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(Stroke. 2000;31:2325.)
© 2000 American Heart Association, Inc.

Original Contributions

Proinflammatory Cytokines and Early Neurological Worsening in Ischemic Stroke

Nicolás Vila, MD; José Castillo, MD; Antonio Dávalos, MD Ángel Chamorro, MD

From the Institut Clínic Malalties Sistema Nerviós, IDIBAPS, Hospital Clínic, Barcelona (N.V., A.C.); Neurology Service, Hospital Clínico Universitario, Santiago de Compostela (J.C.); and Neurology Service, Hospital Universitario Doctor Josep Trueta, Girona, Spain (A.D.).

Correspondence to Ángel Chamorro, MD, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain. E-mail chamorro{at}medicina.ub.es

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The mechanisms for clinical deterioration in patients with ischemic stroke are not completely understood. Several proinflammatory cytokines are released early after the onset of brain ischemia, but it is unknown whether inflammation predisposes to neurological deterioration. We assessed the implication of interleukin (IL)-6 and tumor necrosis factor (TNF)- in early neurological worsening in ischemic stroke.

Methods—Two hundred thirty-one patients consecutively admitted with first-ever ischemic cerebral infarction within the first 24 hours from onset were included. Neurological worsening was defined when the Canadian Stroke Scale (CSS) score fell at least 1 point during the first 48 hours after admission. IL-6 and TNF- were determined in plasma and cerebrospinal fluid (CSF; n=81) obtained on admission.

Results—Eighty-three patients (35.9%) deteriorated within the first 48 hours. IL-6 in plasma (>21.5 pg/mL; OR 37.7, CI 11.9 to 118.8) or in CSF (>6.3 pg/mL; OR 13.1, CI 2.2 to 77.3) were independent factors for early clinical worsening, with multiple logistic regression. The association was statistically significant in all ischemic stroke subtypes as well as in subjects with cortical or subcortical infarctions. IL-6 in plasma was highly correlated with body temperature, glucose, fibrinogen, and infarct volume. CSF and plasma concentrations of TNF- were also higher in patients who deteriorated, but the differences observed did not remain significant on multivariate analysis.

Conclusions—In addition to participating in the acute-phase response that follows focal cerebral ischemia, IL-6 levels on admission are associated with early clinical deterioration. The association between IL-6 and early neurological worsening prevails without regard to the initial size, topography, or mechanism of the ischemic infarction.

Key Words: interleukins • prognosis • stroke • tumor necrosis factor

	Introduction

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In 25% to 40% of patients with ischemic stroke, neurological symptoms progress during the initial hours. Early clinical deterioration results in increased mortality and functional disability.^{1 2 3} The basic mechanisms underlying early clinical worsening in patients with ischemic stroke are not well understood. Although several clinical, radiological, and biochemical factors have been associated with early neurological deterioration, most of them have a low predictor value.^{1 2 3 4} Release of excitatory amino acids and oxygen free radicals, iron accumulation, and nitric oxide production or apoptosis have been suggested as mechanisms for clinical worsening.^{5 6}

Over the past few years, a body of evidence has stressed the role of inflammation in the pathophysiology of acute brain ischemia.⁷ Most inflammatory reactions are mediated by cytokines, small glycoproteins expressed by many cell types in response to acute cerebral ischemia. Cytokine release results in upregulation of adhesion molecules, recruitment and activation of leukocytes, promotion of leukocyte-endothelium interaction, and conversion of the local endothelium to a prothrombotic state.⁷ Increases of proinflammatory cytokines (interleukin [IL]-1, tumor necrosis factor [TNF]-, and IL-6) have been detected in the ischemic cortex 1 hour after middle cerebral artery (MCA) occlusion in experimental models of brain ischemia.⁸ Moreover, intraventricular injection of IL-1 and TNF- enlarges infarct volume and brain edema after MCA occlusion in rats, whereas the injection of antibodies against IL-1 and TNF- reduces brain injury.^{8 9} Several studies have reported elevations of proinflammatory cytokines in peripheral blood^{10 11 12 13 14 15} as well as in cerebrospinal fluid (CSF) in patients with ischemic stroke.^{13 16} In this study we analyzed the relationship between proinflammatory cytokines in plasma and CSF and the early worsening of neurological symptoms in patients with acute cerebral ischemia.

