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Autoregulation 55
Heart Macrocirculation Microcirculation
1
closedclosed
openopenTap 1:
Fig. A3.1 Model of the pulsatile pump function of the heart. A rigid
pipe is connected to a filled water barrel. Opening (systole) and
closing (diastole) of the tap results in a pulsatile flow within the
pipe. Ultrasound analysis will detect flow in systoleonly and there will
be an absence of flow in diastole.
circulation can be introduced into the model (Fig. A3.3): A
reduction of outflow (closed microcirculation) will lead to
mildly reduced systolic flow velocities but distinctly lowered diastolic flow velocities and subsequently higher
pulsatility. Opening of the microcirculation, i. e., a reduction in peripheral resistance, will lead to slightly higher
systolic flow velocities and distinctly higher diastolic velocities, i. e., reduced pulsatility.
Heart Macrocirculation Microcirculation
1
closedclosed
openopenTap 1:
Fig. A3.2 Model of the pulsatile pump function of the heart: Awater
hose is connected instead of the pipe, similarly to the arteries with
their elastic vessel walls. During diastole, the diameter of the hose
reduces (modeling the Windkessel function), thus leading to a detectable diastolic flow.
Heart
Macrocirculation Microcirculation
1
2
Autoregulation
In contrast with other organ systems, but analogous to the
kidney, the brain has an autoregulatory system that ensures constant tissue perfusion. Factors that influence cerebral perfusion are the cerebral perfusion pressure (CPP =
arterial blood pressure [ABP]—intracranial pressure [ICP])
and the cerebrovascular resistance (CVRes), determined by
the functional status of the arteriolar vessels of the cerebral microcirculation. Under physiologic circumstances,
when ICP is normal, (at rest about 10 mg Hg) CPP can be
assumed to be equal to the ABP .
CBF = ABP/CVRes (Ohm’s law of hemodynamics).
The above formula shows that CBF can be kept stable
during changes in ABP if compensatory alterations are
made in the cerebrovascular resistance, i.e., the microcirculation. Low blood pressure requires a reduction of
resistance, i. e., dilation of the peripheral arterial vessels.
High blood pressure requires peripheral vasoconstriction.
As CBF is closely related to the blood flow velocities in the
main arteries supplying the brain, the above mechanism
will result in stable flow velocities during changes in blood
pressure (Diehl 2002). However, this mechanism only
works under physiologic conditions within a certain range
of blood pressure, as changes in the diameter of the pe-
almost closed
Fig. A3.3 Model of the pulsatile pump function of the heart. A
second tap is introduced to simulate the microcirculation. While
tap 1 is open, closing tap 2 reduces the systolic flow but to a larger
extent the diastolic flow, resulting to high-pulsatile signals.
wide openTap 2:
ripheral arterial vessels only occur over a certain range.
Above and below this range the mechanism fails and blood
pressure and CBF are directly coupled. An abolished or
impaired autoregulation, for example in ischemic stroke,
also implies direct coupling of cerebral perfusion and
blood pressure. Therefore, a reduction in blood pressure
in impaired autoregulation will lead to a reduction of brain
perfusion, which should be avoided. Conversely, in acute
stroke normal or slightly raised blood pressure is desired
(Fig. A3.4).
Testing of Autoregulation
For cerebral functional and regulatory testing, the transcranial Doppler (TCD) method is preferred; commercial
ultrasound probe holding systems are available which
3 Intracranial Hemodynamics and Functional Tests56
Arteriolar
diameter
Normal
50BP 100 150 (mmHg)
Fig. A3.4 Therelation of bloodpressure (BP) and cerebral blood flow
(CBF) under physiologic (red lines) and pathologic conditions (blue
lines). Intact autoregulation leads to a constant CBF over a wide
pressure range caused by a continuous decrease of small artery
diameter with increasing BP. In impaired autoregulation, BP directly
translates into CBF, because the small arteries do not constrict with
increasing BP. Continuous lines: BP/CBF relation, dashed lines: BP/
smallarterialdiameterrelation.
Fig. A3.5 Example of a holding device for continuous bilateral TCD
monitoring with two 2 MHz probes.
CBF
Normal
permit continuous online monitoring over time without
the risk of change in probe position. In contrast with
current duplex ultrasound systems, TCD permits simultaneous measurement in more than one blood vessel, i. e.,
bilateral monitoring is possible (Fig. A3.5).
