Levels of Anti-Inflammatory Cytokines and Neurological

Worsening in Acute Ischemic Stroke

Nicolás Vila, MD; José Castillo, MD; Antonio Dávalos, MD; Anna Esteve, PhD;
Anna M. Planas, PhD; Ángel Chamorro, MD

Background—Mechanisms involved in stroke progression are incompletely understood. Ischemic brain injury is
characterized by acute local inflammatory response mediated by cytokines. Anti-inflammatory cytokines act in a
feedback loop to inhibit continued proinflammatory cytokine production. We assessed the implication of interleukin
(IL)-10 and IL-4 in deteriorating ischemic stroke.
Methods—Two hundred thirty-one patients with ischemic stroke within the first 24 hours from onset were included.
Neurological worsening was defined when the Canadian Stroke Scale score fell at least 1 point during the first 48 hours
after admission. Anti-inflammatory cytokines were determined in plasma obtained on admission.
Results—Eighty-three patients (35.9%) worsened within the first 48 hours after stroke onset. Significantly lower
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concentrations of IL-10 were found in patients with neurological worsening (P⬍0.05), but IL-4 levels were similar in
patients with or without deterioration. Lower plasma concentrations of IL-10 (⬍6 pg/mL) were associated with clinical
worsening on multivariate analysis (odds ratio⫽3.1, 95% CI⫽1.1 to 8.9) independently of hyperthermia, hyperglyce-
mia, or neurological condition on admission. Further analysis disclosed that early worsening was independently
associated with lower IL-10 plasma levels in patients with subcortical infarcts or lacunar stroke but not in patients with
cortical lesions.
Conclusions—Anti-inflammatory cytokine IL-10 is associated with the early clinical course of patients with acute ischemic
stroke, especially in patients with small vessel disease or subcortical infarctions. (Stroke. 2003;34:671-675.)
Key Words: cytokines 䡲 inflammation 䡲 interleukin-4 䡲 interleukin-10 䡲 neuroprotection 䡲 stroke, ischemic

O ne third of patients with acute ischemic stroke develop

early neurological worsening, a situation associated
with increased mortality and long-term functional disabili-
ty.1,2 The underlying basic mechanisms involved are not
completely understood, although biochemical factors have
been suggested.1,2 Cerebral ischemia evokes an inflammatory
response characterized by activation and release of cytokines,
chemokines, endothelial-leukocyte adhesion molecules, and
proteolytic enzymes that exacerbate tissue damage.3,4 In-
creased production of proinflammatory cytokines and chemo-
kines has been detected in experimental models of brain
ischemia as well in patients with acute stroke.3,4 Moreover,
increased levels of proinflammatory cytokines are related to a
greater extent of cerebral infarct and poorer clinical outcome
in patients with ischemic stroke.4 – 6
Ischemic tissue damage can be reduced in experimental
models with a variety of anti-inflammatory agents including
antibodies against adhesion molecules, neutrophil depletants,
inhibitors of proinflammatory cytokines, and anti-inflammatory
cytokines.7–10 Interleukin (IL)-10 and IL-4 are anti-inflammatory
molecules, mainly secreted by lymphocytes and monocytes/
macrophages, that block proinflammatory actions.11 IL-10 and
IL-4 may provide a negative feedback mechanism to limit
production of proinflammatory cytokines in ischemic stroke.
Administration of IL-108,10 or gene transfer9 in experimental
models of focal brain ischemia reduces infarct volume, suggest-
ing that it may have neuroprotective effects.8 –10 In patients with
acute stroke, a transient increase in IL-10 concentrations in
plasma, cerebrospinal fluid (CSF), and blood mononuclear cells
have been detected.12–14 Moreover, low levels of IL-10 have
been associated with an unstable clinical course in patients with
angina.15 Therefore, in this prospective study we evaluated
whether plasma concentrations of anti-inflammatory cytokines
(IL-10 and IL-4) are associated with early worsening of neuro-
logical symptoms in patients with acute ischemic stroke.
Methods
From a cohort of 249 consecutive patients with first-ever acute
ischemic stroke admitted within 24 hours of the onset of symptoms