	Subjects and Methods

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A group of 231 patients with first-ever acute ischemic stroke had blood and CSF (n=81) samples collected within 24 hours from the onset of symptoms to evaluate biochemical markers of stroke progression. These patients were selected from a larger cohort of 249 patients admitted consecutively between October 1992 to December 1996 in a prospective clinical investigation conducted to analyze clinical, biochemical, and radiological factors related to stroke progression. Only patients with stored plasma samples available were evaluated in the present study. Therefore, the selection of this cohort did not depend on stroke outcome, and it was done before cytokine determinations. To avoid the confounding effect on inflammatory markers of clinical conditions that can be associated with ischemic stroke, subjects with inflammatory or infectious diseases, cancer, hematological diseases or severe renal or liver failure, or current daily treatment with anti-inflammatory drugs were not included in the study. The protocol was approved by the local Ethics Committee, as described elsewhere.^{4 5} Informed consent was given by patients themselves or by relatives as legally required. Patients were admitted to neurological wards and attended to by specialized medical and nursing staff. Blood pressure and temperature measurements, blood chemistry, basic hematology, chest X-rays, electrocardiography, and nonenhanced brain CT scan were performed for all patients on hospital arrival. Thrombolytics, hemodilution, corticosteroids, or nimodipine were not permitted. Antiplatelet drugs were used in atherothrombotic and lacunar infarcts and anticoagulants in suspected cardioembolic infarcts when cranial CT scan and clinical examination did not suggest a large cerebral lesion.^{4 5} The type of stroke was classified according TOAST definitions.¹⁷ The severity of stroke was scored on admission and after 48 hours by the same neurologist, using the Canadian Stroke Scale (CSS).¹⁸ The CSS measures level of consciousness, aphasia, orientation, facial paresis, and power in arm, hand, and leg on a score from 1.5 (maximum deficit) to 10 (absence of deficit).¹⁸ Early neurological worsening was diagnosed when the CSS score dropped at least 1 point in the second neurological examination.^{4 5} Patients whose condition worsened exclusively in the area of orientation or who remained stable or improved in the same period were classified as nonworsening.⁴ Brain CT signs of infarction on admission, such as focal hypodensity, obscuration of the lenticular nucleus, obscuration of the cortex, midline shift, and hyperdensity of intracranial arteries were assessed in all instances by a neuroradiologist blinded to the clinical and laboratory data. On days 4 to 7 after clinical onset, a second nonenhanced brain CT scan was performed to assess the volume (in cubic centimeters) of the infarction, according to the formula 0.5xaxbxc, where a and b represented the largest perpendicular diameters measured on CT scan and c the slice thickness).^{4 5}

Blood for chemistry, basic hematology, and cytokine determination was drawn at the same time on emergency admission. For cytokines, blood and CSF samples were collected in tubes with potassium edetate, centrifuged at 3000g for 5 minutes and 2000g for 10 minutes, respectively, and immediately frozen and stored until analysis. IL-6 and TNF- concentrations in plasma and CSF samples were measured with commercially available quantitative sandwich enzyme-linked immunoadsorbent assay (Quantikine) kits obtained from R&D Systems. Cytokine determinations were performed blinded to clinical and radiological data.

For statistical analysis, the ² test, Student t test, or Mann-Whitney test were used as appropriate. Because cytokine levels were not normally distributed, the Spearman correlation coefficient was used to analyze the association between cytokines and temperature, fibrinogen, glucose, and infarct volume. Neurological worsening was assessed by forward stepwise logistic regression analysis based on the maximum likelihood ratio. Factors available on admission with a value of P0.1 on univariate testing were included. These factors were plasma IL-6, plasma TNF-, body temperature, fasting serum glucose, fibrinogen, total leukocyte count, admission delay, and presence of early infarct signs on brain CT scan. Age and baseline CSS score were forced into the model. Infarct volume and stroke subtypes were not included into the regression models because they were not available on admission. Continuous variables without normal distribution were analyzed after their logarithmic transformation. Another regression model was performed, including the same variables but with IL-6 and TNF- in CSF. Cutoff values for IL-6 with the highest sensitivity and specificity in plasma and CSF were calculated as described by Roberts et al,¹⁹ given the different distribution of IL-6 according to outcome groups. These values were 21.5 pg/mL for IL-6 in plasma and 6.3 pg/mL for IL-6 in CSF. ORs and 95% CIs were calculated from beta coefficients and their standard errors. A value of P<0.05 was established as statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Eighty-three patients (35.9%) worsened within the first 48 hours after stroke onset: 41 (17.7%) worsened by 1 point, 24 (10.4%) by 2 points, and 18 (7.8%) by 3 points. In 69 patients (29.9%), no changes were detected in the CSS score. Seventy-nine patients (34.2%) improved their CSS score within the first 48 hours: 54 (23.4%) improved by 1 point, 21 (9.1%) by 2 points, and 4 by 3 points. The main characteristics of the studied population are shown in Table 1. It can be seen that compared with patients with a stable clinical course, those who experienced early neurological worsening had a slightly longer delay to hospital admission and a stronger acute-phase response that was reflected by higher baseline glucose, fibrinogen, and body temperature. However, the 2 clinical groups defined according to clinical course disclosed similar stroke subtypes and degrees of neurological impairment on admission.