Several methods of autoregulatory testing by means of
blood pressure alteration have been proposed. Aaslid and
co-workers (1989) published a thigh-cuff method in which
sudden blood pressure drops can be induced. Two thigh
cuffs are inflated above systolic blood pressure values for
more than 2 minutes causing temporary leg ischemia. A
sudden cuff release results in leg hyperemia and an approximately 20 % systemic blood pressure drop, lasting 10
seconds. In normal autoregulation, this maneuver leads to
an initial reduction of blood flow velocity within the MCA.
Compensatory autoregulatory flow increase starts after
1 second and flow velocities reach normal values after 5 seconds. Other published methods are the performance of
a standardized Valsalva maneuver and the analysis of
spontaneous blood pressure oscillations. The former test
comprises expiration into a tube containing a closed pressure valve over 15 seconds, resulting in a transient blood
pressure reduction as well as a less pronounced temporary
reduction of blood flow velocity within the MCA, caused by
the autoregulatory response (Tiecks et al. 1996). The latter
method analyzes spontaneous blood pressure oscillations
(M-waves) or oscillations induced by slow breathing. High
frequencies of more than 0.2 Hz were found to virtually
result in direct changes of MCA flow velocity. Blood pressure oscillations at lower frequencies led to phase-shifted
MCA velocity changes of up to 70°, i. e., the observation of
an autoregulatory response (Diehl 2002, Diehl et al. 1995).
All three reported methods have been shown to detect
impaired autoregulation in patients with, for example, a
high-grade ICA stenosis. So far, these methods are mostly
used in specialized centers either because an additional
continuous blood pressure monitoring is required (thighcuff and Valsalva method) or because of the lack of availability of commercial evaluation software (spontaneous
oscillation method).
Fig. A3.6 TCD, transtemporal approach, P2-PCA segment insonation. A flow velocity with the subject’seyesclosed(TAV
PI: 0.78) B Flow in the same vessel segment after eye opening
(TAV
:56cm/s,PI:0.5).
max
:36cm/s,
max
Neurovascular Coupling
Coupling of activity and blood flow is an ubiquitary mechanism of all organ systems. In neurovascular coupling of
the brain, a raised metabolic demand, due to activation, for
example, of particular brain regions leads to an increase of
blood flow and a proportional rise of blood flow velocity. A
typical example of this mechanism is the use of a visual
stimulus paradigm under continuous insonation of the
PCA (Fig. A3.6). While the detailed translational mechanisms from activated brain cells to increased flow are
currently being extensively studied, the effector mechanism is a dilatation of the peripheral arteries (resistance
vessels), i.e., the microcirculation which leads to a flow
increase (as explained in Fig. A3.3).
Testing of Neurovascular Coupling
A simple and easily applicable method is the visual stimulation test (visual evoked Doppler [VED]), in which repetitive visual stimuli are used and the flow velocity in the
PCA is analyzed. As a stimulus, a flashing light or any other
standardized visual stimulus that can be applied over a
computer screen can be used. To improve signal-to-noise
ratio, a repetitive averaging, comparable to the electric
visual evoked potential is being used (Sturzenegger et al.
1996). As the PCA mainly supplies the visual cortex, only a
few repetitive stimuli (we recommend 20–40 stimuli) are
necessary to achieve evaluable curves (Fig.A3.7). For evaluation, the baseline velocity is adjusted to 100 % and the
flow increase assessed in percent over baseline levels.
From these curves, peak increase and time to peak can
be derived and used for evaluation. Diehl et al. reported a
mean increase of 40 ± 8 % in the Doppler sonographic P2-
PCA segment in a group of 30 healthy volunteers (Diehl
and Berlit 1996). Apart from the opportunity to noninvasively study the physiology of neurovascular coupling, this
method is potentially useful in patients with cerebral ischemia in the posterior circulation or in patients with
suspected vegetative state. Instead of the visual stimulus
paradigm, other cognitive stimuli may be used for analysis
and measurements of other basal cerebral arteries. However, as the amplitude of the vascular reaction is smaller,
usually higher numbers of averaged repetitive cycles are
required to separate the signal from the background noise.
An example of a first clinical application is the determination of language lateralization by bilateral assessment of
MCA flow velocities during a cued word generation task
(Knechtetal.1998)
Metabolic Coupling
Metabolic coupling is an ubiquitous mechanism whereby
changes of CO
lead to changes in perfusion and flow velocity. CO
waste product of cell metabolism is a strong vasodilator.
Increases inpCO
velocity, whereas low pCO
reduction and decreased velocities (Fig.A3.8). Again, the
effector mechanism isthe change in cross-sectional area of
the peripheral resistance arteries in the microcirculation
(Fig. A3.4). The ability of these arteries to dilate and constrict (= cerebrovascular reactivity [CVR]) can easily be
assessed by ultrasound methods.
