(Stroke. 2000;31:924.)
© 2000 American Heart Association, Inc.
Original Contributions |
From the Departments of Neurology, Friedrich-Schiller University of Jena (C.T., F.G., C.W., J.R.) and University Hospital Eppendorf (C.W., J.R.), Hamburg, Germany.
Correspondence to Christoph Terborg, MD, Department of Neurology, Friedrich-Schiller University of Jena, Philosophenweg 3, 07740 Jena, Germany. E-mail Terborg{at}landgraf.med.uni-jena.de
| Abstract |
|---|
|
|
|---|
MethodsWe compared the VMR of 46 patients with cerebral microangiopathy with 13 age-matched control subjects. Patients were classified with the Erkinjuntti scale. We monitored cerebral blood flow velocity (CBFV) in both middle cerebral arteries by TCD, changes in concentration of oxyhemoglobin (HbO2), deoxyhemoglobin (Hb) and blood volume (HbT) by NIRS, mean arterial blood pressure, and end-tidal CO2 (EtCO2) during normocapnia and hypercapnia. VMRs were calculated as percent change of CBFV (NCR) and as absolute change in concentration of HbO2, Hb, and HbT per 1% increase in EtCO2 (CR-HbO2, CR-Hb, CR-HbT).
ResultsNCR and NIRS reactivities were significantly reduced in patients with cerebral microangiopathy. CR-HbO2 and CR-Hb showed a close correlation with NCR, and NCR and NIRS reactivities were related to the severity of cerebral microangiopathy according to the Erkinjuntti scale. Validity of NCR and NIRS reactivities were similar.
ConclusionsVMR is reduced in patients with cerebral microangiopathy and can be noninvasively assessed in basal arteries (with TCD) and brain parenchyma (with NIRS). Reduction of CO2-induced VMR, as measured by NIRS and TCD, may indicate the severity of microangiopathy.
Key Words: cerebral blood flow microangiopathy spectroscopy, near-infrared ultrasonography, Doppler, transcranial vasomotor reactivity
| Introduction |
|---|
|
|
|---|
NIRS measures changes in concentration of the chromophores HbO2 and Hb, and enables the assessment of cerebral hemodynamics noninvasively (see References 12 14 ). NIRS has been applied to test CO2-induced VMR, and correlations with cerebral blood flow and cerebral blood volume measurements were found in preterm neonates15 and newborn infants.16 In adults with various neurological diseases, CO2 reactivity measured by NIRS was similar to changes in jugular venous oxygen saturation.17 Simultaneous assessment of CO2-induced VMR by TCD and NIRS revealed correlating results in adult volunteers and patients with different degrees of carotid artery stenosis.18 19
TCD measurements of VMR reflect autoregulatory changes of the whole downstream microcirculatory bed. In contrast to TCD, NIRS semiquantitatively measures changes of the regional cerebral blood volume (rCBV) in cerebral tissue and therefore assesses VMR from a different location.
The aim of our study was therefore to evaluate whether cerebral microangiopathy is associated with a reduced CO2-induced VMR, whether VMR measured by NIRS correlates with NCR, and whether there is a correlation between impairment of autoregulation and the pattern and extent of white matter changes on CT or MRI.
| Subjects and Methods |
|---|
|
|
|---|
1 ischemic events
consistent with transient ischemic attack or lacunar
infarction (n=33), dementia (n=13), or both (n=3), and white matter
changes on CT or MRI in concordance with cerebral microangiopathy.
Patients or volunteers with insufficient temporal bone window,
significant carotid artery stenosis, or territorial brain
infarction were excluded. All gave informed consent prior to the
reactivity test. Patients were classified in a blinded manner according to their MRI scans with the Erkinjuntti scale20 by one of the authors as follows. For periventricular hyperintensities: 0 indicates lesions absent; 1, caps; 2, pencil-thin lining; 3, smooth halo; and 4, irregular hyperintensities extending to the deep white matter. For other white matter hyperintensities: 0 indicates absent; 1, <5 small focal and/or <2 large focal lesions; 2, 5 to 12 small and/or 2 to 4 large focal lesions; 3, >12 small focal and/or >4 large focal or some confluent lesions; and 4, predominantly confluent lesions.
