Systemic Inflammatory Response Depends on Initial Stroke

Severity but Is Attenuated by Successful Thrombolysis

Heinrich J. Audebert, MD; Michaela M. Rott, MD; Thomas Eck, MD; Roman L. Haberl, MD

Background and Purpose—To determine whether body temperature, c-reactive protein (CRP), and white blood cell
(WBC) count within the first days after stroke onset correlate with infarct size and stroke severity, and to examine
whether successful thrombolysis reduces poststroke inflammation.
Methods—Out of 1500 consecutive acute ischemic stroke patients, 346 cases (43 patients with thrombolysis) were selected
according to the following criteria: admission to hospital ⱕ24 hours after event, absence of prestroke and poststroke
infectious disease, no intracerebral hemorrhage or brain stem stroke, and data availability. Body temperature, WBC
within 3 days, and CRP within 5 days of event were determined daily. Lesion volume was measured by planimetry on
computed tomography or MRI scans. Successful thrombolysis was defined as improvement on the National Institutes
of Health Stroke Scale of ⱖ4 points within 24 hours.
Results—Increase of inflammatory parameters correlated significantly with lesion volume and stroke severity. This was
shown for body temperature on days 2 and 3 (P⬍0.001), CRP on days 1 to 5 (P⬍0.05), and WBC on days 1 to 3
(P⬍0.01). Patients with successful thrombolysis had reduced body temperature on day 3, WBC on days 2 and 3, and
CRP on days 3 to 5 (P⬍0.05).
Conclusions—Patients with a larger stroke volume and more severe stroke deficits have higher body temperature, CRP,
and WBC count in the acute phase after stroke. Successful thrombolysis is related to a significantly attenuated
inflammatory response. (Stroke. 2004;35:2128-2133.)
Key Words: c-reactive protein 䡲 cerebral infarction 䡲 inflammation 䡲 leukocytes 䡲 stroke, acute
䡲 temperature 䡲 thrombolysis
Downloaded from http://ahajournals.org by on July 17, 2022

S troke is known to produce an inflammatory response with

an increase of white blood cell (WBC) count in periph-
eral blood1 as well as body core temperature2 and brain
Patient Selection
Methods

Approximately 1500 consecutive stroke patients who were admitted

temperature.3 As a consequence of the association of in-
creased body temperature and poor functional outcome,
antibiotic treatment of infections and antipyretic treatment for
elevated body temperature after stroke are recommended for
the therapy of stroke patients in the acute phase.4,5
So far, little is known about the time course of most
inflammatory parameters in the acute phase of ischemic
stroke. This study was performed to assess the hypothesis that
the systemic inflammatory response after stroke results from
a response to the necrotic tissue itself but not from a
cryptogenic infection. The correlation between lesion size
and routinely available inflammatory parameters such as
body temperature, c-reactive protein (CRP), and WBC was
therefore analyzed. The inflammatory reaction seen in pa-
tients with initial ischemic deficit but reduced cerebral
necrosis due to successful thrombolysis should be attenuated.
Return of the acute phase parameters to normal ranges should
occur earlier.
to the Munich-Harlaching Hospital were screened in a retrospective
analysis. Three hundred forty-six patients were selected according to
the following criteria: admission ⱕ24 hours of event, accessibility of
necessary clinical data, and computed tomography (CT) or MRI
scans.
Exclusion criteria included intracerebral hemorrhage, including
secondary hemorrhage on control CT/MRI (to avoid confounding
effects of hematoma-induced inflammation); pre-existing and post-
stroke infectious disease; brain stem stroke (because of difficult
planimetry in CT scans and high risk of swallowing disorders);
trauma and vascular events ⬍4 weeks before stroke; vascular events
⬍4 weeks before stroke; chronic inflammatory or malignant disease;
and patients with antiinflammatory treatment (eg, corticoids, nonste-
roidal antiinflammatory medication excluding aspirin).
Neuroradiological Data
CT scans were routinely done at hospital admission and repeated
when symptom progression occurred or when no adequate lesion
could be detected on the first scan. In patients with atypical findings,
an MRI scan was performed. A neurologist and a radiologist who
were blinded to the clinical course and the inflammatory parameters
assessed stroke volume by CT planimetry using the formula de-

Received April 22, 2004; accepted June 11, 2004.

