCLA, Los Angeles, CA; Raul G Nogueira; Massachusetts General Hosp,
Boston, MA
Purpose: Angiographic characterization of occlusive lesions and compensatory collateral flow
in acute ischemic stroke may be standardized with the use of various scales. As endovascular
therapy for acute stroke rapidly expands in both investigational studies and routine clinical
practice, familiarity with scale terminology and implementation is critical. We describe the
methodology utilized for the application of angiographic scales employed in the central review
of angiography studies obtained in the MERCI and Multi MERCI studies. Methods: The
angiographic scales used in central readings of baseline and postprocedural angiograms
obtained as part of MERCI and Multi MERCI were analyzed in detail. Scales incorporated various
aspects relating to arterial patency, distal perfusion, and extent of collaterals. Application of
these scales by 2 blinded, central readers was compared, resulting in a standardized algorithm
that allows for routine use and addresses discrepancies or unusual patterns that may impede
standard definitions. A subset of angiograms was selected to underscore distinctive features of
scale performance and consensus definitions. Results: Seven scales were employed by 2
independent reviewers to generate central readings on baseline and post-procedural angiograms in MERCI and Multi MERCI. Two scales were heavily weighted on arterial patency, 4
scales focused mainly on perfusion of the distal territory, and 2 scales assessed collateral flow
at a different level of detail. Considerable agreement occurred on review of baseline
angiograms, whereas greater discrepancies were noted on post-procedural views. Discriminant
ability varied across scales, with subtle and potentially subjective distinctions frequently noted.
Scale performance was influenced by site of vascular occlusion on both initial and
posttreatment angiograms. Specific criteria were needed to define extent of the ischemic bed,
incomplete filling or rate of distal opacification. Scale use on hard copies or films was
distinguished from cases where electronic copies allowed for detailed evaluation of temporal
resolution. Recanalization and reperfusion were often, yet not universally, coincident. Posttreatment embolism was underestimated by most scales. Particular advantages and disadvantages of each scale were noted and lack of prior validation identified. Conclusion: Although
commonly used scales utilize seemingly discrete grades or patterns to define angiographic
views, considerable variation may be noted without elaboration of a standardized algorithm for
implementation. Scales that neglect to address antegrade or retrograde flow to the distal
ischemic bed may have poorer correlation with clinical outcomes. Advantages and disadvantages, including lack of prior validation, of each scale may influence future use in clinical trials
and routine care.
Objective: The need for rapid evaluation and treatment of acute stroke patients has been
well-documented. To reduce time intervals from emergency department (ED) arrival to
treatment, making critical pathway and reducing physical distance from ED to CT room could
be an effective strategy. The present study investigated whether moving CT room into the ED
can reduce more time delay in the thrombolytic treatment. Methods: To reduce the time from
a patient’s arrival at the ED to thrombolysis, multidisciplinary team approach program was
developed and named the Fast Acute Stroke Therapy (FAST). To develop FAST program, delay
factors were analyzed, and roles of stroke team members were assigned. Cellular phones and
interphones were used for rapid communication between team members, and written protocol
was made. The FAST program was initiated from August 2006, and a CT room was located in
the ED at March 2007. The study period was divided into pre FAST and post FAST, the post
FAST period was subdivided into pre EDCT, and post EDCT. Efficacy was investigated by
comparing time intervals from arrival to evaluation and IV tissue type plasminogen activator
(tPA) treatment before and after FAST or EDCT. Results: From January 2000 to July 2007, 99
patients were received IV tPA. Among them, 14 patients were excluded, because of 4 patients
suffered in-hospital attack, and remaining 11 patients were performed the CT image from the
other hospitals. According to FAST program, 61 patients were classified in pre FAST, 24
patients in post FAST (15 pre EDCT, and 9 post EDCT). Median onset-to-door time was not
different before and after FAST (60 vs. 60 minutes, p⫽0.366). After FAST program
implementation, door-to-CT time was reduced from 30 to 17 minutes ( p⬍0.001). Finally,
door-to-needle time was markedly reduced by 34 minutes (from 75 to 41 minutes, p⬍0.001).
After moving CT room in the ED, both door-to-CT (16 vs. 17 minutes, p⫽0.42) and
door-to-needle (40 vs. 42 minutes, p⫽0.609) time were not improved. Conclusions: In the
thrombolytic treatment, no additional reduction of in-hospital delay was observed. Making a
critical pathway might be a more effective and cost saving strategy than moving CT room in
the ED.
P134
Prospective Study of Stroke Subtype and Anti-inflammatory Cytokine in
Relation to Risk of Early Progression.
Satoshi Takaishi, Bunta Katou, Kouji Yamada, Toshikazu Hirayama, Yasuhiro Hasegawa;
Dept of Neurology St. Marianna Univ Sch of Medicine, Kawasaki, Japan
Background and Purpose: In more than 10% of patients with ischemic stroke, early
neurological deterioration occurs after admission, and is associated with increased risk of
dependency. Early progression is a potential therapeutic target. Several studies demonstrated
an important role of inflammation in the pathophysiology. We aimed to identify the clinical
significance of early diagnosis of stroke subtype and measurements of several biomarkers for
the prediction of early clinical progression. Subjects and Methods:Patients admitted within 24
hours after ischemic stroke onset were prospectively enrolled from Jan 2006 to Jun 2007. On
admission, routine blood chemistry, blood cell count, PT, APTT, D-dimer, fibrinogen, and high
sensitivity CRP were measured. Blood samples were stored at -80°C and plasma levels of
interleukin-10 (IL-10) were measured using commercially available ELISA kit. Occlusive lesions
of major cerebral arteries were evaluated by 3D-CT angiography, MR angiography or carotid
ultrasonography immediately after admission. Then the stroke subtype was determined
according to the TOAST classification. Neurological deficits were serially evaluated by NIH
Stroke Scale (NIHSS) on admission, Day-3, Day-7 and at discharge. Early clinical progression
was defined when the NIHSS score increased at least 1 point during the first 48 hours after
admission. Logistic regression analysis was used to determine predictive values of early
diagnosis of stroke subtype and levels of biomarkers on admission by adjusting age, sex, initial
NIHSS score, and co-morbidity. Results:A total of 127 ischemic stroke patients with mean age
of 72.5 (SD 11.0) years old were enrolled. Early progression was demonstrated in 32 patients
(25.2%). Mean value of plasma IL-10 levels in these patients was significantly higher than that
in patients without progression (9.7 ⫾ 10.4 Pg/ml vs. 16.77 ⫾ 14.95 Pg/ml, P⬍0.05). Major
cerebral artery occlusion was demonstrated in 41 patients on admission and 16 of them
(39.0%) demonstrated early progression. Logistic regression analysis demonstrated that initial
assessment of major cerebral artery occlusion (OR 2.26, 95%CI 0.013 - 0.841), plasma level
of IL-10 on admission (OR 0.067, 95%CI 0.888 - 0.985) were significantly associated with early
progression. Stroke subtype according to the TOAST classification, CRP, and fibrinogen were
not associated with early progression. Conclusions: Major cerebral artery occlusion, and low
plasma level of anti-inflammatory cytokine IL-10 are found to be important predictors for the
early clinical progression within 48 hrs after admission in patients with ischemic stroke.
P135
Role Of Contralateral Flow In Predicting Symptomatic Vasospasm With Tcd.
Carol Derksen, Maher Saqqur, Mohamed Ibrahim, Michael Chow, Jim Kutsogiannis, Ashfaq
Shuaib, Khurshid Khan; Univ of Alberta Hosps, Edmonton, Canada
Background: TCD correlation of symptomatic vasospasm is poor when the mean flow velocities
(MFVs) are in the intermediate range, (150 –200cm/s). We evaluated the changes in MFVs on
the aneurysmal side versus the contralateral in predicting clinical or angiographic vasospasm
(CA-VSP). Method: Forty patients with aneurysmal subarachnoid hemorrhage (aSAH) were
assessed between October 2006 and August 2007. Daily TCD started on day 3 until clinical
improvement or death. Correlation was made with cerebral angiogram (CA). MFVs were defined
as intermediate (150 - 199 cm/s) and severe ⬎ 200 cm/s in MCA, ACA or terminal ICA. Result:
Transcranial Doppler, cerebral angiogram and clinical data from 28 patients was analyzed.
Twelve patients were excluded due to early death or poor insonating window. Interpretation:
These results indicate that all the patients developed CA-VSP if the MFV increased to ⬎ 150
m/s (intermediate range) on the contralateral side prior to Ispsilataral. Three (75%) among
those who developed high MFV (intermediate range) first on the ipsilateral but later
accompanied by an increased MFV on contralateral side also developed CA-VSP. Only one
(17%) among those who showed MFV increase (intermediate range) on the Ispsilataral side
alone developed CA-VSP. None of the ten patients developed CA-VSP with MFV ⬍ 150cm/s on
either side. This proportion was statistical highly significant with P-value of ⬍0.0001.
Conclusion: Hemodynamic changes with MFVs ⬎150 cm/s on the contralateral side of the
ruptured aneurysm may predict the onset of clinical or angiographic vasospasm. This likely
reflects hemispheric dys-autoregulation.
RELATIONSHIP BETWEEN CA-VSP AND TCD FLOW.
TCD
CA-VSP developed
Yes
Contralateral side prior to ipsilateral increase
(150 - 199cm/s)
Ipsilateral side prior to contralateral increase
(150 -199cm/s)
Ipsilateral side only increase (150 - 199
cm/s)
Both sides ⬍ 150 cm/s
No
8(100%)
0
3(75%)
1(25%)
1(17%)
5(83%)
0
10(100%)
P136
Initial Results From The Michigan Stroke Network.
Richard D Fessler, John Whapham, Connie Parliament, Robert Fisher, St. Joseph Mercy
Oakland, Pontiac, MI; Michigan Stroke Network Participants
INTRODUCTION: The Michigan Stroke Network (MSN) is a collaborative network of hospitals
linked by a common website (www.michiganstrokenetwork.com) and wireless remote presence robots (RPRs). Network members, regardless of location, size, or resources, have access
to treatment algorithms and stroke specialists 24/7. Creation of the MSN was based on the
presumption that improving member hospital access to stroke specialists would increase the
delivery of tPA to eligible patients. METHODOLOGY: The MSN was created by Trinity Health
Corporation as a mission-driven initiative to enhance the delivery of stroke care within the state
of Michigan. As the 9th hospital in the United States with primary stroke center certification, St.
Joseph Mercy Oakland Hospital received a capital investment over several years to recruit
neuro-critical care specialists, stroke fellowship trained neurologists, neuroendovascular
specialists, and to create a dedicated website. RPRs are stationed at member hospitals in
603
emergency rooms. A 1– 800 number alerts the MSN on call physician. Wireless laptops allow
the MSN stroke specialist access to RPRs for 2-way audio-video communication. MSN stroke
specialists assist in patient evaluation, answer questions regarding treatment options, and help
determine suitability for intravenous tPA administration. The MSN contracts with statewide
medical helicoptor services in the event that transfer to a tertiary facility is warranted. Incoming
calls, response times, robot utilization, as well as patient interactions/interventions are tracked.
RESULTS: During the first nine months of the program, 18 hospitals joined the MSN. An
additional 6 are undergoing RPR installation, and 6 are in process of joining the MSN. To date,
90 RPR consultations involving patients from 20 Michigan counties have been performed. All
consults were initiated within 9 –12 minutes. Approximately 70% of all patients eligible for
intravenous tPA (3 hours) were treated (16/23). An additional 3 patients were transferred for
embolectomy. Twelve doses of tPA were administered at institutions in which tPA had never
been given. Twenty-seven patients were transferred to a tertiary center. CONCLUSION: The
MSN allows member hospitals rapid access to stroke specialists on a case-by-case basis. To
date, the majority of intravenous tPA eligible patients evaluated via the MSN have received tPA.
Improved access to stroke specialists through RPRs enhances the rate of tPA delivery to eligible
stroke patients.
P137
Platelet Aggregation Unit Inhibition to Guide Abciximab Therapy in Acute
Ischemic Stroke: Preliminary Results.
Pitchaiah Mandava, Jane Anderson, Perumal Thiagarajan, Thomas A Kent; MEDVAMC/BCM,
Houston, TX
Background: Glycoprotein (GP) IIb/IIIa inhibitors are employed in stroke patients as adjunct in
intra-arterial (IA) and intravenous (IV) protocols and post-angioplasty/stenting. Experimental
data indicate that thrombosis is abolished at ⬎80% inhibition of GP IIb/IIIa receptors while
clinical data indicate that bleeding complications are limited to patients with ⬎ 90 % inhibition
[Tambarella et al, Am J Card 2002]. While not reported in ischemic stroke, therapy guided by
platelet aggregation inhibition has been utilized in the setting of coronary syndromes.
AbESTT-II, a randomized trial of intravenous abciximab in stroke, utilized the usual cardiac
dosage, but this phase III trial was abandoned due to an unfavorable risk/benefit ratio. The dose
of abciximab used in AbESTT-II produced 95⫾4% and 96⫾10% platelet aggregation unit (PAU)
inhibition respectively in cardiac trials [Steinhubl et al, Circ 1999 & 2001]. We previously
hypothesized a lower dose of abciximab would result in less PAU inhibition than the usual
cardiac dose but still sufficient for clinical efficacy and initiated a case series of acute ischemic
stroke patients treated with a lower dose of abciximab potentiated by the simultaneous use of
heparin. Methods: A lower dose of abciximab (bolus: 0.20 mg/kg, max of 16 mg; and a 12 hr
infusion of 0.05 ug/kg/min, max of 2.9 mg) and time-limited heparin to patients has been
offered to 35 patients with large vessel or cardioembolic stroke. This dose is approximately
30% lower than standard. PAU was measured at baseline and 10 –20 minutes after the bolus.
Baseline and 24 hour follow-up CT of the head and bleeding complications were monitored, and
3 month mortality and mRS obtained. Results: PAU was obtained on 15 of the 35 patients.
Mean baseline NIHSS of these patients was 16.2 (Range: 6 –36), mean age was 69. Mean PAU
inhibition post bolus was 90.8% (SD: 5.88; 95% CI: ⫾3.5; Range: 78 –100; p⫽.001 vs
Steinhubl 1999). There was one symptomatic intra-cerebral hemorrhage in protocol patients
(2.9%), occurring in a patient treated for basilar artery thrombosis 23.5 hours after onset. There
were no serious systemic hemorrhages and a 11% incidence of asymptomatic hemorrhage.
The determination of the relationship of PAU with efficacy awaits completion of 3 month follow
up in all subjects, but this IV protocol has already suggested comparable efficacy to published
IA series with similar baseline stroke severity [Mandava and Kent, 2005]. Conclusion:
Adequate platelet inhibition was found at this lower dose of abciximab. This finding could
explain lack of serious symptomatic hemorrhagic events in our patients despite severity of
NIHSS and use of heparin. The higher dose of abciximab used in AbESTT-II likely produced
excess PAU inhibition leading to increased hemorrhagic risk without improved efficacy. We
suggest PAU measurement may guide abciximab treatment in stroke.
P138
Intracerebral Haemorrhage and Haemorrhagic Transformation in Patients
Treated with Tinzaparin Versus Aspirin for Acute Ischaemic Stroke: Data
From the “Tinzaparin in Acute Ischaemic Stroke Trial” (TAIST).
Timothy England, Gray J Laura, Gillian M Sare, Chamilla Geeganage, Philip M Bath, Univ of
Nottingham, Nottingham, United Kingdom; on behalf of the TAIST Investigators
Background: The incidence of haemorrhagic transformation of infarcts is unclear (with quoted
rates between 6% and 60%), including in-patients taking aspirin early after ischaemic stroke.
Methods: TAIST was a randomised, controlled trial assessing the safety and efficacy of
tinzaparin (a low molecular weight heparin, LMWH) at two doses (medium 100 IU/kg and high
175 IU/kg) versus aspirin (300 mg) in 1,484 patients with acute ischaemic stroke. CT head
scans were performed at baseline and after a treatment period of 10 days. The scans were
independently adjudicated for presence of haemorrhage, haemorrhagic transformation, intrainfarct haematoma, mass effect and midline shift. The relationships between treatment group
and these parameters were assessed with adjustment for age, sex, baseline stroke severity,
and systolic blood pressure. Results: At 10 days, the frequency of haemorrhagic infarction did
not differ between aspirin (32.7%) and medium dose tinzaparin (35.9%, odds ratio [OR] 1.18,
95% confidence interval [CI] 0.86 - 1.62) or high dose tinzaparin (32%, OR 0.95, 95% CI
0.69 –1.32). Asymptomatic haemorrhage also did not differ between aspirin and medium and
high dose tinzaparin (OR 2.68, 95% CI 0.51–13.99, and OR 3.10, 95% CI 0.62–15.58
604
Stroke
Vol 39, No 2
February 2008
respectively). Similarly, there were no differences in size of haemorrhagic transformation,
presence of intra-infarct haematoma, mass effect, or midline shift at day 10. In contrast,
symptomatic intracranial haemorrhage was increased with LMWH in a dose dependent manner
(medium dose: OR 2.91, 95%CI 0.31–77.0; high dose: OR 7.15, 95% CI 1.10 –163 [Bath et al,
Lancet 2001]). Conclusion: Approximately one third of patients with acute ischaemic stroke
treated with early aspirin have asymptomatic haemorrhagic transformation of the infarct. The
incidence does not appear to increase with LMWH, a finding that has also been seen with
intravenous thrombolysis.
P139
AIRDOC: A Randomized Acute Stroke Intervention Trial During The Novel
Setting Of Early Helicopter Evacuation To A Comprehensive Stroke Center.
Enrique C Leira, Azeemuddin Ahmed, Diane L Lamb, Richard C Callison, Heena Maiseri,
James C Torner, Harold P Adams, Jr.; Univ of Iowa, Iowa City, IA
Background: Stroke patients in remote or rural areas are often initially evaluated at small
community hospital emergency departments (ED), and then evacuated by medical helicopter to
a stroke care center. Currently, enrollment in clinical trials is delayed until the patient reaches
the receiving hospital. If acute stroke trials could be initiated at the outside community hospital
or en-route to the stroke center, patients could be enrolled and treated sooner after stroke.
However, the feasibility and safety of such an approach needs to be tested. Objectives: 1) To
test if an intervention trial could be safely implemented during early medical helicopter
evacuation of stroke patients using flight crews as co-investigators , and 2) If a strategy of a
co-investigator calling the subject and faxing the consent form while flying to pick up the
patient facilitates subsequent consent among patients and their surrogates in this timeconstrained setting. Methods: We implemented the AIRDOC trial (Antiacids In-flight Reduce
Disability and Overcome Complications) as a vehicle to test our hypothesis. AIRDOC was a
randomized placebo-controlled trial of a low-risk intervention (ranitidine 50 mg IV) aimed to
prevent aspiration pneumonitis. Eligible patients were subjects with ischemic or hemorrhagic
stroke who were about to be transferred by the air medical helicopter service of the University
of Iowa Hospitals and Clinics for further care. The outbound flight-crew investigator first
randomized the potential subject or surrogate to either receive advanced information about
AIRDOC (through an explanatory radio phone call and faxed consent form) versus no advanced
information. Upon arrival at the ED, the flight crew approached the patient or surrogate about
entry into AIRDOC. Those who consented were screened, and if eligible, were randomly
assigned to a single dose IV ranitidine vs. placebo that was administered during the helicopter
flight. The primary outcome measures are the number of subjects or surrogates that provided
informed consent for AIRDOC as affected by advanced notification status. Secondary outcomes
include number of mis-randomizations, protocol violations, complications, and the rate of
aspiration pneumonitis by AIRDOC treatment assignment. Results: At the time of this
preliminary report 67 of the targeted 100 patients had enrolled (34 to advanced notification,
and 33 to no advanced notification). Informed consent for AIRDOC was obtained from 56%
patients with advance notification and 44% without such early notification. Of those 36, 18
were eligible for AIRDOC and received the study infusion in flight. Conclusions: It is feasible
and safe to conduct an acute stroke intervention trial during early helicopter evacuation to a
comprehensive stroke center. The trial is expected to be completed by February 2008.
P140
ⱕ2 (p⬍0.0013).Conclusion. As compared with an NIHSS ⱖ1, the two percent of acute
ischemic stroke patients with an NIHSS of zero much more frequently have posterior circulation
strokes, normal acute CTs, absence of significant arterial pathology, and excellent short term
outcome. These findings confirm the favorable prognostic value of low NIHSS scores and
suggest insufficient sensibility of the NIHSS for posterior circulation strokes.
P141
Efficacy and Limitations of Intravenous Low-Dose Alteplase Therapy at 0.6
mg/kg for Hyperacute Ischemic Stroke.
Takahiro Nakashima, Kazunori Toyoda, Masatoshi Koga, Hideki Matsuoka, Kazuyuki
Nagatsuka, Tatsuro Takada, Shoichiro Sato, Hiroyuki Kawano, Sohei Yoshimura, Hiroaki
Naritomi, Kazuo Minematsu; National Cardiovascular Cntr, Suita, Osaka, Japan
Objectives: The internationally approved dosage of 0.9 mg/kg may not be the optimum for
intravenous alteplase therapy in hyperacute ischemic stroke. In Japan, intravenous alteplase
therapy with a 0.6 mg/kg dose was approved in October 2005, being based on the results by
Japan Alteplase Clinical Trial (Stroke 2006;37:1810 –1815). We determined the efficacy and
limitations of the low-dose alteplase therapy. Methods: A prospective observational study in a
single stroke center. Fifty six consecutive patients (46 men, 55 - 94 years) who received
intravenous alteplase at 0.6mg/kg for hyperacute stroke between October, 2005 and April,
2007 were enrolled. Ischemic changes and vascular lesions were identified using diffusionweighted MRI, MRA (unless contraindicated), and ultrasound as well as CT. Occlusion at the
common or internal carotid artery or at the origin of the middle cerebral artery trunk on MRA
or ultrasound was defined as the carotid trunk occlusion. Results: The median National
Institutes of Health Stroke Scale (NIHSS) score declined from 12 at baseline to 8 at 24 hours,
and 3 at 3 weeks. At 24 hours, the NIHSS score of 26 patients (46%) improved by ⱖ4 points.
After adjustment for underlying features, absence of the carotid trunk occlusion (odds ratio
2.63, 95% CI 1.28 - 6.03) and lower systolic blood pressure on admission (odds ratio 1.02,
95% CI 1.00 - 1.04, per increase by 1 mmHg) were independently predictive of the
improvement. Two patients (4%) had symptomatic intracranial hemorrhage within the initial 36
hours. At 90 days, all the patients survived; overall, 27 of 55 patients (49%: excluding one
patient who needed a wheelchair before the onset from the analysis) had a favorable functional
outcome corresponding to the modified Rankin Scale (mRS) score ⱕ1. However, only 2 of 15
patients (13%) with the carotid trunk occlusion on admission had the favorable outcome. After
adjustment for underlying features, lower NIHSS score on admission (odds ratio 1.23, 95% CI
1.05 - 1.53, per decrease by 1 point) and absence of the carotid trunk occlusion (odds ratio
3.12, 95% CI 1.23 - 10.35) were independent predictors of the favorable outcome at 90 days.
Conclusions: Intravenous alteplase therapy at 0.6 mg/kg in our stroke center resulted in better
efficacy and safety as compared with the results of previous studies using 0.9 mg/kg of
alteplase, including STARS, CASES, and SITS-MOST. The low-dose alteplase, however, may not
be effective for the patients with the carotid trunk occlusion.
P142
Use of Quantitative Multimodal Magnetic Resonance Imaging Following
Intravenous Thrombolytic Therapy in Predicting Outcomes.
Mahmut E Gurol, Harold P Adams Jr., Patricia H Davis; Univ of Iowa, Iowa City, IA
Nihss Zero Strokes: Are localization, imaging and outcome different?
Mitra Houchmand-zadeh, Vancianne Rey, Neurology Service Univ and Institute of Social and
Preventive Medicine. Cntr Hospier Universitaire Vaudois and Univ of Lausanne, Switzerland,
Lausanne, Switzerland; Mohamed Faouzi, Institute of Social and Preventive Medicine. Cntr
Hospier Universitaire Vaudois and Univ of Lausanne, Switzerland, Lausanne, Switzerland;
Patrik Michel; Neurology Service Univ and Institute of Social and Preventive Medicine. Cntr
Hospier Universitaire Vaudois and Univ of Lausanne, Switzerland, Lausanne, Switzerland
Background. The NIHSS is widely used to measure stroke severity and is a strong predictor
of outcome. Patients may have zero points on this scale despite a clinical stroke, given that
some neurological deficits are not counted in the NIHSS. We sought to determine whether these
patients differ from NIHSS ⱖ1 patients Methods. Between 1/2003 - 4/2007, all consecutive
ischemic stroke patients admitted within 24 hours after symptom onset to a single stroke unit
were entered prospectively in a registry. Patients who had persistent signs or symptoms ⬎ 24
hours were considered to have a stroke. Demographic data, time to hospital arrival since last
well time, arterial territory of stroke, pathogenesis using modified TOAST criteria, early
ischemic signs on acute parenchymal imaging (mostly CT), ⱖ50% stenosis on extra- or
intracranial arterial imaging (mostly CT-angiography), and short term prognosis (modified
Rankin scale at 7 days) were determined. Patients with an NIHSS of zero on admission (Z) were
compared with patients whose NIHSS was above zero (A), using univariate non parametric tests
for statistical analysis (Wilcoxon1, chi-square2, and Fisher’s exact test3). Results. Of 1’254
acute ischemic stroke patients (mean age 68.8 years -sd⫽15.8-, 54.3% male, median delay
to admission 222.5 min.). The A group had a median NIHSS score of 6. Of the 25 (2.0 %), Z
patients 14 (56%) had pure vestibulo-ocular signs and 7 (28%) pure mild corticospinal signs.