Testing of Metabolic Coupling
Several ultrasound tests have been proposed for controlled alteration of partial CO
monitor bilaterally using fixed TCD probes, and mostly,the
MCA is assessed. Under the assumption that the M1-MCA
diameter remains almost constant during pCO
partial pressure (pCO2)inthebodytissues
2
2
(hypercapnia) will lead to raised CBF and
2
(hypocapnia) leads to a flow
2
pressure (pCO2). They all
2
changes
2
as a
Metabolic Coupling 57
Fig. A3.7 Setup and results of visual evoked Doppler studies. A Pair
of goggles with integrated light emitting diodes for visual stimulation with different flash frequencies. Holding system for two TCD
probes, adjusted for both PCAs. B Registration of control sequence,
down: stimulation off, up: stimulation on. C Resulting time-averaged maximum velocities within the right PCA (red) and the left PCA
(green). D Averaged sequence of a healthy volunteer with a sequence of 10 seconds stimulation (flicker frequency: 10 Hz) and 10
seconds pause. Note the velocity increase up to 124.5 % after a time
delay of 11.6 seconds. E Result achieved with identical settings in a
patient with persistent vegetative state.
(Huber and Handa 1976, Valdueza et al. 1998), the increased peripheral dilatation caused by hypercapnia leads
to a directly correlating rise in MCA flow velocity. Baseline
levels are commonly set as 100 %, and any increase or
decrease in flow is documented as a relative change in
percent. Under physiologic conditions, MCA flow velocity
can be reduced to 50% below baseline flow velocityduring
hypocapnia and may riseup to 200 % abovebaseline values
under hypercapnia. A linear relation exists within a range
of 30–70 mmHg pCO
(Fig. A3.8).
2
The following sections briefly describe the main pub-
lished CVR tests.
Breath-holding Index
The patient is asked to hold his or her breath for at least 30
seconds during continuous MCA flow velocity monitoring.
Index calculation is shown in Figure A3.9.Normalvalues
are 1.2 ± 0.6 %/sec. Capnometer recordings are not required, but the sensitivity of the test is low (Markus and
Harison 1992).
Hyperventilation (Apnoea Test)
The patient is asked to hyperventilate for 40 seconds followed by a breath-holding phase of at least 30 seconds.
Flow velocity values under maximal hyperventilation and
hypoventilation are compared. A relative difference
greater than 15 % argues against a relevant impairment
of CVR (Widder et al. 2004).
3 Intracranial Hemodynamics and Functional Tests58
Fig. A3.8 Left: Doppler spectra analysis of the MCA in a single
subject during hypoventilation, end-tidal CO
moventilation, end-tidal CO
ventilation, end-tidal CO
of the end-tidal CO
2
: 40 mmHg (B), and controlled hyper-
2
: 25 mmHg (C). Right: Schematic diagram
2
-MCA blood flow velocity relation.
:55mmHg(A), nor-
2
Breath-holding Index (BHI)
V
BHI=
apnea–Vbaseline
V
baseline
x
100
x t
apnea
CO2 inhalation test/acetazolamide test
V
CO
acetazolamide–Vbaseline
/
CVR=
Fig. A3.9 Calculation of the breath-holding index (BHI) and the
cerebrovascular reactivity (CVR) according to the CO
test and acetazolamide test. V = flow velocity.
2
V
baseline
x
100 (%)
inhalation
2
CO2Inhalation Test
The test consists of controlled inhalation of a CO2-enriched
gas mixture, for example Carbogen gas (5 % CO
95 % O2).
2,
The latter leads to an increase of approximately one volume percent CO
Volume percent and pCO
within the air flow of the studied subject.
2
do not directly correlate as the
2
latter depends on the current atmospheric pressure and
the height above the mean sea level. However, the above
estimation is sufficient to be applied as follows. The reported mean flow increase per volume percent is 23 ± 5%
(Widder et al. 1986). As a clinical cut-off we recommend
using the mean –2 × SD = approximately 10%. Flow in-
creases below 10% should therefore be evaluated as impaired CVR. In our experience, older patients in particular
might become anxious or be uncomfortable with inhalation of the gas, and we recommend using the acetazolamide test described below. In addition, CO
inhalation
2
should be avoided in patients with severe pulmonary disease or dyspnea.
Acetazolamide Infusion Test
Acetazolamide is a carboanhydrase inhibitor, which if administered intravenously results in a local increase of CO
2
Acetazolamide 1 g (for optimal standardized test: 15mg/
kg/body weight) is slowly injected into a peripheral vein,
and the blood flow velocity in the MCA is monitored over
15 minutes. Baseline flow velocities are set as 100 %
(Fig. A3.9). Mean flow increase caused by acetazolamide
is 38 ± 15 % (Widder et al. 2004). As a clinical cut-off we
recommend using the mean—2 × SD = approximately 10 %.