From the Department of Neurology, Hospital Munich-Harlaching, Germany.
Correspondence to Dr H. Audebert, Abteilung für Neurologie, Städtisches Krankenhaus München-Harlaching, Sanatoriumsplatz 2, 81545
München-Harlaching, Germany. E-mail neuro.audebert@khmh.de
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000137607.61697.77

2128
 Audebert et al Poststroke Inflammation Depends on Stroke Severity
TABLE 1. Epidemiological and Clinical Data
Total N⫽346 Male n⫽206 Female n⫽140
Age
Infarct volume, mL
Delay between onset and admission, h
Antipyretic treatment ⱕ48 h, in 138 patients
scribed by Kothari et al6: Vol (ml)⫽[A(mm)⫻B(mm)⫻C(mm)]/2. A
is the greatest diameter by CT, B is the diameter 90° to A, and C is
the approximate number of CT slices with lesion multiplied by the
slice distance. To assure the comparability of the assessment, the CT
scans of 23 patients were measured by both the neurologist and the
radiologist. There was a high level of agreement between both
investigators with an intraclass correlation coefficient of 0.9504
(98% CI). CTs used for planimetry (N⫽281) were performed 1 to 5
days after stroke onset. Infarct volume on MRI scans (N⫽65) was
measured in T2 and fluid-attenuated inversion recovery images.
Residual lesions of former cerebral infarcts were not included.
Exclusion of Prestroke and Poststroke Infections
All patients with anamnestic information about fever or any other
inflammation ⬍4 weeks before stroke were excluded. An analysis of
the medical documentation was done to exclude poststroke infectious
disease. According to the stroke unit protocol, a search for infectious
diseases was started in patients presenting with clinically relevant
symptoms or within laboratory parameters for suspicion of
inflammation.
The measures consisted of a daily physical examination including
chest auscultation. Chest radiography, urine status, and laboratory
tests for systemic infection including complete blood count and CRP
were performed routinely on admission. If patients showed clinical
Downloaded from http://ahajournals.org by on July 17, 2022
or laboratory signs of inflammation, such as fever, elevated WBC,
CRP, purulent sputum, or clinical symptoms of urinary/pulmonary
tract infections, the diagnostic procedures were repeated. In addition,
urine or sputum cultures were performed depending on the clinical
results. If fever exceeded ⬎38.5°C, blood culture was taken to detect
bacteremia or systemic mycosis. The presence of urinary tract
infection and appropriate clinical symptoms was defined as signifi-
cant bacteriuria (ⱖ105 cells/␮L) or leukocyturia (ⱖ20 cells per
visual field). The diagnosis for pulmonary infection was established
according to clinical and radiological findings (auscultation of rales,
positive results of sputum culture, or radiological evidence of
pulmonary infiltration).
Clinical Evaluation and Monitoring
The National Institutes of Stroke Scale (NIHSS) score was deter-
mined at hospital admission during the participation period in the
German Stroke Databank. For correlation of stroke severity with
inflammatory parameters, only patients without recombinant tissue
plasminogen activator (rtPA) treatment were included.
In all patients who received systemic rtPA, NIHSS score was
assessed on admission and 24 hours after thrombolysis. Systemic