The Z and A groups did not differ in gender2, age1 or delay to hospital arrival1. The proportion
of posterior circulation strokes was clearly higher in Z than A (71.4% vs. 27.9%, p⬍0.0013),
but stroke causes were not different3. Acute imaging (92 % CT) showed the acute ischemic
lesion in 8.7% in Z and in 34.7% in A (p⫽0.0073). Similarly, acute arterial imaging (81 %
CT-angiography) showed significant pathology only in 5.0% in Z but in 49.0% in A (p⬍0.0013).
All Z patients had a mRS ⱕ2 at 7 days (21 had mRS ⱕ1), whereas only 54.4% of A had a mRS
Background/Purpose: Despite its established efficacy in the first 3 hours, intravenous tissue
plasminogen activator (IV t-PA) is not effective in all cases and rescue reperfusion strategies
may need to be considered in the acute phase. We aimed to evaluate the accuracy of
quantitative MRI/MRA analysis to predict outcome, as this might improve selection of patients
for endovascular interventions. Methods: Over the last 1.5 years, 30 out of 50 consecutive
stroke patients admitted to a tertiary care center after receiving IV t-PA had brain MRI in the
first 8 hours. The volume of the infarction on diffusion weighted imaging (DWI) and perfusion
deficit on TTP (time to peak) maps (PWI) were segmented using computer assisted techniques
by a neurologist blinded to clinical data and mismatch was noted when PWI/DWI⬎1.4. Another
outcome predictor was the modified TIMI (Thrombolysis in Myocardial Ischemia) grade that
shows the recanalization status of arteries supplying the ischemic areas. Outcome measures
were the volume of the infarction on a CT obtained 24 hour after IV t-PA, modified Rankin Scale
(mRS) on discharge and neurologic worsening over the first 48 hours. All predictive models
were further adjusted for age and for performance of endovascular intervention (5 patients).
Results: MRA TIMI grade 1 was found in 38% (total occlusion, no anterograde distal flow), 35%
had grade 2 (partial recanalization, decreased distal flow) and 27% grade 3 (complete
recanalization, unimpeded distal flow). The mean volume of lesion on DWI was 37.3 cc (range
0 –198), on PWI was 101.2 cc (range 0 – 416), and the mean final infarct volume was 46.2 cc
(range 0 –291). A PWI/DWI mismatch was found in half of the patients. In univariate analyses,
DWI lesion volume (r⫽0.93, p⬍0.001), PWI volume(r⫽0.86, p⬍0.001), and MRA TIMI grade
(r⫽-0.6, p⫽0.001) were strongly correlated with final infarct volume; DWI volume (p⫽0.001)
and PWI volume (p⫽0.05) remained as independent predictors in multivariate analysis. At
discharge, 40% of patients had a mRS score of 0 –2. MRA TIMI grade (r⫽-0.66, p⬍0.001) and
DWI infarct volume (r⫽0.47, p⫽0.002) were correlated with mRS on discharge; only MRA TIMI
score (p⫽0.004) was an independent predictor on multivariate analysis. Neurological
worsening was noted in 23% of patients. Higher DWI volumes were independently associated
with risk of early deterioration (p⬍0.001). Presence of mismatch was not associated with any
of the outcome measures. Conclusions: A combination of quantitatively measured DWI and
PWI lesions and MRA TIMI grade may improve the accuracy of outcome prediction immediately
after IV t-PA. The association of MRA TIMI score to the outcome may be important as the
presence of persistent arterial stenosis and distal flow compromise are potential targets for
endovascular interventions.
P143
Combined Extracranial and Intracranial Interventions as a
Revascularization Strategy for Anterior Circulation Tandem Occlusions.
Nirav Vora, Ridwan Lin, Ajith Thomas, Rishi Gupta, Syed Zaidi, Vivek Reddy, Maxim
Hammer, Ken Uchino, Lawrence Wechsler, Michael Horowitz, Tudor Jovin; Univ of
Pittsburgh, Pittsburgh, PA
Background: Acute anterior circulation tandem occlusions (TO) of the internal carotid artery
(ICA) origin and intracranial ICA or middle cerebral artery (MCA) have been poorly studied. Our
aim is to evaluate our intra-arterial (IA) strategy for these lesions. Methods: We retrospectively
reviewed case records of patients presenting to our center with an acute anterior circulation
TO. Data collected included stroke risk factors, baseline National Institutes of Health Stroke
Scale (NIHSS), intracranial site of occlusion, and IA treatments implemented. All patients first
received angioplasty and stenting of the proximal ICA origin occlusion with emboli protection.
Subsequent intracranial interventions if required included IA tPA, urokinase, angioplasty,
stenting, or mechanical embolectomy. Our study had 3 endpoints: successful reperfusion
defined as Thrombolysis in Myocardial Infarction (TIMI) score ⱖ 2 post-procedure, incidence
of post-procedure parenchymal hematomas (PH), and good functional outcome defined as
hospitalization discharge to home or an acute rehabilitation facility. Multivariate analysis was
performed to determine predictors of successful reperfusion and good functional outcome.
Results: We identified 40 patients with mean age 64⫾10 years and mean NIHSS 15⫾5. Mean
time to reperfusion was 593⫾454 minutes after clinical symptom onset. Intracranial occlusions
included the following: 10 ICA terminus, 23 MCA M1, 5 MCA M2. Twenty-one patients (52.5%)
achieved successful reperfusion. Fifteen patients were treated with proximal ICA stenting only
with 10 achieving successful reperfusion. Nine patients (22.5%) sustained a PH with 8
occurring in the 25 patients treated with proximal stenting and an intracranial intervention. Two
patients had distal embolization during their procedure; one of these recanalized spontaneously. Twenty-two patients (55%) achieved good functional outcomes. Combination intracranial
pharmacologic and mechanical interventions (OR 50.4, 3.98 –2035 95% CI, p ⫽0.01) and
intracranial occlusion distal to the ICA terminus (OR 22.9, 2.2– 607 95% CI, p⫽0.02) were
statistical predictors of successful recanalization. Baseline NIHSS was the only statistically
significant predictor for functional outcome (OR 0.00004, 1.4x10-9-0.02 95% CI, p⫽0.01).
Conclusions: Endovascular therapy can be safely performed in the setting of an anterior
circulation TO particularly when proximal ICA stenting is performed initially. This approach
requires further prospective study.
605
P145
Staged Versus Single Stage Treatment Of Intracranial Aneurysm Using
Neuroform Stent.
Yahia (former Abutah M Lodi (former Yahia), Upstate Med Univ, Syracuse, NY; Vickie
Gordon, John Whapham, Ali Malek, Richadr Fessler; Dept of Neursurgery, Providence Hosp,
Southfield, MI
Background: Neuroform stent facilitates endovascular treatment of difficult intracranial
aneurysm. Complications associated with neurofm stent have been described previously. The
effects of multi-staged versus single stage procedure on the rate of complications associated
with Neuroform stent-assisted coiling of intracranial aneurysm are not known. Objectives: To
compare the incidence of complications between single stage and staged neuroform
stent-assisted coiling of intracranial aneurysms. Methods: Consecutive patients undergoing
treatment of intracranial aneurysm using Neuroform, either single stage or staged procedure,
from January 2003 to November 2006 are enrolled. Information of patient demographics,
aneurysm size, location, and complications events are gathered. Additionally, clinical outcomes
are measured using Glasgow Outcome Scale (GOS) and National Institute of Health Stroke Scale
(NIHSS) at 90 days. Results: Neuroform stents are successfully implanted in 66/68 (97%)
patient. Patient mean age is 50.5 ⫾ 13.7 years and 57/68 (83.8%) are woman. There are 6
complication events; five in single stage and one in staged procedure. Complications in the
single stage are ruptured of aneurysm in two (both basilar artery bifurcation aneurysms
required Y-neck reconstruction), thromboembolic event in two (stroke in one on day 14,
transient ischemic event in other on day 6) and herniation of stent into aneurysm in one. In the
staged procedure, the only event is an ischemic stroke on day 7, after a second stent to
reconstruct a middle cerebral artery bifurcation aneurysm. The event is not associated with
patient’s age, gender, cerebrovascular risk factors, size or location of the aneurysm. But, three
of six events have been observed on patients, who require Y-stent neck reconstruction. Most
of the patient have good outcome (GOS 1 or NIHSS 0 was observed in 63/67 (94%) cases. GOS
2 or NIHSS 2, GOS 3 or NIHSS 4 was observed in another 3). Conclusion: Higher rate of
complications are observed in single than staged endovascular treatment of intracranial
aneurysms using neuroform stent. These are intraoperative rupture of aneurysm and
thromboembolic event. Therefore, caution should be made during single stage coiling of the
aneurysm using neuroform stent. Further study is warranted.
P146
Relationship Between Inaccurate Thrombolytic Dosing and Hemorrhagic
Complications in Acute Stroke.
P144
Changes in Triage Stroke Panel Correlate with Outcome in Ischemic Stroke
Patients Treated with Thrombolysis.
Byron R Spencer, Jr., Molly A Smith, Maria I Aguilar, Mayo Clinic Hosp, Phoenix, AZ;
Bentley J Bobrow, Mayo Clinic Hosp and Arizona Dept of Health Services, Phoenix, AZ;
Timothy J Ingall, David W Dodick, Nadine F Lendzion, Patricia H Miller, Bart M
Demaerschalk; Mayo Clinic Hosp, Phoenix, AZ
Raf Brouns, Rishi Sheorajpanday, Jan Kunnen, Didier De Surgeloose, Peter Paul De Deyn;
ZNA Middelheim, Antwerp, Belgium
Background: Hemorrhagic complications are the major adverse events associated with
thrombolytic therapy. The dose of thrombolytic used is based upon body weight. Incorrect
dosing of thrombolytic therapy occurs in approximately 5–12% of cases and has been
associated with major hemorrhage and increased mortality. Since body weight may not be
accurately determined in the emergency department in the setting of acute ischemic stroke, the
incorrect dosing of tissue plasminogen activator (t-PA) may occur more frequently than
previously recognized. Hypothesis: The overdosing of t-PA based on estimated versus (vs.)
actual patient weight in the setting of acute ischemic stroke is associated with a higher rate
of hemorrhagic complications. Methods: We used a registry of ischemic stroke patients
receiving t-PA to conduct a retrospective study of the estimated (patient, family, or healthcare
provider best estimate) and actual (admission bed measured) weight of 122 consecutive
patients who presented to our Joint Commission certified Primary Stroke Center (JC PSC)
emergency department between Jan 2004 and Aug 2007 and received intravenous (IV) t-PA for
ischemic stroke. Overdosing (OD) or under dosing (UD) were defined arbitrarily in the instances
when the difference between estimated and actual weight was ⱖ 1kg (equivalent to 0.9mg
dose of t-PA). The cohort was divided in two categories: Overdose group versus correct dose
(CD) and under dose (CD⫹UD) group. Hemorrhagic complications were defined as follows:
Asymptomatic intracranial hemorrhage (ASICH), symptomatic intracranial hemorrhage (SICH),
fatal symptomatic intracranial hemorrhage (FSICH), and major systemic hemorrhage (MSH).
Proportions of hemorrhagic complications were compared between the two groups with chi
square statistics. Results: Baseline characteristics (mean age, gender, stroke severity) of the
OD group did not significantly differ from the CD⫹UD group. OD group 32/122 (26.2%) and
CD⫹UD group 36/122 (29.5%) and 54/122 (44.3%) respectively. ASICH occurred in 12.5 %
(OD) versus 17.8% (CD⫹UD) [OR 0.66 (0.00 to 1.84)]. SICH occurred in 9.4% (OD) vs. 7.8%
(CD⫹UD) [OR 1.23 (0.00 to 2.64). FSICH occurred in 3.1% (OD) vs. 5.6% (CD⫹UD) [OR 0.55
(0.00 to 2.73)]. MSH occurred in 0% (OD) vs. 4.4% (CD⫹UD) [OR 0 (not significant)]. Any
hemorrhage occurred in 21.9% (OD) vs. 30.0% (CD⫹UD) [OR 0.65 (0.30 to 1.61)]. Conclusion:
In this retrospective study of 122 patients with acute ischemic stroke who received IV t-PA, the
incidence of excessive dosing was 26.2%, higher than previously recognized. There was no
statistically significant association between overdosing of t-PA based on estimated vs. actual
patient weight and hemorrhagic complications.
Introduction: Identification of easily accessible markers for short-term and long-term
prognosis after thrombolysis for ischemic stroke may be of use. Hypothesis: We investigated
the possible added value of the bedside biomarker assay Triage® Stroke Panel over clinical
evaluation and infarct volume for prediction of both short-term and long-term outcome after
thrombolysis. Methods: We evaluated sixteen consecutive ischemic stroke patients treated
with intravenous recombinant tissue plasminogen activator (n⫽12) or intra-arterial administration of urokinase (n⫽4) by means of the National Institutes of Health Stroke Scale (NIHSS)
and the multimarker index MMX (Triage姞 Stroke Panel) before thrombolysis and 72 hours after
stroke onset. The Triage姞 Stroke Panel measures brain natriuretic peptide, D-dimer, matrix
metalloproteinase-9 and S100␤ and calculates the composite multimarker index MMX based
on the single biomarker concentrations. Standardized infarct volumetry after thrombolysis was
obtained in every patient. The predictive value of infarct volume, change in NIHSS score and
Triage® Stroke Panel results for stroke outcome at 7 days and 3 months (modified Rankin
Scale, mRS) was evaluated. Results: Changes in MMX results and NIHSS scores before
thrombolysis and 72 hours after stroke onset were significantly correlated with stroke outcome
both at 7 days and at 3 months after stroke onset (␳⫽0.67 and 0.75 for change in MMX
(P⫽.004 and .001); ␳⫽0.58 and 0.60 for change in NIHSS (P⫽.019 and .013)). These findings
indicate that decreases in MMX and NIHSS are correlated with good outcome. Increases in
MMX and NIHSS are correlated with poor outcome. Using cut point 0.0 for change in MMX and
0 for change in NIHSS, the overall accuracy for predicting good outcome (mRS 0 to 2) at 7 days
after stroke was 81% for both parameters. For prediction of good outcome at 3 months, the
overall predictive accuracy was 88% and 75% respectively. Infarct volume was not significantly
correlated with and had poor predictive accuracy for outcome. In a multivariate stepwise
regression analysis only change in MMX and change in NIHSS emerged as an outcome
predictor that was independent of age, gender, stroke severity, stroke etiology, vascular risk
factors, blood pressure before thrombolysis, blood glucose, type of thrombolysis, and time
between onset of symptoms and start of thrombolysis. Conclusions: The use of the Triage®
Stroke Panel before thrombolysis and 72 hours after stroke onset may be of more predictive
value for short-term and long-term outcome than change in NIHSS score or infarct volume.
606
Stroke
Vol 39, No 2
February 2008
P147
Frequent Anti-hypertensive Treatment During Revascularization Therapy Is
Associated With Intracerebral Hemorrhage In The First 24 Hours.
Rakesh Khatri, Pooja Khatri, Jane Khoury, Joseph Broderick, Thomas Tomsick, Dawn
Kleindorfer, Daniel Woo; Univ of Cincinnati, Cincinnati, OH
Background: Intracerebral hemorrhage (ICH) may occur as a consequence of ischemic stroke
and its risk is increased in the setting of thrombolytic therapy. Some patients receiving
thrombolysis require multiple treatments with anti-hypertensive medications to maintain blood
pressure parameters. We hypothesized that an increased number of anti-hypertensive
treatments would be associated with ICH after thrombolytic treatment for ischemic stroke.
Methods: We examined a registry of patients treated with IV/IA or IA-only rtPA for ICA-terminus,
M1, or M2 occlusions (n⫽64). The number and type of anti-hypertensive treatments before,
during and after revascularization therapy were recorded. Post-procedure follow up CTs of
patients at 24 hours (⫹/- 6 hours) after symptom onset were reviewed for ICH, including
symptomatic and asymptomatic ICH. We categorized ICH by ECASS criteria. We tested the
association between the number of anti-hypertensive drug treatments and ICH after adjusting
for significant covariates. Covariates considered were sex, race, baseline NIHSSS, type of
thrombolysis (IA vs IVIA), lytic dose, atrial fibrillation, history of diabetes, history of hypertension,
antiplatelet use and serum glucose. Anti-hypertensive treatments included labetolol, hydralazine, sodium nitroprusside, nitroglycerine and enalapril. Results: Of 64 patients included
between 1999 and 2005, the average age was 63 years, 41 (64%) were female, 12 (19%) were
black, the median baseline NIHSS score was 19 and 52 (81%) proceeded to have IA therapy
(12 required only the original 0.6 mg/kg IV dose). ICH occurred in 30 (47%) cases, including
5 (8%) PH1s and 7 (11 %) PH2s. Anti-hypertensive treatment was administered in 25 (39%)
cases (range 1–10 doses). In bivariate analysis, use of any anti-hypertensive treatment was
associated with increased risk of ICH (p⫽0.02). When examined by the number of treatments,
use of 1–2 treatments was not significantly associated with ICH at 24 hours (OR⫽3.1; 95% CI
0.5–17.8) while ⱖ 3 treatments was associated with increased risk of ICH (OR⫽9.6; 95% CI
1.5– 60.4) after adjustment for significant covariates of lytic dose (p⫽0.007), diabetes
(p⫽0.03), and serum glucose (p⫽0.04). Considering only anti-hypertensive treatments before
and during revascularization therapy, treatment was also associated with increased risk of ICH
(p⫽ 0.01). Conclusions: Hypertension requiring more than two treatments during revascularization therapy is an important risk factor for ICH at 24 hours. Excessive antihypertensive
treatment may be a surrogate marker for uncontrolled hypertension or a consequence of ICH.
Our results suggest that the need for 3 or more treatments of hypertension should raise clinical
suspicion for ICH.
P148
Predictors For Good Pial Collateral Formation In Acute Ischemic Stroke.
Gregory Christoforidis, Yousef Mohammad, Marinos Kontzialis, Louis Caragine, Andrew
Slivka; Ohio State Univ, Columbus, OH
Purpose: The extent of pial collateral formation to an ischemic territory during acute stroke
influences outcomes. This study sought to identify clinical factors which can be predictive of
good pial collateral formation prior to intra-arterial thrombolyitic treatment for acute ischemic
stroke. Methods: This study reviewed prospectively collected clinical information and arteriograms from 79 consecutive patients with anterior circulation infarctions involving either the
horizantal portion of the middle ceerebral artery (MCA), or the terminal internal carotid artery
(ICA) in patients who underwent intra-arterial thrombolysis within 6 hours following symptom
onset. Pial collaterals were assessed on the basis of anatomic extent. Good pial collaterals in
this study were equivalent to grades 3 and 4 described by Higashida (1). Logistic regression
analysis for good pial collateral formation used the following predictors: pretreatment National
Institutes of Health Stroke Scale Score (NIHSSS), age, time to treatment, sex, presenting
systolic and diastolic blood pressure (DBP), admitting glucose level, admitting platelet level and
site of occlusion (ICA vs. MCA). All factors with p⬍.10, were entered into the final model as
predictors of clinical outcome using backward selection. Results: Logistic regression analysis
(whole model test: p⬍0.0001; r2 ⫽0.13) identified clot location within the MCA versus the ICA
terminus (p ⬍.0001), lower presenting NIHSSS (p⫽0.0449) and lower presenting DBP
(p⫽0.0497) to be associated with better pial collateral formation. The median presenting
NIHSSS for patients with good versus poor pial collateral formation was 15 versus 18.5
respectively (p⫽0.0070; 2-sample Wilcoxan rank sums test). The mean DBP was 81mmHg
versus 89mmHg respectively (p⫽0.0396; analysis of variance).Good pial collateral formation
was associated with 35.3% of patients with carotid terminus occlusions versus 79.4% of
patients with m1 segment occlusions (p⫽0.0004; Pearson). Conclusion: Clinical predictors for
good pial collateral formation in the setting of anterior circulation acute ischemic stroke include:
MCA location versus carotid terminus location, lower presenting NIHSSS and lower DBP.
References: 1) Higashida RT, Furlan AJ. Trial design and reporting standards for intra-arterial
cerebral thrombolysis for acute ischemic stroke. Stroke 2003; 34:109 –137.
P149
Absence of Atrial Fibrillation is A Risk of Neurological Deterioration in
Ischemic Stroke Patients Who are Excluded from Intravenous Tissue
Plasminogen Activator Treatment Because of Mild or Improving Symptoms.
Kuniyasu Wada, Yasuyuki Hara, Tadashi Terasaki, Daisuke Higashi, Japanese Red Cross
Kumamoto Hosp, Kumamoto, Japan; Teruyuki Hirano, Makoto Uchino; Kumamoto Univ,
Kumamoto, Japan
Background and Purpose: Acute ischemic stroke patients with mild or improving neurological
symptoms are excluded from intravenous tissue plasminogen actibator (tPA) treatment.
Occasionally, after the decision on eligibility of tPA treatment, neurological deterioration (ND) is
observed in the patients who are regarded as “mild to treat with tPA” (MTT). The purpose of
this study is to find the predictors of poor outcomes in the data that was obtained before tPA
decision in emergency rooms. Methods: One hundred and seven consecutive patients
presenting at our hospital within 3 hours of stroke onset between October 2005 and April 2007
were entered the analysis. We defined early rapid improvement (ERI) as a 4-point NIHSS score
improvement from the time of initial evaluation to the time of tPA decision, minor symptom (MS)
as NIHSS score⬍/⫽4 at the time of tPA decision and ND as 2-point worsening in NIHSS score
from the time of tPA decision to the time of hospital discharge. MTT patients were regarded
those with ERI or MS. To find predictors of poor outcomes, the data obtained before tPA
decision were compared between MTT patients with and without ND. Stroke pathophysiology
was determined at hospital discharge. Results: Fifty (48%) of all were MTT patients (35 men
and 15 women, 70⫾12 years old). (Twenty-six (24%) patients were treated with tPA.) The
average NIHSS score of MTT patients at the time of initial evaluation was 4.7 and at the time
of tPA decision was 1.8. Nine MTT patients had ND. Thirteen of 41 MTT patients without ND
had atrial fibrillation on admission, while none of the patients with ND had atrial fibrillation
(31% vs. 0; p⬍0.05). Eighty-nine percent of patients with ND were diagnosed as large-artery
atherosclerosis (LAA) at discharge. The percentage of LAA in MTT patient with ND was higher
than in that without ND (p⬍0.05). Conclusion: Absence of atrial fibrillation on admission is a
risk of ND in MTT patients. This may reflect that stroke pathophysiology is LAA in most of the
MTT patient with ND.
P150
Telestroke Shortens Onset to Treatment Times for Intravenous tissue
Plasminogen Activator in Acute Ischemic Stroke.
Jeffrey A Switzer, Hartmut Gross, Christiana E Hall, Robert J Adams, Fenwick T Nichols,
David C Hess; Med College of Georgia, Augusta, GA
Introduction More than half of the over 5000 hospitals in the U.S. have less than 100 beds.
These hospitals seldom have stroke specialists available to provide acute consultations and
guide the administration of tPA. At the Medical College of Georgia (MCG), we have developed
a web-based telestroke (REACH) system to facilitate intravenous (IV) tissue plasminogen
activator (tPA) administration in rural emergency departments. Early treatment with tPA is
associated with better outcomes. We report our treatment times in the first 94 patients treated
with tPA and compare the results to the published literature. Our hypothesis was that the use
of REACH would shorten onset-to-treatment time (OTT). Methods Using the REACH system, six
stroke specialists at MCG provide 24 hour per day, 7 day per week acute stroke consultations
to 9 rural emergency departments in hospitals with 10 –75 beds. Video and CT transmission
across the internet allows for real time neurologic assessment and determination of the
appropriateness of tPA use. A systematic review of the literature was conducted to examine IV
tPA use in other stroke care delivery systems. We excluded studies that did not document OTT,
included treatments beyond three hours or intra-arterial tPA, required MRI prior to treatment,
included only MCA occlusions, or enrolled less than twenty patients. We compared the
treatment times using REACH with these systems. Results To date 94 patients have received
IV tPA using REACH. Ten patients were treated beyond three hours from time of onset. These
patients were excluded from further analysis. The mean OTT was 121.2 and door-to-needle
was 75.9 minutes. 18 (21%) and 45 (54%) of the 84 patients were treated within 90 and 120
minutes respectively. There have been 4 symptomatic intracerebral hemorrhages (NINDS
criteria), but no type 2 parenychymal hematomas (ECASS criteria). Fourteen studies were
identified that fulfilled our search criteria. OTT using REACH was significantly shorter than all
other published systems with the exception of a single center study from Cologne, Germany
(Grond et al). Conclusions The REACH system facilitates rapid treatment of acute ischemic
stroke patients within a rural telestroke network. Using REACH, OTT was shorter than in
community and academic centers that relied on an “in-person” recommendation for
administration. Telestroke could be used to speed treatment in urban communities as well.