View this table: [in this window] [in a new window]   Table 1. Main Characteristics of Patients With and Without Early Neurological Worsening

As illustrated in Table 2, plasma and CSF concentrations of IL-6 and TNF- were significantly higher in patients with clinical deterioration than in patients who remained stable or improved during the first 48 hours. A highly significant correlation was found between plasma and CSF concentrations of IL-6 (Spearman coefficient 0.89, P<0.0001) and between plasma concentrations of IL-6 and TNF- (Spearman coefficient 0.86, P<0.0001). Plasma IL-6 was positively correlated with body temperature (Spearman coefficient 0.53, P<0.001), serum glucose (Spearman coefficient 0.46, P<0.001), and fibrinogen (Spearman coefficient 0.38, P<0.01). Finally, the infarct volume on days 4 to 7 was also highly correlated with admission plasma levels of IL-6 (Spearman coefficient 0.56, P<0.001). The sensitivity, specificity, and positive predictive value on clinical deterioration were 92%, 83%, and 85%, respectively, for IL-6 >21.5 pg/mL in plasma, and 84%, 81%, and 76%, respectively, for IL-6 >6.3 pg/mL in CSF.

View this table: [in this window] [in a new window]   Table 2. Plasma and CSF Levels of IL-6 and TNF in the Study Population

As shown in Table 3, the variables that on multivariate analysis remained independently associated with early clinical deterioration included IL-6 >21.5 pg/mL in plasma or IL-6 >6.3 pg/mL in CSF, temperature, serum glucose, admission CSS score, and presence of early infarct signs on brain CT scan. Although CSF and plasma concentrations of TNF- were significantly higher in patients with neurological deterioration, differences did not remain statistically significant on multivariate analysis.

View this table: [in this window] [in a new window]   Table 3. Factors Associated With Early Neurological Worsening

Patients with cortical infarcts had significantly higher levels of IL-6 than those with subcortical infarcts in plasma (20.9±16.3 pg/mL versus 14.8±13.1 pg/mL, P<0.001) and CSF (21.4±22.8 pg/mL versus 7.9±12.0 pg/mL, P<0.001). Significantly lower plasma and CSF levels of IL-6 were found in patients with lacunar infarcts (9.6±9.3 pg/mL, P<0.01 and 5.1±9.8 pg/mL, P<0.01) compared with atherosclerotic infarcts (24.5±14.2 pg/mL and 21.9±22.4 pg/mL), cardioembolic infarcts (18.0±16.4 pg/mL and 19.2±22.9 pg/mL), and infarcts of undetermined cause (18.9±18.4 pg/mL and 16.3±19.4 pg/mL). Because cortical infarcts were larger than subcortical infarcts and lacunar infarcts were smaller than infarcts of other etiologies, comparisons in plasma levels of IL-6 between patients with and without neurological worsening were analyzed separately. As indicated in Figures 1 and 2, the association between higher levels of IL-6 and clinical deterioration in both cortical and subcortical infarcts and in all stroke subtypes was confirmed.

View larger version (38K): [in this window] [in a new window]   Figure 1. Patients with clinical deterioration had significantly increased levels of IL-6 in plasma compared with patients without clinical deterioration in cortical (n=77, P<0.01) and subcortical (n=99, P<0.01) infarcts.

View larger version (37K): [in this window] [in a new window]   Figure 2. Patients with clinical worsening had significantly higher concentrations of IL-6 in plasma than patients without clinical worsening in all stroke subtypes (P<0.01). LAC indicates lacunar infarct (n=33); ATH, atherosclerotic infarct (n=84); CEMB, cardioembolic infarct (n=76); and IUC, infarct of undetermined cause (n=38).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found higher baseline levels of IL-6 in plasma and CSF in patients with acute ischemic stroke and early neurological deterioration compared with patients who remained clinically stable or improved within the first 48 hours after clinical onset. Overall, plasma and CSF levels of IL-6 were lowest in patients with lacunar stroke. However, the independent association between IL-6 and the risk of early clinical worsening was equally observed in patients with lacunar stroke, cardioembolism, atherothrombotic stroke, or stroke of undetermined cause. Although TNF- was also higher in patients with early clinical worsening, the relationship was confounded by other factors, because it did not remain statistically significant on multivariate testing.