The above groups and all patients were divided into mild and severe white matter changes. In 14 patients with a CT scan only, the Erkinjunti scale was applied in an analogous manner.
Recordings
We recorded simultaneously the CBFV in both
middle cerebral arteries by transcranial Doppler
sonography (X4, DWL), changes in concentration of
HbO2, Hb, and HbT by near-infrared
spectroscopy (NIRO 500, Hamamatsu Photonics), and end-tidal
CO2 (Kapnograph, Datex-Engström) during
normocapnia and hypercapnia. Mean arterial blood pressure
was measured continuously by a noninvasive, beat-to-beat finger
blood-pressure monitor (Portapres, TNO Biomedical Instrumentation). The
transmitting probe of the NIRS was placed on the left side of the
forehead 2 cm beside the midline and 3 to 4 cm above the supraorbital
ridge, and the receiving probe (photomultiplier) was fixed laterally at
a distance of 5 cm with an elastic bandage.
Reactivity Test
For baseline conditions, subjects lay in a supine position,
breathing room air through a breathing mask. After registration of a
stable signal for at least 5 minutes, a CO2 test
was performed by their breathing carbogene gas (5%
CO2 and 95% O2), until a
1% increase in EtCO2 was achieved.
Figure 1
shows a typical
recording.
|
Data Collection and Processing
For offline analysis, data were collected and digitized
with use of an AD converter with a sampling rate of 50 Hz, averaged,
and stored on a laptop personal computer by means of a data collecting
software (Dasylab, Synotech). CO2-induced VMRs
were calculated as percentage change of the CBFV in TCD (NCR) and as
absolute change in concentration (µmol/L) of the chromophores
HbO2, Hb, and HbT per 1% increase in end-tidal
CO2 (CR-HbO2, CR-Hb,
CR-HBT). To increase signal-to-noise ratio, we calculated Hbdiff as the
difference between HbO2 and Hb, and CR-Hbdiff as
an additional reactivity index.
Vasomotor Reactivities
![]() |
![]() |
![]() |
Statistic Analysis
For statistical analysis we used the
nonparametric Mann-Whitney U test, because most
values did not show normality. Differences in VMR between control
subjects and patients with mild and severe white matter
hyperintensities according to the Erkinjuntti scale were tested by a
Kruskal-Wallis 1-way ANOVA. Post hoc tests (2x2) were performed by the
use of the Scheffé test.
The correlation coefficients between reactivity indices and between VMRs and the extent of microangiopathy according to the Erkinjuntti scale were tested with the nonparametric Pearson and Spearman formulas. The validity of all reactivity indices was assessed by sensitivity, specificity, and receiver operating characteristic (ROC) analysis.
| Results |
|---|
|
|
|---|
|
|
NIRS reactivities showed a significant correlation with the NCR
(Spearman and Pearson correlation coefficients; P<0.05)
except for the parameter CR-HbT (Table 3
, Figure 2
).
|
|
Blood pressure usually rose during CO2 tests (mean 6.8 mm Hg, SD 7.1 mm Hg). Changes in blood pressure during reactivity tests did not correlate with NCR but did correlate with CR-HbO2, CR-Hb, and CR-Hbdiff (P<0.05).
The reduction of CO2-induced VMR was highest in
patients with white matter changes qualified as "severe"
(Erkinjuntti scale 5 to 8) and less in patients with "mild"
abnormalities (Erkinjuntti scale 1 to 4) compared with the controls.
The global difference between the groups was significant (NCR,
P<0.05; CR-HbO2, P=0.0001;
CR-Hb, P<0.003; CR-Hbdiff, P<0.002; Figures 3 through 7![]()
![]()
![]()
![]()
).