Study
Grond et al. Stroke
1998;29:1544 –9
Chiu et al. Stroke
1998;29:18–22
Wang et al. Stroke
2000;31:77–81
Chapman et al. Stroke
2000;31:2920–4
Albers et al. JAMA
2000;283:1145–50
Grotta et al. Arch Neurol
2001;58:2009–13
Koennecke et al. Stroke
2001;32:1074–8
Merino et al. Stroke
2002;33:141–6
Walters et al. Cerebrovasc
Dis 2005;20:438–42
Dick et al. Neurologist
2005;11:305–8
Sims et al. Ajnr
2005;26:246–51
Mouradian et al. JNNP
2005;76:1234–7
# treated
OTT
p-value
⬍90
minutes
100
126
0.1755
26%
30
157
⬍.0001
57
148
⬍.0001
11%
46
165
⬍.0001
389
164
⬍.0001
269
137
⬍.0001
75
144
⬍.0001
9%
4%
82
148
⬍.0001
120
139
⬍.0001
101
130
0.0143
47
132
0.0029
65
145
⬍.0001
⬍120
minutes
4%
28%
Study
Hill et al. CMAJ 2005;172:
1307–12
Sattin et al. Stroke
2006;37:2935–9
# treated
OTT
p-value
1135
155
⬍.0001
45
133
0.0012
⬍90
minutes
⬍120
minutes
44%
P151
Matrix Metalloproteinase-9 And Early CT Changes In Patients With
Thrombolytic Treatment.
Hye-Yeon Choi, Young Dae Kim, Hye Sun Koh, Hyun Ji Cho, Eung Yeop Kim, Ji Hoe Heo;
Yonsei Univ, Seoul, Republic of Korea
Background and objectives The Alberta Stroke program early CT score (ASPECTS), which is
CT-based grades of early ischemic changes, and the plasma MMP-9 levels are known as
surrogate markers to predict hemorrhage after thrombolytic treatment in stroke. This study was
aimed at determining whether the MMP-9 levels are associated with ASPECTS. We also
investigated their predictabilities of initial neurologic severity and outcomes. Methods Among
patients who received thrombolytic treatment, those whose blood samples could be obtained
before the treatment and who had a stroke in the anterior circulation were included. ASPECTS
was scored from baseline CT scans by consensus approach of two neurologists. Plasma
MMP-9 levels were measured by using a commercially available enzyme-linked immunosorbent assays kit. National Institutes of Health Stroke Scale (NIHSS) score was used to determine
the severity of neurologic deficits at baseline, 24 hours and 7 days. The early or late
improvement ratio (IR) was defined as [(initial NIHSS scores - 24 hours (early) or 7 days (late)
NIHSS scores) X 100/ baseline NIHSS scores]. Results Forty three patients were included (27
men, mean age 69 years). ASPECTS values were dichotomized into ⱕ8 (moderate/severe
change, 22 patients) and ⬎8 (mild/no change, 21 patients). Mean NIHSS scores were 15 at
baseline, 12 at 24 hours, and 10 at 7 days. Mean early IR was 24.4% and late IR was 41.3%.
Hemorrhagic transformation occurred in 23 patients (symptomatic in ten). Hemorrhage was
common in patients with ASPECTS ⱕ8 (p⬍0.05). Patients with symptomatic hemorrhage
showed a tendency of higher MMP-9 levels (52.40 ⫾ 32.40 vs. 70.52 ⫾ 36.98). However,
plasma MMP-9 levels were not different between patients with ASPECTS ⱕ8 and ⬎8. NIHSS
scores and mortality were higher in the patients with ASPECTS ⱕ8 than those with ⬎8
(p⬍0.05). Early and late IRs were higher in the patients ASPECTS ⬎8 (early 45.0 vs 1.9%; late
53.2 vs 17.3%; p⬍0.05). In contrast, plasma MMP-9 levels showed no association with initial
NIHSS or ealry and late IR. Conclusions Plasma MMP-9 levels were not predictive of neurologic
severity or degree of neurologic improvement, while ASPECTS was associated with them.
Although both plasma MMP-9 levels and ASPECTS may be markers to predict hemorrhagic
transformation after thrombolysis, there was no direct relationship between them. Plasma
MMP-9 levels and ASPECTS seem to be surrogate markers, which reflect different aspects of
mechanisms leading to hemorrhagic transformation.
607
P153
The Impact of Improved Hospital Reimbursement on National Rates of
Rt-PA Use.
Dawn Kleindorfer, Univ of Cincinnati, Cincinnati, OH; Irene Katzan, Cleveland Clinic,
Cleveland, OH; Dilib Pandey, Univ of Illinois, Chicago, IL; Richard Hornung, Joseph P
Broderick; Univ of Cincinnati, Cincinnati, OH
Introduction: We have shown that national rates of rt-PA use were not increasing between
fiscal years (FY) 2001– 04. In FY 2006, a new hospital reimbursement diagnosis related group
(DRG) code 559 was introduced, which more than doubled the reimbursement for stroke
patients treated with thrombolytic therapy. We hypothesized that the new DRG would be
associated with a significant increase in the use of rt-PA for ischemic stroke. Methods: The
Premier database is currently partnered with the FDA to study drug utilization in hospitalized
patients and contains approx. one out of every six inpatient discharges in the U.S, has no age
exclusion, and has the ability to access pharmacy billing records. All stroke-related (ICD-9
codes 430 – 436) admissions were queried using the DRG codes 14, 15, 524, and 559 for FY
2001– 06. Rt-PA administration was described using the ICD-9 code 99.1 (cerebral thrombolysis), and rt-PA utilization documented in pharmacy records. Differences in proportions were
tested using the Chi-square statistic. Results: The rates of rt-PA use increased in FY 2006
when compared to the pooled treatment rate of FY 2001–2005 (3.0% vs. 1.8%, p⬍0.0002).
However, there was a also significant increase between FY 2004 vs 2005, and FY2005 vs. 2006
(p⬍0.001 for both). See table for rt-PA rates among patients with ischemic stroke ICD-9 codes
over a six year period. Patients given thrombolytic, yet coded with hemorrhagic stroke or TIA
ICD-9 codes represented 12% of rt-PA treats in both FY 2005 and 2006, and 5% of DRG 559
discharges in FY 2006. Within the DRG 559 discharges, 13% did not administer thrombolytic
therapy according to pharmacy records. Discussion: In contrast to 2001– 04, we found that the
rates of rt-PA use in the U.S. increased in FY 2005 and 2006, a relative increase of more than
60% over two years. However, the new DRG 559 was not introduced until FY 2006, so likely
other factors were influencing this increase, such as JCAHO stroke center certification and
other quality improvement programs. Patients receiving rt-PA are often miscoded by billing
personnel, which makes interpretation of national statistics problematic. The “drip and ship”
model of care may explain the 13% of DRG 559 discharges that did not bill for thrombolytic,
since the patients are transferred after receiving thrombolytic at an outside hospital. However,
the DRG 559 is not supposed to not be billable to either the receiving or transferring institution,
an issue which has yet to be addressed by the Centers for Medicare and Medicaid Services
(CMS).
total number of cases,
DRG 12/15/524/559
# with ICD-9 code 99.1
(%)
# with pharmacy billing
for thrombolytic (%)
FY
2001
FY
2002
FY
2003
FY
2004
FY
2005
FY
2006
ALL
DRGs
54,772
59,893
58,570
56,129
54,012
59,334
572
(1.04)
875
(1.60)
632
(1.06)
1002
(1.67)
616
(1.05)
956
(1.63)
646
(1.20)
1021
(1.82)
811
(1.50)
1332
(2.47)
1447
(2.44)
1781
(3.0)
FY 2006
DRG 559
Only
1,437
1437(100)
1256 (87.4)
P152
Does Hyperacute Diffusion and Perfusion Weighted Imaging Predict
Outcome in Acute Ischemic Stroke?
Elizabeth Barak, Javier Romero, Shahmir Kamalian, Leila R Gharai, Ramon G Gonzalez,
Pamela Schaefer; Massachusetts General Hosp, Boston, MA
Purpose: To evaluate whether initial lesion volume on diffusion weighted imaging(DWI) and
perfusion weighted imaging(PWI) in acute ischemic stroke is associated with clinical outcome.
Material and Methods: 54 patients with acute strokes who underwent DWI and PWI within 9
hours of symptom onset were evaluated. Visually detected DWI and mean transit time(MTT)
abnormalities were segmented with a commercial analysis program and volumes were
calculated. Clinical outcomes, abstracted from medical records, were considered good if the
modified Rankin scale(mRS) was 0 to 2 and poor if the mRS was 3– 6. T Test was used to
analyze DWI and MTT volumes relative to good versus poor outcome and Receiver Operating
Characteristic(ROC) curves were calculated. Results: 33/54 (61%) patients had a good clinical
outcome. Mean DWI lesion size was 54cc. Patients with good clinical outcomes had
significantly smaller initial DWI lesion volumes (mean 15cc) versus patients with poor outcomes
(115cc)(p⫽0.0001). Mean MTT lesion volume was 126cc. Patients with good clinical outcomes
had significantly smaller MTT lesion volumes (65cc) versus patients with poor outcomes
(218cc)(p⬍0.0001). ROC curves for DWI and MTT relative to poor outcome, had areas under
the curve of 0.896 and 0.894, respectively. To maximize the specificity of DWI lesion volume,
(all patients above the cutpoint have a poor outcome) we chose a cut-off point of 72cc with
97% specificity and 62% sensitivity for poor outcome. 13/13 (100%) patients with DWI lesion
size ⬎ 72cc and 8/41 (20%) patients with DWI lesion size ⬍ 72cc had a poor outcome. To
maximize the sensitivity of MTT lesion volume (no patients below the cut-off point have a poor
outcome), we chose a cut-off point of 47cc with 49% specificity and 96% sensitivity for poor
outcome.0/16 (0%) of patients with MTT lesion size ⬍47cc and 21/47 (47%) patients with MTT
lesion size ⬎ 47cc had a poor outcome. Conclusion: Patients with good clinical outcome had
smaller DWI and MTT lesion size on admission MRI. An initial DWI lesion size ⬎ 72cc is highly
specific for poor outcome (all patients with a large DWI have a poor outcome) and a MTT lesion
size ⬍ 47cc is highly sensitive for poor outcome (no patients with MTT ⬍ 47cc have a poor
outcome, ie: all have good outcome). DWI and PWI in acute ischemic stroke can help choose
candidates most likely to benefit from thrombolysis without taking unnecessary risk.
P154
Increasing ThrombolyticTreatment Rates: Results Utilizing Revised
Treatment Criteria And A Multidisciplinary Stroke Education Program.
David C Tong, Jack Rose, Jeffrey Thomas, Jackie Phan, Ann Bedenk, Jerome Barakos, Dan
A McDermott; California Pacific Med Cntr, San Francisco, CA
Stroke treatment with rt-PA remains dismally low. We hypothesized that a rapid stroke triage
system using revised criteria reported to permit safe thrombolysis, coupled with a comprehensive education program could substantially increase thrombolysis treatment rates even
without the presence of a stroke network. METHODS: A rapid triage stroke code system was
implemented where patients are considered for treatment with revised criteria that have been
reported to permit safe thrombolysis. Clinical factors such as recent surgery or possible seizure
at symptom onset are considered relative rather than absolute contraindications to treatment.
Patients of any age are eligible for treatment. Complete reporting of laboratory values is not
necessary prior to the initiation of therapy if there is no reason to suspect a clinically relevant
abnormality. Patients are treated if the neurological deficit is considered disabling, but without
a specific NIHSS score cut off. All stroke codes alert the CT technologist to facilitate rapid
imaging. Intra-arterial therapy is used in patients with contraindications to IV treatment such
as recent surgery or anticoagulation with a significantly elevated PTT or INR. A comprehensive
hospital wide educational program was instituted with emphasis on early recognition of
stroke-like symptoms. Our stroke code system permits any health care provider to initiate a
stroke code. RESULTS: After implementation of the new system, on average 23.8% of all acute
ischemic stroke patients were treated. Monthly treatment rates ranged from 13–38%. The
mean age was 73 ⫾ 16 years. 51% were male, 39% (16/41) were ⱖ 80 years old. Median
door to needle time was 67 minutes (95% CI 28 –152), and median symptom onset time to
treatment was 130 minutes (95% CI 87–290). 13/41 (32%) received IA treatment, primarily due
to a post surgical state (n⫽6; 46%) or anticoagulation at the time of symptoms (n⫽3; 23%).
Symptomatic intracerebral hemorrhage rate was 7%, and mortality was 18%. At discharge,
52% (21/41) of patients had good outcome (mRS 0 –2), despite the older population treated.
CONCLUSION: A system of rapid triage, revised treatment criteria, and education can result in
a substantial increase in the rate of thrombolytic treatment and outcomes comparable to
608
Stroke
Vol 39, No 2
February 2008
published series. Outcomes were comparable to those in clinical trials, despite the significantly
older population treated. Widespread adoption of these techniques could greatly increase the
safe and effective use of thrombolysis for acute stroke.
P157
The Role of Stroke Severity in Transfer and Treatment Decisions.
Marilyn M Rymer, Duane Thrutchley, Saint Luke’s Hosp, Kansas City, MO; Saint Luke’s
Hosp Stroke Team
P155
Timing And Delivery Of Acute Stroke Therapy: Does Place Or Day Of The
Week Matter?
Rakesh Khatri, Dawn Kleindorfer, Jane C Khoury, Pam Schmit, Irene Ewing, Edward Jauch,
Pooja Khatri, Arthur Pancioli, Brett Kissela, Daniel Woo, Matthew L Flaherty, Brian A Stettler,
Christopher W Nichols, Opeolu Adeoye, Joseph P Broderick; Univ of Cincinnati, Cincinnati,
OH
Background: There remains a concern whether the timing and delivery of tissue plasminogen
activator (t-PA) and potential study interventions are similar in Community Hospitals (CH)
compared with Academic Centers (AC). Methods: We collected data from our local SPOTRIAS
registry about academic centers and community hospitals in the Greater Cincinnati- Northern
Kentucky area about stroke onset-to -treatment time, percentage of t-PA treatments and study
enrollment rates. Our multidisciplinary stroke team provides rapid consultation to a total of 31
hospitals (3 AC and 28 CH) either by phone (N ⫽ 31) and/or in person (N ⫽ 16) to evaluate
acute stroke patients 24 hours a day and seven days a week. We compared stroke symptom
onset to treatment time between ACs and CHs. We also compared rates of study enrollment and
percentage of treatments on weekdays and weekends. Results: Our stroke team evaluated a
total of 2556 cases (including phone calls without an in-person evaluation) from a period of
January 2005 to June 2007. A total of 807 cases (296 at ACs and 574 at CHs) were evaluated
by a stroke team physician in person. From a total of 292 thrombolytic treatments, 127 cases
(60 arriving directly and 67 transferred from CHs) were eventually treated at an AC and 185
cases were treated at a CH. Time-to-treatment at CHs was 145 minutes (range 120, 170)
compared to 132 minutes at AC for 60 cases arriving directly (range 114, 162) with p⫽ 0.07
. On combined analysis of both AC and CH, time-to-treatment on weekdays was 140 minutes
(range 115, 167) compared to weekend time of 146 minutes (range 119, 170) with p⫽ 0.49.
The distribution of 292 patients treated with t-PA on any day of the week was not statistically
different with most treats occurring on Friday (43%) and fewest on Thursday (26%). Study
enrollment rates of these 292 patients were comparable during any day of the week with
maximum on Saturday 25 (23%) and minimum on Thursday 16 (12%) for a total of 144 cases.
Conclusion:Rapid evaluation by on-call regional stroke team physicians at both community and
academic hospitals was associated with similar time-to-treatment at both types of institutions
with a trend toward longer times at CHs. The proportion of thrombolytic treatments and study
enrollment are comparable on weekdays and weekends if there is continuous on-call support
by stroke team physicians.
P156
Rates and Predictors of Clinical and Radiological Outcomes in Acute
Ischemic Stroke Patients without Angiographic Occlusion. A Multicenter
Review.
Background: The National Institutes of Health Stroke Scale (NIHSS) score is a strong predictor
of clinical outcome, and a score ⬎10 is highly correlated with large artery occlusions that may
be more difficult to treat successfully with intravenous (IV) thrombolysis alone. As a regional
referral center for acute ischemic stroke (AIS) we sought to analyze the spectrum of stroke
severity in our cases as measured by the NIHSS score at presentation, determine whether the
case was transferred in, and analyze treatment patterns within the NIHSS severity spectrum.
Methods: All AIS cases from 1/2000 to 7/2007 were reviewed for presenting NIHSS scores
using 5 point groupings, transfer status and whether treatment with IV or intra-arterial (IA)
tissue plasminogen activator (tPA) and/or mechanical embolectomy was used.The data was
then dichotomized into cases with NIHSS ⬍ 10 and cases with NIHSS ⬎10 and analyzed for
significant differences in transfer status and treatment decisions. Results: NIHSS scores were
available for 1791(71%) of 2518 ischemic stroke cases. Overall, 36.6% (655/1791) received
acute therapy with lytic and/or mechanical embolectomy and 49.4% (855/1791) were
transferred. Of the treated cases 67.9% (445/655) were transferred to our center.Significant
differences were found in transfer and treatment decisions in milder (NIHSS ⬍ 10) vs more
severe strokes (NIHSS ⬎10) Conclusions: The distribution of NIHSS scores indicate that milder
strokes occur more frequently than severe strokes.Severe strokes are significantly more likely
to be transferred to a comprehensive stroke center, to receive acute treatment, and to receive
intra-arterial tPA and/or mechanical embolectomy rather than IV tPA alone.
NIHSS SCORES OF TRANSFERRED AND TREATED CASES OF AIS
Baseline
NIHSS
Score
Number of
Cases
Transferred
Cases
Treated
Cases
IV tPA
only
Transferred
Treated
IV tPA only
0 –5
754
(42.1%)
322/
754
(42.7%)
100/
754
(13.3%)
69/
100
(69.0%)
6 –10
364
(20.3%)
181/
364
(49.7%)
123/
364
(33.8%)
75/
123
(61.0%)
11–
15
16 –
20
21–
15
235
206
138
(13.1%) (11.5%) (7.7%)
132/
122/
78/
235
206
138
(56.0%)
(59%) (56.5%)
141/
129/
98/
235
206
138
(60.0%) (62.6%) (71.0%)
42/
14/
13/
141
129
98
(29.8%) (10.9%) (13.3%)
26 –30
>30
Total
68 (3.8%)
26 (1.5%)
1791
34/68
(50.0%)
16/26
(61.5%)
46/68
(67.6%)
18/26
(69.2%)
2/68
(4.3%)
3/18
(1.7%)
885/
1791
(49.4%)
6551791
(36.6%)
218/
655
(33.3%)
ⱕ10 NIHSS
Score N⫽1118
⬎10 NIHSS Score
N⫽673
p-value
503(45%)
233(20%)
144(65%)
382(57%)
432(64%)
74(17%)
⬍0.0001
⬍0.0001
⬍0.0001
Qaisar A Shah, M. Fareed K Suri, Haitham M Hussein, Zeenat Qureshi Stroke Rsch Cntr,
Univ of Minnesota, Minneapolis, MN; Yousef M Mohammad, Dept of Neurology, Ohio State
Univ, Columbus, OH; Adnan I Qureshi; Zeenat Qureshi Stroke Rsch Cntr, Univ of Minnesota,
Minneapolis, MN
Background: Approximately 15% of the patients with acute ischemic stroke do not have
any occlusion demonstrated on initial angiography. The optimal management strategy in
these patients is not known. Objective: To determine the rates and predictors of clinical and
radiological outcome of the acute ischemic stroke patients without an angiographic occlusion.
Methods: Patients were identified from a multiple single-center registries and a literature
search of MEDLINE, PubMed, and Cochrane databases supplemented by a review of
bibliographies of relevant articles and personal files. All patients underwent serial neurological
assessment with National Institutes of Health Stroke Scale (NIHSS) score and modified Rankin
Scale (mRS). Radiological assessment was performed with computed tomography scan (CT)
and magnetic resonance imaging (MRI) obtained at 24 –72 hours. Predictors of favorable
clinical outcome and radiological cerebral infarction were determined using multivariate
analysis. Results: A total of 85 patients were analyzed (mean age 63 years; 31 were women)
with acute ischemic stroke patients without an angiographically demonstrated occlusion. The
median NIHSS score was 8 (range 2–25). A total of 10 patients received intravenous tissue
plasminogen activator (t-PA) prior to angiography. Neurological improvement (defined by ⱖ4
points reduction in NIHSS score) was observed in 26 (48%) of the 54 patients with serial
examinations. Favorable outcome defined by mRS 0 –2 ascertained at follow-up was seen in
47 (57%) of the 85 patients. After adjusting for confounding variables, patients with diabetes
mellitus have a trend towards higher risk (odds ratio [OR] 3.7, 95% confidence interval [CI] 0.93
- 17.07) of poor functional outcome. Cerebral infarction was detected in 64 (77%) of the 83
patients with CT or MRI located in cortical (n⫽48) or sub-cortical (n⫽15) distribution. There
were (n⫽44) anterior circulation strokes, (n⫽20) posterior circulation stroke, and (n⫽19)
normal; CT data on two patients were not available. After adjusting for confounding variables,
the risk of cerebral infarction was higher in patients aged more than 65 years (OR 23, 95% CI
1.9 - 357) and in men (OR 7.3, 95% CI 1.9 - 33). Conclusion: High rates of new infarcts in
follow-up radiological assessment, and disability or death subsequent to the ischemic event are
observed, particularly among older patients, men, and patients with diabetes.
P158
Early Clinical Experiences With A New Thrombectomy Device For The
Treatment Of Ischemic Stroke.
Thomas Liebig, Kinikum rechts der Isar - TUM, Munich, Germany; Joerg Reinartz, Robert
Janker Klinik, Bonn, Germany; Thomas Guethe, Katharinen Hosp, Stuttgart, Germany;
Christian Roth, Universitätsklinikum des Saarlandes, Homburg/Saaar, Germany; Elina
Miloslavski, Hans Henkes; Katharinen Hosp, Stuttgart, Germany
A new flexible micro filament device for intraarterial thrombectomy, the phenox Clot Retriever
(pCR) has become available for use in patients experiencing acute ischemic stroke in Europe
since October 2006. The device consists of an array of radially circumferential oriented
polyamid microfilaments on a highly flexible nitinol/platinum-alloy compound core wire. It is
available in three sizes that range from 3 to 1mm proximally and 5 to 2mm distally and it can
be deployed through a standard microcatheter. The smallest version is capable of recanalizing
vessel diameters well below 2mm such as the distal MCA branches. In three centers, 48
treatments in 45 patients with ischemic stroke were performed with one or more PCRs so far.
The distribution of vascular territories was as follows: ICA (terminal and bifurcation) 13, MCA
18, vertebrobasilar 13, ACA and PCA 4. Recanalization was achieved in 33/48 treatments
(68,8%) whereas in 12/48 no recanalization was possible. There were 3 failed attempts were
the device and/or microcatheter could not be deployed. Of all 33 recanalizations, 27 were TIMI
scores II or III (56,3%). In 11 treatments the vessel diameter was 2mm or less. The average
number of devices needed was 2,6. Apart from a recanalization of more than 70% (failed
attempts excluded), it was most remarkable that there was no device related morbidity and
mortality recorded during these 48 treatments which is most likely attributable to the highly
flexible and atraumatic design together with a simple application. From our experience we
conclude that the pCR is a potentially useful supplement to the repertoire of currently available
devices for endovascular intracranial thrombectomy.
P159
Multimodal CT to Define a Tissue Window for Thrombolysis in Acute
Ischemic Stroke.
Imanuel Dzialowski, Jasmin Renger, Dept. Neurology, Univ of Dresden, Dresden, Germany;
Olaf Wunderlich, Dept. Neuroradiology, Univ of Dresden, Dresden, Germany; Kristian Barlinn,
Ulf Becker, Hjordis Hentschel, Katja E Wartenberg, Dept. Neurology, Univ of Dresden,
Dresden, Germany; Ernst Klotz, Siemens Med Solutions, Forchheim, Germany; Georg Gahn,
Dept. Neurology, Univ of Dresden, Dresden, Germany; Ruediger von Kummer; Dept.
Neuroradiology, Univ of Dresden, Dresden, Germany
Objectives: To date, thrombolysis in acute ischemic stroke has been restricted to a three-hour
time window. We sought to define a CT-based tissue window for thrombolysis instead of a time
window. Methods: We prospectively studied patients presenting with anterior circulation
ischemic stroke within 12 hours of symptom onset and a National Institute of Health Stroke
Scale (NIHSS) score ⱖ 3. All patients underwent cranial non-contrast computed tomography
(NCCT), CT angiography (CTA), and CT perfusion imaging (CTP). Parameter maps of
time-to-peak (TTP), cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated.
Patients were treated with IV, IA, or combined IV/IA thrombolysis according to current
guidelines. We determined intracranial occlusion status and applied the Alberta Stroke Program
Early CT Score (ASPECTS) to all NCCT scans and CTP parameter maps. A normal scan scored
10, a complete middle cerebral artery (MCA) lesion scored 0. We defined three different types
of tissue windows in this population: 1) good NCCT scan (ASPECTS ⬎ 7), 2) favorable NCCT
scan (ASPECTS ⬎ 5) in the presence of a MCA occlusion, and 3) CBV-ASPECTS minus
CBF-ASPECTS ⱖ 2. We analysed feasibility, incidence and prognosis with and without
thrombolysis for each tissue window. We defined favorable outcome as modified Rankin Scale
scores 0 –2 at 3 months. Results: From 12/06 to 06/07, we screened a total of 138 patients,
of which 46 fulfilled inclusion criteria. Mean age was 70 years, 48% were male, time-topresentation was 204 min, median NIHSS score 7 (range 3–31), ASPECTS 9 (range 2–10),
20/46 (43%) of patients had occlusions within the MCA territory, 23/46 (50%) received
thrombolysis. Tissue windows 1 and 2 could be assessed in all, tissue window 3 in 33/46 (72%)
of patients, mostly due to motion artefacts (5/13). Incidence was 27/46 (58%), 14/46 (30%) and
7/46 (15%) for tissue window 1,2, and 3, respectively. Tissue window 1 characterized less
severely affected patients (median NIHSS score ⫽ 5, ASPECTS ⫽ 10, 6/27 (22%) MCA
occlusions) compared to tissue window 2 (NIHSS score ⫽ 13.5, ASPECTS ⫽7, 14/14
occlusions) and 3 (NIHSS score ⫽ 14, ASPECTS ⫽ 6, 6/7 (86%) occlusions). We observed
favorable outcome without thrombolysis in 6/15 (40%), 1/7 (14%) and 0/2 patients with tissue
window 1,2, and 3, respectively. With thrombolysis, proportions for favourable outcome were
6/12 (50%), 2/7 (28%) and 1/5 (20%) for tissue window 1,2, and 3, respectively. Conclusion:
Performing multimodal CT in patients with anterior circulation ischemic stroke presenting
within 12 hours from symptom-onset might help to define a tissue window for thrombolysis.