There is debate over whether the release of proinflammatory cytokines after focal cerebral ischemia indicates a pathogenic step leading to tissue necrosis or simply reflects the amount of ischemic brain injury, because the highest concentrations of IL-6 are usually found in patients with large infarctions.^{11 13} In the present study, we confirmed the direct correlation between IL-6 and the bulk of tissue loss. In agreement with this observation, we also found a positive association between IL-6 and the strength of the acute-phase response, which was recently described²⁰ as a sensitive predictor of poor short-term clinical outcome. Nevertheless, the direct relationship between IL-6 and the risk of early neurological deterioration remained significant after adjustment for other prognostic markers, such as the severity of the stroke at clinical onset or the magnitude of the acute-phase response at hospital entry. Taken together, these findings supported the observation that an increased level of IL-6 at hospital entry equally reflected the extent of tissue damage at the time of blood and CSF sampling and the risk of further tissue disruption and accompanying clinical worsening. As previously noted, the relationship was applicable to patients with any of the stroke subtypes that were assessed.

Previous studies showed higher levels of IL-6 in patients with cortical infarctions than in patients with subcortical lesions,^{13 14} including lacunar infarctions.¹⁰ Tarkowski et al¹³ suggest that this finding indicates a different pattern of cytokine release between gray matter and white matter (eg, glial cells versus neurons) in response to ischemia. Other authors suggest,¹⁰ to the contrary, that the magnitude of the IL-6 response appears more sensitive to the extent of the infarction than to the mechanism of the stroke. Our results gave support to the relevance of the extent of tissue damage at the time of cytokine determination, because the greater concentration of IL-6 encountered in patients with cortical infarctions disappeared after adjustment for the larger size of these lesions compared with subcortical infarctions. Further support for the influence of the extent of tissue damage was derived from the lowest IL-6 values observed in the group of patients with lacunar stroke. Despite the unchallenging influence of tissue destruction on IL-6 release, a new finding of our study was that greater IL-6 increments predicted a higher risk of early clinical worsening, irrespective of the initial size, topography, or mechanism of the infarction.

A few methodological aspects of the study deserve attention. First, patients with early clinical deterioration were admitted slightly later than patients with stable or rapidly improving clinical course. Because the release of IL-6 is time dependent,^{11 13} we controlled for this confounding effect by including in the predictor model of early neurological worsening the delay to blood sampling. Therefore, it cannot be argued that higher IL-6 levels in patients with clinical deterioration responded to the longer time interval between stroke onset and blood and CSF collection. Second, we did not perform at hospital admission appropriate serologies that might have detected the presence of asymptomatic infections. Because recent infections have been associated with an increased risk of impending stroke and the release of cytokines,²¹ it is theoretically possible that our measurement of IL-6 was swayed by a history of recent infection. To partially control for such effect, we included in the analysis indirect markers of infections, such as body temperature and total leukocyte count on admission.

Although we did not measure cytokines at the time of symptom deterioration, our results may support that cytokine-mediated cerebral damage participates in the mechanisms that lead to neurological worsening. However, we recognize that we only partially evaluated the effects of the cytokine cascade on clinical deterioration. We did not evaluate the action of other important inflammatory or inhibitory cytokines that increase in the acute phase of cerebral ischemia, such as IL-1ß, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-10.¹⁶ For example, the release of IL-10, which inhibits TNF-, might be responsible for the lack of association between TNF- and neurological deterioration. Cytokines have been implicated in several mechanisms that may potentiate ischemic brain injury, including the release of the inducible form of nitric oxide synthase by astrocytes,²² ; the recruitment, activation, and adhesion to the endothelium of infiltrating leukocytes^{23 24} ; the promotion of a local procoagulant state²⁵ ; and the regulation of apoptotic programs.²⁶ Other deleterious actions of proinflammatory cytokines after focal brain ischemia include the initiation and potentiation of the acute-phase stress response²⁷ ; previous studies^{1 2 3 4 5} have demonstrated the independent contribution of this factors to clinical deterioration. As expected, we found a positive correlation between IL-6 levels in plasma with components of the acute-phase reaction, such as body temperature, serum glucose, and fibrinogen.

In conclusion, we demonstrated that early neurological worsening was associated with higher concentrations of IL-6 in plasma and CSF. The deleterious effect of IL-6 was present irrespective of the initial size, topography, and mechanism of the ischemic infarction. Therefore, development of new neuroprotective therapies targeted to modulate cytokine-induced inflammation could be a promising way to prevent early deterioration in acute ischemic stroke.

	Acknowledgments

 
The authors are grateful to Carlos Ascaso, Rosa Abellana, and Jaume Aguado for statistical advice.

Received May 9, 2000; revision received June 26, 2000; accepted June 26, 2000.

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