thrombolysis was performed according to the National Institute of
Neurological Disorders and Stroke (NINDS) protocol. Successful
thrombolysis was defined as an NIHSS-improvement of ⱖ4 points
within 24 hours.
According to the stroke unit protocol, body temperature was
measured on admission and during the subsequent 3 days with
intervals between 2 and 12 hours, depending on temperature eleva-
tion. Measuring temperature was performed orally or rectally. If
patients could not cooperate sufficiently (eg, complete occlusion of
the mouth), only rectal measures were recorded. Patients with a
temperature of ⬎37.5°C were treated with paracetamol or metamizol
(oral, rectal, or IV administration) according to the stroke unit
protocol. For statistical analysis, the earliest body temperature
recorded on day of admission and the highest temperature on days 2
and 3 were determined.
2129
Mean Min Max SD
65.9 27 91 12.7
42.0 0 499 81.5
6.7 0 (onset in hospital) 24 6.4
2 1 11 2.0
Laboratory Analysis
WBC (normal range, 4.0 to 10.0/nL) and CRP (normal range, ⬍0.5
to 0.8 mg/dL) were determined using routine laboratory methods.
For statistical analysis, WBC and body temperature on hospital
admission and on days 2 and 3 were determined. CRP was measured
on admission and on days 2 to 5. For all CRP values ⬍0.5 mg/dL, a
value of 0.4 mg/dL was used for statistical tests.
Statistical Analysis
Statistical analysis was performed using Microsoft Excel and
SPSS software. Spearman correlation coefficient and the Mann–
Whitney U test were used to determine the correlation between
stroke volume and inflammatory parameters. Differences between
NIHSS scores were assessed applying Fisher exact test. The
findings were considered statistically significant when the prob-
ability value was ⬍0.05.
Results
Epidemiological and clinical data are shown in Table 1.
Correlation of Inflammatory Parameters and
Stroke Volume
Temperature, Antipyretic Treatment, and Stroke Volume
Spearman correlation coefficient yielded significant values
(P⬍0.001) for body temperature on days 2 and 3 and the
number of antipyretics administered within the first 48 hours
(Table 2).
CRP, WBC, and Stroke Volume
CRP and stroke volume showed a significant correlation
using Spearman correlation coefficient for all 5 days (day 1,
P⬍0.05; days 2 to 5, P⬍0.001). The results for the correla-
tion between WBC and stroke volume were significant for the
3 assessed days (day 1, P⬍0.01; days 2 and 3, P⬍0.001).
Correlation Between Initial Stroke Severity and
Inflammatory Parameters
Spearman correlation coefficient indicated that more severe
strokes were associated with a higher leukocyte count from
the first day forward (day 1, P⬍0.01; day 2, P⬍0.001; day 3,
P⬍0.05). NIHSS score on admission was significantly cor-
related with body temperature on days 2 and 3 (P⬍0.001) and
N° of administered antipyretic drugs within 48 hours
(P⬍0.01) (Figure 1). Similar results were found for the
increase of CRP on day 2 (P⬍0.01), day 4 (P⬍0.05), and day
5 (P⬍0.01).
Patients With and Without Successful Thrombolysis
Sixty-five patients received systemic rtPA treatment.
Forty-three patients were selected in the analysis according to
the inclusion criteria. Twenty-three patients (group A) were
treated successfully with a median NIHSS score at admission
of 10.0⫾3.4 and median NIHSS score 24 hours later of
 2130 Stroke September 2004