Feasibility of a CTP-based tissue window might be limited. Patients with a favourable NCCT
scan and a MCA occlusion might be a target group for thrombolysis within a tissue window.
However, the number of patients in this ongoing study is a limit to draw definite conclusions.
609
patients (age; 73.8 ⫾ 8.9 years, male; 14, median NIHSS; 15.3 ⫾6.6) into the present study.
MRA immediately after t-PA therapy showed early recanalization in 14 of 31 (45.2%) patients.
Before IV t-PA therapy, median infarct volume was 5.6 cm3 in non-recanalization group and
10.7 cm3 in recanalization (p⫽0.93) and mean NIHSS score was 16 in occlusion group and 16
in recanalization group (p⫽0.95). Immediately after IV t-PA, median infarct volume was 32 cm3
in non-recanalization group and 10.8 cm3 in recanalization (p⫽0.93) and NIHSS score was 17
in occlusion group and 14 in recanalization group (p⫽0.35). However, at 24 h of onset, infarct
volume was larger in non-recanalization group than recanalization group (65.4 cm3 vs. 12.1,
p⫽0.02) and NIHSS score more elevated in non-recanalization group than recanalization group
(19 vs. 12, p⫽0.02). After 7 days of onset, similar tendency was observed between
non-recanalization and recanalization groups (infarct volume; 133.6 cm3 vs. 19 cm3, p⫽0.01,
and NIHSS score; 19 vs. 11, p⫽0.01). Conclusion: Early recanalization immediately after IV
t-PA infusion in acute ischemic stroke can avoid the enlargement of ischemic volume.
P161
Orolingual Angioedema After Thrombolysis For Acute Stroke.
Maria I Aguilar, Bart M Demaerschalk, David W Dodick, Timothy J Ingall, Nadine F
Lendzion, Patricia H Miller, Mayo Clinic Arizona, Phoenix, AZ; William D Freeman, Nancy L
O’Keefe, Mayo Clinic Jacksonville, Jacksonville, FL; Gustavo Saposnik, Univ of Toronto,
Toronto, Canada; Brian Silver, Panayiotis D Mitsias, Wayne State Univ, Detroit, MI; Vladimir
Hachinski; Univ of Western Ontario, London, Canada
Background: Orolingual angioedema, which can be a life-threatening emergency, occurs in up
to 5% of patients with ischemic stroke who receive IV recombinant tissue plasminogen
activator (rtPA). It has been postulated that the incidence may increase with the concomitant
use of angiotensin-aonverting-anzyme inhibitors (ACE-I). No information is available regarding
the risk when re-exposed to rtPA. The exact pathophysiologic mechanism is unknown, but it
is believed to be due to increased production of bradykinin by rtPA and inhibited degredation
of bradykinin by ACE-I (figure). Bradykinin facilitates inflammatory and allergic reactions.
Objective: Identify common characteristics among subjects who develop angioedema after or
during the administration of rtPA for acute ischemic stroke, which could serve as risk factors
for this entity. Methods: Acute stroke databases for Mayo Clinic Arizona, Mayo Clinic
Jacksonville and London Health Sciences Centre, Canada were searched for the development
of this complication. (Table 1) Results: We found 6 cases of angioedema among 447 subjects
treated with rtPA for acute ischemic stroke (table 2). This is lower (1.3%) than previously
reported (5%). The use of ACE-I was common (4/6 or 5/6). Four of six strokes were located on
the right hemisphere and with cortical involvement. The mean NIHSS prior to treatment was 11.
Only 1 of the 6 subject had been exposed to rtPA before. Five subjects were alive upon
discharge. Conclusions: Angioedema due to use of rtPA for acute ischemic stroke is a rare
complication. The prior or concomitant use of ACE-I may be a risk factor. Stroke location in the
right hemisphere and with cortical involvement was common in these cases. Only one of the
6 subjects had been exposed to rtPA in the past. Severity of stroke symptoms (NIHSS) does not
seem to influence the development of angioedema.
P160
Early Recanalization Immediately After IV rt-PA in Acute Ischemic Stroke
Can Avoid The Enlargement of Infarct Volume.
Kazuto Kobayashi, Yasuyuki Iguchi, Kenichirou Sakai, Junya Aoki, Yoko Okada, Yuka
Terasawa, Junichi Uemura, Shinji Yamashita, Masao Watanabe, Kensaku Shibazaki, Noriko
Matsumoto, Takeshi Inoue, Kazumi Kimura; Kawasaki Med Sch, Kurashiki, Japan
Purpose: Intravenous administration of tissue plasminogen activator (t-PA) dissolves the clot
and can improve clinical outcome in patients with acute ischemic stroke. Sveral studies have
reported that neurological improvement is caused by early recanalization after IV t-PA. Our aim
of the present study is to investigate whether early recanalization immediately after IV t-PA can
avoid the enlargement of infarct volume during 7days of onset. Materials and Methods: Acute
ischemic stroke patients treated with IV t-PA were prospectively registered in the present study.
In order to measure infarct volume and assess early recanalization, MRI studies including DWI,
MRA and FLAIR were performed four times (on admission, immediately after IV t-PA, 24 h of
onset and 7 days). We evaluated neurological symptoms by National Institute of Health stroke
scale (NIHSS) score in accordance with each MRI studies. We divided patients into two groups;
early recanalization and no-recanalization groups, and compared serial infarct volume and
NIHSS score between two groups. Results: We had consecutive 49 patients treated with IV
t-PA. We excluded 18 patients without occluded arteries on initial MRA, and enrolled 31
P162
Reported Stroke Onset Times are Clustered and Imprecise.
Don B Smith, Chris V Fanale, Colorado Neurological Institute, Englewood, CO; Christy L
Casper, Kathryn A Leonard, Swedish Med Cntr, Englewood, CO; Judith A Hinchey; St
Elizabeth’s Med Cntr, Brighton, MA
Introduction: Time is an important factor in the decision to administer intravenous tissue
thromboplastin activator (TPA) for stroke. Guidelines recommend that TPA be started within
610
Stroke
Vol 39, No 2
February 2008
three hours of symptom onset, and “strict adherence” to guidelines is generally advocated. Yet,
time of onset can be difficult to establish. Different sources may report notably different times
for same event. Hypothesis: Onset time is an imprecise variable. It may be imprecise enough
to call into question onset-to-treatment calculations. Methods: We sought to determine the
precision of onset time (and several other timed variables). We queried two stroke databases,
containing 6733 patients, for whom time of onset was reported in 3234. We assumed that
these values, if precise, would be distributed randomly among the possible values of 0 to 59,
when expressed as minutes-after-the-hour. We compared database values with a set of
computer-generated random values for minutes-after-the-hour. Results: Nearly 75% of the
database values were on the hour or the half-hour. The time of onset was factorable by 5 in
98% of database values. In contrast, the random data were evenly distributed across the
allowable range, with no single minute occurring more 2.6% of the time. The odds ratios (95%
CI) –when compared to random data– that a database onset value would be 5-factorable in the
two databases were: 252.6 (141– 453) and 151.9 (113–204), respectively. The 5-factorability
of times for Hospital-Arrival and Starting-TPA were also significantly different from the random
values, but these showed no clustering on the hour or half hour. Discussion: Calculated
onset-to-treatment times for stroke have been assumed to be fairly reliable. In some reports,
values up to 185 minutes are not considered protocol violations, but anything higher is a
violation. In our study stroke onset times were strongly clustered on the hour or the half hour.
If onset is typically measured in half-hour increments, it is unlikely that onset-to-treatment
times are accurate to within five minutes. The precision of time of onset might be improved if,
in addition to encouraging a call to 911, we encourage a look at the clock as soon as stroke
symptoms are recognized. It likely, however, that time of onset will remain inexact. This
limitation adds weight to the argument for relying less on the history and more on physiologic
measures of tissue viability in determining when acute stroke treatment would be “too late”.
P163
Initial Experience With Combined 64-slice Ct Perfusion (ctp) And Ct
Angiography (cta) In Routine Practice. Potential And Pitfalls.
David Tong, Jack Rose, Jerome Barakos, Jeffrey Thomas, Ann Bedenk, Jackie Phan, Dan A
McDermott; California Pacific Med Cntr, San Francisco, CA
Few data are available on the utility of 64 slice CT in stroke evaluation. This technique covers
2– 4x more brain than prior methods. We evaluated the utility of 64 slice CTA/CTP in routine
practice. We hypothesized that 64 slice CTP would be feasible and add value to the
management of patients with acute ischemic neurological symptoms. Methods: We reviewed
our experience with 64 slice CTA/CTP in patients with acute neurological symptoms ⱕ6h after
symptom onset. Patients with cerebral hemorrhage were excluded. Follow up MRI including
DWI and MRA was routinely performed in patients when clinically appropriate. Results: From
5/06 to 7/07, 70 ⱕ 6h patients received CT/CTP/CTA. CTA/CTP was successful in 60/70 (86%).
Mean age was 70 (range 32–93). There were 35 strokes and 12 TIAs (47/70;67%). Median
NIHSS of stroke patients was 12 ⫾ 9. CTP detected reduced perfusion in 24/31 (77%) acute
stroke patients, and in 2/11 (18%) TIA patients. DWI was negative in 2/4 (40%) stroke patients
with a negative CTP who received an MRI. Median NIHSS was 3.5 in these cases, and outcome
was excellent, with no major neurological sequelae on follow up. All of the non-stroke/TIA
patients (n⫽22) had negative CTP/CTA, and experienced a good outcome. Eighteen patients
received rt-PA (4 intra-arterial). CTA was negative in 8/25 (32%) patients with acute stroke and
abnormal CTP. 4 of these received rt-PA (2 intra-arterial) with good recovery in 75% (3/4). CTP
also revealed focal hypo perfusion in 1/4 (25%) seizure patients, and elevated perfusion in one
brain tumor patient. No patients with a negative CTP/CTA experienced subsequent stroke or
deterioration within the next 48h. Conclusions: 64-slice CTP/CTA is feasible and practical in
acute stroke evaluation. It detects abnormalities in many patients (32%) in which no occlusion
is identified on CTA, and that respond to thrombolytic therapy. A negative CTP/CTA predicts a
good outcome in most patients, particularly those with a questionable diagnosis of stroke/TIA.
However, despite its greater brain coverage it can still miss some smaller lesions in a minority
of patients (14%), although most of these patients do not experience early recurrence or
significant persistent deficits. The combination of CTA and CTP using 64 slice technology is a
practical and useful addition to the evaluation and management of patients with acute
neurological symptoms, especially those patients who may respond to thrombolytic therapy.
P164
Ultrasound Energy Levels in the CLOTBUST Trial: A Step towards
Optimization of Clinical Sonothrombolysis.
Rajan Ramaswami, Yufeng Zhou, ImaRx Therapeutics, Inc, Tucson, AZ; Mark Schafer, Sonic
Tech Inc, Philadelphia, PA; Reena Zutshi, ImaRx Therapeutics, Inc.,, Tucson, AZ; Andrei V
Alexandrov; Comprehensive Stroke Cntr,Univ of Alabama at Birmingham, Birmingham, AL
Background and Purpose: Low intensity ultrasound augments arterial recanalization with
systemic TPA therapy for stroke. However, the optimal intensity and other parameters of patient
exposure to ultrasound remain unknown. As a step towards development of an operatorindependent device for sonothrombolysis, we aimed to determine acoustic output parameters
of the commercially available transcranial Doppler (TCD) devices used in the CLOTBUST trial.
Materials and Methods: Standard diagnostic 2 MHz TCD equipment, with pulsed wave single
element transducers, were evaluated in a water tank with a calibrated hydrophone and acoustic
output data acquisition equipment and data analysis software. Energy parameters of the emitted
ultrasound beams were measured at the maximum power output produced by TCD equipment.
Beam attenuation caused by the temporal bone was measured in an in-vitro water tank model,
again using a hydrophone. Results: 2 MHz TCD units emitted pulsed wave ultrasound beams at a
Mechanical Index range of 0.19 - 0.24. The range of spatial peak temporal average intensities (ISPTA)
was 125 - 467 mW/cm2 at pulse repetition frequencies of 8 - 11.5 kHz. Beam attenuation was
measured at 5 cm depth after its passage through the temporal bone. The presence of bone reduced
ISPTA by 16 - 94%, depending upon the exact beam path through the temporal window. The peak
rarefactional acoustic pressure after passage through the bone was 128 - 247 kPA at the depth of
5 cm. Conclusions: We measured the output parameters of standard diagnostic ultrasound units
to understand the levels of patient exposure achieved in the CLOTBUST trial. Even in the presence
of the temporal bone, a substantial amount of energy can be delivered by a single element 2 MHz
transducer. These data will be used in development and optimization of an operator-independent
device for sonothrombolysis.
P165
The Relationship Between Baseline Blood Pressure and CT Findings in
Acute Stroke: Data from the “Tinzaparin in Acute Ischaemic Stroke
Trial”(TAIST).
Gillian M Sare, Laura J Gray, Timothy England, Chamilla Geeganage, Philip M Bath, Univ of
Nottingham, Nottingham, United Kingdom; on behalf of the TAIST Investigators
Introduction: High blood pressure (BP) is present in ⬃80% of patients with acute ischaemic
stroke; high and low BP are associated independently with poor outcome. The relationship
between BP and acute, and subacute CT findings in patients with stroke has yet to be
examined. Data from the TAIST trial has previously shown hypertension to be related to poor
outcome. Methods: TAIST was a randomised controlled trial assessing the safety and efficacy
of tinzaparin (a low molecular weight heparin) at two doses (medium and high,100 and175
IU/kg) versus aspirin (300 mg) in 1,484 patients with acute ischaemic stroke (⬍48h). Systolic
BP (SBP) was measured at baseline. CT head scans were performed at baseline and after a
treatment period of 10 days; scans were independently adjudicated for the presence of
infarction, dense MCA signs, mass effect, cerebral oedema, haemorrhagic transformation,
leukoariosis, and old infarctions. The relationships between BP and CT findings were adjusted
for age, sex, baseline severity, time to randomisation, and treatment assignment. Results: High
SBP was associated with a normal baseline CT, the presence of leukoariosis (odds ratio [OR]
1.011, 95% confidence interval [CI] 1.005–1.016) and old infarcts (OR 1.011, 95% CI
1.006 –1.016). A lower baseline SBP was associated with signs of early infarction (OR 1.01,
95% CI 1.00 –1.01), and a higher baseline SBP was associated with visible infarction at day 10
(OR 1.008, 95% CI 1.003–1.013) in both univariate and adjusted analyses. There was no
association between BP and haemorrhagic transformation. Conclusions: In acute stroke, lower
BP is more likely to have CT signs of early infarction. High BP is associated with visible
infarctions on late CT and is not associated with an increased risk of haemorrhagic
transformation. The relationship between BP and poor outcome appears to be related to factors
which may be detected in CT findings.
P166
Prognostic Factors In Patients With Acute Basilar Artery Occlusion Treated
With Multi-modal Reperfusion Therapy.
Ronen R Leker, Guy Raphaeli, Ronie Eichel, Tamir Ben-Hur, Jose Cohen; Hebrew Univ
Hadassah Med Cntr, Jerusalem, Israel
Background: Acute basilar artery occlusion (ABAO) is associated with poor outcome when treated
conservatively. Intra-arterial thrombolysis (IAT) has been advocated for treatment of ABAO and
several prognostic factors were identified in these patients. To date this approach is replaced by
multi-modal endovascular treatments that includes intra-arterial infusion of thrombolytics and/or
antiplatelet agents, mechanical clot disruption with microguidewires, microcatheters and balloon
angioplasty with stent placement. Objectives: We aimed to identify prognostic factors in patients
with ABAO that underwent multi-modal endovascular treatment. Methods: Clinical and radiological
data from consecutive BAO patients treated at our center over the last 2 years were analyzed. In all,
BAO was documented by CT or MR angiography and by plain angiography. All patients presented
with acute basilar stroke and underwent multi-modal endovascular treatment on an emergency
basis. Stroke subtypes were categorized according to TOAST criteria. Good outcome was defined as
a modified Rankin score (mRS) ⬍2 and poor outcome as a mRS⬎2 at 30 days post-stroke. The
results were compared to those observed historically in patients that were treated conservatively or
with IA treatment alone. Results: Twenty four patients were included (21 male) with a mean age of
54.7 (range 26 –70). Eight patients died (33%) and 6 of the surviving 16 (37.5%) patients achieved
a mRS ⬍2 at 30 days. We could not identify any clinical or radiological variable that were associated
with a greater likelihood of good or poor outcome at 30 days. Specifically, age, presenting symptoms
and signs, risk factor profile, acute vs. progressive stroke onset, stroke subtype, time from onset to
treatment and time from onset to reperfusion as well as lesion location within the BA, lesion length,
lesion irregularity on the angiography and the presence of collateral flow did not significantly differ
between the groups. All patients with mRS⬍2 had reperfused with TIMI 2 or 3 scores but so did
also 8/10 patients with MRS⬎2. Conclusions: Multi-modal endovascular treatment resulted in
higher than expected survival and good outcome rates when compared with patients treated
conservatively or with IA therapy alone. We couldn’t identify prognostic factors in patients with ABAO
treated with multi-modal endovascular approach. Our results imply that patients should not be
excluded from treatment based on clinical or radiological parameters and that all patients with ABAO
should be given the chance to benefit from therapy.
P167
Approaching Stroke Similar to Trauma Improves Door to Needle Time for
IV tPA.
Batya R Radzik, Rebecca F Gottesman, Peter M Hill, Rafael H Llinas, Cathleen
Carlen-Lindauer, Eric M Aldrich; Johns Hopkins Hosp, Baltimore, MD
Introduction: Eleven years after its introduction IV tPA continues to be the only FDA approved
treatment for acute ischemic stroke. However, less than 5% of stroke patients nationwide
receive it. There are a number of factors identified that contribute to this low percentage. Some
of these factors are community based. Others are intrinsic to the hospital system. These include
hesitancy on the part of the physician to administer tPA and failure to triage strokes in a rapid
and timely fashion. Furthermore, an efficient tPA program requires healthcare providers from
multiple disciplines and departments to coordinate efforts to provide optimal care. Our
hypothesis was that adopting the clinical care process for trauma would improve tPA
administration and door to needle time. Methods: In 2004 a workgroup consisting of
representatives from Neurology and Emergency Medicine was created to review and revise our
tPA program. The national goals of door to needle time (DTN) of less than 1 hour were targeted.
The following changes were instituted: acute strokes are triaged similarly to trauma and treated
in critical care areas, pre-printed tPA related documentation is kept in a specified location, and
the ED physicians perform an exam and call the brain attack team. Data for all patients who
received tPA in the ED at our institution from 2000 –2006 were entered into a database. Time
specific data included symptom onset to ED arrival, door to CT time, door to needle time, and
total time to treat. A t-test was used to compare mean time intervals from 2000 –2004 before
the changes and 2004 –2006 after the changes. A linear regression model was used to
determine the linear effect of time (year) on the chronology intervals in tPA administration.
Results: From 2000 –2004, our primary target of door to needle time averaged 93 minutes.
After these changes were instituted, our DTN decreased to 68 minutes (p⫽0.0002). The
proportion of patients who met the goal of DTN⬍ 60 minutes was only 16% prior to 2004 and
43% (p⫽0.04) afterward. Conclusion: Door to needle time significantly improved since 2004.
Adopting the clinical care processes used for trauma patients to improve an IV tPA program
demonstrated consistent results over a two year time period.
P168
Withdrawn
611
reperfusion injury. In this study, we attempted to examine the time window of nitrite effect in
the experimental stroke, and to develop the preventive therapy for potential oxidative stress.
Methods: Solutions of sodium nitrite (480 nanomol) were infused intravenously in the
ischemia-reperfusion (90 minutes MCA occlusion) and permanent occlusion models of the adult
male SD rats, at the various injection time points (90 min-12 hr). Also, nitrite (480, 4800 nmol)
were infused with alpha-lipoic acid (␣-LA, 100mg/kg), an anti-oxidant for preventing the
potential toxicity. Infarct volumes and functional outcomes were measured. Results: Nitrite
infusion reduced infarction volume, and enhanced functional recovery at the time of
reperfusion, and 90 minutes and 3 hours after reperfusion, but not 6 hours after. However, the
nitrite treatment in permanent model was less effective with a shorter time window. The
potential oxidative toxicity of high dose of nitrite was inhibited significantly by the combinational
treatment of ␣-LA. Conclusions: Nitrite exerted profound neuroprotective effects in the
ischemic brains up to 3 hours after reperfusion, and the potential nitrite toxicity could be
attenuated by an anti-oxidant combinatorial treatment. These results suggest that nitrite may
be a safe and effective therapeutic agent in the setting of acute ischemic stroke.
In-hospital Treatment
P170
Comparison of Primary Angioplasty and Stent Placement for Intracranial
Atherosclerosis.
Farhan Siddiq, M. Fareed K Suri, Robert A Taylor, Zeenat Qureshi Stroke Rsch Cntr, Univ of
Minnesota, Mineapolis, MN; John C Chaloupka, Interventional Neuroradiology, Univ of Iowa,
Iowa City, IA; Adnan I Qureshi; Zeenat Qureshi Stroke Rsch Cntr, Univ of Minnesota,
Mineapolis, MN
Objective: To determine and compare the rate of short and long-term out-comes of primary
angioplasty and stent placement for intracranial atherosclerosis. Background: Primary angioplasty and stent placement has been used to treat intracranial atherosclerosis refractory to best
medical treatment. There are no large studies to compare the clinical outcomes of these two
procedures. Methods: We analyzed the clinical and angiographic data of 190 patients treated
with 98 intracranial stents and 95 angioplasty procedures in three tertiary care centers. Only
patients with adequate clinical follow-up were included in the analysis. Rates of one month
stroke and/or death were compared for angioplasty and stenting. Stroke rates and combined
stroke and death rates were identified as clinical endpoints during follow-up. The effect of
angioplasty and stenting on clinical outcome was evaluated using Cox proportional hazards
analysis to adjust for potential confounders (age, sex, location, and severity of post-procedure
stenosis). Results: The mean age (⫾standard deviation) of the treated patients was 61.9 (⫾
12.6) years. Three patients suffered fatal peri-procedural complications (1 in angioplasty and
2 in stent treated group). There were 14 stroke events in the peri-procedure period (10 in
angioplasty and 4 in stent treated group) (Relative Risk [RR] 1.06, 95%, confidence interval [CI]
0.97–1.16, p⫽0.182). The mean follow-up time (⫾standard deviation) for 187 patients
(excluding 3 peri-procedure deaths) was 20.8 ⫾20.5 months. Eight patients suffered stroke
during follow-up period (4 each in the angioplasty and stent treated groups). In the Cox
proportional hazard analysis, stroke event rate was not significantly different between the two
groups (RR 1.7, 95% CI 0.13–10.02, p⫽0.83), but there appears to be a trend towards
increased risk of combined endpoints of stroke and death in the stent treated group (8 in
angioplasty and 10 in stent treated group, RR 2.4, 95% CI 0.8 – 6.7, p⫽0.09) after adjusting
for age, sex, location and post-procedure stenosis. Conclusion: Primary angioplasty appears to
have trend towards a lower rate of stroke and death than stent placement for intracranial
atherosclerosis.
P171
Predictors of Infection following Ischemic Stroke.
Angela Kalil, Patricia Tanzi, J. M Gee, Kevin Cain, Kyra Becker; Univ of Washington Sch of
Medicine, Seattle, WA
P169
Optimal Treatment Of Sodium Nitrite In The Acute Ischemic Stroke: Time
Window Study And Combination With Anti-oxidants.