Therefore a flow increase below 10 % should be considered
as impaired CVR, which is comparable with the
inhalation test. Unwanted side effects of acetazol-
CO
2
amide injection are oral dysesthesias, headaches, dizziness, nausea, or vomiting. Younger patients tend to be
more sensitive to these side effects, so we recommend
using the CO
inhalation test as the first-line test in these
2
patients. However, in elderly people, we prefer to use
acetazolamide because it is generally very well tolerated
and is not dependent on patient cooperation. Analysis of
CVRwithbothtestsmayresultinpreservedorimpaired
reactivity. A decrease of flow velocity (commonly described as a “steal phenomenon”) may occur in total loss
of CVR.
All of the above ultrasound tests have some common
limitations: They cannot be performed if the transcranial
bone window is not sufficient for reliable flow velocity
monitoring, i. e., an exact fitting of the envelope curve to
the Doppler spectrum is required. Measurements cannot
be taken if the vessel to be measured (generally the MCA)
is itself stenotic. Finally, results might be compromised if
the patient has severely impaired cardiac output or cardiac
arrhythmia. In these patients,acetazolamidesingle photon
emission computed tomography (SPECT) should be considered. While its principle—blood flow measurements at
rest and during acetazolamide provocation—is the same,
SPECT directly visualizes the parenchymal perfusion pattern. Usually a radioactive tracer, such as
99 m
Tc, is admin istered intravenously, and its distribution throughout the
brain assessed by a gamma camera system. In healthy
subjects, the regional CBF increases 1.7 times (Sullivan et
al. 1987). In patients with extracranial or intracranial stenoses different perfusion patterns can be found:
• Type 1: normal baseline and normal acetazolamide-ac-
tivated flow.
• Type 2: normal baseline and impaired activated flow.
• Type 3: impaired baseline but normal activated flow.
• Type 4: impaired resting and activated flow.
Impaired CVR tends to be associated with either leptomeningeal or extra-intracranial collateral pathways, such as
via the ophtalmic artery (Ozgur et al. 2001, Smith et al.
.
1994). SPECT and Doppler derived CVRs have been shown
to correlate highly, yielding similar results in patients with
ICA stenoses (Engelhardt et al. 2004). Because of its restricted availability, higher costs, and greater personnel
requirements, SPECT is reserved for selected patients
only. More recently MRI and CT perfusion studies, analyzing CBF, CBV, and mean transit time (MTT) before and
during acetazolamide provocation have been introduced.
Although not yet well established, correlation studies with
PET or SPECT have yielded significant correlations between the techniques (Bisdas et al. 2006, Chen et al.
2006, Endo et al. 2006, Grandin et al. 2005, Ma et al.
2007). As of now there are no standardized protocols or
accepted cut-off values for the latter, and we recommend,
if feasible, to use the ultrasound-derived CVR as the routine diagnostic method of choice.
Other Tests to Assess Differences Between the Right and Left Sides as Markers of Impaired Collateral Function
Metabolic Coupling 59
Delayed contrast filling of the MCA is a well-known phenomenon in conventional angiography in patients with
ipsilateral extracranial ICA occlusion. It is considered to
present insufficient collateralization via the anterior and/
or posterior communicating arteries (Boczko and Caplan
1967, Huber 1982) (Fig. A3.10B).
Ultrasound Delay Test
Ultrasound is able to simulate conventional angiography
in this respect. The aim of the test is to analyze the quality
of the collateral function of the anterior and posterior
communicating arteries in patients with extracranial ICA
stenosis or occlusion, by assessing differences between the
echo-contrast bolus arrival in the MCAs. The technical
setup is the same as for the above described TCD CVR
method with two fixed 2 MHz ultrasound probes continuously analyzing both MCA Doppler spectra (Fig. A3.5). An
intravenousLevovistorSonovuebolusisthenappliedand
the contrast-induced signal rise in both Doppler spectra is
registered. Time-intensity curves allow determination of
the actual difference between the right and left sides in
milliseconds (Fig. A3.10).Healthy individuals demonstrate
mean delays of 0.16 ± 0.13s (range 0 to 0.48) while highgrade ICA stenoses and occlusions reveal delays of
1.16 ±0.87 s and 0.61± 0.41s, respectively (Schreiber et al.
1999). Applying receiver operating characteristic (ROC)
curve analysis, a cut-off value of 0.27 s differentiates patients from controls with a diagnostic sensitivity of 0.79
and a specificity of 0.87.