TABLE 2. Results of Correlations

Infarct Volume NIHSS

N Spearman-Rho P N Spearman-Rho P
Temperature
Day 1 290 0.077 0.095 83 0.073 0.255
Day 2 292 0.421 ⬍0.001 89 0.510 ⬍0.001
Day 3 264 0.472 ⬍0.001 86 0.445 ⬍0.001
⌺ Antipyretics 301 0.444 ⬍0.001 88 0.355 ⬍0.001
WBC
Day 1 318 0.154 0.003 90 0.248 0.003
Day 2 264 0.396 ⬍0.001 82 0.360 ⬍0.001
Day 3 184 0.371 ⬍0.001 62 0.230 0.036
CRP
Day 1 308 0.122 0.016 90 0.010 0.464
Day 2 253 0.334 ⬍0.001 84 0.306 0.002
Day 3 176 0.417 ⬍0.001 58 0.161 0.113
Day 4 146 0.366 ⬍0.001 45 0.315 0.018
Day 5 127 0.390 ⬍0.001 38 0.430 0.003

2.0⫾2.7. Twenty patients (group B) did not have a significant
improvement (median NIHSS score of 15.0⫾4.6 at admission
and 16.5⫾9.3 24 hours after thrombolysis). The differences
between the NIHSS scores at admission (P⬍0.05) and 24
hours after thrombolysis (P⬍0.001) were statistically signif-
icant. Lesion volumes in control CT/MRI (days 2 to 5) were
larger in group B (mean value 140.8⫾137 mL versus
Downloaded from http://ahajournals.org by on July 17, 2022
with the clinical severity and outcome of stroke. This increase
in body temperature starts within 24 hours of the event,
whereas fever due to infections seems to have a later
onset.2,8 –10
This is a retrospective analysis that contains some limita-
tions. Concomitant infections cannot be excluded totally,

despite the standardized protocol. Accuracy of overall tem-

36.2⫾46 mL).
Baseline parameters of temperature, WBC, and CRP
were similar in groups A and B. Differences between
groups A and B are listed in Table 3. The correlation
between inflammatory parameters and time course after stroke
are shown in Figure 2.
Discussion
Elevation of inflammatory parameters in the acute phase of
ischemic stroke is a well-known phenomenon and may result
from infectious complications or from the inflammatory
reaction of the damaged brain tissue. Necrotic tissue is
eliminated by cellular, humoral, and metabolic mechanisms,
which are all part of the inflammatory reaction.7 Previous
studies have already shown that high systemic inflammatory
parameters, especially high body temperature, are associated
perature measurement depends on correctness of the assess-
ments. Oral and rectal measures are widely comparable if
conducted properly.
In our sample of ischemic stroke patients without evidence
of infection, the elevation of body temperature and WBC
(within the first 3 days) as well as CRP (within the first 5
days) were significantly correlated with initial stroke severity
and the resulting stroke volume. The number of antipyretic
drugs administered within the first 48 hours was also in-
creased in patients with larger lesion size. Correlation with
infarct volume was highly significant for body temperature
on days 2 and 3 as well as for the number of antipyretic drugs
(P⬍0.001) and for WBC for all assessed days. CRP and
stroke volume revealed a significant correlation using Spear-
man correlation coefficient for all 5 days.

Figure 1. Correlation between NIHSS

score and temperature or WBC on day 2.
 Audebert et al Poststroke Inflammation Depends on Stroke Severity 2131

TABLE 3. Epidemiological and Clinical Data of Patients With prognostic relevance is the early increase in body tempera-
Thrombolytic Therapy ture. It is also known that in acute stroke intracerebral
Group A: Improvement Group B: No Improvement temperature is usually higher than body core temperature.3
of ⱖ4 in NIHSS of ⱖ4 in NIHSS Moderate hypothermia as a therapeutic option is associated
Total No. of patients 23 20
with a higher rate of infectious complications.3,19
Our results yield an association between lesion size and
Male 14 10
body temperature on the second and third days, which is
Female 9 10
confirmed by the association between lesion size and number
Mean SD Mean SD of antipyretic drugs administered within the first 48 hours. In
our cohort there was no significant correlation between lesion
Age, y 61.8 10.3 65.0 11.3
size and first measurement of body temperature after hospital
Infarct volume, mL 36.2 45.8 140.8 137.0
admission (mean 6.7 hours after stroke onset). Boysen and
No. of antipyretics 1.4 1.2 1.6 1.5 Christensen demonstrated that body temperature starts to rise
within 4 to 6 hours after onset. A significant correlation with
a bad outcome was found for body temperature after 10 to 12
CRP and WBC seem to be very early indicators for lesion
hours,2 several hours later than the average in our analysis.
size, especially because the value assessed for day 1 was the
first measured after hospital admission. Elevated CRP and Lesion Size
There are no reports so far on the association between lesion
Elevated Body Temperature and Lesion Size size and elevated CRP in the acute phase of ischemic stroke.
Other authors have already demonstrated that high body We found a significant correlation between lesion size and
temperature in the acute phase of ischemic stroke is associ- CRP in the first 5 days after onset. Clinical stroke severity
ated with neurological deficit, clinical progression, bad out- was correlated with increased CRP levels on days 2, 4, and 5.
come, and increased lesion size.2,8 –18 The crucial point for The studies conducted so far analyzed the prognostic value of
CRP for progression and outcome.20 –22 Whereas Canova et
al23 came to the conclusion that CRP at hospital admission
was not suitable for predicting outcome, Napoli et al22,24
found an association between elevated CRP within the first
48 hours and bad outcome.
Downloaded from http://ahajournals.org by on July 17, 2022