Keun-hwa Jung, Kon Chu, Soon-Tae Lee, Hee-Kwon Park, Seoul National Univ Hosp, Seoul,
Republic of Korea; Eun-Cheol Song, Inha Univ Hosp, Incheon, Republic of Korea; Sang Kun
Lee, Jae-Kyu Roh; Seoul National Univ Hosp, Seoul, Republic of Korea
Backgrounds: The rate of NO generation from sodium nitrite is linearly dependent on
reductions in oxygen and pH levels. We recently reported that nitrite-derived nitric oxide (NO)
has been reported to exert a profound protection against transient focal cerebral ischemia-
Background: Infection following stroke is common and associated with worse outcome, yet
prophylactic antibiotics have not been shown to improve outcome in large cohorts of patients
with stroke. If one could identify patients at the highest risk for developing infection, it might
allow for more selective prophylaxis. The goal of this study was to test whether clinical and
immunological variables from the first 72 hours post-stroke were predictive of subsequent
infection. Methods: The study was approved by the local IRB. Patients with ischemic stroke
were enrolled within 72 hours of stroke onset and followed prospectively. Infection was
diagnosed by the constellation of clinical signs, symptoms, imaging findings and culture
results. A number of clinical and immunological variables were assessed at 72 hours and their
association with the occurrence of infection by day 14 determined. To ensure that the 72 hour
biomarkers were not affected by concurrent infection, patients diagnosed with infection in the
first 5 days after stroke onset were excluded from analysis. Results: Among 55 consecutive
patients enrolled in the study, 2 died within 1 week and are excluded from further analysis. Of
the remaining 53 patients, 65% were male with a mean age 55 (SD 14); the median NIHSSS
was 13. Among these 53 patients, 18 (34.0%) developed infection within 14 days of stroke
onset; 6 of these infections were noted within the first 5 days and these patients are excluded
from analysis. Of the 12 remaining patients with infections, 4 developed pneumonia (PNA), 8
612
Stroke
Vol 39, No 2
February 2008
developed urinary tract infection (2 of whom also had PNA) and 2 developed other non-severe
infections. Increased risk of infection on days 6 –14 was associated with higher NIHSSS
(OR⫽1.22, 1.08 –1.37), older age (OR⫽1.07, 1.00 –1.14), intubation (OR⫽22.5, 2.2–229.4),
and elevated levels of hsCRP (OR⫽1.77, 1.14 –2.74), IL-6 (OR⫽2.19, 1.04 – 4.64), and TNF␣
(OR⫽4.45, 1.14 –17.43) at 72 hours. Weaker and not quite significant associations were seen
with total leukocyte count, lymphocyte count and IL10 levels. After controlling for the NIHSSS,
only age (OR⫽1.10, 1.01–1.20) and TNF␣ levels (OR⫽7.70, 1.16 –51.22) remain predictive of
infection. Conclusions: Infection following stroke is common. The risk of infection appears to
be related primarily to stroke severity, as assessed by NIHSS, and age. A strong early
inflammatory response, as measured by plasma levels of TNF␣, also appears to predict
infection within the first 14 days after stroke onset. Further analyses with a larger sample are
needed to confirm this association.
P172
Efficacy Of A Free Radical Scavenger, Edaravone, On Acute Lacunar
Infarction.
Yasuyuki Ohta, Ota Memorial Hosp, Fukuyama, Japan; Tomoko Fukushima, Fukuyama
Transporting Shibuya Longevity Health Foundation, Fukuyama, Japan; Kazuhiro Takamatsu,
Satomi Ikegami, Ikuko Takeda, Taisei Ota, katsuya Goto; Ota Memorial Hosp, Fukuyama,
Japan
[Preface] Free radicals are thought to be important in the occurrence of neural damage during
cerebral infarction. There are many in vitro and in vivo studies showing that a free radical
scavenger, edaravone, inhibited brain edema after ischemia, tissue injury, delayed neuronal
death and vascular endothelial cell injury. Though there is a randomized, placebo-controlled,
double blind study at multiple centers in Japan showing the effect of edaravone on acute
cerebral infarction, clinical studies are scanty yet. This study investigated the effect of
edaravone on the outcome of patients with acute lacunar infarction. [Materials and Methods]
We retrospectively evaluated 124 consecutive patients with first-ever acute lacunar infarction
who were admitted to our hospital within 24 hours after the onset between January 2004 and
June 2007. Of these, 59 patients underwent both edaravone and conventional therapy
(edaravone group), and other 65 patients underwent conventional therapy only (non-edaravone
group). The clinical outcome was assessed by the National Institutes of Health Stroke Scale
(NIHSS) scale. [Results] 1. There was no significant difference in patients’ baseline characteristics and the incidence of administration of conventional therapy for acute lacunar infarction
between the two groups. 2. The reduction of NIHSS scale during hospitalization (1.51⫾1.01 vs.
1.03⫾1.08; p⫽0.007) and the percentage of patients with favorable outcome (NIHSS at
dischargeⱕ1) (91.5% vs. 78.5%; p⫽0.044) was significantly larger in edaravone group than
non-edaravone group. [Conclusion] This study showed that edaravone improves the outcomes
of patients with acute lacunar infarction irrelevant to the different conventional therapy
concomitantly performed.
CLINICAL CHARACTERISTICS AND OUTCOME OF STUDY SUBJECTS
Edaravone group
(n⫽59)
Age / years,
mean⫾SD
Men, n (%)
History, n (%)
Hypertension
Diabetic mellitus
Hyperlipidemia
Coronary heart
disease
Smoking
Drinking
NIHSS on
admission,
mean⫾SD
Time to treatment
after stroke onset /
hour, mean⫾SD
Conventional
therapy, n (%)
Ozagrel sodium
Argatroban
Heparine
Oral antiplatelet
drugs
Duration of
hospitalization / day,
mean⫾SD
NIHSS at discharge,
mean⫾SD
Reduction of NIHSS
scale during
hospitalization,
mean⫾SD
Favorable outcome
(NIHSS at
dischargeⱕ1), n (%)
Non-edaravone group
(n⫽65)
Hsiang-Kuo Yuan, Ping-Huang Tsai, Kun-Ping Lin, Neurological Institute, Taipei Veterans
General Hosp, Taipei, Taiwan; Chen Lin, Dept of Physiology, National Yang Ming Univ,
Taipei, Taiwan; Meng-Tzung Lo; Rsch Cntr for Adaptive Data Analysis, National Central Univ,
Tao-Yuan, Taiwan
Introduction: The influence of angioplasty on central autonomic system remains largely
unknown. Although angioplasty, such as carotid artery stent (CAS) implantation and carotid
endarterectomy has been increasingly utilized as a stroke-preventing therapy for patients with
carotid artery stenosis, its effect on the carotid body function or the intracranial vascular
auto-regulation requires further understanding. Heart rate variability provides a non-invasive
analysis of the autonomic modulation whereas a newly-developed non-linear HRV technique,
approximate entropy (ApEn), will be adopted in our study to assess the complex interaction of
autonomic and central nervous system in the acute phase after CAS. Patients and Methods:
During the study period, thirteen male patients (mean age 70⫹-9.5 years), who visited
Neurological Institute at Taipei Veterans General Hospital for stroke prevention, were enrolled
in this study. Each candidate for CAS was thoroughly evaluated by the experienced neurologist
and neuro-radiologist followed by a 30-minute electrocardiograph (ECG) recording at 3
intervals: before CAS, 1-hr and 24-hour after CAS. In addition to conventional spectral analysis
of HRV, ApEn was used to quantify the irregularity in heart rate complex dynamics. Repeated
measure ANOVA and Wilcoxon signed ranks test were prescribed for statistical analysis.
Results: Within-subject differences at 3 intervals were found significant on the non-linear
analysis ApEn (1.07⫹-0.27 -⬎ 1.25⫹-0.24 -⬎ 1.26⫹-0.24, p⫽0.03) but not on other linear
analyses: mean RR interval (905.5⫹-163.2 -⬎ 937.2⫹-152.8 -⬎ 883.8⫹-150.9 ms,
p⫽0.37), low frequency power (176.0⫹-143.7 -⬎ 214.5⫹-141.9 -⬎ 141.2⫹-112.8 ms2,
p⫽0.11), high frequency power (65.5⫹-54.4 -⬎ 110.1⫹-101.0 -⬎ 95.7⫹-84.8 ms2,
p⫽0.18) and low/high frequency ratio (3.5⫹-3.3 -⬎ 2.9⫹-1.8 -⬎ 2.0⫹-1.3, p⫽0.25). ApEn
increased significantly at 1-hr (p⫽0.04) and 24-hr (p⫽0.03) post-stent-implantation. Conclusion According to our study, CAS could enhance the dynamic complexity of HRV whereas
conventional spectral analysis of HRV remained unchanged. This is for the first time to reveal
the active modulation of human autonomic system during the acute recovery phase of CAS by
means of the non-linear ApEn technique. Thus, we presume that conventional HRV indexes fail
to fully characterize the quick autonomic response within 24 hours after the stent implantation.
Furthermore, while reduction of ApEn has been related to aging and pathology, it is likely that
CAS may potentially improve the survival by means of autonomic modulation. More future
studies are worthy to further clarify the underlying mechanism in the response of the autonomic
nervous system induced by stent.
P174
Weekends are Worse for Stroke Care in the United States.
p value
63.4⫾7.0
64.1⫾7.7
0.189†
40 (67.8)
46 (70.8)
0.720‡
42 (72.4)
17 (22.8)
37 (62.7)
5 (8.5)
39 (60.0)
22 (33.8)
40 (61.5)
7 (10.8)
0.147‡
0.547‡
0.893‡
0.350‡
28 (47.5)
15 (25.9)
2.2⫾1.0
29 (46.8)
19 (30.6)
2.0⫾1.3
0.940‡
0.561‡
0.058†
9.2⫾5.8
9.8⫾7.0
0.900†
39 (66.1)
14 (23.7)
5 (8.5)
47 (79.7)
53 (81.5)
11 (16.9)
2 (3.1)
58 (89.2)
0.065‡
0.345‡
0.193‡
0.140‡
9.4⫾2.6
8.5⫾2.7
0.080†
0.7⫾0.7
1.0⫾1.2
0.525†
1.5⫾1.0
1.0⫾1.1
0.007†
54 (91.5)
51 (78.5)
0.044‡
†Mann-Whitney test, ‡chi-square test. NIHSS: National Institutes of Health Stroke Scale.
P173
Enhancement in Dynamic Complexity of the Heart Rate Variability following
Carotid Artery Stent Implantation.
Darrin J Lee, David S Liebeskind; UCLA, Los Angeles, CA
Objective: To characterize inpatient stroke care in the United States over a broad time span
based upon admission on the weekday versus the weekend. Background: Previous studies in
Canada and Europe have suggested that patients admitted for stroke on the weekends have
poorer care and a higher risk-adjusted mortality. This study aims at describing the outcomes
and factors associated with stroke care in the United States based upon weekday and weekend
admissions. Methods: A comprehensive analysis of the Nationwide Inpatient Sample of the
Healthcare Cost and Utilization Project (Releases 1–13, 1988 –2004) based on ICD-9-CM codes
430 – 438 was performed. Ischemic stroke was defined as a primary diagnosis categorized as
ICD-9-CM codes of 433– 434 and 436. Annual percentages and trends analyses were
conducted for demographic variables, admission characteristics, procedures and outcomes.
Results: 2,409,043 admissions of stroke cases were analyzed (1,397,883 ischemic stroke
cases). These cases were reported across a wide geographic distribution throughout the United
States. Age at admission was not statistically significant between the weekday (mean 71.49
years, SD 13.86) and weekend groups (mean 71.90 years, SD 14.32). In addition, stroke
admissions were consistent across the 12 months. Race, gender and socioeconomic variables
did not differ significantly between the two cohorts. Patients admitted on the weekend versus
weekday were admitted more often emergently (70.2% versus 53.5%), although hospital stay
did not differ dramatically in the overall stroke population (6.0 days, weekends versus 5.9 days,
weekdays) or the ischemic stroke subpopulation (6.51 days, weekends versus 6.45 days,
weekdays). The mortality rate for weekday admissions was remarkably lower than weekend
admissions (7.9% versus 10.1%, p⬍0.001). A similar finding was noted in the ischemic stroke
cases (7.3% versus 8.2%, p⬍0.001). Furthermore, patients were more likely to be routinely
discharged if they were admitted on weekdays versus weekends (53.2% versus 43.8%,
p⬍0.001). Patients admitted for ischemic stroke were more likely to be routinely discharged
if they were admitted on the weekday (43.1% versus 38.9%, p⬍0.001). Based upon the years
1998 –2004, the 2 cohorts had a similar number of procedures done; however, those patients
in the weekend cohort did not undergo their first procedure as soon (2.65 ⫹/- 4.31 days versus
1.76 ⫹/- 3.98 days). Conclusions: Weekend admissions for stroke in the United States from
1988 –2004 were associated with a higher mortality rate compared with weekday admissions.
Other measures of patient care, including discharge type also suggested a weekday admission
benefit. This phenomenon may be due to the apparent delay in procedures and other staffing
differences.
P175
Impact of the Approval of Intravenous Recombinant Tissue Plasminogen
Activator Therapy on the Processes of Acute Stroke Management: The
Stroke Unit Multicenter Observational (SUMO) Study.
Shoichiro Sato, Toshiyuki Uehara, Kazunori Toyoda, Hiroaki Naritomi, National
Cardiovascular Cntr, Osaka, Japan; Yasuhiro Hasegawa, St. Marianna Univ, Kawasaki,
Japan; Kazuo Minematsu, National Cardiovascular Cntr, Osaka, Japan; The Stroke Unit
MultiCntr Observational (SUMO) Study Group
Objectives: The Ministry of Health, Labor and Welfare, Japan approved the use of recombinant
tissue-type plasminogen activator (rt-PA) for the treatment of acute ischemic stroke in October,
2005. We evaluated an impact of the regulatory approval of rt-PA on the processes of acute
stroke management. Methods: A prospective, multicenter, observational study was conducted
between December 2004 and December 2005 in 84 Japanese institutes, including 24 institutes
where the stroke unit (SU) was placed. We enrolled 4662 consecutive patients who were
hospitalized within 72 hours after the onset of completed ischemic stroke; 1099 of them were
hospitalized after the rt-PA approval. Patient characteristics and processes of stroke
management were compared between the periods before and after the rt-PA approval. Results:
Age, sex, stroke subtype, time from onset to hospital visit, and National Institutes of Health
Stroke Scale score on admission were similar between the two periods. According to the
approval, the rate of intravenous rt-PA therapy increased from 0.7% to 2.5% (p⬍0.001). The
rate increased from 0.9% to 5.1% in the institutes with SU (p⬍0.001), but did not increase in
the others (p⫽0.583). Within 24 hours of stroke onset, conventional MRI (p⫽0.002), diffusion
weighted MRI (p⬍0.001), MRA (p⫽0.001), carotid ultrasound (p⫽0.005), blood coagulation
tests (p⫽0.042), and evaluation for swallowing functions (p⫽0.022) were performed more
frequently after the rt-PA approval. Conclusion: The present results indicate that the approval
of intravenous rt-PA therapy resulted in dramatic changes in the processes of management for
acute stroke patients, particularly in the institutes having SU.
P176
Inpatient Acute Ischemic Stroke: Patient Characteristics, Process Measures
and Thrombolytic Rates.
Soojin Park, Shihab Masrur, Abdul R Abdullah, Ahmed El-Ghandour, Renzo Hidalgo, Lee H
Schwamm; Massachusetts General Hosp, Boston, MA
Introduction Little is known about the frequency or severity of acute ischemic stroke (AIS)
among hospitalized patients. We sought to analyze patient characteristics, in-hospital delays
and acute stroke process measures in this population compared to the population presenting
to our emergency department (ED). Methods We obtained IRB approval to retrospectively review
prospectively collected cases (1/1/05–12/31/06) in our web-enabled Acute Stroke Log (ASL),
including initial NIHSS and key process measures. Patient characteristics were abstracted per
Get With the Guidelines-Stroke. We identified a cohort of patients who required rapid evaluation
(Rapid Eval) for thrombolytic therapy based on stroke severity and time from symptom
discovery by healthcare team minus last seen well (SxD-LSW). To compare hospital-based
acute stroke response for patients in hospital (INPT) vs. in ED, we defined time of symptom
discovery for patients arriving via the ED (contact with healthcare provider or HCP) as the
earliest of either the triage time or the time of a pre-arrival stroke team notification. Rapid Eval
for IV tPA was NIHSS ⬎ 4 and SxD-LSW ⬍ 2 hr; for intra-arterial therapy (IAT), NIHSS ⬎ 8 and
HCP-LSW ⬍ 4.5 hr. Results From 1/05–12/06, 548 /1025 (53.4%) calls entered in the ASL
were from our hospital (INPT, 136; ED, 412). Stroke was the diagnosis in 284/548 (45.3%),
evenly split between INPT and ED calls (51.5% vs. 51.9%, p⫽NS). Patient characteristics and
treatment rates are shown below. INPT strokes were more likely than ED patients to require
rapid evaluation for IV tPA based solely on severity of stroke and time of discovery, but were
also more likely to have a reason for non-treatment with IV tPA; especially increased risk of
bleeding (68.4% vs. 23.3%, p⬍.001). They received IV tPA less frequently. They had much
longer times for key inhospital process measures. INPT strokes were more likely than ED
patients to require rapid evaluation for IAT based solely on severity of stroke and time of
discovery, but were equally likely to have a reason for non-treatment with IAT and received IAT
equally often. Overall treatment with IV tPA or IAT at our hospital, regardless of NIHSS or time
criteria, was more likely in ED patients. Discussion Inpatient Stroke calls made up ⬃25% of
all stroke consults to our service. Despite shorter times from LSW to symptom discovery, the
evaluation times are longer and the number of patients actually eligible for intervention remains
low. However, for those inpatients who are eligible for treatment, more work is needed in
symptom detection and in reducing time to imaging and time to treatment.
Characteristic of stroke
patients
Age (mean)
NIHSS
Female (%)
AF (%)
DM (%)
HTN (%)
HL (%)
CAD/prior MI (%)
Prior Stroke/TIA (%)
PVD (%)
IV tPA Rapid Eval (%)
INPT
(nⴝ70)
70.1⫹15.9
10.9 ⫹
8.2
64.3
34.3
30
55.7
51.4
38.6
18.6
14.3
54.3
ED (nⴝ214)
p
72.3 ⫹ 14.1
10.6⫹8.4
0.28
0.84
47.2
33.2
25.2
77.1
57.5
27.1
24.8
6.5
36.5
0.01
0.86
0.43
0.001
0.38
0.07
0.29
0.04
0.008
Characteristic of stroke
patients
Medical reason for no IV tPA
(%)
Rapid Eval who received IV
tPA (%)
IAT Rapid Eval (%)
Medical reason for no IAT
(%)
Rapid Eval who received IAT
(%)
Overall treatment IV or IAT
for any NIHSS or LSW
Mean Time Intervals for
Rapid Eval Patients
SxD-LSW (min)
AST Consult-SxD (min)
CT-SxD (min)
tPA-SxD (min)
INPT
(nⴝ70)
94.3
613
ED (nⴝ214)
51.9
p
⬍.001
10.5
56.2
⬍.001
37.1
73.4
22.9
72.9
0.02
0.93
34.6
32.7
1.0
17.1
29.4
0.04
INPT
(nⴝ64)
27.6
49.8
129.7
97
82.6
6.2
36.8
71.9
ED (nⴝ122)
⬍0.001
⬍0.001
⬍0.001
0.046
P177
Temporal Trends and Predictors of rt-PA Use Among All Florida Acute
Ischemic Stroke Patients, 2001–2005.
Elizabeth Barnett, USF College of Public Health, Tampa, FL; Michael Sloan; USF College of
Medicine, Tampa, FL
Background: Clinical guidelines recommend intravenous tissue plasminogen activator (rt-PA)
for the treatment of appropriate ischemic stroke patients who present to hospital within 3 hours
of symptom onset. However, previous research has shown significant variation in rt-PA
utilization across the U.S.A. In this study of Florida stroke patients, we asked: 1) Were there
important patient-level predictors of rt-PA use? and 2) After controlling for patient factors, did
rt-PA use increase significantly over time? Methods: We studied all acute ischemic stroke
patients aged ⬎18 years who were admitted to Florida hospitals through the emergency
department during 2001–2005. We examined hospital discharge data, with up to 10 detailed
ICD-9-CM diagnosis and procedure codes per patient. Any mention of code 99.10 defined rt-PA
use. Logistic regression models estimated the odds of receiving rt-PA for potential predictors,
including demographics [age, gender, ethnicity, SES], stroke risk factors [hypertension,
diabetes, smoking or COPD, obesity, hyperlipidemia, alcohol abuse], and co-morbid medical
conditions [congestive heart failure (CHF), and end-stage renal disease (ESRD)]. We also
included dummy variables for year to assess temporal trends in rt-PA use. Results: Among
111,836 patients, we found a crude rate of rt-PA use of 1.78%. After control for all other
factors, there was no evidence of an upward trend in rt-PA use for 2001–2004, but patients
admitted in 2005 were significantly more likely to receive rt-PA than those admitted earlier (OR
1.5, 95%CI 1.3–1.7; p⬍0.0001). Most of the demographic factors were significant predictors
of rt-PA use in the full model, with patients who were male, white, and younger than age 75
all significantly more likely to receive rt-PA than the referent groups (p⬍0.0001 for each).
Among stroke risk factors, patients with hypertension were significantly less likely to receive
rt-PA (OR 0.8, 95%CI 0.7– 0.9; p⫽0.0002). Similar results were found for diabetes (OR 0.6,
95%CI 0.5– 0.7 p⬍0.0001). Patients with co-morbid ESRD were less likely to receive rt-PA (OR
0.7, 95%CI 0.6 – 0.9 p⫽0.003). However, CHF was a significant predictor of receiving rt-PA (OR
1.4, 95%CI 1.3–1.7; p⬍0.0001). Conclusion: We found a 50% increase in rt-PA use in Florida
ischemic stroke patients between 2001 and 2005. In this population, use of rt-PA varied
significantly by patient demographic characteristics and co-morbid medical conditions.
P178
Ampulla (Tako-Tsubo) Cardiomyopathy Associated with Acute Ischemic
Stroke.
Sohei Yoshimura, Kazunori Toyoda, Tomoyuki Ohara, Noriko Ohtani, Hikaru Nagasawa,
Takahiro Kuwashiro, Hiroaki Naritomi, Kazuo Minematsu; National Cardiovascular Cntr,
Osaka, Japan
Objectives: Ampulla (tako-tsubo) cardiomyopathy is characterized by transient left ventricular
apical ballooning which resembles the Japanese octopus catcher pot (tako-tsubo). It is a known
complication of subarachnoid hemorrhage, while the association with ischemic stroke is not
clarified. We determined the clinical characteristics of ampulla cardiomyopathy associated with
acute ischemic stroke. Methods: All the acute ischemic stroke patients, who were hospitalized
between 2005 and 2006, underwent ECG monitoring during the initial several days. We studied
the patients who did not have ECG abnormality on admission, but showed changes in ECG and
abnormal echocardiographic findings which indicated ampulla cardiomyopathy during the acute
stage. Results: Seven patients were diagnosed as developing ampulla cardiomyopathy. They
were all women, and mostly aged (75 - 90 years) except for a 47-year-old young woman. Initial
National Institutes of Health Stroke Scale score ranged between 3 and 28 (9 in median). Four
patients had embolic infarcts (cardiogenic embolism in 3 and aortogenic embolism in 1) which
expanded to the insular cortex; their ECG showed negative giant T wave within 10 hours after
the stroke onset. Two patients developed progressing stroke (branch atheromatous disease) in
the basal ganglia which finally expanded close to the insular area; ECG changes appeared
within 5 hour in a patient and on day 6 in the other. The remaining young patient developed
severe cerebellar and pontine infarcts with the basilar artery occlusion possibly due to the
dissection; her ECG showed negative giant T on day 12. In all the 7 patients, echocardiography
614
Stroke
Vol 39, No 2
February 2008
showed localized left ventricular hypokinesis around the apical area, which improved within 1
month except for a patient who dropped out of the follow-up. The peak creatine kinase level
ranged 53 - 308 IU/L, and the brain natriuretic peptide level increased to 266 - 1182 pg/ml,
although the level of troponin-T was normal. Four patients did not complain cardiac symptoms
or show changes in vital signs even when ECG showed the abnormal findings. All patients
received anticoagulant therapy after detecting the cardiomyopathy to prevent the embolic
events from the hypokinetic wall. Five patients needed the wheelchair for the daily living at
discharge. Conclusions: The ampulla cardiomyopathy can occur during acute ischemic stroke,
in particular for aged women, and patients were often asymptomatic. Monitoring of long-term
ECG is useful to detect the cardiomyopathy.
In-hospital Treatment II
patients, 119 (43.6%) had 150 protocol violations (89 with one, 30 with two or more). Patient
characteristics (age, stroke severity, time from onset to arrival) did not predict violations (all
p⬎.4). Pre-treatment deviations included: exceeding 3h time limit (46; median 3.25 hr); BP ⬎
185/110 (8); platelet count ⬍100k; glucose ⬍50 or ⬎400, and history of seizure (5 each);
recent history of MI (2); prior ICH/SAH, recent major surgery, mild stroke severity and abnormal
aPTT (1 each). Post-treatment deviations included: early (⬍24h) antiplatelet use (30), early
(⬍24h) anticoagulant use (19) and failure to maintain BP within guidelines (28). Overall,
patients with protocol violations had slightly more sICHs (OR 1.10, 95% CI 0.48 –2.60) than
those without violations. Multiple violations increased this risk (OR 1.21). There were
insufficient data to determine risk by each type of violation. Deviations occurring only after
treatment with tPA, however, conveyed the highest risk of sICH (OR 3.57, 95% CI 0.67–18.27)
as compared to violations occurring only prior to treatment. Conclusions: In these data,
protocol deviations were common but were not generally associated with significantly
increased risk of sICH. Focusing quality improvement efforts on reducing protocol violations
after tPA is given may have the highest yield in minimizing patient risk.
P179
P181
Is Reflex Cough Protective in Stroke Patients with Dysphagia and at
Increased Aspiration Risk?
Reactivation of Old Stroke Symptoms. Defining a Clinical Entity.