Fig. A3.10 Top: DSA of a patient with a 95 % left ICA stenosis.
A Selective left CCA filling, lateral view. B Aortic arch filling, postero-
anterior projection. Contrast on the right side has already reached
the M2-MCA branches. On the left side, only the proximal M1-MCA
is visible, filling via retrograde A1-ACA flow. Bottom: Left: Simultaneous bilateral registration of the MCA Doppler signals of the same
patient. Bolus arrival is indicated by the color change in the spectrum; the white lines indicate peak intensity values, used for delay
calculation. Right: Offline data analysis. Right MCA—raw data (dark
gray) and polynomial fit (black line), left MCA—raw data (light gray)
and polynomial fit (dashed line). The two red lines indicate the
turning point of the curves. Difference between the right and left
MCAs: 0.96 s.
Magnetic Resonance Imaging—Dynamic Arterial Spin
Labeling
Dynamic arterial spin labeling is a new, noncontrast MRI
technique that provides information on function of collaterals comparable to angiographic or ultrasound delay
studies. Its basic principle is that magnetically labeled
intravascular blood can be traced for a few seconds
(Fig. A3.11). The special advantages of the technique are
the dynamic approach and its noninvasiveness, as contrast
agents are not needed. Its use is limited due to the small
field of view, which does not permit examination of all the
arteries that supply the brain, and the short analysisperiod
which prohibits analysis of long duration washout kinetics. Also, there are limitations of the spatial resolution,
which do not permit sensible analysis of vessel pathology
or grades of stenosis. However, it seems to be an excellent
tool for dynamic analysis of CW collaterals and subsequent
hemodynamic effects. Warmuth and co-workers analyzed
35 patients with unilateral ICA stenosis of varying degrees.
They looked at the time difference of arrival of the labeled
3 Intracranial Hemodynamics and Functional Tests60
Fig. A3.11 Dynamic spin labeling MRA, circle of Willis. Healthy in-
dividual with equal filling of carotid siphon (A)andmainbranchesof
the circle of Willis (B). C, D patient with a left extracranial ICA
occlusion. Note the absent carotid siphon filling (arrow in C)and
the delayed MCA filling (arrow in D).
blood bolus in the intracranial ICA and the MCA, using a
time resolution of 25 images per second. They found a
significant correlation between the degree of stenosis
and the observed delay. The cut-off separating stenoses
< 70 % from > 70 % (NASCET criteria, corresponding ECST
> 82 %) was an ICA delay of 0.45 s, yielding a sensitivity of
96 % and a specificity of 80%. In some patients, the observed ICA delay persisted up to the MCA level. Successful
surgery or stent implantation led to normalized arterial
arrival times on the previously affected side (Warmuth et
al. 2005).
Magnetic Resonance Imaging—Contrast-enhanced
Perfusion Analysis
Perfusion MRI also allows analysis of the differences between the two sides after gadolinium injection, when
looking at the mean time-to-peak contrast enhancement.
A study of 18 patients with 50–69 % ICA stenosis (NASCET
criteria, corresponding ESCT grade of 70–82%) presented a
mean MTT delay of 0.49 s (range: 0–1.44 s) on the stenosed
side (Trivedi et al. 2005). A separate analysis of gray and
white matter MTTs in a group of eight patients with ICA
occlusion yielded even higher values of 0.7s and 1.5s,
respectively (Apruzzese et al. 2001).
Dynamic CTA
Similar approaches have recently been reported with CT
techniques. In dynamic 3D CTA, using a rough time resolution of two images/s Matsumoto and co-workers demonstrated a time delay of 0.5–1 s in a patient with an
extracranial ICA occlusion (Matsumoto et al. 2007). Analyzing patients with unilateral symptomatic ICA stenosis a
mean transit time (MTT) difference of 1.4s was detected
within the MCA territory whereas MTT within the PCA
territorywas0.2sonly(Waaijeretal.2007).
Parameters of Cerebral Hemodynamics
Cerebral Blood Flow Velocity
Flow velocity parameters are derived from the Doppler
spectrum, which documents all registered velocities
within a given sample volume. As described before, the
Doppler spectrum is a mixture of different velocities. For
analysis of velocity parameters, the fastest detectable velocities are used. For this purpose all ultrasound systems fit
an envelope curve to the spectrum, from which the peaksystolic velocity (PSV) and the end-diastolic velocity (EDV)
can be calculated (see Chapter 1 and Fig. A1.13). From
these two parameters, the time-averaged maximum velocity TAV
max
(TAV
TCD practice TAV
velocity”. A frequently used parameter, which is important
for volume flow assessments, is the time-averaged mean
velocity (TAV
mean
ringaboveorbelowthebaselineoveratleastthreecomplete cardiac cycles.