Elevated White Blood Cell Count and Lesion Size

Figure 2. Time course of inflammatory parameters in patients
with and without successful thrombolysis.
Several studies have already been conducted concerning the
association between WBC count and lesion size. In some of
them, leukocyte migration and accumulation was measured
using leukocytes labeled with radioactive markers and ␥
scintigraphy or single-photon emission computed tomogra-
phy. In animal models as well as in humans these leukocytes
migrate and accumulate in the damaged tissue after ischemic
stroke. Accumulation progressively increases during the first
6 to 24 hours after onset, remains at a high level for 6 to 9
days, and then decreases but stays measurable for up to 5
weeks.25–27 The activation of leukocytes is accompanied by
an increase of WBC in the peripheral blood.1,20,25,26,28,29 The
prognostic value of this leukocytosis for outcome and its
association with clinical extent (but not with infarct size) has
already been investigated.1,25,30 –32 The analysis of single-
photon emission computed tomography imaging and WBC
also indicates that there may be an association between
leukocyte activation in the brain and the resulting stroke
volume.25 Silvestrini et al32 reported that WBC and leukocyte
aggregation in the peripheral blood of stroke patients were
significantly higher than in the control group, and that
leukocyte aggregation (but not leukocyte count!) was signif-
icantly higher on days 2 and 4 for patients with large
infarctions than for patients with small lesions. Emsley et al33
investigated the time course of peripheral inflammatory
parameters such as CRP and WBC in a small sample of acute
stroke patients and reported elevated levels until 3 months
after stroke.
 2132 Stroke September 2004
In our analysis, we found a significant correlation between
stroke volume or stroke severity and the increase of WBC in
the peripheral blood for the first 3 days. This result is
consistent with the temporal profile of leukocyte accumula-
tion in the damaged brain tissue as demonstrated by Akopov
et al.25
In the subgroup of patients treated with systemic
thrombolysis, patients with a clinically significant improve-
ment of neurological functions developed a significantly
attenuated inflammatory reaction. The induced salvage of
brain tissue can be interpreted as a model of reduced systemic
inflammation by avoiding cerebral necrosis.
Conclusions
Necrosis in the brain produces a strong inflammatory reac-
tion. Therefore, the association between lesion size and
elevated inflammatory parameters is a sufficient explanation
of previous observations that elevated inflammatory param-
eters in acute stroke patients are predictive for the functional
outcome.
Tissue necrosis in the brain initiates fever, CRP elevation,
and WBC elevation, which can be measured as a systemic
inflammatory response. The activation of cellular, humoral,
and metabolic mechanisms in the brain results in an inflam-
matory reaction, which may lead to an increase of necrotic
tissue in the tissue at risk (ischemic penumbra). Apart from
these deleterious effects, neuroprotective mechanisms of
inflammation are being discussed.34 –38
Possible Implications for Clinical Decision Making
Downloaded from http://ahajournals.org by on July 17, 2022
Considering that inflammatory parameters correlate with
lesion size, diagnosis and therapy of suspected infectious
complications in stroke patients can be interpreted in a
differentiated way. In patients with small lesions, a marked
increase of body temperature, CRP, or WBC should be
taken as an indicator for infection. On the other hand,
patients with large lesions often show a moderate increase
of inflammatory parameters but a search of possible
infections does not yield positive results. In these cases,
antibiotic treatment should be considered very carefully,
taking into account possible side effects and costs of
treatment. Moreover, patients with larger lesions may
show a slower decrease of inflammatory parameters be-
cause of the cerebral necrosis rather than because of
insufficient antibiotic treatment.
The postulated negative effects of the inflammatory