Katie Ward, John Seymour, Caroline Jolley, Joerg Steier, King’s College London, London,
United Kingdom; Michael Polkey, National Heart and Lung Institute, Imperial College,
London, United Kingdom; Kerry Mills, John Moxham, Lalit Kalra; King’s College London,
Background and Objectives: Nearly 50% of acute stroke patients have dysphagia and are at
increased aspiration risk. Although several studies have shown weak voluntary cough (VC) in
these patients, reflex cough (RC), a brainstem reflex, may be preserved and is assumed to be
protective against aspiration. We tested the validity of this assumption by studying the
physiological characteristics of VC and RC in 15 acute stroke patients (5 female) and 17
controls (5 female). To do this, we performed volitional and non-volitional expiratory muscle
tests on all subjects. Methods: Patients with first ever middle cerebral artery infarcts (median
NIH score ⫽ 6) were included within the first 14 days of stroke onset (median ⫽ 6 days). RC
was induced using suprathreshold concentrations of nebulised tartaric acid. The following
measurements were made under standardised laboratory conditions: VC and RC: maximum
cough flow rate (CFR); maximum cough gastric pressure (Pgas); cough expired volume (exp
vol). Volitional expiratory muscle test: maximum expiratory mouth pressure (PE max);
Non-volitional expiratory muscle test: maximum gastric pressure achieved after magnetic
stimulation of the T10 nerve roots (Tw T10 Pgas). Unpaired t-tests were used to compare means
of groups. Results: see Table 1. Conclusion: Reflex and voluntary cough flow rates and volumes
are both impaired after acute stroke and hence, reflex cough may not be protective in acute
stroke patients. Muscle strength (as measured by Pgas ) is not impaired for reflex cough
suggesting that the reflex may be modulated by cortical inputs which are affected by stroke.
TABLE 1: RESULTS
Age
VC CFR
VC exp vol
VC Pgas
RC CFR
RC exp vol
RC Pgas
PE max
TwT10Pgas
normal value
stroke patients (n⫽15)
mean (sd)
controls
(n⫽17) mean
(sd)
p-value
⬎130
⬎130
⬎80
⬎16
59.9 (14.5)
239.4 (147.0)
2.345 (1.419)
103.0 (83.7)
199.9 (124.6)
1.197 (0.626)
193.0 (85.4)
71.4 (51.3)
29.4 (6.8)
49.9 (16.6)
516.3 (124.1)
4.681 (1.596)
206.6 (55.5)
397.4 (90.7)
2.060 (1.091)
204.8 (79.5)
119.2 (33.6)
34.6 (15.4)
0.083
⬍0.001
0.001
⬍0.001
⬍0.001
0.044
0.719
0.005
0.447
Jose A Cardenas, Dion F Graybeal, Mark D Johnson; Univ of Texas Southwestern Med Cntr,
Dallas, TX
Background and Purpose: There is a subgroup of stroke patients presenting to the Emergency
Department (ED) with similar complains to those they experienced with a previous stroke.
These patients have sometimes been diagnosed as having a “stroke reactivation” and either
are discharged home or are admitted to the hospital for further evaluation. The evaluation of
these patients varies widely between institutions and there is no standardized clinical protocol.
We sought to analyze the clinical characteristics of this group of patients in an attempt to better
characterize and explain this phenomenon. Methods: From Aug 2005 through March 2006, we
conducted a prospective observational study. 323 patients were evaluated by the UTSW Stroke
Service and 16 (5%) of them were diagnosed as “Stroke Reactivation”. Charts were reviewed
and 14 patients included in the study according to determined inclusion/exclusion criteria.
Patient information was collected into a de-identified database. Results: Data on 16 patients
was available for analysis, 2 patients were excluded. Of the 14 patients, 4 were male and 10
female. All MRI’s failed to show restricted diffusion supporting the absence of a new ischemic
infarct. Every patient had previous imaging studies and clinical notes to document the existence
of a chronic ischemic infarct with symptoms very similar or even identical to the latest
presentation. In all cases, we were able to identify a medical condition other than Stroke, and
after treatment the symptoms resolved. The most common triggers for the “Reactivation of
Stroke” were urinary tract infections, Hypo/Hyper glycemia, and dehydration. Some patients
had more than 1 medical condition that may have played a role into the pathogenesis of their
symptoms. Conclusion: “Reactivation of Old Stroke Symptoms” is a commonly used clinical
term, however not well defined in the literature. To our knowledge there are no prospective
trials in the literature describing this event. In our case series, we were able to identify medical
conditions other than stroke, causing the reappearance of previous symptoms and once
treated, these previous stroke symptoms resolved. Further investigation is needed to clarify the
pathophysiology of this phenomenon. A proposed mechanism could be a metabolic or
neurochemical stressor triggering a dysfunction within recently formed or recruited neural
networks, causing the reemergence of previous stroke signs and symptoms. More information
is needed to determine the correct treatment for this syndrome and the appropriate diagnostic
testing necessary when these patients present to an ED. Furthermore, clarification is needed
to formalize a definition of this clinical entity and determine clinical guidelines to aid in its
recognition, diagnosis, and management.
P182
Transfusion of Blood Products Predicts Poor Clinical Outcome Independent
of Stroke Severity in Acute Ischemic Stroke Patients.
Units: pressure in cm H2O; flow in litres/minute; volume in litres.
P180
Patterns and Importance of Protocol Deviations in use of Tissue-type
Plasminogen Activator in Stroke.
Angela F Caveney, William J Meurer, Zhenzhen Xu, Shirley Frederiksen, Annette Sandretto,
Robert Silbergleit, Phillip A Scott,; Univ of Michigan, Ann Arbor, MI
Objectives: Limited data suggest deviation from tPA-treatment guidelines may increase
hemorrhage risk in stroke, however few data are available on what deviations are most
common and when they are most likely to occur. This study characterizes protocol deviations,
and their timing and association with symptomatic intracranial hemorrhage (sICH) in a large
regional sample of tPA treated stroke patients. Methods: All ED stroke patients treated with IV
tPA in 4 hospitals, without dedicated acute stroke teams, serving a single region over 9 years
were retrospectively analyzed. Protocol deviations and outcomes in this previously described
dataset were determined by rigorous explicit chart review with 20% dual abstraction,
re-interpretation of brain imaging by two neuroradiologists blinded to clinical history, and
formal adjudication of disagreements. The number and distribution of violations, whether they
occurred prior to or after tPA treatment, and the associated risk of sICH were analyzed with
descriptive statistics. Odds ratios were calculated to compare risks. Results: Among 273
Kachi Illoh, Miriam Morales, James Grotta, Orieji Illoh; UTHSC, Houston, TX
Background: Acute ischemic stroke (AIS) patients often receive blood products to correct
anemia or bleeding disorders. However, blood transfusion through inflammatory and prothrombotic mechanisms has been associated with poor outcome in a variety of disease conditions.
There is paucity of data establishing benefit of blood transfusion in AIS patients. We sought to
determine whether transfusion of blood products predicted clinical outcome after AIS. Our
hypothesis was that outcome differs between transfused and non-transfused AIS patients
independent of stroke severity. Methods: We studied AIS patients consecutively admitted to the
stroke service of a 900-bed tertiary care center. Transfusion history for each patient was
verified from the Blood Bank records. Poor clinical outcome was defined as a modified Rankin
Scale of ⬎3. We examined the characteristics of the patients who received blood products
(packed red blood cells, fresh frozen plasma, platelets and cryoprecipitate) and compared their
clinical outcome to the non-transfused using t tests and chi-squared tests as appropriate.
Logistic regression was used to examine the association between transfusion and outcome
while adjusting for age, length of stay, NIH Stroke Scale (NIHSS), laboratory tests (hematocrit,
creatinine level, platelet count and total cholesterol), and medications (antiplatelets, statins, and
thrombolytics). All tests were two-sided with P values ⬍0.05 considered statistically
significant. Results: A total of 1,213 AIS patients with a mean age of 65 ⫹ 16 years (51%
males) were enrolled; 13% (152/1,213) received blood products. Transfusion of blood products
was an independent predictor of clinical outcome, such that transfused patients after adjusting
for covariates were 2 times (OR ⫽ 2; 95% CI ⫽1.02 - 3.91; p⫽0.043) more likely to have a
poor outcome than the non-transfused (70% versus 25%). Similarly, mortality during
hospitalization was 6 times more likely to occur in the transfused group compared to the
non-transfused (23% versus 4%; p⬍0.0001). The transfused patients had 8 days longer
hospital stay and more severe strokes by 6 points on NIHSS score than the non-transfused
(p⬍0.0001). Among the 106 patients who received packed red blood cell (pRBC) units, the
higher the number of units transfused the worse the outcome, as 88% (22/25) transfused with
more than 6 units had poor outcome compared to 64% (52/81) who got less than 6 units
(p⫽0.026). Conclusion: In patients hospitalized for AIS, transfusion therapy predicted poor
clinical outcome independent of stroke severity and is associated with longer hospital stays.
This information warrants further scrutiny of the inflammatory properties of blood products and
the liberal use of transfusion in stroke patients.
P183
The Lombardia Stroke Unit Registry: Study Protocol and Preliminary Data.
Giuseppe Micieli, IRCCS Istituto Clinico Humanitas, Rozzano (MI), Italy; Anna Cavallini, IRCCS
Istituto Neurologico C. Mondino, Pavia, Italy; Silvana Quaglini, Dipartimento di Informatica e
Statistica, Università di Pavia, Pavia, Italy; SUN Lombardia Collaborators
Stroke Unit care represents the major advancement in stroke management and it is applicable
to all stroke patients. The development of stroke registries has been recognised as a critical
step to document treatment pathways, procedures and use of resources to objectively guide
improvements in the quality of stroke care. In 2006 on the behalf of the Lombardia Stroke Unit
Network (SUN) a web-based registry has been developed with the aim of improving the quality
of hospital stroke care. At to-day 36 departments have joined the SUN registry. Its first objective
is to verify adherence of units to Italian Guideline (IG) SPREAD recommendations and to
evaluate their impact on stroke outcome. Methods The registry has been developed, validated
and implemented in the second part of 2006. At the 1st of January 2007 the first Centre started
data collection. The recruitment will stop at the 31st of December 2007. The registry includes
information of the acute stroke episode from onset through treatment to follow-up (3⫹1
months) and of the adherences to IG’s recommendations (RCs). The RCs considered are: grade
A: 10.2⫽t-PA considered, 10.5⫽antithrombotics within 24 hours of hospitalization,
11.35⫽FKT within 48 hours of hospitalization, 12.2–12.4⫽discharged on antithrombotics,
12.10⫽patients with AF discharged on anticoagulation therapy; grade B: 5.11⫽carotid duplex
scan, 10.10⫽patients with AF receiving anticoagulation therapy during hospitalization,
10.18⫽DVT prophylaxis, 12.1⫽Smoke cessation/diet education, 12.7–12.8⫽ discharged on
anti-hypertensive and/or statin therapy if indicated; grade D: 9.1⫽quickly and standardized
neurological evaluation, 9.7–9.10⫽CT scan or MRI on admission and within 7 days of
hospitalization, 10.19⫽early mobilization, 11.1⫽monitoring of vital signs during the first 48
hours, 11.20⫽screen for dysphagia. Results At the 30th June 2007 1681 cases have been
enrolled and 647 completed the follow-up at three months. The percentage of adherences to
IG RCs were: 10.1⫽100%, 10.2⫽ 90%, 10.5⫽65%, 11.35⫽ 48%, 12.2–12.4⫽77%,
12.10⫽61%, 5.11⫽78%, 10.10⫽57%, 10.18⫽49%, 12.1⫽ 46%, 12.7⫽ 71%, 12.8⫽ 54%,
9.1⫽ 99%, 9.7⫽87%, 10.19⫽65%, 11.1⫽77%, 11.20⫽46%. A significant correlation
between Rankin scale score at discharge and number of non-compliance (NNC) has been
detected (Spearman test, p⬍0.0006). At the follow-up visit the NNC was slightly higher for
dead patients and significantly higher (Wilcoxon test p⬍0.008) for those with stroke
recurrence. Conclusions Our data support the usefulness and adequacy of registry to describe
and monitor process of care and implementation of guidelines. It can identify system criticity,
such as the underused of diagnostic techniques and/or therapeutical procedures which can
significantly influence outcome and recurrences.
615
of hospitalization, and prognosis before and after the implementation of new program. Results:
One-hundred ninety eight (Season 1) and 44 patients (Season 2) were eligible for stroke critical
pathway, respectively. Among them, 164 and 39 patients had ischemic infarction. After
program implementation, time from arrival to acceptance of thrombosis panel was shortened
from 52 to 27 min (p⬍0.001), and time from arrival to CT scan was slightly reduced from 31
to 24 min (p⫽0.21). There was little difference of thrombolysis rate by 26.8%(44/164) and
30.8%(12/39) (p⫽0.69). Times from arrival to injection of intravenous rtPA and intraarterial
urokinase were reduced by 19 min (from 65 to 46 min;p⫽0.03) and 52 min (from 136 to 84
min;p⫽0.08), respectively. In addition, some trends suggesting good prognosis were observed
that the duration of hospitalization was shortened by 6 days(from 21 to 15 days;p⫽0.09), and
discharge NIHSS score was lowered by 2.1(from 6.1 to 4.0;p⫽0.17) after revised critical
pathway. Conclusions: Our results indicate that powerful critical pathway shortened the
door-to-lab time, door-to-needle time, and hospitalization period than previous ordinary critical
pathway. Moreover, some tendencies were observed that it shortened door-to-CT time and
improved stroke scale at discharge. Not only the presence of critical pathway but also fast
communication network of related departments promotes the quality of critical pathway of
stroke.
P185
Hyperosmolar Hypothermic Normoglycemia (H2N) for Preventing Cerebral
Edema after Large Hemispheric Infarction - a Pilot Study.
Katja E Wartenberg, Carl Gustav Carus Univ Dresden, Dresden, Germany; Sheetal J Sheth,
Columbia Univ, New York, NY; Jennifer A Frontera, Mount Sinai Med Cntr, New York, NY;
Noeleen D Ostapkovich, Neeraj Badjatia, Columbia Univ, New York, NY; Stephan A Mayer;
Columbia Univ, New, NY
Background and Purpose: Large hemispheric infarction carries a mortality rate of 40 – 80%.
Despite the introduction of decompressive hemicraniectomy, the medical management of brain
swelling after large hemispheric infarction is still not satisfactory. Methods: We treated 22
patients with large hemispheric infarctions between July 2004 and February 2006 with the
combination of insulin infusion (target glucose 100 –120 mg/dl), mild hypothermia (35.5°C)
using a surface cooling or intravascular heat exchange device, and hypertonic saline (3%
sodium acetate) at a rate 1ml/kg (goal osmolarity 310 –320 mosmol/l) within 72 hours of
symptom onset. Primary outcome was progression or evolution of the midline shift on
computed tomography (CT). Secondary outcome measures were Glasgow Coma Scale (GCS) at
hospital discharge, modified Rankin Scale (mRS) at 3 months, and complications. Results: Of
the 22 patients 13 had right-sided infarctions and median age was 64.5 (range 41– 84) years.
Baseline NIHSS was 19 (6 –26). H2N was started on average one day (range 0 –5 days) after
symptom onset; median duration of treatment was 9.5 (range 4 –20) days. Mean septal midline
shift was 2.1⫾2.8 mm on admission; peaked at 8.9⫾5.9 mm, and was 5.1⫾3.7 mm on
discontinuation of the protocol. The median GCS of the patients alive at time of discharge was
11 (range 4 –15). At 3 months, ten patients had died (45%); support had been actively
withdrawn in six cases. The mRS was 2 in one patient, 3 in three patients, 4 in two patients,
and 5 in four patients. Complications included pulmonary edema (n⫽10), aspiration and
ventilator-acquired pneumonia (n⫽5), blood stream infection (n⫽3), urinary tract infection
(n⫽3), atrial fibrillation with rapid ventricular response (n⫽3), bradycardia (n⫽2), acute renal
failure (n⫽2), coagulopathy (n⫽2), septic shock (n⫽1), cerebral edema and herniation after
discontinuing H2N (n⫽1), while receiving H2N (n⫽2), and before H2N therapy was maximized
(n⫽1), thrombocytopenia (n⫽1), upper extremity deep vein thrombosis (n⫽1), and upper
extremity ischemia (n⫽1). Conclusions: The combination of mild hypothermia (35.5°C),
infusion of hypertonic saline, and insulin infusion offers a feasible alternative strategy to
minimize massive cerebral edema after large hemispheric infarction and needs to be studied
in a standardized trial.
P184
Wireless Dispatch Call System Promotes Quality of Critical Pathway in
Stroke.
Sung Hyuk Heo, Kyusik Kang, Dept of Neurology, Clinical Rsch Cntr for Stroke, Seoul
National Univ Hosp, Seoul, Republic of Korea; Hee-Kwon Park, Seoul National Univ Hosp,
Seoul, Republic of Korea; Seung-Hoon Lee, Dept of Neurology, Clinical Rsch Cntr for Stroke,
Seoul National Univ Hosp, Seoul, Republic of Korea; Jae-Kyu Roh, Seoul National Univ Hosp,
Seoul, Republic of Korea; Kyung Cheon Chung, Kyung Hee Univ College of Medicine, Seoul,
Republic of Korea; Byung-Woo Yoon; Dept of Neurology, Clinical Rsch Cntr for Stroke, Seoul
National Univ Hosp, Seoul, Republic of Korea
Background: It is widely known that time factor in acute stroke patients is very important. To
reduce in-hospital time delay, it has been reported that critical pathway is useful. Because it
is team approach, how fast the communication process will be is most important for effective
critical pathway. Methods: The stroke critical pathway in our hospital was started on the
September of 2005. Our emergency center adopted Korea Telecom Powertel service, wireless
dispatch call service by using integrated digital enhanced network system, because it is
possible to call specified group simultaneously. We revised the stroke critical pathway by using
Powertel service, and updated critical pathway was started on the late March, 2007. If the
patients who arrived at emergency room within 6 hours from when their symptoms or signs
were detected for the first time are suspicious of stroke, critical pathway is started on
broadcasting simultaneously to laboratory room, CT & MRI room, neurologist, radiologist, and
intervention doctor. We selected 2 periods, one initial critical pathway program [Season 1:
2005/9 –2007/2] and the other revised critical pathway program [Season 2: 2007/3/22– 6/21],
and efficacy was investigated by comparing time factors of diagnosis and treatment, duration
P186
Lack of Impact of EMS Training and Use of the Cincinnati Prehospital
Stroke Scale.
Daniel M Frendl, David G Strauss, Duke Univ, Durham, NC; Kevin Underhill, Durham County
EMS, Durham, NC; Larry B Goldstein; Duke Univ, Durham, NC
Background: The Cincinnati Prehospital Stroke Scale (CPSS) evaluates facial droop, arm drift,
and speech clarity. Its use by Emergency Medical Service (EMS) responders is recommended
for identifying stroke patients for rapid hospital transport. There are only limited data assessing
its performance outside of the research setting. Purpose: Our aim was to assess the impact
of routine training and use of the CPSS on the accuracy of paramedics’ stroke diagnosis and
on-scene time. Methods: A 1-hour long interactive educational presentation for paramedics
providing emergency transport services to an academic center’s emergency department
focusing on stroke recognition and the use of the CPSS was conducted in November 2004.
Transported patients diagnosed with stroke were identified retrospectively by review of
computerized and paper-based paramedic records and the academic center’s prospective
stroke registry for the year before and after the training. Patients identified by EMS as being
“unresponsive” were excluded from the assessment of the CPSS. The paramedic’s stroke
diagnosis was compared to the final diagnosis after physician evaluation. Results: Of the 184
patients identified, 57% were women, 52% white and 46% African American (mean age of
68⫹/-6 years); 30 patients were noted by EMS as being “unresponsive.” There was no
difference in paramedics’ use of the CPSS (37.5% vs. 23.8%, p⫽0.123), on-scene time
(18⫹/-6 vs. 17⫹/-7 min, p⫽0.140), or the accuracy of the paramedic stroke diagnosis (40.5%
vs. 38.9%, p⫽0.859) before and after training. Of responsive patients with a paramedic
616
Stroke
Vol 39, No 2
February 2008
diagnosis of stroke, 57% had an abnormality in at least one CPSS item with no effect on
on-scene time (17⫹/-1 min with a normal CPSS vs. 18⫹/-1 min, p⫽0.492). Those with a final
diagnosis of stroke (n⫽61, 40%) more frequently had at least one abnormal CPSS item (49%
vs. 27% with no CPSS abnormality, p⫽0.008; sensitivity 0.30, 95% CI 0.20 to 0.42; specificity
0.52, 95% CI 0.42 to 0.62). Conclusions: Simple EMS training in the CPSS, or its use, had no
impact on paramedic’s stroke diagnostic accuracy or on scene time. Only half of patients with
a final diagnosis of stroke had at least one noted CPSS abnormality. Whether improvements can
be achieved with more extensive training or through ongoing performance improvement
programs requires further study.
histological examinations suggest an enhanced EPO-induced dendritogenesis. Gene expression
profiles will be presented at the conference. Developing a hematopoietic factor therapy such
as EPO with multimodality concentrated in 1 compound appears to be fundamental to improve
future stroke treatment. Interestingly, a small pilot study demonstrated beneficial effects for the
treatment in acute human stroke (2). A randomized, multicenter, placebo-controlled phase II
trial with EPO is currently ongoing to assess the safety in acute stroke patients and is expected
to conclude in September 2007. REFERENCES: (1) Wang, L. et al. (2004). Treatment of Stroke
With Erythropoietin Enhances Neurogenesis and Angiogenesis and Improves Neurological
Function in Rats. Stroke 35:1732–7. (2) Ehrenreich H. et al. (2002). Erythropoietin therapy for
acute stroke is both safe and beneficial. Mol.Med. 8:495–505.
P187
The Prevalence of Positional Sleep Apnea Among Patients with Acute
Ischemic Stroke and Transient Ischemic Attacks.
Dawn M Bravata, Indiana Univ; VAMC, Indianapolis, IN; John Concato, Terri Fried, Noshene
Ranjbar, Tanesh Sadarangani, Frederick Struve, Yale Univ; VAMC, New Haven, CT; Mark
Gorman, Univ of Vermont, Burlington, VT; Vincent McClain, Albert Lo, George B Richerson,
Yale Univ; VAMC, New Haven, CT; Linda S Williams, Indiana Univ; VAMC, Indianapolis, IN;
Joseph Agostini, Henry K Yaggi; Yale Univ; VAMC, New Haven, CT
Background Sleep apnea is an independent risk factor for cerebrovascular disease and is
associated with poor outcomes following an acute stroke or transient ischemic attack (TIA).
Given both the high prevalence of sleep apnea among patients with cerebrovascular disease
and the association between sleep apnea and adverse events, the treatment of sleep apnea in
the acute stroke or TIA period may improve clinical outcomes. Continuous positive airway
pressure (CPAP) is the first-line treatment for sleep apnea, however, CPAP is difficult to
implement in acute cerebrovascular disease patients. Positional therapy (having a patient sleep
in the lateral position) is a simple and effective treatment for positional sleep apnea. The
objective of this study was to determine the prevalence of positional apnea and positional sleep
apnea among acute cerebrovascular disease patients. Methods This was a secondary analysis
of data from two on-going randomized controlled clinical trials that are evaluating the efficacy
of a strategy of diagnosing and treating sleep apnea in acute ischemic stroke and TIA patients.
Unattended polysomnography was performed within 48 hours of symptom onset in acute stroke
and TIA patients. The apnea-hypopnea index (AHI) is the total number of apneas and hypopneas
per hour of sleep. Sleep apnea was defined as an AHI of ⱖ5. The positional AHI was calculated
for the supine position (supine-AHI) and for the combination of all of the non-supine positions
(non-supine-AHI). Positional apnea was defined by a supine-AHI ⱖ2 times the non-supine-AHI.
Positional sleep apnea was defined by a supine-AHI ⱖ2 times the non-supine-AHI and where
the total-AHI was ⱖ5. Results Among 28 patients (13 stroke and 15 TIA) with baseline
polysomnographic data, 17 had sleep apnea (prevalence of 61%; 95%CI 42–76%). The
prevalence of positional apnea was 9/28 (32%, 95%CI 18 –51%). Overall positional sleep apnea
was present in 8/28 (29%, 95%CI 15– 47%). Prevalence rates were similar between stroke and
TIA patients. Discussion New therapies are needed to improve clinical outcomes for
post-stroke and post-TIA patients. Positional apnea appears to be common among patients with
acute ischemic stroke and TIA. Cerebrovascular disease patients who have positional sleep
apnea and who do not tolerate CPAP therapy may benefit from sleeping in the lateral position.
Recovery
P188
Erythropoietin Improves Motor Skill Learning In An Accelerated Training
Paradigm After Focal Ischemia.
Andreas Rogalewski, Jens Minnerup, Kai Diederich, Wolf R Schäbitz; Univ of Muenster,
Muenster, Germany
BACKGROUND AND PURPOSE: Erythropoietin (EPO) promotes proliferation and differentiation of
erythroid progenitors and the survival of maturing erythroid cells. EPO enhances neurogenesis
and angiogenesis after stroke, which could contribute to functional recovery (1). The present
investigation explored beneficial effects of EPO on improvement of motor skill learning in an
accelerated rotarod training paradigm after focal ischemia. METHODS: 28 Wistar rats were
randomly treated with either recombinant human EPO or saline daily for 7 days starting at 24
hours after photothrombotic stroke of sensory-motor cortex. Rats were trained on an
accelerated rotarod over ten consecutive days each with ten trials beginning at day 3 after
stroke. At day 7 and 14 after ending of the rotarod task, we examined the consolidation of
motor skill. Postmortem Golgi-Cox staining was performed to examine neurite growth
(dendritogenesis). Furthermore, for gene expression changes samples was taken from the ipsiand contralateral cortex. The complete available rat Genome chip was used (rat 230 A and B),
encompassing all known genes and expressed sequence tags (EST) for the rat. RESULTS:
Therapy with EPO significantly improves motor skill learning in the accelerated rotarod training
paradigm after focal ischemia. After 7 and 14 days of pause, the enhancement of the rotarod
skill was retained indicating an improved consolidation. Preliminary data of histological
examinations revealed an enhanced dendritogenesis after EPO treatment. We currently analyze
gene expression profiles to evaluate the precise mechanism of EPO-induced neurogenesis.