Received April 17, 2002; revision received September 25, 2002; accepted September 27, 2002.
From the Hospital Clínic (N.V., A.C.), Clinical Institute of Nervous System Diseases, Instituto Investigaciones Biomédicas August Pi i Sunyer,
Barcelona; Hospital Clínic Universitario (J.C.), Santiago de Compostela; Hospital Universitario Doctor Josep Trueta (A.D.), Girona; Centre Estudis
Epidemiològics sobre la SIDA de Catalunya (A.E.), University Hospital Germans Trías i Pujol, Badalona; and Department of Pharmacology and
Toxicology (A.M.P.); Instituto Investigaciones Biomédicas Consejo Superior Investigaciones Cientı́ficas, Barcelona, Spain.
Correspondence to Ángel Chamorro, MD, Clinical Institute of Nervous System Diseases, IDIBAPS, Hospital Clínic, Villaroel 170, 08036 Barcelona,
Spain. E-mail chamorro@medicina.ub.es
© 2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000057976.53301.69

671
 672 Stroke March 2003

in a prospective investigation evaluating factors related to stroke TABLE 1. Main Characteristics of Study Population
deterioration, a group of 231 patients who had available stored
plasma samples were evaluated in the present secondary analysis. To Neurological Stable
avoid the confounding effect on inflammatory markers, subjects with Worsening Course
inflammatory or infectious diseases, cancer, hematological diseases, (n⫽83) (n⫽148)
or severe renal or liver failure were not included in the study. The Male, n (%) 9 (59) 83 (56.1)
protocol was approved by the local Ethics Committee, and the
methodology was described previously.1,6 Briefly, patients were Age, y 8.5 (8.6) 68.2 (10.3)
admitted to neurological wards and managed according to evidence- Admission delay, h*** 0.2 (6.2) 7.6 (5.3)
based stroke guidelines. Thrombolytics, hemodilution, corticoste- Admission CSS 0.2 (1.9) 5.6 (2.5)
roids, or nimodipine were not permitted. Antiplatelet drugs were
used in atherothrombotic and lacunar infarcts and anticoagulants in SBP, mm Hg 60 (26.6) 160.9 (28.2)
suspected cardioembolic infarcts when cranial CT scan and clinical DBP, mm Hg 1.7 (16.8) 92.1 (15.6)
examination did not suggest a large cerebral lesion. Stroke subtype Serum glucose, mg/dL* 29.8 (54.4) 156.1 (58.9)
was classified according to TOAST definitions.16 Stroke severity
was scored on admission and after 48 hours by the same neurologist Body temperature, °C* 7.8 (0.6) 36.8 (0.6)
using the Canadian Stroke Scale (CSS).17 The CSS measures level of Fibrinogen, mg/dL 28.7 (135.5) 419.7 (105.2)
consciousness; aphasia; orientation; facial paresis; and power in arm,
Leukocyte count, ⫻109/L 0.9 (1.6) 7.5 (2.1)
hand, and leg on a score from 1.5 (maximum deficit) to 10 (absence
of deficit). Stroke with neurological deterioration was diagnosed Early CT signs* 4 (89.2) 71 (48)
when the CSS score dropped at least 1 point in the second Infarct volume on day 4–7, cc* 63.7 (54.1) 15.7 (18.3)
neurological examination.1,6 We used this cutoff value because a
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decrease in 1 point or an increase in 1 point in the CSS between the
first 24 and 48 hours after acute stroke is clinically relevant in terms
of 30-day mortality and disability using the Barthel Index.18 Patients
whose condition worsened exclusively in the area of orientation or
who remained stable or improved in the same period were classified
as nonworsening.1 On admission, body temperature and blood
pressure were recorded. Then, chemistry, basic hematology, chest
X-rays, electrocardiography, and non-enhanced brain CT scan were
performed. Early CT signs of infarction on admission were assessed
in all instances by a neuroradiologist blinded to clinical and
laboratory data. Between days 4 and 7 after clinical onset a second
nonenhanced brain CT scan was performed to calculate infarct
volume and to classify the final infarct subtype and topography.