reaction on the penumbra could possibly be prevented by
an antiinflammatory treatment in the acute phase of stroke.
Such a treatment in the very early, ideally in the preclin-
ical, phase might help prevent this secondary cell damage.
Drugs with an antipyretic as well as antiphlogistic effect
would be suitable.39 – 42 Coimbra et al demonstrated the
effectiveness of the combination of hypothermia and
antipyretic/antiphlogistic drugs for diminishing the lesion
size in an animal model.43 Clinical trials are therefore
warranted.
References
1. Kazmierski R, Guzik P, Ambrosius W, Kozubski W. [Leukocytosis in the
first day of acute ischemic stroke as a prognostic factor of disease
progression]. Wiad Lek. 2001;54:143–151. In Polish.
2. Boysen G, Christensen H. Stroke severity determines body temperature in
acute stroke. Stroke. 2001;32:413– 417.
3. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. Brain tem-
perature monitoring and modulation in patients with severe MCA
infarction. Neurology. 1997;48:762–767.
4. Hacke W, Kaste M, Olsen TS, Orgogozo JM, Bogousslavsky J. European
Stroke Initiative: recommendations for stroke management. Organisation
of stroke care. J Neurol. 2000;247:732–748.
5. Hacke W, Kaste M, Skyhoj OT, Orgogozo JM, Bogousslavsky J.
European Stroke Initiative (EUSI) recommendations for stroke man-
agement. The European Stroke Initiative Writing Committee. Eur
J Neurol. 2000;7:607– 623.
6. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuc-
carello M, Khoury J. The ABCs of measuring intracerebral hemorrhage
volumes. Stroke. 1996;27:1304 –1305.
7. Kogure K, Yamasaki Y, Matsuo Y, Kato H, Onodera H. Inflammation of
the brain after ischemia. Acta Neurochir Suppl (Wien). 1996;66:40 – 43.
8. Davalos A, Castillo J, Pumar JM, Noya M. Body Temperature and
fibrinogen are related to early neurological deterioration in acute ischemic
stroke. Cerebrovasc Dis. 1997;7:64 – 69.
9. Castillo J, Davalos A, Noya M. Aggravation of acute ischemic stroke by
hyperthermia is related to an excitotoxic mechanism. Cerebrovasc Dis.
1999;9:22–27.
10. Castillo J, Davalos A, Marrugat J, Noya M. Timing for fever-related brain
damage in acute ischemic stroke. Stroke. 1998;29:2455–2460.
11. Georgilis K, Plomaritoglou A, Dafni U, Bassiakos Y, Vemmos K.
Aetiology of fever in patients with acute stroke. J Intern Med. 1999;246:
203–209.
12. Reith J, Jorgensen HS, Pedersen PM, Nakayama H, Raaschou HO,
Jeppesen LL, Olsen TS. Body temperature in acute stroke: relation to
stroke severity, infarct size, mortality, and outcome. Lancet. 1996;347:
422– 425.
13. Fukuda H, Kitani M, Takahashi K. Body temperature correlates with
functional outcome and the lesion size of cerebral infarction. Acta Neurol
Scand. 1999;100:385–390.
14. Wang Y, Lim LL, Levi C, Heller RF, Fisher J. Influence of admission
body temperature on stroke mortality. Stroke. 2000;31:404 – 409.
15. Hajat C, Hajat S, Sharma P. Effects of poststroke pyrexia on stroke
outcome: a meta-analysis of studies in patients. Stroke. 2000;31:
410 – 414.
16. Jorgensen HS, Reith J, Nakayama H, Kammersgaard LP, Raaschou HO,
Olsen TS. What determines good recovery in patients with the most
severe strokes? The Copenhagen Stroke Study. Stroke. 1999;30:
2008 –2012.
17. Grau AJ, Buggle F, Schnitzler P, Spiel M, Lichy C, Hacke W. Fever and
infection early after ischemic stroke. J Neurol Sci. 1999;171:115–120.
18. Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G,
D’Alessandro R. Fever in acute stroke worsens prognosis. A prospective
study. Stroke. 1995;26:2040 –2043.
19. Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK.
Optimal depth and duration of mild hypothermia in a focal model of
transient cerebral ischemia: effects on neurologic outcome, infarct size,
apoptosis, and inflammation. Stroke. 1998;29:2171–2180.
20. Audebert H, Pellkofer S, Wimmer ML, Haberl RL. Progression in lacunar
stroke is related to elevated acute phase parameters. Eur Neurol. 2004;
51:125–131.
21. Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR. C-reactive protein
and outcome after ischemic stroke. Stroke. 1999;30:981–985.
22. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an