CONCLUSIONS: Our data demonstrate that EPO significantly and permanently improves
functional recovery after stroke as a result of enhanced neurogenesis. Futhermore, preliminary
P189
Neuronal Predictors Of Stroke Recovery.
Carmen Cirstea, Cary Savage, Hoglund Brain Imaging Cntr, Kansas Univ Med Cntr, Kansas
City, KS; Randolph Nudo, Landon Cntr on Aging, Kansas Univ Med Cntr, Kansas City, KS;
William Brooks; Hoglund Brain Imaging Cntr, Kansas Univ Med Cntr, Kansas City, KS
Stroke is the leading cause of long-term motor disability worldwide and identifying predictors
of motor recovery following stroke is the objective of considerable research. Although,
functional neuroimaging biomarkers might be helpful in understanding the neural systems
level, to date, no valid functional biomarker has been found accurate enough to predict gain
in individual stroke survivors. It is clear that a complete understanding of brain plasticity and
prognosis of intervention response following stroke requires an understanding at two neural
levels, system and cellular. However, research focused on cellular biomarkers has received
limited attention in this stage of stroke The goal of this study was to determine the predictive
values of two neuroimaging biomarkers for further functional improvement following an
arm-focused intervention in late stroke. The neuroimaging biomarkers are: (i)
N-acetylaspartate, as a metabolic neuronal biomarker (NAA, a compound localized exclusively
in neurons and their dendritic and axonal processes, measured on MRS in radiologically
normal-appearing primary motor cortex, M1), and (ii) spatial extent of M1 motor-related
activation on fMRI as a functional biomarker. Subcortical stroke survivors participated in a
repetitive practice of a reach-to-grasp task with the impaired arm (90 repetitions on each of
12 days over four weeks). Each participant underwent kinematic (trunk movement) and
neuroimaging (magnetic resonance spectroscopy, MRS; functional MRI, fMRI) testing on three
separate occasions: one month (Baseline) and immediately prior to (PRE), and immediately after
(POST) the motor practice. Functional recovery was evaluated by decreased compensatory
trunk use based on the correlations between this variable and other movement variables, such
as angular motions and interjoint coordination. For the proposed study, the changes PRE vs.
Baseline were used to examine whether the patients are at their stable behavioral/neural status
while the changes POST vs. PRE to study the intervention effects. The preliminary results
suggest that the intervention-related changes of NAA in bilateral M1 seem to be better
correlated with the rate of functional recovery than changes in spatial extent of motor-related
M1 activation. The results of the present study might be especially useful for the design of
randomized clinical trials by estimating sample size and define inclusion criteria. In addition,
this information might be useful for enabling clinicians to set realistic therapeutic goals, by
selection of individualized rehabilitation strategies based on the prediction of functional
potential.
P190
Effect Of Forced Arm Use And Voluntary Exercise On Functional Motor
Recovery And Gene Expression Profiles After Focal Ischemia.
Andreas Rogalewski, Univ of Muenster, Muenster, Germany; Rico Laage, SYGNIS Bioscience,
Heidelberg, Germany; Katharina Kuhnert, Jens Minnerup, Univ of Muenster, Muenster,
Germany; Armin Schneider, SYGNIS Bioscience, Heidelberg, Germany; Wolf R Schäbitz; Univ
of Muenster, Muenster, Germany
BACKGROUND AND PURPOSE: Both the immobilization of the unaffected arm combined with
physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched
environment are promising approaches to enhance recovery after stroke. The genomic
mechanisms involved in long-term plasticity changes after different means of rehabilitative
training post-stroke are largely unexplored. The present investigation explored the effects of
these physical therapies on behavioral recovery and molecular markers of regeneration after
experimental ischemia. METHODS: 42 Wistar rats were randomly treated with either FAU
(1-sleeve plaster cast onto unaffected limb at 8/10 days), VE (connection of a freely accessible
running wheel to cage), or a cage control condition for 10 days starting at 48 hours after
photothrombotic stroke of sensory-motor cortex. Functional outcome was measured using a
battery of sensory-motor tests at baseline before ischemia, after ischemia, after the training
period of 10 days, and at 3 and 4 weeks after ischemia by an investigator blinded to the
experimental groups. For gene expression changes samples was taken from the ipsi- and
contralateral cortex. The complete available rat Genome chip was used (rat 230 A and B),
encompassing all known genes and expressed sequence tags (EST) for the rat. RESULTS:
Therapy with both FAU and VE compared to cage control condition significantly improved
functional recovery after focal ischemia. The enhancement of functional outcome was retained
over 4 weeks after ischemia. Furthermore, FAU-treated animals had significant better
functional recovery compared to the VE-treated group. A number of genes were detected as
induced in the ipsi- and contralateral cortex due to treatment conditions. CONCLUSIONS: Our
data demonstrate that physical training modeled by FAU and VE treatment for 10 days initiated
48 hours after photothrombotic stroke significantly and permanently improve functional
recovery after stroke. Furthermore, we suggest that FAU is superior to voluntary physical
activity after small ischemia. Effects of FAU treatment on functional outcome are not completely
understood. Although human studies indicate that FAU in the chronic phase after stroke
improves functional recovery, experimental studies are more controversial. Here we can
substantiate the positive effect of FAU on functional recovery after small ischemia. Moreover,
we highlight the degree of transcriptional changes in the cortex after post-stroke physical
training, and provide insight into functional pathways of relevance for compensatory recovery
mechanisms in neural networks.
P191
Nitric Oxide Mediates Proliferation Of Endothelial Progenitor Cells In
Human Ischemic Stroke.
Tomás Sobrino, Dept of Neurology, Clinical Neuroscience Rsch Laboratory, Hosp Clı́nico
Universitario, Univ of Santiago de Compostela, Santiago de Compostela, Spain; Marı́a A
Moro, Dept of Pharmacology, Sch of Medicine, Univ Complutense, Madrid, Spain; Miguel
Blanco, Dept of Neurology, Clinical Neuroscience Rsch Laboratory, Hosp Clı́nico
Universitario, Univ of Santiago de Compostela, Santiago de Compostela, Spain; Juan F
Arenillas, Dept of Neurosciences, Hosp Germans Trias i Pujol, Badalona, Spain; Mar
Castellanos, Dept of Neurology, Hosp Doctor Josep Trueta, Girona, Spain; David Brea,
Octavio Moldes, Pedro Ramos-Cabrer, Rogelio Leira, Dept of Neurology, Clinical
Neuroscience Rsch Laboratory, Hosp Clı́nico Universitario, Univ of Santiago de Compostela,
Santiago de Compostela, Spain; Antonio Dávalos, Dept of Neurosciences, Hosp Germans
Trias i Pujol, Badalona, Spain; José Castillo; Dept of Neurology, Clinical Neuroscience Rsch
Laboratory, Hosp Clı́nico Universitario, Univ of Santiago de Compostela, Santiago de
Compostela, Spain
Background and purpose: The increase in circulating Endothelial Progenitor Cells (EPCs)
number after acute ischemic stroke is associated with good functional outcome, reduced
infarct growth and neurological improvement. In experimental models, it has been suggested
that vascular endothelial growth factor (VEGF), which mediates EPC proliferation, up-regulates
nitric oxide (NO) through the activation of endothelial nitric oxide synthase (eNOS). Likewise,
EPC migration is mediated by active metalloproteinase 9 (MMP-9). On the other hand, statins
are known to enhance vascular expression of endothelial (eNOS), inducible (iNOS) and neuronal
nitric oxide synthase (nNOS). Therefore, as vascular repair and angiogenesis may be
therapeutic targets in cerebral ischemia, our aim was to study the role of these molecular
factors as well as statin treatment in the proliferation of EPCs in human ischemic stroke.
Patients and methods: Forty-eight patients (24 males, average 70.9⫾10.1 years) with a
first-ever episode of non-lacunar ischemic stroke (⬍12 hours from onset) were prospectively
studied. EPC colonies were quantified as early outgrowth colony forming unit-endothelial cell
(CFU-EC). We defined the increment of EPC colonies during the first week as the difference in
the number of CFU-EC between day 7 and admission. Serum levels of VEGF and active MMP-9
(determined by ELISA) and nitric oxide metabolites (NOx)(determined by HPLC) were measured
at admission, 24 and 72 hours, and at day 7. Atorvastatin (20 mg) was administered during the
acute phase of stroke in 16 patients. ROC analysis was used to select the best cut off value
for CFU-EC increment as predictor of good outcome due to a lack of linearity. Results: Patients
with EPC increment ⱖ4 CFU-EC (n⫽22) showed higher serum levels of VEGF, active MMP-9
and NOx at 24 hours in comparison with the patients with EPC increment ⬍4 CFU-EC during
the first week (all p⬍0.0001). Likewise, patients treated with statins showed higher serum
levels of VEGF (p⫽0.004), active MMP-9 (p⫽0.002) and NOx (p⬍0.0001). Serum levels of NOx
ⱖ990 ␮M was the only variable associated with EPC Increment ⱖ4 CFU-EC (OR, 47.1; CI95%,
2.9 –778.1, p⫽0.007) after adjustment for baseline stroke severity, body temperature, glucose
levels, the presence ⬎ 2 vascular risk factors and statin treatment. Conclusion: High serum
levels of NOx at 24h from stroke onset are associated with an EPC increment ⱖ4 CFU-EC
during the first week in acute ischemic stroke.
617
was 29 ⫹/- 2 cc. Aspiration was well tolerated, with Visual Analog Pain scores of 2.4 ⫹/- 1.4
(out of 10). Specimen cooler temperatures remained in the target range during round-trip
transportation between the marrow donor center and the marrow processing lab. A median of
40 (range 20 –225) x 10^6 MNC were available for plating from the marrow. The MSC yield
at 21 d was median 2.1 (range, 0.9 – 4.4) x 10^6 MSC/kg. Median cell viability was 98.5%. All
samples were formally cleared for release within the allotted time period, and post-release
bacterial and fungal cultures were furthermore negative. Viability of MSC was well maintained
in saline at 1 x 10^6 MSC/mL for 24 h at 4 C, but not after 48 h or if stored at room
temperature. Subject age correlated with number of marrow nuclear cells (p⬍.05) but not with
yield of MSC. CONCLUSIONS: This study suggests the feasibility of a two-hospital, GTPcompliant system for use of autologous MSC to treat subjects with a time-sensitive condition
such as subacute stroke. Sufficient MSC that are suitable for human therapy can be rapidly and
reliably generated, and the resultant MSC may be preserved for up to 24 h.
P193
An Active and Repetitive Robot Assissted Training Improves Functional
Motor Recovery of the Arm in Sub-acute Stroke Patients.
Samuel Faran, Institute for Med Psychology and Behavioral Neurobiology, Univ of Tübingen,
Tübingen, Germany; Stefanie van Kaick, Christel Eickhoff, Charité- Berlin
Universitaetsmedizin, Dept of Neurological Rehabilitation, Clinic Berlin, Berlin, Germany;
Richard Mahoney, Motorika USA, Mount Laurel, NJ; Karl-Heinz Mauritz; Charité- Berlin
Universitaetsmedizin, Dept of Neurological Rehabilitation, Clinic Berlin, Berlin, Germany
Background and Propose: Loss of arm function is one of the most devastating consequences
of stroke and the affected limb may cause severe disability. During the last years many studies
have described the contribution of robotic devices in improving upper-extremity functions in
chronic patients with hemiparesis following stroke. The purpose of this study was to test the
hypothesis that a robot-assisted repetitive unilateral movement training effects upper limb
motor function in sub-acute stroke patients. Methods: A single blinded, randomized controlled
study in twenty (20) sub-acute stroke patients with a first ischemic stroke between 3 weeks
and 3 months prior to study entry, and with a upper limb muscle strength grades between 2
to 3 on the Medical Research Council (MRC) motor power scale. In addition to daily common
physiotherapy and occupational therapy sessions patients received during 4 weeks of
treatment 20 sessions of one hour each an upper extremity treatment with either the Reo
Therapy System robotic device (group A) or an air splint therapy (group B). The robot-assistance
was provided by the Reo Therapy System (Motorika USA Inc. New Jersey, USA), that interacts
with the patient in real-time and applies forces to the affected forearm during goal-directed
movements. The primary outcome measures were the blindly assessed Fugl-Meyer, Motor
Power Score (MP), and the Motor status score for shoulder and elbow (MS-SE). As secondary
endpoints we assessed the Action Research Arm Test (ARAT), the point-to-point (PtP) reach
performance measured automatically by the Reo Therapy System, and the Barthel Index.
Assessments were performed at baseline, one day after the 4 week training period and at
follow up 3 months later. Adverse effects were continuously monitored. Results: Patients in the
experimental group performed better on the Fugl-Meyer and ARAT tests than those in the
control group with significant differences at the end of the study (P⬍.05). The effect of the
robotic therapy was attributed to the intensive and repetitive reach movements which led to
increased muscle activity. The treatment was most effective in patients with a moderate motor
deficit of the upper-extremity (20⬍FM⬍ 60). No adverse effects due to the intervention were
found. Conclusions: The ReoTM Therapy System produced a superior improvement in upper
limb motor control and power compared with air splint therapy in subacute stroke patients.
Future studies should address different variables of the treatment effects in subacute stroke
patients and determine the optimum treatment intensity and motion modus for an individual
patient.
P194
P192
Feasibility of Autologous Marrow Stromal Cell Therapy in Human Stroke.
Safety And Behavioral Effects Of A Single Session Of High Frequency
Repetitive Transcranial Magnetic Stimulation In Chronic Stroke.
Steven C Cramer, Univ of California, Irvine, Orange, CA; Davina Garls, Sanjivan S Kohli,
Ellen Mackintosh, UCSD, La Jolla, CA; Randall Holcombe, Univ of California, Irvine, Orange,
CA; Murat Digicaylioglu, Thomas A Lane; UCSD, La Jolla, CA
Nuray Yozbatiran, Univ of California, Irvine, Orange, CA; Miguel Alonso-Alonso, Beth Israel
Deaconess Med Cntr, Boston, MA; Jill See, Univ of California, Irvine, Orange, CA; Asli
Demirtas-Tatlidede, Alvaro Pascual-Leone, Beth Israel Deaconess Med Cntr, Boston, MA;
Steven C Cramer; Univ of California, Irvine, Orange, CA
INTRODUCTION: Prior studies suggest the potential for autologous marrow stromal cell (MSC)
therapy to improve outcome after stroke. The purpose of this study was to evaluate a system
to obtain human bone marrow at one institution (UCI), culture MSC at a second institution
(UCSD), and returning MSC to the first institution for infusion, under Good Tissues Practice (GTP)
conditions. No subjects were treated–this report describes the feasibility of the approach.
METHODS: A bone marrow sample was aspirated from the iliac crest of healthy subjects, then
transported 82 miles under sterile, temperature-controlled conditions. A mononuclear cell
(MNC) fraction was prepared from the marrow, a portion of which was suspended in solution
with 20% pre-screened fetal bovine serum and plated in culture flasks. This was maintained
at 37 deg C in a 5% CO2 incubator, non-adherent cells were removed at 48 hr, and a portion
of the cells were passaged (at 12–14 d, when 80% confluent) into additional flasks. MSC were
harvested at 21 d, washed, and resuspended in sterile saline. MSC were identified according
to ISCT criteria, including adherence, morphology, growth characteristics, and flow cytometry
(⫹CD73, CD90, CD105; -CD14, CD34, CD45, HLA-DR), plus differentiation into adipocytes.
Criteria for releasing specimens from the marrow processing lab to the marrow donor/
treatment center included Gram stain, and Mycoplasma and Endotoxin assays. RESULTS: A
total of 8 subjects were enrolled, age 56 ⫹/- 22 (mean ⫹/- SD). The marrow volume aspirated
INTRODUCTION: Non-invasive electromagnetic brain stimulation might be of value to reduce
motor deficits after stroke, by either increasing ipsilesional excitability or decreasing
contralesional excitability. The safety of these methods requires further study. The current
study examined safety and behavioral effects of increasing ipsilesional excitability, delivered
during a single session of high frequency repetitive transcranial magnetic stimulation (rTMS) to
the ipsilesional primary motor cortex. METHODS: This unblinded, active-treatment-only,
single-dose, two-center study was approved by the U.S. FDA and local IRBs. Entry criteria
included age 18 – 85 years; infarct ⬎ 11 weeks prior, hemispheric in location, and ⬎ 15 mm
from the stimulation target; and no contraindication to TMS or MRI. Anatomical MRI was
obtained and used to define the rTMS target, the center of the hand area knob within gray
matter of posterior precentral gyrus. Each subject’s head was registered to his/her MRI using
frameless stereotaxy. Single pulse rTMS applied to the stroke-affected hemisphere with a
figure-of-8 coil defined the motor threshold (0 –100% of TMS device output) for the paretic first
dorsal interosseus muscle, after which rTMS was applied at 90% of this threshold. If TMS
elicited no motor response, stimulation was set at 65% of device output. rTMS application
consisted of 40 trains, each having 40 pulses (20 Hz X 2 sec), each train separated by 28 sec
618
Stroke
Vol 39, No 2
February 2008
of silence, for a total of 1600 pulses over 20 min. Subjects were assessed before, during the
hour after, and 1 wk after rTMS. RESULTS: The 12 subjects enrolled were 4.7 ⫹/- 4.9 y
post-stroke (mean ⫹/- SD), age 67 ⫹/- 12 y, baseline NIHSS score 4 ⫹/- 2, and arm motor
Fugl-Meyer 34 ⫹/- 16 (of 66). rTMS was well tolerated and without adverse events. SBP
increased from pre- to immediately post-rTMS by 7 mm Hg (p⫽.043). None of the 7 behavioral
measures assessed across rTMS showed a decrement, and several showed improvement. The
total # pegs placed on 9-hole pegboard increased 83% (p⫽0.04) from pre- to 1 hr post-rTMS,
accounted for by 4/12 subjects, among whom baseline motor status was significantly greater
than those not showing pegboard gains; a trend (p⫽.057) suggested retention of these gains
at 7 days post-rTMS. Grip strength and range of motion each increased (p⬍.03 each), in 7 or
more subjects, during the hour post-rTMS. Arm motor Fugl-Meyer score increased by 1.5 ⫹/1.7 points by 1 week post-rTMS (p⬍.02), a gain seen in 8/12 patients. CONCLUSIONS: A single
session of high frequency rTMS to motor cortex was safe. Results suggest gains in several
measures of arm motor function, though no control group was included. Gains lasted days
beyond the session, and might be most likely in those with lesser deficits. Future studies can
have larger sample size, include sham-treatment controls, employ multiple rTMS sessions, and
evaluate interactions with concomitant secondary therapies.
potential confounders. Results: Participants (63% female, 54% Caucasian, and 81% with IS)
had mean age of 67 years (SD 14) and mean admit FIM score of 47 (SD 16). For subjects with
left HP and SI, no difference was found in FIM gain between those with left side facing door
[Mean⫽18 (SD15), n⫽27] compared to right side facing door [Mean⫽19, (SD 15), n⫽37],
p⫽0.863. Therefore, no multivariate modeling was performed. Among subjects with right HP
and SI, those with right side facing door had a significantly greater FIM gain [Mean⫽24, (SD
13), n⫽22] compared to those with left side facing door [Mean⫽16, (SD 11), n⫽26], p⫽0.02.
For these subjects, differences in the proportion with IS vs. ICH and Caucasian race were
present in relationship to side facing door. The multivariate linear regression model of FIM gain
found a negative association with left side facing door and IS vs. ICH, p⬍0.05 for both
predictors. Race was not statistically significant. For rehab efficiency, the linear regression
model demonstrated a negative association with left side facing door and IS vs. ICH and a
positive association with Caucasian race and admit FIM score. p⬍0.05 for all predictors
Conclusion: For subjects with right HP and SI undergoing stroke rehabilitation, bed orientation
that forces attention to the affected side is independently associated with greater FIM increase
and greater rehab efficiency.
P197
Sildenafil Treatment Of Subacute Ischemic Stroke: A Safety Study At 25
Mg Daily For 2 Weeks.
Recovery II
P195
Repetitive Transcranial Magnetic Stimulation in Acute Stroke Patients: A
Preliminary Report.
A-Hyun Cho, Sang-Ho Pae, Seung-Jae Lee, Dong-Won Yang, Beum-Saeng Kim, Young-Min
Shon; The Catholic Univ, St.Mary’s Hosp, Seoul, Republic of Korea
Background: Repetitive transcranial magnetic stimulation (rTMS) has been reported as a
method to modify cortical excitability in rehabilitation of chronic stroke patients. Although brain
plasticity begins to work immediately after brain injury, there is only one report about rTMS in
acute stroke period showing short-term outcome results. We hypothesized that rTMS might be
safe even in acute stroke patients and improve neurological outcome. Methods: We
consecutively included stroke patients 1) who were admitted within 14 days, 2) with aphasia
or limb weakness, 3) without epileptiform discharge on electroencephalogram after stroke.
About 2–14 days after stroke onset, rTMS was applied over the cortical motor area of index
stroke hemisphere (120% of resting motor threshold of the non-stroke hemisphere, 3-second
trains of 10-Hz stimulation with 27 seconds between each train, 10 sessions, 5 days). We
evaluated an adverse effect, NIHSS before rTMS and at the end of the last rTMS session, and
modified Rankin scale (mRS) at 3 months. Results: Between October 2005 and June 2007,
total 47 patients underwent rTMS. Mean age was 63.4 ⫾ 13.8 years and 20 (42.5%) was mal.
Most common stroke location was MCA territory infarction followed by corona radiata or basal
ganglia lacunar infarct. Adverse effects were observed in 6 patients (fatigue in 2, headache,
dizziness, somnolent, seizure in a patient respectively). However, all the symptoms were
transient. In the patient with seizure after rTMS, intermittent rhythmic slowing was observed
at electroencephalogram before rTMS. Early improvement (any improvement of NIHSS) was
observed in 23 (51.1%) patients and favorable outcome (mRS 0 –2) in 27 (81.8%) patients
among 33 patients in whom mRS could be checked, and excellent outcome (mRS 0 –1) in 14
(42.4%). Conclusion: Repetitive transcranial magnetic stimulation as a therapeutic trial after
acute ischemic stroke seems to be safe. Randomized controlled study for proving long-term
clinical outcome is required.
P196
A Naturally Occurring Forced-Use Study of Stroke Patients Undergoing
Inpatient Rehabilitation.
Aninda B Acharya, Yang Liu, Saint Louis Univ, St Louis, MO; Genevieve N Olucha, SSM
Rehab, St Louis, MO; R. Charles Callison, Saint Louis Univ, St Louis, MO; Megan A Markey,
Paula M Juelich, Gerard J Erker; SSM Rehab, St Louis, MO
Objective: To determine how the physical orientation of a patient in relation to the hospital
room door affected stroke outcome in those with ipsilateral spatial inattention (SI) undergoing
inpatient rehabilitation. Methods: Adults undergoing inpatient rehabilitation at SSM Rehab in
St. Louis, Missouri (June 2005-April 2007) with hemispheric ischemic stroke (IS) or
intracerebral hemorrhage (ICH) and evidence of SI, and residing in same room during entire
hospital stay were eligible subjects for this study (n⫽112). Side affected by stroke and
presence of SI were determined by clinical exam and neuropsychological evaluation, including
a clock drawing task. Clocks drawn asymmetrically or predominantly on one side of the
drawing area were considered evidence of SI. Subjects with SI were grouped by side of
hemiparesis (HP) and side oriented to hospital room door, right or left. Disability level was
measured with the Functional Independence Measure (FIM). Outcomes of interest were (1)
change from admission to discharge in FIM score (FIM Gain) and (2) FIM gain divided by length
of stay (rehab efficiency). Descriptive statistics for baseline sociodemographic and medical
characteristics were performed. Independent t-tests compared subjects’ FIM Gain by side
affected and orientation in relation to door. If the t-test was statistically significant, then
multivariate linear regression models of both FIM gain and rehab efficiency were developed to
determine the association between these outcomes and side facing door correcting for
Brian Silver, Sharon McCarthy, Mei Lu, Panayiotis Mitsias, Andrew Russman, Angelos
Katramados, Daniel C Morris, Christopher Lewandowski, Michael Chopp; Henry Ford Hosp,
Detroit, MI
Background: In several animal studies of young and aged rats with ischemic stroke, treatment
with sildenafil (which augments cyclic guanine monophosphate [cGMP] in the central nervous
system) has been correlated with neurogenesis, angiogensis, synaptogenesis, and improved
functional outcomes compared with placebo. We studied whether a daily dose of 25 mg of
sildenafil could be given safely to patients with subacute ischemic stroke. Methods: Patients
with ischemic stroke were recruited between days three and seven after onset. Inclusion
criteria included ages 18 – 80 and NIH stroke scale score (NIHSS) 2–21. Exclusion criteria
included use of other CYP450 3A4 inhibitors, nitrates, and alpha blockers. Patients were treated
for two weeks with 25 mg daily. The primary outcome measure was the occurrence of any of
the following during the treatment period: stroke worsening, new stroke, myocardial infarction,
or death from any cause. Secondary outcome measures were NIHSS, Barthel indices (BI), and
modifed Rankin score (mRS) at 90 days. Results: Twelve patients were recruited (mean age
60, five females). Median NIHSS at entry was 9.5 (range 2–20). During the treatment period
with sildenafil, there was one death which was attributed to pulmonary embolism. Another
patient developed an asymptomatic deep vein thrombosis detected during random surveillance.
