Department of Neurology,
St Mary's Hospital,
London, UK
Department of Clinical Biochemistry
Department of Medicine,
King's College School of Medicine and Dentistry,
London, UK
To the Editor:
We read with interest the work of Missler et al1 and
Büttner and colleagues2 and agree with both sets of
researchers on the need for reliable, noninvasive markers of neuronal
damage following acute stroke. Such markers may allow prognostication
of future clinical outcome and may be useful in acute therapy trials as
surrogate markers of efficacy.
However, neither study cited our publication on serum S-100 protein
levels in acute stroke,3 4 a study that examined 81
patients (68 with ischemic stroke and 13 with hemorrhagic
stroke) within 48 hours of stroke ictus and compared them with 51 age-,
race-, and gender-matched control subjects.3 As with both
recent papers in Stroke, we found significantly higher serum
S-100 protein levels in the stroke population than in the control
group. Furthermore, the highest S-100 protein levels were seen in the
hemorrhagic stroke group, and differentiation between the two stroke
populations almost reached statistical significance. We also performed
a temporal study (24, 48, 72, and 96 hours after ictus) in 13 patients
and, unlike the recent Stroke studies, did not find
differences between these time points. Convalescent samples were also
analyzed in 57 of the 74 patients still alive at 3 months after
stroke; S-100 protein levels had significantly fallen (2
P<.0001) at this time but were still above the level seen
in the control population, suggesting partial restoration of glial cell
integrity.
We have previously shown5 that neuron-specific enolase
level and carnosinase activity are individually associated with
clinical outcome, determined with use of the Rankin Scale score and
Barthel Index, although their ratio has the strongest association. We
also found that S-100 levels were associated with clinical
outcome.3
The results of our S-100, neuron-specific enolase, and carnosinase
activity work and the recent S-100 protein studies show that serum
biochemical markers can be readily measured using commercially
available assays and appear to provide useful prognostic information.
We believe the combination of the results of two (or more) markers, as
used in our neuron-specific enolase/human serum carnosinase
article,5 may improve their usefulness and reliability. We
are currently assessing whether early drug therapy can modulate these
serum markers in patients with acute stroke, thereby supporting their
use as surrogate markers of efficacy.
References
1.
Missler U, Wiesmann M, Friedrich C, Kaps M. S-100
protein and neuron-specific enolase concentrations in blood as
indicators of infarction volume and prognosis in acute ischemic
stroke. Stroke. 1997;28:1956–1960.
2.
Büttner T, Weyers S, Postert T, Sprengelmeyer R,
Kuhn W. S-100 protein: serum marker of focal brain damage after
ischemic territorial MCA infarction. Stroke. 1997;28:1961–1965.
3.
Abraha HD, Butterworth RJ, Bath PMW, Wassif WS,
Garthwaite J, Sherwood RA. Serum S-100 protein, relationship to
clinical outcome in acute stroke. Ann Clin Biochem. 1997;34:366–370.
4.
Butterworth RJ, Abraha HD, Sherwood RA, Bath PMW.
Serum S-100 predicts outcome after acute stroke. Cerebrovasc
Dis. 1996;6(suppl 2):50. Abstract.
5.
Butterworth RJ, Wassif WS, Sherwood RA, Gerges A,
Poyser KH, Garthwaite J, Peters TJ, Bath PMW. Serum neuron-specific
enolase, carnosinase, and their ratio in acute stroke: an enzymatic
test for predicting outcome? Stroke. 1996;27:2064–2068.
Abteilung für Neuroradiologie,
Klinikum Großhadern,
München, Germany
We thank Butterworth et al for their additional remarks
concerning our work on S-100 protein in cerebral infarction.
The mechanisms leading to delivery of S-100 protein into blood are not
yet understood in detail. It has been widely accepted that S-100
protein leaks from structurally damaged central nervous system cells
into the cerebrospinal fluid and secondarily into the blood. Thus,
elevated levels of S-100 in cerebrospinal fluid as well as in blood
have been found to be a sensitive, although nonspecific, indicator of
nervous system damage in patients with various neurological disorders.
On the other hand, the group of S-100 proteins is involved in a variety
of physiological functions.1 There is
evidence that S-100 not only leaks from damaged cells, but may also be
actively secreted by central nervous system cells and may be a mediator
of glial reformation.2 3 In addition, the ratio between
S-100 concentrations in cerebrospinal fluid and blood may be altered by
impairment of the blood-brain barrier. It is not known how these
factors influence S-100 measurements in cerebral infarction.
The significance of these pathophysiological
mechanisms may differ in hemorrhagic and nonhemorrhagic stroke. To
obtain a homogeneous patient population, we included in our
study only patients suffering from nonhemorrhagic cerebral stroke.
Thus, we could perform CT volumetry of the infarction and establish a
quantitative correlation between S-100 level and infarct volume.
Since measurement of S-100 protein in blood is not specific for the
type of damage to the central nervous system, we do not believe it is a
suitable parameter to differentiate between hemorrhagic and
nonhemorrhagic stroke. Butterworth et al4 found that the
S-100 levels differed almost significantly between hemorrhagic and
nonhemorrhagic stroke. This can be caused by differences between the
two patient groups with respect to severity of neurological damage. In
addition, the time course of S-100 concentrations may be different in
hemorrhagic and nonhemorrhagic stroke due to different mechanisms of
the release of S-100 into the blood.
Butterworth et al reported only partial restoration of the S-100 level
3 months after cerebral infarction. With respect to a possible role of
S-100 in glial reformation, this is a very interesting finding.
Unfortunately, they did not comment on whether S-100 levels in patients
3 months after infarction differed significantly from those in healthy
control subjects. In our study, S-100 levels of the majority of
patients had returned to normal 10 days after infarction. In contrast
to the findings of Butterworth et al, we could demonstrate significant
changes of S-100 levels during the first 8 days after cerebral
infarction (n=8). We observed the highest concentration of S-100 on day
3, and S-100 levels on days 2 and 3 did not differ significantly.
However, the S-100 concentration on day 3 differed significantly from
those on days 1 and 4. Our data are supported by the findings of
Büttner et al.5
References
1.
Zimmer DB, Cornwall EH, Landar A, Song W. The S100
protein family: history, function, and expression. Brain Res
Bull. 1995;37:417–429.[Medline]
[Order article via Infotrieve]
2.
Donato R. Perspectives in S-100 protein biology.
Cell Calcium. 1991;12:713–726.[Medline]
[Order article via Infotrieve]
3.
Fanó G, Biocca S, Fulle S, Mariggió MA,
Belia S, Calissano P. The S-100: a protein family in search of a
function. Progr Neurobiol. 1995;46:71–82.[Medline]
[Order article via Infotrieve]
4.
Abraha HD, Butterworth RJ, Bath PMW, Wassif WS,
Garthwaite J, Sherwood RA. Serum S-100 protein, relationship to
clinical outcome in acute stroke. Ann Clin Biochem. 1997;34:366–370.
5.
Büttner T, Weyers S, Postert T, Sprengelmeyer R,
Kuhn W. S-100 protein: serum marker of focal brain damage after
ischemic territorial MCA infarction. Stroke. 1997;28:1961–1965.
© 1998 American Heart Association, Inc.
Letters to the Editor
Serum S-100 Protein in Acute Stroke
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