Methods to calculate infarct volume and infarct topography defini-
tions were previously reported.6,19
For cytokine determination, blood samples of patients were
collected on admission in tubes with potassium edetate, centrifuged
at 3000g for 5 minutes, and immediately frozen and stored until
analysis (5 to 7 years at ⫺80°). Mean admission delay from stroke
onset was 8.2⫾5.7 hours (range⫽1.5 to 23 hours). Samples were
collected within 12 hours in 80% of patients and within 6 hours in
50%. Samples were also obtained in 43 patients admitted without
neurological disorders (29 men and 21 women; mean age 56⫾17
years). Plasma concentrations of IL-10 and IL-4 were measured with
a commercially available quantitative immunoassay (Quantikine)
obtained from R&D Systems. The minimum detectable doses for
human IL-10 and IL-4 provided by the manufacturer were 0.5 and 10
pg/mL, respectively. Cytokine determinations were done blinded to
clinical and radiological data.
For statistical analyses, the ␹2 test, the Student t test, and the
Mann-Whitney test were used as appropriate. Stroke deterioration
was assessed by stepwise logistic regression analysis entering into
the model all variables with probability value ⱕ0.10 on univariate
testing, which included IL-10, body temperature, fasting serum
glucose, fibrinogen, total leukocyte count, baseline CSS, admission
delay, and presence of early infarct signs on brain CT scan.
Continuous variables without normal distribution were analyzed
after their logarithmic transformation. Cutoff values for plasma
IL-10 were calculated as described by Robert et al20 given the
different distribution of IL-10 according to outcome groups. Odds
ratios and 95% confidence intervals were calculated from ␤ coeffi-
cients and their SEs. A probability value ⬍0.05 was established as
statistically significant.
Results
In 69 patients (29.9%), no changes were detected in the CSS
score. Seventy-nine patients (34.2%) improved their CSS
score, as follows: 54 (23.4%) by 1 point, 21 (9.1%) by 2
Infarct topography†
Cortical 32 (28.6) 45 (71.4)
Subcortical 21 (21) 78 (79)
Stroke etiology
Cardioembolic 30 (36.1) 46 (31.1)
Lacunar 7 (8.4) 26 (17.6)
Atherosclerotic 35 (42.2) 49 (33.1)
Undetermined 11 (13.3) 27 (18.2)
Numbers represent mean (SD) or percentage as appropriate. CSS indicates
Canadian Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood
pressure.
*P⬍0.001; ***P⬍0.05.
†Restricted to 176 patients with cortical or subcortical lesions.
points, and 4 by ⱖ3 points. Eighty-three (35.9%) patients
worsened their CSS score within the first 48 hours after stroke
onset, as follows: 41 (17.7%) by 1 point, 24 (10.4%) by 2
points, and 18 (7.8%) by ⱖ3 points. The main characteristics
of the studied population are shown in Table 1. Patients with
early stroke deterioration had a slightly longer delay to
hospital admission and higher baseline glucose, fibrinogen,
and body temperature compared with patients with a stable
clinical course. However, the two clinical groups disclosed
similar stroke subtypes and degree of neurological impair-
ment on admission.
Although plasma concentrations of IL-10 were not differ-
ent between control group (5.9⫾1.6 pg/mL) and stroke
patients (6.0⫾2.2 pg/mL), IL-10 levels were significantly
higher in those stroke patients who remained stable or
improved during the first 48 hours than in patients with
clinical deterioration (6.2⫾2.2 pg/mL versus 5.6⫾2.0 pg/mL;
P⬍0.05) (Figure 1). However, concentrations of IL-4 were
similar in both outcome groups (21.2⫾5.3 versus 20.3⫾5.5
pg/mL).
As shown in Table 2, the following variables remained on
multivariate analysis independently associated with clinical
worsening: IL-10 ⬍6 pg/mL in plasma, body temperature,
admission CSS, and serum glucose. Overall, levels of IL-10
were similar in patients with cortical and subcortical infarcts
(Table 3). However, significantly lower IL-10 levels were