Resistance Indices
The relation of systole and diastole as a measure of peripheral resistance such as within the microcirculation can
be described in different indices. Most frequently used are:
pulsatility index (PI = (PSV– EDV)/TAV
brain-supplying arteries; and the resistance index (RI =
(PSV—EDV)/PSV) usually < 0.75. The diastolic flow component also reflects the status of resistance and EDV/PSV
should be less than a third.
Cerebral Blood Flow
If the TAV
cm
calculated (BVF (mL/min) = TAV
plex ultrasound permits assessment of this data. Thus if
BVF calculations are being performed in both ICAs and
both VAs, the sum of volume flows reveals the global CBF
(Fig. A3.12). Ultrasound derived data has been shown to lie
well within the range of data published by other imaging
techniques like SPECT, PET, radioactive labeled erythrocytes, perfusion CT or MRI (Ta b l e A3 . 1 ). CBF alterations
can be observed in a number of cerebral diseases, for
example in stroke, dementia, or brain death (Scheel et al.
1999, Schöning et al. 2005, Schreiber et al. 2005). Volume
flow can also be measured by color M-mode imaging
yielding comparable results (Ho and Metreweli 2000).
mean
2
) are known, the local blood volume flow (BVF) can be
= (PSV + 2EDV)/3) can be derived. In
max
is often misleadingly named “mean
max
), i. e., the mean of all frequencies occur-
)whichis<1.0in
max
and the cross-sectional area of a vessel (A,
× A). Extracranial du-
mean
Parameters of Cerebral Hemodynamics 61
Tab l e A 3 .1 Published CBF data. Depending on the applied method, either local or global values are given. Values in italics are calculated data
assuming an average brain weight of 1400 g (Ho et al. 1980)
Authors Method Global CBF CBF/100 g
Kashimada et al. 1995 MRI 694 mL/min 50 mL/min
Buijs et al. 1998 MRI 616 ± 143 mL/min 44 mL/min
Shirahata et al. 1985 SPECT 784 mL/min 56 ± 7mL/min
Waldemar et al. 1991 SPECT 756 mL/min 54± 9mL/min
Huang 1983 PET 588 mL/min 42 ±8mL/min
Steiger et al. 1993 CT 700 mL/min 50 ±13 mL/min
32
Nylin et al. 1961
Schöning et al. 1994 Ultrasound 701 ± 104 mL/min 50 mL/min
Dörfler et al. 2000 Ultrasound 630 ± 97 mL/min 45 mL/min
Scheel et al. 2000 Ultrasound 657 ± 120 mL/min 47 mL/min
Doepp et al. 2003 Ultrasound 737 ± 100 mL/min 53 mL/min
Schreiber et al. 2005 Ultrasound 733 ± 54 mL/min 52 mL/min
p erythrocytes 879 ± 55 mL/min 63 mL/min
Fig. A3.12 A–D Extracranial duplex assess-
ment of global CBF by measuring blood volume flow (BVF) in both ICAs and VAs. For
cross-sectional areas the vessel diameter (d)
derived from the longitudinal plane is used for
calculation, assuming a circular-shaped artery
(A = (d/2)
ICA: 320 and 300 mL/min. C, D BVF of the right
and left VA: 30 mL/min and 180 mL/min, respectively. In this case a global CBF of 830 ml/
min is calculated.
2
× π. A, B BVF of the right and left
Cerebral Circulation Time
A new, recently developed ultrasound technique is the
analysis of cerebral circulation times, similar to the wellknownmeasurementsinconventionalangiography.Itis
based on the ability to follow the intravascular distribution
of an intravenously applied echo-contrast bolus that is
able to traverse the pulmonary circulation. The published
nomenclature of circulation times is rather inconsistent.
Some authors use the term “transit time,” others use “circulation time,” while the points of analysis within the
vascular system and therefore the resulting circulation
times vary greatly (Table A3.2).
We recommend using “transit time” for artery-to-artery
analyses, and “circulation time” for arteriovenous assessments. A global cerebral circulation time (gCCT), i. e., the
timethebloodneedstopassthroughthebrain,canbe
assessed if the time-delay of bolus arrival between the
extracranial ICA and the extracranial internal jugular
vein (IJV) is measured. This can be achieved by either a
Doppler or duplex sonographic approach.