There were no occurrences of stroke worsening, new stroke, or myocardial infarction during
the study period. One patient died following suicide two months after study entry (and six
weeks after treatment with sildenafil had been completed). Including the two patients who died,
data are available for 90 day follow-up on ten patients. Among the eight survivors, median
NIHSS was 2 (range 0 –11), median BI was 92.5 (range 35–100), median mRS was 1 (range
0 – 4). Two patients have been followed less than 90 days with data pending. Conclusion:
Sildenafil 25 mg daily for two weeks appeared to be safe in this group of patients with mild
to moderate severity stroke. Further studies of higher doses will be tested.
P198
Response to Exercise Tolerance Testing in Subacute Stroke across Severity
Levels.
Dorian K Rose, Andrea L Behrman, Univ of Florida, Gainesville, FL; Yong Cen, Kathy J
Sullivan, Univ of Southern California, Los Angeles, CA; A. Danny Martin, Richard S
Schofield, Univ of Florida, Gainesville, FL; Julie K Tilson, Univ of Southern California, Los
Angeles, CA; Steve E Nadeau, Univ of Florida, Gainesville, FL; Bruce H Dobkin, Univ of
California, Los Angeles, Los Angeles, CA; Sam Wu, Univ of Florida, Gainesville, FL; Pamela
W Duncan; Duke Univ, Durham, NC
Background/Purpose: Atherosclerotic lesions throughout the vascular system are a common
co-morbidity associated with cardiovascular-related diseases including stroke. Post-stroke
hemiparesis with mobility limitations further contributes to cardiovascular deconditioning. To
ensure adequate cardiovascular functional capacity and exercise tolerance during an exercisebased RCT, an Exercise Tolerance Test (ETT) was incorporated into the screening phase. The
purpose of this study was to determine if there were differences in ETT performance between
individuals with moderate versus severe walking impairment at 2 months-post-stroke.
Methods: Participants included a cohort of 145 individuals with subacute stroke (58⫹/-10 dys
post onset) prospectively enrolled in the Locomotor Experience Applied Post-Stroke (LEAPS)
RCT, stratified as either severe (walking velocity ⬍ 0.4 m/sec; n⫽69; age: 62⫹/-17 yrs) or
moderate (walking velocity ⬎0.4 m/s ⬍ 0.8 m/s; n⫽76; age: 66⫹/-12 yrs). Screening via
chart review 5–30 days post-stroke excluded those with serious cardiac conditions. Minimum
ability to walk 10 feet and advance the paretic limb was determined during this initial phase
with the ETT as the final screen prior to enrollment in the exercise phase of the study. After
baseline vitals and ECG recording, pedaling commenced at 0 Watts (W) with workload
increasing 10 W/minute while maintaining cycling cadence between 40 - 60 revolutions per
minute. The ETT, supervised by a cardiologist, was terminated according to a prescribed list
of cardiac criteria, subjective fatigue or inability to maintain the required pedaling cadence.
Results: Those with moderate stroke pedaled longer (6.4⫹/-2.3 min) than those with severe
stroke (5.5 ⫹/- 1.9 min; p ⬍ .05), with an estimated maximum exercise capacity of 3.7 (95%
CI: 1.7–5.7) METS for the moderate and 3.4 (95% CI: 1.4 –5.4) METS for the severe group (p
⫽ NS). Reasons for test termination were similar across groups: peripheral fatigue (53%
moderate; 52% severe) or attainment of 90% THR or a Borg Rate of Perceived Exertion of 18
(39% moderate; 41% severe). Mean percent THR achieved was identical for both severity
groups, 75⫹/-13%. Mean percent THR achieved was 73⫹/-11% for those whom the ETT was
terminated secondary to fatigue. In the overall cohort, 97% (141/145) proceeded to trial
participation. Failures were due to severe hypertension, ischemia, and lower extremity
claudication. Conclusions: ETT performance was similar regardless of stroke severity. Despite
the presence of hemiparesis participants were able to exercise at increasing workloads. The
maximum exercise capacity, estimated by MET level, of the entire cohort indicates deconditioning at just two months post-stroke.
619
patients with unfavorable outcome (n⫽26, median 23.0 ml, IQR 1.2 - 60.2 ml) (p⫽0.07). The
smallest ischemic lesion volume at which the PPV for unfavorable outcome was 100% was 70
ml; none of the patients with DWI lesion volume ⱖ 70 ml achieved a good clinical outcome.
The sensitivity and specificity for unfavorable outcome at this cutoff were 19% and 100%
respectively. All patients in the validation cohort who had DWI lesion volume ⱖ 70 ml attained
an unfavorable clinical outcome as well. Conclusion: Patients with infarcts ⱖ 70 ml are not
likely to achieve good clinical outcome if untreated. If confirmed in larger datasets, this volume
threshold on DWI can be used as a selection tool or prognostic marker in therapeutic trials or
clinical stroke research.
P199
Long-Term Behavioral Symptoms in Ischemic Stroke Survivors.
Beth K Rush, Thomas G Brott, Mayo Clinic, Jacksonville, FL; Robert D Brown, Jr, Mayo
Clinic, Rochester, MN; Scott L Silliman, Univ of Florida College of Medicine, Jacksonville,
FL; Dale M Gamble, Sothear H Luke, Alexa N Richie, Mayo Clinic, Jacksonville, FL; Colleen
S Albers, Mayo Clinic, Rochester, MN; Rebecca B McNeil, Jorge A Trejo, James F Meschia;
Mayo Clinic, Jacksonville, FL
Background: Behavioral sequelae of stroke are poorly characterized, yet can complicate
rehabilitation, recovery, and quality of life. Prior studies have focused on depression or anxiety,
without parallel inquiry into other symptoms. This study hypothesized a wider array and higher
prevalence of behavioral symptoms in stroke survivors relative to age-comparable stroke-free
controls. Methods: We conducted a case-control study of behavioral symptoms. Cases were
recruited from St. Luke’s Hospital and Shands Hospital (Jacksonville, FL), and Saint Mary’s
Hospital (Rochester, MN). Non-demented stroke-free community controls were concurrently
enrolled. National Institutes of Health Stroke Scale (NIHSS) was administered to cases after
hospitalization for acute stroke. Mini Mental State Exam (MMSE) and Beck Depression
Inventory-2 (BDI-2) were administered to cases and controls in an outpatient appointment;
participant informants completed the Neuropsychiatric Inventory Questionnaire at that time.
MMSE and BDI-2 scores were compared using multivariable regression, with control for
covariates of age, education, and premorbid cognitive status. Prevalence and number of
Neuropsychiatric Inventory Questionnaire symptoms were compared using Fisher’s Exact and
Cochran-Armitage tests, respectively. Results: Fifty-three cases and 30 controls were enrolled.
Cases were 72% (38/53) men, median age was 71 years (IQR: 63 - 79 years), and median
education was14 years (IQR: 12 - 16 years). NIHSS was administered at a median of 3 days
from stroke onset (IQR: 2 - 6.5 days). Median NIHSS score was 2 (IQR: 1 - 4). Median time from
stroke onset to behavioral evaluation was 31 months (IQR: 12 - 39 months). Controls were 33%
(10/30) men, median age was 74 years (IQR: 63 - 79 years), and median education was16
years (IQR: 14 - 17 years). Cases and controls did not significantly differ on MMSE (Mean: 27.4
vs. 28.3, p ⫽ .64) or BDI-2 (Mean: 7.8 vs. 5.3, p ⫽ .07). A wider array of overall behavioral
symptoms was reported for cases vs. controls on the Neuropsychiatric Inventory Questionnaire
(Median: 2 vs. 0.5, p ⫽ .02). Cases had a higher prevalence of irritability/lability than controls
(40% vs. 13%, p ⫽ .01) with similar results noted for apathy/indifference (21% vs. 3%, p ⫽
.05), and agitation/aggression (32% vs. 13%, p ⫽ .07). There were no significant differences
on other Neuropsychiatric Inventory Questionnaire items including depression and anxiety.
Conclusions: Mild ischemic stroke survivors have a wider array and a higher prevalence of
long-term behavioral symptoms compared to stroke-free controls, even in the absence of
depression or clinically significant cognitive impairment.
P200
An Infarct Volume Threshold on Early DWI to Predict Unfavorable Clinical
Outcome.
Ethem Murat Arsava, Hakan Ay, AA Martinos Cntr for BioMed Imaging, Massachusetts
General Hosp, Boston, MA; Aneesh B. Singhal, Massachusetts General Hosp, Boston, MA;
Ona Wu, AA Martinos Cntr for BioMed Imaging, Massachusetts General Hosp, Boston, MA;
Karen L. Furie, Massachusetts General Hosp, Boston, MA; A.Gregory Sorensen; AA Martinos
Cntr for BioMed Imaging, Massachusetts General Hosp, Boston, MA
Background: Although the mismatch between DWI and perfusion-weighted MRI indicates
salvageable brain tissue and therefore is an attractive target for therapeutic intervention, the
correlation between baseline mismatch volume and clinical outcome is only moderate
(r⫽0.46 – 0.67). Because the volume of ischemic tissue on DWI is also important in determining
the clinical outcome, we sought to identify a volume cut-off for DWI lesion that can correctly
identify patients with unfavorable clinical outcome. Methods: We calculated the volume of
acute lesion on DWI obtained within 12 hours of symptom onset in a prospective cohort of 72
consecutive patients who did not receive any thrombolytic or experimental treatment (derivation
cohort). The clinical outcome was assessed using modified Rankin Score (mRS) at 3 months
(interquartile range 2 - 4 months). The mRS was dichotomized with unfavorable outcome
defined as mRS ⱖ 3. The positive predictive value (PPV) for unfavorable outcome for each
decimal of ischemic lesion volume on DWI was calculated. The minimum volume at which a
PPV of 100% was achieved was defined to be the cutoff for unfavorable outcome. The
reproducibility of results was assessed in a separate cohort of 44 untreated patients using the
same methodology (validation cohort). Results: Ischemic lesion volume on DWI ranged from
0.0 to 264.8 ml (median 6.4 ml, IQR 1.4 - 29.9 ml). There was a statistically significant
correlation between DWI lesion volume and mRS (r⫽0.25, p⫽0.04). Patients with good
outcome had smaller DWI lesion volume (n⫽46, median 4.8 ml, IQR 1.4 - 24.1 ml) than
P201
Brain-Behavior Relationships of Gait Asymmetry in the Chronic Stage of
Stroke Recovery.
Lisa D Alexander, 1. Heart and Stroke Foundation Cntr for Stroke Recovery at Sunnybrook
Health Sciences Cntr, 2. Sunnybrook Health Sciences Cntr Rsch Institute, 3. Univ of
Toronto, Toronto, Canada; William E McIlroy, 1,2,3, Dept of Kinesiology, Univ of Waterloo,
Waterloo, Canada; Fuqiang Q Gao, 1,2,3, & 4: L.C. Campbell Cognitive Neurology Rsch Unit,
Toronto, Canada; Kara Patterson, 1,2,3, Toronto Rehabilitation Institute, 5: Graduate Dept of
Rehabilitation Science, Univ of Toronto, Toronto, Canada; Sandra E Black; Univ of Toronto,
Rotman Rsch Institute, Baycrest, Toronto, Canada
Background: While much is known about altered motor patterning and spatiotemporal
characteristics of hemiparetic gait, associations of site of lesion damage and control of walking
are poorly understood. In particular, correlations between lesion location and post-stroke gait
asymmetry have not been investigated. Temporal symmetry is an important parameter in the
control of walking. Temporal gait asymmetry after stroke is a salient index of walking
competency which significantly impacts daily ambulation. The current study investigated
whether subtraction lesion analysis methods could distinguish brain regions associated with
persisting temporal gait asymmetry in chronic stroke patients. Methods: Preliminary retrospective analysis of 19 chronic stroke patients with neuroimaging and gait data available revealed
8 patients with symmetric gait and 11 with asymmetric gait. Chedoke-McMaster and NIH
stroke scales quantified clinical impairment. Spatiotemporal gait parameters were recorded
using a GaitRite instrumented walking surface. From a 95% confidence interval created around
mean values for 24 healthy adults, temporal symmetry values from 0.9 to 1.1 were considered
normal. Lesions were traced from digital 3-D T1-weighted MRI and co-registered to the
Montreal Neurological Institute brain template. Region of interest images were generated and
lesion overlays were created for both symmetric and asymmetric groups. The lesion overlay of
symmetric patients was subtracted from asymmetric patients to highlight voxels more
frequently lesioned in asymmetric patients and relatively spared in symmetric patients. Results:
Demographic data and clinical measures were comparable between groups. Average temporal
gait symmetry was 1.01 (SD 0.05) for symmetric and 2.26 (SD 0.96) for asymmetric patients.
After subtraction analysis, damage to specific portions of the external capsule (Talairach
coordinates x,y,z: -31,4,0), extreme capsule (-34,8,–5), insula (-36,7,–9), periventricular
corona radiata (-27,-17,26) and posterolateral putamen (-28,-12,9) was evident 80 –100%
more frequently in asymmetric patients than symmetric patients. Conclusions: Our lesion
analysis approach which dichotomized patients by temporal gait symmetry suggests that
damage to multiple structures in a distributed functional network of cerebral regions is
correlated with the control of walking. Additional recruitment currently underway should further
advance our understanding of these hitherto unexplored cortical and subcortical networks.
Such knowledge may guide therapy in the early phase of stroke by highlighting the need to
prioritize gait re-training when there is damage to key regions.
620
Stroke
Vol 39, No 2
February 2008
Prevention
P202
Cerebral Glycolysis Metabolism during Physical Exercise and
Neuroprotection in Stroke.
Miao Guo, Yimin Wu, Shane Sprague, Univ Texas Health Science Cntr, San Antonio, TX;
Xunming Ji, Xuanwu Hosp Capital Med Univ, Beijing, China; David F Jimenez, Yuchuan
Ding; Univ Texas Health Science Cntr, San Antonio, TX
It has been reported that physical exercise increases the metabolism rate in muscles. The
purpose of this study was to test whether exercise preconditioning increases cerebral glycolysis
metabolism in association with hypoxic induced factor1␣ (HIF-1␣), leading to reduced brain
injury after stroke. HIF-1␣ and downstream key molecules in glycolysis, including glucose
transporter 1(GLUT1), glucose transporter 3(GLUT3), phosphofructokinase (PFK), and lactate
dehydrogenase (LDH) were investigated. Adult male Sprague Dawley rats were subjected to a
30 minute exercise program on a treadmill each day for 1 to 3 weeks. Stroke was induced by
a 2-hour middle cerebral artery (MCA) occlusion using an intraluminal filament in exercised rats
for 3 weeks and non-exercised controls. Brain infarct volume was determined by Nissl staining.
The gene and protein expressions of HIF-1␣, GLUT1, GLUT3, PFK, and LDH were determined
in the brain region supplied by MCA using real time PCR and Western Blot. Pre-ischemic
exercise significantly (p⬍0.05) reduces brain infarct volume and neurological deficits in stroke.
HIF-1␣ mRNA and protein levels were significantly (p⬍0.05) increased during exercise prior to
ischemia/reperfusion injury (I/R). As compared to non-exercised rats, I/R injury did not further
increase HIF-1␣ expression. Physical exercise also significantly (p⬍0.05) raised the levels of
mRNA and protein of GLUT1, GLUT3, PFK, and LDH. Interestingly, this increase after physical
exercise was further significantly (p⬍0.05) enhanced during ischemia and reperfusion at 6, 12,
and 24 hours. Our results indicated that the metabolic function in brain after stroke can be
enhanced by the pre-ischemic exercise, leading to reduction in brain injury. This neuroprotection caused by physical exercise may be attributable to the increased level of HIF-1␣ which
regulates glycolysis factors.
P203
What Predict Severe Carotid Disease In Patients Presenting with Transient
Ischemic Attack?
Mai N Nguyen-Huynh, UCSF, San Francisco, CA; Stephen Sidney, Alan S Go, Allan
Bernstein, Div of Rsch, Kaiser Permanente Med Care Program, Oakland, CA; S Claiborne
Johnston; UCSF, San Francisco, CA
What Predict Severe Carotid Disease In Patients Presenting with Transient Ischemic
Attack? Background. Expedited performance of carotid ultrasound in patients with transient
ischemic attack (TIA) may significantly improve stroke prevention after TIA. However, urgent
ultrasound in all patients with TIA may not be feasible or cost-effective. Among a large
community-based sample of patients presenting with TIA, we examined whether there were
characteristics predictive of having severe carotid stenosis that may benefit from early
intervention. Methods. We identified all patients diagnosed with TIA by emergency medicine
physicians from 16 hospitals in Kaiser Permanente of Northern California during 2003. We
reviewed medical records of all cases with severe (70 –99%) stenosis by ultrasound in either
internal carotid artery within 3 months of the TIA, and of an equal number of randomly selected
controls without severe carotid disease (0 – 69% stenosis). Patient demographics, comorbidities, presenting symptoms, exam findings, hospital and factors associated with an early
increased risk of stroke after TIA (age, symptom duration, diabetes, hypertension, speech
disturbance, weakness) were evaluated. To evaluate associations with severe carotid disease,
we used logistic regression with robust standard errors (clustering at the hospital level) in order
to account for management differences between hospitals. Results. Among 2912 patients with
TIA, 1942 (66.7%) had carotid ultrasounds performed, and 166 (8.5%) of these showed
70 –99% stenosis. We randomly selected 166 controls with 0 – 69% stenosis and excluded six
due to missing or incomplete records. Mean age was 73.2 years and 49% were female. In
multivariable analysis, patients with severe carotid stenosis were more likely to be smokers, or
have a history of atrial fibrillation, coronary disease, peripheral arterial disease, or known
carotid disease; but less likely to present with symptoms of numbness, speech changes, or
dizziness [Table]. However, a sizeable number of patients complaining of numbness anywhere,
speech changes, or dizziness were also found to have severe carotid disease on ultrasound
[Table]. Conclusions - Severe carotid stenosis is not uncommon in patients presenting with TIA
and is detected in all patient types. Independent predictors of severe carotid disease included
current smoking, known vascular disease, and prior atrial fibrillation. Although all patients with
TIA should have carotid imaging as part of the work-up, our findings identified a subset of
patients who may be targeted for expedited carotid ultrasound.
TABLE. SIGNIFICANT PREDICTORS OF SEVERE CAROTID DISEASE IN PATIENTS
PRESENTING WITH TIA.
Univariate
analysis Odds
ratio (p-value)
Multivariate
analysis Odds
ratio (p-value)
Cohort
characteristics
# of patients with
severe stenosis (%)
Age ⱖ 70 years
(n⫽220)
Gender (n⫽326)
123 (55.9)
1.85 (0.01)
1.43 (0.24)
166 (50.9)
0.75* (0.30)
0.87 (0.70)
Univariate
analysis Odds
ratio (p-value)
Multivariate
analysis Odds
ratio (p-value)
145 (54.3) 5 (31.3)
5 (33.3) 9 (50.0)
–** 0.38 (0.09)
0.42 (0.24) 0.84
(0.75)
– 0.43 (0.14) 0.65
(0.55) 1.01 (0.99)
25 (73.5)
2.97 (<0.001)
2.37 (0.013)
56 (63.6)
2.03 (<0.001)
1.72 (0.04)
18 (81.8)
4.74 (0.005)
3.65 (0.03)
32 (82.1)
5.22 (0.002)
–
29 (65.9)
2.05 (0.01)
2.73 (0.01)
71 (45.8)
0.67 (0.03)
0.51 (<0.001)
58 (45.0)
0.67 (0.03)
0.54 (0.001)
13 (36.1)
0.50 (0.04)
0.52 (0.05)
Cohort
characteristics
# of patients with
severe stenosis (%)
Race White
(n⫽267) African
American
(n⫽16) Asian
(n⫽15) Hispanic
(n⫽18)
History of atrial
fibrillation
(n⫽34)
History of CAD
(n⫽88)
History of
peripheral
vascular disease
(n⫽22)
History of
carotid disease
(n⫽39)
Current smoking
(n⫽44)
Speech changes
(n⫽155)
Symptom
numbness
(n⫽129)
Symptom dizzy
(n⫽36)
*female vs. male gender; **white as the reference group.
P204
NR2 Peptide Indicates Early Neurological Adverse Events During Carotid
Revascularization.
Svetlana A Dambinova, Emory Univ, Atlanta, GA; Robert E Brightwell, Imperial College
London, St. Mary’s Hosp, London, United Kingdom; German A Khunteev, Galina A Izykenova,
Dept. Neurology, Pavlov’ State Med Univ, St. Petersburg, Russian Federation; Nicholas J
Cheshire; Imperial College London, St. Mary’s Hosp, London, United Kingdom
Objectives. Complication rates in terms of clinical stroke for carotid revasculization have fallen
since their inception. As overt complication rates decline, it would be reasonable to use
biomarkers of cerebral ischemia to assess the sub-clinical morbidity caused by carotid
endarterectomy (CEA) and carotid artery stenting (CAS). This study attempts to evaluate the
profile of NR2 peptide in patients underwent CEA and CAS. NR2 peptide, the fragment of NMDA
receptors proposed as a biomarker of cerebral ischemia (Dambinova et al, 2003), will be
correlated with haemodynamic and embolic events detected using trans-cranial Doppler (TCD).
Methods. 50 patients with internal carotid artery stenosis requiring intervention were recruited.
23 patients underwent CAS, and 27 underwent CEA. Patients were stratified as suffered from
previous TIA/stroke with infarct registered on MRI or CT (n⫽20) and those with events but no
radiological findings (n⫽23). TCD was performed peri-operatively to record mean Middle
Cerebral Artery (MCA) velocity and number of High Intensity Transient Signals (HITS) in the MCA
of the operated side. Plasma was drawn at six time points in a 48 hour post-operative period,
and then assayed for NR2 peptide using ELISA technique. Results. Treatment modality (CAS
versus CEA) had direct effect on NR2 peptide and level of the biomarker was associated with
changes in MCA velocity (p ⬍ 0.05) defined by TCD. CAS caused more HITS (p 1/4 0.028) that
correlated with high levels of NR2 peptide. NR2 peptide levels declined after revasculization in
the CAS group but not after CEA (p⬍0.01). NR2 peptide increased significantly at 1 and 6 hours
in those patients with a post-operative neurological deficit assessed by NIHSS (ROC curve
0.99). CAS caused 2 times less new brain injuries (26% cases) than CEA (52% cases) defined
by MRI. Conclusions. NR2 peptide indicates acute cerebral ischemia within 6 hours of
procedure and associated with adverse neurological events after carotid revasculization.
Trans-cranial Doppler findings suggest that the mechanisms of rise in NR2 peptide levels may
be due to increased micro-embolization and cerebral hypoperfusion respectively.
P205
Strokes Following Open Heart Surgery Aren’t Directly Related to the
Stenotic Carotid Artery.
Yuebing Li, Karen Boutron, Joanne Rodgers, Debra Walicki, Claranne Mathiesen, Qiang Li,
Yevgeniy Isayev, John Castaldo; Lehigh Valley Hosp, Allentown, PA
Background: Severe carotid stenosis increases the risk of stroke in the general population.
Whether it also increases the risk of perioperative stroke during open heart surgery remains
controversial. There is no consensus whether patients requiring open heart surgery should
receive preoperative non-invasive carotid assessment, and whether carotid revasculization
procedures are warranted preoperatively when significant carotid stenosis exists. Methods: We
did a retrospective analysis of 4332 patients receiving non-emergent coronary artery bypass
grafting and/or valve replacement in a single institution over the last five years. 76 cases with
clinically significant ischemic stroke and 239 patients with ⬎⫽ 50% carotid stenosis or
occlusion (5 symptomatic, 231 asymptomatic) were identified. All the stroke cases were
classified according to the standard TOAST criteria. The involved vascular territory was
determined with an independent review of the imaging and definitive clinical information.
Results: Of the 76 stroke cases, 57 (75%) were cardioembolic, 4 (5.3%) large vessel, 12
(15.8%) lacunar, 3 (3.9%) undetermined subtypes. A total of 18 patients were found with
significant carotid stenosis. Only 1 patient suffered from stroke in the territory of the diseased
carotid. Presurgical carotid revasculization was performed in 74 patients. 7 (13.2%) of 53
patients having combined carotid endarterectomy/open heart surgery developed postoperative
stroke. None of the 16 patients receiving staged surgery (CEA then CABG) suffered from stroke.
Of the 5 patients having received carotid stenting, 1 had a stroke. Postoperative strokes
occurred on 12 (10.3%) of the 116 patients with ⬎⫽ 80% carotid stenosis or carotid occlusion,
and 6 (4.9%) of the 123 patients with 50 –79% carotid stenosis. Of the 165 patients without
any carotid revasculization procedures, 10 (6.1%) suffered from stroke; 16 patients had ⬎ ⫽
80% stenosis (without occlusion) but none developed stroke postoperatively. Conclusions:
Most postoperative strokes following cardiac surgery are not related to ipsilateral carotid
stenosis. While high-grade carotid stenosis is an indicator for higher incidence of postoperative
cerebrovascular complications, carotid revasculization procedure has little role in preventing
such complications in this group of patients.
P206
Continuous Cerebral Hemodynamics Monitoring during Cardiac Surgery
Decreases Perioperative Stroke and Neurological Complications.
Alexander Razumovsky, Sentinent Neurocare Services, Inc., Cockeysville, MD; Stephen M
Oppenheimer, Sentinent Med Services, Inc., Cockeysville, MD; John C Laschinger;
Midatlantic Cardiovascular Associates, PA, Towson, MD
Cardiac surgery (CS)-related stroke incidence increases with age and risk factor multiple.
Generally no intraoperative monitoring of intracerebral hemodynamic variables (s

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