Comments, Opinions, and Reviews
Early Stroke: A Dynamic Process
Gudrun Boysen, MD, MDSc; Hanne Christensen, MD
I
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n the acutely infarcted brain, cytokines are released into
cerebrospinal fluid and blood. Interleukin (IL)-1␤, IL-6,
and tumor necrosis factor (TNF)-␣, among others, may
play a role in the acute increases in plasma adrenocorticotropic hormone, cortisol, epinephrine, norepinephrine, and
vasopressin.1– 6 Increases in cytokines and hormones may in
turn induce changes in other variables. When recorded on
admission in acute stroke patients, many variables have been
found to be associated with poor outcome in acute stroke.
Body temperature7 is one such variable, blood glucose
another,8 –18 and C-reactive protein (CRP)19 –22 and white
blood cell count (WBC)20,23 serum cortisol and ferritin24 are
further examples. Elevated plasma and cerebrospinal fluid
levels of glutamate, glycine,25 ferritin,26 and IL-627 were also
associated with deteriorating stroke.
It seems plausible that these variables generally are unaffected at stroke onset and then increase in the early hours after
onset, depending on the severity of the stroke. We found this
to be the case with temperature,28 which in a large series of
patients was normal when measured within 2 hours of stroke
onset, but which rose at 4 to 6 hours after stroke onset in
patients with severe neurological deficits. At 8 to 10 hours
after stroke onset, elevated temperature was associated with
poor outcome. This association arose several hours after onset
of severe stroke. Thus, the initial severity of the stroke
preceded the increase in temperature.
Many studies on blood glucose and stroke prognosis share
the same kind of problem. In most studies, blood glucose was
measured fairly late after stroke onset and may have changed
in the interval between onset of stroke and arrival at hospital.
Researchers are divided into 2 groups on this question: those
who maintain that elevated blood sugar is a stress response
and reflects the severity of the stroke8,15,18 and those who
believe that blood sugar is an independent predictor of poor
outcome.9 –14 The issue is complicated by the fact that diabetic
patients are reported to have worse outcome than nondiabetic
patients. The same is probably true for latent diabetics, who
already may have widespread vascular damage. The discussion concentrates on patients without diabetes with mildly
elevated blood glucose, which has been statistically associated with poor prognosis.
In such series of stroke patients, the timing of blood
glucose measurement was not always well specified. Most
often, measurements were performed within 12 to 24 hours
after stroke onset or even later. A severe stroke may cause
blood sugar to rise early after onset, thereby creating a “false”
association between elevated blood sugar and poor outcome.
An ongoing study in the United Kingdom29 randomizes
stroke patients with blood glucose levels ⬎7 mmol/L to
insulin treatment or placebo. This study may help to clarify
whether increased blood glucose is harmful or just an
epiphenomenon. Serial measurements of blood glucose in the
early hours after stroke onset are another way to elucidate the
question.
For the other variables claimed to be prognostic markers,
such as WBC and CRP, it also seems likely that early changes
occur in the interval between stroke onset and arrival at
hospital and blood sampling. Peripheral WBC measured
within 3 days of stroke onset was associated with poor
outcome.20,23 CRP was found to be a prognostic marker in
acute stroke by some investigators19,22 and not by others.21 In
the cited studies, blood samples were taken too late to
determine which came first—the stroke or the elevation of
WBC or CRP. Much more clinical research is needed to
evaluate the importance of these and other markers of stroke
outcome. Plasma ferritin,26 another acute-phase reactant, was
significantly elevated in patients with subsequent deteriorating stroke, and elevated ferritin was associated with poor
outcome.24 Increased body iron stores were thought to enhance the cytotoxic mechanisms in cerebral ischemia, but the
increased ferritin might also reflect an inflammatory reaction
to stroke.
A plausible explanation may be that many variables are
interrelated: it is likely that severe stroke generates a
metabolic as well as an inflammatory response. The
inflammatory response may induce fever mediated by
IL-1,30 induce systemic inflammation (eg, rise in CRP,
WBC, and acute-phase reactants primarily mediated by
IL-1, IL-6, and TNF), and enhance excitotoxicity.31,32 The
metabolic response may cause an increase in blood sugar,
cardiac arrhythmia,33 and a rise in troponins T and I.34 In
this hypothesis, all of these variables would be found to be
associated with severe stroke and unfavorable outcome; it
would only be meaningful to consider them in groups and
avoid including them individually in multivariate analysis,
because they primarily reflect the size of the inflammatory
and the metabolic reactions. Fever, aspiration, elevated
blood glucose, and other variables may contribute to
worsen the prognosis.
The anatomical brain lesion is usually not fully established before 12 to 24 hours or more after stroke onset.
Within this period neuroimaging by MRI, PET and
SPECT35–38 may demonstrate penumbral tissue potentially
Received April 12, 2001; final revision received June 12, 2001;
accepted June 25, 2001.
From the Department of Neurology, Bispebjerg Hospital, University of
Copenhagen, Copenhagen, Denmark.
Correspondence to Gudrun Boysen, MD, Department of Neurology,
Bispebjerg Hospital, 2400 Copenhagen, Denmark. E-mail
[email protected]
(Stroke. 2001;32:2423–2425.)
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
2423
2424
Stroke
October 2001
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salvageable or reperfusion of ischemic tissue, which may
indicate a fairly good prognosis. The results of such
studies are valuable in the acute situation, to guide
treatment decision and for information of the patient and
the relatives about the outlook. In the majority of patients
in whom such studies are not performed, the severity of the
neurological deficit, primarily the level of consciousness
and the presence of gaze deviation are the immediate, and
easily available variables to guide prediction of prognosis.
Stroke severity in itself as recorded by one or another of
several stroke scales39 – 41 is a major predictor of stroke
outcome.
Many researchers, in describing a prognostic marker (be
it temperature, blood glucose, CRP, WBC, or other), have
adjusted for stroke severity and found that the marker was
independent thereof. To do so, rating scales for stroke are
often used as if they were interval scales, and not nominal
scales with large interobserver and intraobserver variation.
This may have contributed to erroneous conclusions. In a
biological system, it seems unlikely that so many variables
can be causal and predict outcome independently. However, if that is the case, we need to develop models for
entering stroke severity—MRI, PET, and SPECT data;
temperature; blood glucose; CRP; WBC; plasma cortisol;
glutamate; glycine; IL-6; ferritin; and a few others, such as
age and prestroke modified Rankin scale score—to estimate the prognosis. Before doing so, we have to reexamine
the variables within the first 1 to 2 hours after stroke onset
and perform serial measurements to better describe the
relationship over time between stroke severity and the
variables. To investigate the biological relevance of these
variables, we should determine whether they increase as
reflections of the brain lesion or whether they are elevated
at stroke onset. It is conceivable that the increases reflect
the initial severity of the stroke and result from inflammatory or sympaticoadrenergic reactions to severe disease
and then contribute to further tissue damage through
mechanisms similar to those known from major surgery or
septicemia.
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Early Stroke: A Dynamic Process
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KEY WORDS: stroke
䡲
stroke onset
䡲
stroke, acute
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Early Stroke: A Dynamic Process
Gudrun Boysen and Hanne Christensen
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Stroke. 2001;32:2423-2425
doi: 10.1161/hs1001.098155
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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