Figure 1. IL-10 plasma levels (pg/mL) and neurological worsen-
ing according to stroke topography. Patients with neurological
worsening had significantly reduced levels of IL-10 in plasma
compared with patients without neurological worsening only in
subcortical infarcts n⫽99) (P⬍0.01) but not in cortical infarcts
(n⫽77).
Downloaded from http://stroke.ahajournals.org/ by guest on January 23, 2018
detected in patients with subcortical infarcts who deteriorated
compared with patients with subcortical infarcts who re-
mained stable or improved (5.3⫾1.0 versus 6.1⫾0.5 pg/mL;
P⬍0.05). Behavior of IL-10 levels was similar in cortical
infarcts, but differences did not achieve statistical signifi-
cance. In addition, similar levels of IL-4 were found in
patients with and without worsening in both cortical and
subcortical infarcts.
Table 3 also shows that levels of IL-10 were not different
between stroke subtypes. Figure 2 represents IL-10 levels and
stroke progression in relation to stroke subtypes. Levels of
IL-10 were lower in patients with deterioration in all sub-
groups. However, significant differences between plasma
IL-10 levels and stroke worsening were only detected in
patients with lacunar infarcts. Those patients with lacunar
infarcts that deteriorated had lower levels of IL-10 compared
with those with infarcts that remained stable or improved
(5.3⫾1.2 versus 6.5⫾0.9 pg/mL; P⬍0.01). No differences in
levels of IL-4 were found in patients with and without
worsening according to stroke subtypes.
Finally, in 61 patients with nonlacunar infarcts and sub-
cortical topography, small but significant lower plasma con-
centrations of IL-10 were detected in subjects with early
neurological deterioration (n⫽16) compared with those with
stable or improved course (n⫽45) (5.2⫾2.4 versus 5.8⫾2.0
pg/mL; P⫽0.05).
Discussion
IL-10 is one of the anti-inflammatory cytokines that may
regulate the complex network of reactions that occur in acute
TABLE 2. Factors Associated to Neurological Deterioration
Variable ␤ SE OR
IL-10 ⬍6 pg/mL 1.17 0.52 3.2
Body temperature (°C) 3.39 0.59 29.9
Canadian Stroke Scale 0.44 0.13 1.5
Serum glucose (mg/dL) 0.02 0.005 1.02
Other variables included in the model were age, sex, total leukocyte count,
admission delay, and presence of early infarct signs on brain CT scan.
Vila et al Interleukin-10 in Deteriorating Stroke 673
TABLE. 3. Levels of Interleukin-10 (IL-10) According to Infarct
Topography and Stroke Subtypes
No. IL-10 P
Infarct topography NS
Cortical 77 6.1 (2.1)
Subcortical 99 5.9 (2.3)
Stroke subtypes NS
Cardioembolic 76 5.9 (1.9)
Lacunar 33 6.2 (2.5)
Atherosclerotic 84 5.7 (2.2)
Undetermined 38 6.3 (2.2)
IL-10 levels are expressed as mean (SD) in pg/mL.
cerebral ischemia. In the present study, lower levels of IL-10
in plasma measured within 24 hours from stroke onset were
significantly associated with early deterioration of neurolog-
ical symptoms in patients with ischemic stroke. This relation
was independent of other well-known predictors of clinical
worsening such as clinical severity on admission, hypergly-
cemia, and early CT signs of infarction or hyperthermia. In
humans, increased concentrations of IL-10 are found shortly
after stroke onset in CSF and plasma, reaching the highest
level between days 3 and 7.12,14 In addition, patients with
acute stroke have increased IL-10 secreting monocytes in
peripheral blood compared with controls.13 Contrarily, we did
not find differences in IL-4 levels in patients with or without
neurological deterioration. These results suggest that IL-4,
despite its inhibitory capacity on proinflammatory cytokines,
is less important than IL-10 in acute ischemic stroke. In
agreement with this finding, Pelidou et al13 also failed to
demonstrate differences in IL-4 –secreting monocytes in pa-
tients with stroke compared with controls.
The present study also shows an association between lower
levels of IL-10 with neurological deterioration in subcortical
and lacunar infarcts. These findings give further support to
previous observations linking cytokines with early motor
impairment in patients with lacunar stroke.6 Previously, we
had reported that lacunar stroke might result from genetic
(95% CI)
(1.1–8.9) Figure 2. IL-10 plasma levels (pg/mL) and neurological worsen-
ing according to stroke etiology. Patients with neurological
(9.5–94.6)
worsening had significant lower concentrations of IL-10 in
(1.2–2.0) plasma than patients without neurological worsening only in the
(1.01–1.03) subgroup of lacunar infarcts (P⬍0.01). LAC indicates lacunar
infarct (n⫽33); ATH, atherosclerotic infarct (n⫽84); CEMB, car-
dioembolic infarct (n⫽76); and IUC, infarct of undetermined