independent prognostic factor. Stroke. 2001;32:917–924.
23. Canova CR, Courtin C, Reinhart WH. C-reactive protein (CRP) in cere-
brovascular events. Atherosclerosis. 1999;147:49 –53.
24. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased
C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001;
32:133–138.
25. Akopov SE, Simonian NA, Grigorian GS. Dynamics of poly-
morphonuclear leukocyte accumulation in acute cerebral infarction and
their correlation with brain tissue damage. Stroke. 1996;27:1739 –1743.
26. Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK,
Thompson CB, Obrenovitch TP, Contreras TJ. Polymorphonuclear leu-
kocyte accumulation in brain regions with low blood flow during the
early postischemic period. Stroke. 1986;17:246 –253.
27. Wang PY, Kao CH, Mui MY, Wang SJ. Leukocyte infiltration in acute
hemispheric ischemic stroke. Stroke. 1993;24:236 –240.
 Audebert et al Poststroke Inflammation Depends on Stroke Severity
28. Elneihoum AM, Falke P, Axelsson L, Lundberg E, Lindgarde F, Ohlsson
K. Leukocyte activation detected by increased plasma levels of inflam-
matory mediators in patients with ischemic cerebrovascular diseases.
Stroke. 1996;27:1734 –1738.
29. Kochanek PM, Hallenbeck JM. Polymorphonuclear leukocytes and
monocytes/macrophages in the pathogenesis of cerebral ischemia and
stroke. Stroke. 1992;23:1367–1379.
30. Vila N, Filella X, Deulofeu R, Ascaso C, Abellana R, Chamorro A.
Cytokine-induced inflammation and long-term stroke functional
outcome. J Neurol Sci. 1999;162:185–188.
31. Galante A, Silvestrini M, Stanzione P, Pietroiusti A, Baldoni F, Domenici
B, Bernardi G. Leucocyte aggregation in acute cerebrovascular disease.
Acta Neurol Scand. 1992;86:446 – 449.
32. Silvestrini M, Pietroiusti A, Troisi E, Franceschelli L, Piccolo P, Magrini
A, Bernardi G, Galante A. Leukocyte count and aggregation during the
evolution of cerebral ischemic injury. Cerebrovasc Dis. 1998;8:305–309.
33. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan
EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell
PJ. An early and sustained peripheral inflammatory response in acute
ischaemic stroke: relationships with infection and atherosclerosis.
J Neuroimmunol. 2003;139:93–101.
34. Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC.
Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha
impart neuroprotection to an excitotoxin through distinct pathways.
J Immunol. 1999;163:3963–3968.
Downloaded from http://ahajournals.org by on July 17, 2022
2133
35. Castillo J, Leira R. Predictors of deteriorating cerebral infarct: role of
inflammatory mechanisms. Would its early treatment be useful? Cere-
brovasc Dis. 2001;11(suppl 1):40 – 48.
36. Castellanos M, Castillo J, Garcia MM, Leira R, Serena J, Chamorro A,
Davalos A. Inflammation-mediated damage in progressing lacunar infarc-
tions: a potential therapeutic target. Stroke. 2002;33:982–987.
37. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is
it harmful? Arch Neurol. 2001;58:669 – 672.
38. Whitaker JN. The potential for harm or benefit from inflammatory pro-
cesses in stroke. Arch Neurol. 2001;58:674.
39. Nagayama M, Niwa K, Nagayama T, Ross ME, Iadecola C. The cyclo-
oxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in
wild-type mice but not in mice with deletion of the inducible nitric oxide
synthase gene. J Cereb Blood Flow Metab. 1999;19:1213–1219.
40. Iadecola C, Alexander M. Cerebral ischemia and inflammation. Curr
Opin Neurol. 2001;14:89 –94.
41. Gidday J, Campbell J, Perez R, Gonzales E, Shah A, Park T. Mechanisms
of cyclooxygenase-2 induced brain injury following permanent middle
cerebral artery occlusion. Stroke. 2002;33. Abstract.
42. Domoki F, Perciaccante JV, Puskar M, Bari F, Busija DW. Cyclooxy-
genase-2 inhibitor NS398 preserves neuronal function after hypoxia/is-
chemia in piglets. Neuroreport. 2001;12:4065– 4068.
43. Coimbra C, Drake M, Boris-Moller F, Wieloch T. Long-lasting neu-
roprotective effect of postischemic hypothermia and treatment with an
anti-inflammatory/antipyretic drug. Evidence for chronic encephalo-
pathic processes following ischemia. Stroke. 1996;27:1578 –
1585.