Doppler sonographic gCCT can be assessed if two 2-MHz
probes are fixed to the neck, one ipsilateral registering the
ICA, the other analyzing the dominant contralateral IJV,
with simultaneous ongoing recording. Changes of Doppler
signal intensity during bolus arrival can be transferred into
a time-intensity-curve (Fig.A3.13)(Hoffmannetal.2000,
3 Intracranial Hemodynamics and Functional Tests62
Tab l e A3 . 2 Published data on cerebral circulation time
Authors Method CCT definition CCT
Nylin et al. 1960
Fedoruk and Feindel 1960
Hedlund et al. 1966
Schurr and Wickbom 1952 Angiography CCA to venous drainage 5.4–12 s
Tönnis 1959 Angiography C3-ICA to venous drainage 4–8s
Okawara et al. 1974 Angiography C3-ICA to parietal veins 5.4 ± 0.5 s
Milburn et al. 1997 DSA C3-ICA to parietal veins 5.9 ± 0.8 s
Okada et al. 1999 DSA ICA to superior sagittal sinus 3.4 ± 0–1s
Hoffmann et al. 1998 Ultrasound ICA to IJV 5.5± 1.7 s
Puls et al. 1999a Ultrasound PCA to vein of Galen 1.4–5.8 s
Schreiber et al. 2002 Ultrasound ICA to IJV 7 ±1.3 s
Schreiber et al. 2003c Ultrasound ICA to IJV 7.5 ±1.1 s
For abbreviations, see text
32
p erythrocytes ICA to IJV 2–4.9 s
131
J erythrocytes ICA to IJV 7–10 s
131
J erythrocytes ICA to IJV 8.6± 0.3 s
Fig. A3.13 Extracranial dopplersonographic measurement of the
global cerebral circulation time, same subject as in Fig. A03.12.
A bolus arrival in the left ICA B bolus arrival in the right IJV. The
white lines in each spectrum indicate the time-intensity-curves of
the recorded maximal intensities. Global cerebral circulation time,
calculated as the difference between the turning points of both
curves, is 5.4 s. The global cerebral blood volume (CBV), derived
from Fig. A3.12: global CBF (830 mL/min = 13.8 mL/s) × global cerebral circulation time (5.4 s) = global CBV (74.3 mL)
Schreiber et al. 2002). A duplex sonographic global CCTcan
be assessed by unilateral longitudinal or cross-sectional
imaging of the ICA and IJV (see Fig. A3.14 and video)
(Schreiber et al. 2003c). Normal values in healthy individuals are reported between 5.3 s and 10.1s. A marked reductioninglobalCCTcanbeobservedinpatientswith
arteriovenous malformations (AVMs) or occipital dural
fistulas (Schreiber et al. 2002, Schreiber et al. 2004). Prolongation of global CCT has been shown in patients with
vascular and Alzheimer dementia (Schreiber et al. 2005).
Regional duplex sonographic circulation times defined as
Fig. A3.14 Extracranial duplex sonographic measurement of the
global cerebral circulation time using power-mode imaging in two
different subjects. Top: Longitudinal imaging plane. Bottom: Crosssectional imagingplane. ICA = internal carotid artery; ECA =external
carotid artery; IJV = internal jugular vein. A, D Baseline images. B,
E Arterial contrast filling. C, F Venous contrast filling.
the contrast bolus arrival time between the PCA and the
vein of Galen were shown to be prolonged in patients with
vascular dementia and CADASIL, as well as in acute stroke
patients (Liebetrau et al. 2002, Puls et al. 1999a, 1999b,
Ruprecht-Dörfler et al. 2002). Despite these interesting
clinical applications, the discriminatory power of the
method seems actually to be too low for routine clinical
application outside of study settings.
Parameters of Cerebral Hemodynamics 63
Tab l e A3.3 Cerebral blood volume (CBV) data. Depending on the appliedmethod, either relativeor globalvalues are given. Valuesin italics are
calculated data, assuming an average brain weight of 1400 g (Ho et al. 1980)
Authors Method Relative CBV Global CBV
32
Nylin et al. 1961
Grubb et al. 1978 PET 4.3 ± 0.4 mL 60 ml
Phelps et al. 1979 PET 4.2 ± 0.4 mL 59mL
Sakai et al. 1985 SPECT 4.8 ± 0.4 mL 67 mL
Reinstrup et al. 2001 SPECT 4.3 ± 0.6 mL 60 mL
Steiger et al. 1993 CT 5.8 ±1.2 mL 82 mL
Muizelaar et al. 1997 CT 6.1 ± 0.9 mL 85 mL
Rempp et al. 1994 MRT 6.6 mL 92 mL
Vonken et al. 1999 MRT 5.6 mL 78 mL
Elwell et al. 1994 NIRS 2.9± 1mL 41 mL
Doepp et al. 2003 Ultrasound 5.5 mL 77 ± 13 mL
p erythrocytes 6.9 mL 97 ±6mL
Cerebral Blood Volume
Provided that the above two parameters, global CCT and
globalCBF,areknowninanindividualsubject,anewultrasound parameter, the global cerebral blood volume (CBV)
can be calculated as a simple bedside parameter if the
central volume principle is applied (Celsis et al 1985, Hedlund et al. 1966):
CBV (mL) = CCT (s) × CBF (mL/min) (Figs A3.12, A3.13).
