Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production.

BACKGROUND: As critical mediators of local and systemic inflammatory responses, cytokines are produced in the brain following ischaemic stroke. Some have been detected in the circulation of stroke patients, but their role and source is unclear. Focusing primarily on interleukin(IL)-1-related mechanisms, we serially measured plasma inflammatory markers, and the production of cytokines by whole blood, from 36 patients recruited within 12 h and followed up to 1 year after acute ischaemic stroke (AIS). RESULTS: Admission plasma IL-1 receptor antagonist (IL-1ra) concentration was elevated, relative to age-, sex-, and atherosclerosis-matched controls. IL-1beta, soluble IL-1 receptor type II, tumour necrosis factor (TNF)-alpha, TNF-RII, IL-10 and leptin concentrations did not significantly differ from controls, but peak soluble TNF receptor type I (sTNF-RI) in the first week correlated strongly with computed tomography infarct volume at 5-7 days, mRS and BI at 3 and 12 months. Neopterin was raised in patients at 5-7 d, relative to controls, and in subjects with significant atherosclerosis. Spontaneous IL-1beta, TNF-alpha and IL-6 gene and protein expression by blood cells was minimal, and induction of these cytokines by lipopolysaccharide (LPS) was significantly lower in patients than in controls during the first week. Minimum LPS-induced cytokine production correlated strongly with mRS and BI, and also with plasma cortisol. CONCLUSION: Absence of spontaneous whole blood gene activation or cytokine production suggests that peripheral blood cells are not the source of cytokines measured in plasma after AIS. Increased plasma IL-1ra within 12 h of AIS onset, the relationship between sTNF-RI and stroke severity, and suppressed cytokine induction suggests early activation of endogenous immunosuppressive mechanisms after AIS.

Reliability of a semi-automated technique of cerebral infarct volume measurement with CT.

BACKGROUND: A reliable method of infarct volume measurement is needed if infarct volume is to be used as an outcome measure in clinical stroke trials. We investigated the reproducibility of a semi-automated method of computed tomography (CT) infarct volume measurement amongst three stroke research fellows with no formal neuroradiology training and two consultant neuroradiologists. METHODS: CT brain scans for volumetric analysis were performed at 5 to 7 days in 34 patients with acute ischaemic stroke, of which 28 scans showed visible recent infarction. Five observers independently traced the infarct boundary on digitised images with a cursor. Volumetric analysis incorporated pixel thresholding with preset Hounsfield thresholds. One of the observers repeated the analyses on 21 of the scans in order to assess intraobserver variation. RESULTS: Median infarct volume was 35.7 cm3 (range 0.2-318 cm3). The closest limits of observed agreement (mean +/- 1.96 SD) between pairs of observers were between a research fellow and neuroradiologist (-29 to 21 cm3). The widest limits of agreement were between a different research fellow and the same neuroradiologist (-39.1 to 41.4 cm3). The limits of agreement between infarct volumes measured on two separate occasions by one of the research fellows were -7 to 8 cm3. CONCLUSIONS: Intraobserver reliability of CT infarct volume measurements performed by a stroke research fellow was superior to interobserver reliability between any pair of observers. The wide limits of agreement between different observers using manual tracing may not be acceptable in multicentre trials of acute ischaemic stroke treatment, but volume measurement by a single observer appears to be more reliable.

Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome.

BACKGROUND: Cerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome. METHODS: Thirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume. RESULTS: Peak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures. CONCLUSIONS: These data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome.

An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis.

Central nervous system and peripheral inflammation is important in the responses to ischaemic stroke, and may also predispose to its development. We aimed to identify (1) the extent to which a peripheral inflammatory response is activated in patients following acute stroke, and (2) whether there was evidence for preexisting peripheral inflammation. Thirty-six patients with ischaemic stroke within 12 h of onset of symptoms had serial blood samples taken up to 12 months for analysis of markers of inflammation. Thirty-six control subjects, individually matched for age, sex and degree of atherosclerosis, were also studied. Median C-reactive protein (CRP) was elevated, relative to controls (2.08 mg/l), from admission (4.31 mg/l) (p