A 2x2 post hoc test (Scheffé) showed a difference between
controls and patients with severe microangiopathy for NCR right
(P<0.05) and a trend toward a reduced NCR left
(P=0.055). Concerning the NIRS reactivities, differences
between controls and patients with mild microangiopathy and between
controls and patients with severe microangiopathy were significant for
the parameters CR-HbO2
(P=0.001 and P=0.000, respectively), CR-Hb
(P=0.017 and P=0.001, respectively), and
CR-Hbdiff (P=0.003 and P=0.000, respectively).
The homogeneity of variances of these parameters could be
verified. We did not find significant differences between patients with
mild and those with severe microangiopathy (Scheffé test) in
either TCD or NIRS.
|
|
|
|
|
Furthermore, we found a negative correlation between VMR and the extent of microangiopathy according to the Erkinjuntti scale (NCR, P=0.024; CR-HbO2, P=0.000; CR-Hb, P=0.000; CR-Hbdiff, P=0.000; and CR-HbT, P=0.008).
Sensitivity and specificity of NCR left were 72.7% and 64.4%
(P=0.021); NCR right, 69.2% and 60.0%
(P=0.009); CR-HbO2, 92.3% and 65.2%
(P=0.000); and CR-Hbdiff, 76.9% and 63%
(P=0.001; Table 4
). ROC
analysis of all reactivity indices showed the largest areas
under the curve for the indices CR-HbO2, CR-Hb,
and CR-Hbdiff (Table 4
, Figures 8 through 10![]()
![]()
).
|
|
|
|
| Discussion |
|---|
|
|
|---|
In our patients with cerebral microangiopathy (defined as focal
neurological signs and/or dementia in the presence of white matter
abnormalities on CT or MRI), we found a significantly reduced
CO2 reactivity in both noninvasive techniques,
TCD and NIRS. Compared with the control subjects, VMR was more reduced
in patients with severe than with mild microangiopathy (Figures 3 through 7![]()
![]()
![]()
![]()
), and differences (global
comparison) between the 3 groups were significant. The reduction of NCR
and NIRS reactivities correlated with the extent of
periventricular and deep white matter hyperintensities on
the Erkinjuntti scale.
Our results are in line with recent hemodynamic studies: reduction of rCBF and rCBF change to acetazolamide measured by xenon-enhanced CT was described in the cerebral white matter and cortex of patients with single and multiple lacunes. Patients with multiple lacunar infarctions showed a significantly lower VMR in the cerebral cortex than did patients with single lacunes.7 In patients with leukoaraiosis and lacunar infarctions, Oishi et al21 found a more reduced rCBF and acetazolamide reactivity than in patients with leukoaraiosis alone. A negative correlation between vasodilatory capacity to acetazolamide in the cortex and the severity of periventricular hyperintensities on MRI of the brain was also shown in asymptomatic subjects with periventricular hyperintensities (xenon clearance).26 In patients with vascular dementia of the Binswanger type, a decreased CO2 reactivity was demonstrated in cerebral cortex and in the deep white matter (by PET),27 and in lacunar dementia De Reuck et al28 found a decreased blood flow to oxygen metabolism with increased oxygen extraction rate. These studies indicate that cerebral microangiopathy goes along with a reduction of rCBF and, as noninvasively shown in our study, an impaired cerebral autoregulation.
Findings of impaired VMR fit into the concept that the disturbed autoregulation in cerebral microangiopathy results in temporary critical hypoperfusion during episodes of hypotension.1 5 28 29 Recurrent decreases in cerebral perfusion (eg, during blood pressure dysregulation or cardiac arrhythmia) may lead to ischemia in the deep white matter.5 11 30
Functional studies31 with NIRS and PET have shown that the
sample volume of NIRS is located in the superficial part of the brain.