CBV is the total amount of blood in the skull at a given
time. Normal values determined with ultrasound in
healthy subjects are around 77 ±13 mL (Doepp et al.
2003) (Ta b l e A 3 . 3 ). Interestingly, controlled hyperventilation in these subjects leads to a distinct decrease in CBF and
increased CCT but with a nonsignificant trend toward a
reduced CBV. As a simple bedside test, the method has the
potential to help characterize the hemodynamic state of
patients in danger of raised intracerebral pressure, such as
those with head trauma, intracranial hemorrhage, or
global cerebral hypoxia.
Part A: Principles and
Rules
64
4
Pathogenesis of Stroke
Arterial Ischemia ............................... 64
Pathophysiology ................................ 64
ClassificationofArterial Stroke.................... 65
Microembolic Signals ........................... 72
Arterial Ischemia
Pathophysiology
The pathophysiological correlate of cerebral ischemia is
the inadequate delivery of glucose and oxygento the brain.
This is caused by a critical reduction of cerebral blood flow
(CBF), mostly due to occlusion of a brain-supplying vessel.
On the basis of early animal studies (Astrup et al. 1981,
Heiss 1983) and positron emission tomography (PET) analyses in acute stroke patients (Baron 1999) a “three compartment” model of stroke comprising different degrees of
CBF reduction has been developed. The three compartments of the model are: the ischemic core, the penumbra,
and a surrounding region of oligemia (Fig. A4.1). CBF
withintheischemiccoreis<20%ofnormalvalues
(< 10 mL/100 mg/min) which leads to an irreversible tissue
damage. The core is surrounded by the penumbra—an
inhomogeneous zone with a critical reduction down to
Fig. A4.1 Schematic drawing of the three compartments ofcerebral
ischemia: 1 = ischemic core (cerebral blood flow [CBF] < 10 mL/
100 mg/min); 2 = penumbra (CBF 10–20 mL/100 mg/min); 3 = oligemia (CBF 20–50 mL/100mg/min).
SpontaneousMicroemboli........................ 72
Detection of Microemboli in Patent Foramen Ovale . . 74
Venous Ischemia ............................... 74
20–40 % of normal CBF values (10–20 mL/100 mg/min),
which is below the functional threshold but above the
threshold for morphologic integrity. Depending on the
pace and magnitude of reperfusion and the functionality
of collaterals, the flow in the penumbra may either completely normalize without induction of structural damage
and improvement of clinical symptoms, or it may further
decease and lead to an enlargement of the ischemic core.
The penumbra itself is surrounded by a region of oligemia
with only mildly reduced CBF values (20–50 mL/100 mg/
min) which is equally influenced by the above factors. In
addition, the time factor is as important as the magnitude
of malperfusion. Within 3 hours of stroke onset a penumbra can be found in the majority of patients which may
persist for more than 16 hours (Baron 1999).
For analysis of the ischemic penumbra in a clinical setting, modern magnetic resonance imaging (MRI) using
diffusion-weighted (DW) and perfusion-weighted imaging (PWI) has almost completely replaced the PET technique. The MR-defined penumbra is determined by the
mismatch between the area of impaired diffusion (= ischemic core) and the area of impaired perfusion (DWI-PWI
mismatch). However, there are some methodologic peculiarities of MRI that need to be considered. Not all areas
with impaired diffusion will result in infarction. In fact,
there is some regression of the MRI-defined infarct core in
up to 20 % of cases within a 6-hour time window (Fiehler et
al.2004).Furthermore,MRIandPET-definedpenumbrais
not congruent although an MRI-determined time-to-peak
(TTP) delay between 4 and 6 seconds seems to correspond
well with a PET-derived CBF <20mL/100mg/min (Heiss
et al. 2004).
Despite these shortcomings, the MRI mismatch concept
allows us to sufficiently identify the brain tissue with
critically low perfusion and therefore enables selection of
patients with regard to, for example, systemic thrombolysis within the 3–6-hour time window.