cause (n⫽38).
 674 Stroke March 2003
susceptibility to inflammation-mediated damage in concert
with atherosclerotic risk factors.21 A relationship between
proinflammatory cytokines,22 excitatory amino acids,23 and
neurological worsening in lacunar infarcts were also found.
Increase in infarct volume, as demonstrated with diffusion
MRI, has been proposed as the main cause of neurological
deterioration in lacunar infarcts,24 as the likely result of
delayed excitotoxic and inflammatory neuronal death. Thus,
if these findings are validated, patients with lacunar infarcts
would represent ideal candidates to participate in clinical
trials of neuroprotection using anti-inflammatory drugs or
inhibitors of excitotoxicity. In addition, these biological
markers might be useful in the future to detect those patients
with lacunar stroke at risk of motor deterioration, especially
when this stroke subtype is the major cause of progressive
motor deficits.25
A direct implication of IL-10 in the pathophysiology of
ischemic neurological deterioration cannot be extrapolated
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from our results as the levels of anti-inflammatory cytokines
were not determined exactly at the moment of neurological
deterioration. As well, these results must be interpreted with
caution given that plasma concentrations of cytokines do not
necessarily reflect the activity of cytokines within the central
nervous system. Also, we recognize that we have not ex-
plored the potential effect of cytokines on late worsening.
However, a body of experimental evidence8 –10, 15, 26 –27 impli-
cates this anti-inflammatory cytokine in the downregulation
of deleterious actions of proinflammatory cytokines. IL-10
inhibits monocyte/macrophage synthesis of IL-6 and tumor
necrosis factor-␣ by blocking gene transcription and down-
regulates release of intercellular adhesion molecule-1
(ICAM-1) and matrix metalloproteinase (MMP).27–29 Ani-
mals deficient in IL-10 gene exhibited larger infarcts; in-
creased neutrophil infiltration; and raised levels of tumor
necrosis factor-␣, ICAM-1, MMP-2, and MMP-9.27–29 Addi-
tionally, IL-10 may have neuroprotective activities resulting
from other non–anti-inflammatory actions. This cytokine
regulates apoptotic proteins detected in CSF after human
brain ischemia,30 modulates neuronal vulnerability to excito-
toxic ischemic damage,26 and inhibits the inducible form of
NO synthase (iNOS).31 IL-10 – deficient mice also developed
increased levels of iNOS compared with the wild type.26,31
Levels of excitotoxic amino acids,1 NO products,32 proin-
flammatory cytokines,3– 6 and MMP33 in plasma or in CSF
have also been related with clinical outcome in human stroke.
Contrarily, in hemorrhagic stroke it seems that anti-
inflammatory cytokines do not play the same role as in
cerebral ischemia.34 Recently, levels of IL-10 and IL-4 were
found to be unrelated to clinical outcome in patients with
cerebral hemorrhages.34
If levels of IL-10 are markers of neurological deterioration,
an important issue is to determine why stroke patients may
exhibit a different anti-inflammatory profile. Recently, sev-
eral functional IL-10 gene polymorphisms have been de-
scribed in the population.35 Those patients with a specific
IL-10 gene polymorphism, that determine low levels of
IL-10, may be at risk to develop unstable vascular syndromes.
A recent work demonstrated a relationship between low
levels of IL-10 in plasma and the subsequent risk of stroke
and also with mortality when the stroke occurs.36 If this
association is confirmed, those subjects genetically predis-
posed might be treated with exogenous IL-10 to prevent
stroke and clinical worsening in acute stroke. Recombinant
human IL-10 administered by intravenous injection in healthy
volunteers is well tolerated and safe.37 Thus, in addition to
potential indications of IL-10 in chronic inflammatory dis-
eases under current evaluation, this study gives additional
evidence that IL-10 may have a potential role as neuropro-
tectant in acute vascular syndromes.
Acknowledgments
We thank Jordi Casabona (CEESCAT, University Hospital Germans
Trías i Pujol, Badalona, Spain) for statistical data management.
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 Levels of Anti-Inflammatory Cytokines and Neurological Worsening in Acute Ischemic
Stroke
Nicolás Vila, José Castillo, Antonio Dávalos, Anna Esteve, Anna M. Planas and Ángel
Chamorro
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Stroke. 2003;34:671-675; originally published online February 20, 2003;

doi: 10.1161/01.STR.0000057976.53301.69
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