We have hypothesized that measurements with NIRS might therefore
be more sensitive and reliable than those with TCD, because NIRS
measures the hemodynamic response to hypercapnia closer
to the presumed site of the disturbed autoregulation. In our study,
sensitivity and specificity of the reactivity indices
CR-HbO2 and CR-Hbdiff were higher compared with
NCR, and ROC analysis revealed the largest areas under the
curve for CR-HbO2, CR-Hb, and CR-Hbdiff (Table 4
, Figures 8 through 10![]()
![]()
). Validity of VMR
measured by NIRS might therefore be similar (or even better) compared
with TCD in patients with cerebral microangiopathy.
Interestingly, Sabri et al6 32 found that in microangiopathy dementia and neuropsychological impairment correlate with the reduction of regional cerebral blood flow and glucose utilization and not with MRI changes. Whether a normal neurological and neuropsychological status correlates with a preserved autoregulation in patients with cerebral microangiopathy has yet to be determined.
| Acknowledgments |
|---|
Received August 9, 1999; revision received January 27, 2000; accepted January 27, 2000.
| References |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
H. S. Markus Genes, endothelial function and cerebral small vessel disease in man Exp Physiol, January 1, 2008; 93(1): 121 - 127. [Abstract] [Full Text] [PDF] |
||||
![]() |
K.-J. Bar, M. K. Boettger, N. Seidler, H. J. Mentzel, C. Terborg, and H. Sauer Influence of Galantamine on Vasomotor Reactivity in Alzheimer's Disease and Vascular Dementia Due to Cerebral Microangiopathy Stroke, December 1, 2007; 38(12): 3186 - 3192. [Abstract] [Full Text] [PDF] |
||||
![]() |
U. Khan, L. Porteous, A. Hassan, and H. S Markus Risk factor profile of cerebral small vessel disease and its subtypes J. Neurol. Neurosurg. Psychiatry, July 1, 2007; 78(7): 702 - 706. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Birns, H. Markus, and L. Kalra Blood Pressure Reduction for Vascular Risk: Is There a Price To Be Paid? Stroke, June 1, 2005; 36(6): 1308 - 1313. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Yoshitani, M. Kawaguchi, M. Iwata, N. Sasaoka, S. Inoue, N. Kurumatani, and H. Furuya Comparison of changes in jugular venous bulb oxygen saturation and cerebral oxygen saturation during variations of haemoglobin concentration under propofol and sevoflurane anaesthesia Br. J. Anaesth., March 1, 2005; 94(3): 341 - 346. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Walters, S. Muir, I. Shah, and K. Lees Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction Stroke, August 1, 2004; 35(8): 1899 - 1902. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Hassan, B. J. Hunt, M. O'Sullivan, R. Bell, R. D'Souza, S. Jeffery, J. M. Bamford, and H. S. Markus Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction Brain, January 1, 2004; 127(1): 212 - 219. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Zimmermann and R.L. Haberl L-Arginine Improves Diminished Cerebral CO2 Reactivity in Patients Stroke, March 1, 2003; 34(3): 643 - 647. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Hassan, B. J. Hunt, M. O'Sullivan, K. Parmar, J. M. Bamford, D. Briley, M. M. Brown, D. J. Thomas, and H. S. Markus Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis Brain, February 1, 2003; 126(2): 424 - 432. [Abstract] [Full Text] [PDF] |
||||
![]() |
H Tiemeier, S L M Bakker, A Hofman, P J Koudstaal, and M M B Breteler Cerebral haemodynamics and depression in the elderly J. Neurol. Neurosurg. Psychiatry, July 1, 2002; 73(1): 34 - 39. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Yoshitani, M. Kawaguchi, K. Tatsumi, K. Kitaguchi, and H. Furuya A Comparison of the INVOS 4100 and the NIRO 300 Near-Infrared Spectrophotometers Anesth. Analg., March 1, 2002; 94(3): 586 - 590. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Sterzer, F. Meintzschel, A. Rosler, H. Lanfermann, H. Steinmetz, and M. Sitzer Pravastatin Improves Cerebral Vasomotor Reactivity in Patients With Subcortical Small-Vessel Disease Stroke, December 1, 2001; 32(12): 2817 - 2820. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2000 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |