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Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
Intracranial Hemodynamics and Functional Tests
79
Analysis of Cerebral Blood Flow . . . . . . . . . . . . . . . . . 79
Autoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Testing of Autoregulation . . . . . . . . . . . . . . . . . . . . . . . 81
Neurovascular Coupling . . . . . . . . . . . . . . . . . . . . . . . 82
Testing of Neurovascular Coupling . . . . . . . . . . . . . . . . 82
Metabolic Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Testing of Metabolic Coupling . . . . . . . . . . . . . . . . . . . 83
Other Tests to Assess Diff erences Between
the Right and Left Sides as Markers of Impaired
Collateral Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Analysis of Cerebral Blood Flow
In contrast to many other organ systems, the human brain
has several characteristics that are important in analyzing and interpreting cerebral perfusion. At rest, the brain
receives a high proportion of the total cardiac output—in
the order of 15–20%. The global cerebral blood fl ow (CBF)
in an adult amounts to 700–800 mL/min, i.e., 13 mL/s or
55 mL/100 mg per minute assuming a brain weight of
1,400 g. About of 75% of the global CBF derives from the
internal carotid arteries (ICAs) and the remaining 25%
from both vertebral arteries (VAs) (Schöning et al 1994).
The ideal way to assess brain perfusion would be to
analyze CBF directly. However, conventional Doppler fl ow
velocity examination only generally permits fl ow velocity
analysis of proximal arterial or venous vessel segments.
CBF and fl ow velocity are not equal but correlate strongly
with one other. A rising CBF causes rising blood fl ow veloc-
ities, and a low CBF correlates with low blood fl ow veloci-
ties. However, there are other important factors that have
to be considered: Flow velocity correlates with the size of
a vessel’s vascular territory despite the fact that the vessel’s diameter is adapted to it. For example, fl ow velocities
in the middle cerebral artery (MCA), which supplies the
largest cerebral territory, are higher than in the anterior
cerebral artery (ACA) and posterior cerebral artery (PCA).
In the anatomic variation with one A1-ACA segment providing blood supply to both ACA territories, its fl ow veloc-
ity is similar to or even higher than that of the ipsilateral
M 1 - M C A .
Flow velocity also depends on vessel size. Local vessel
narrowing will lead to increased velocities. Vessel dilatation,
Parameters of Cerebral Hemodynamics . . . . . . . . . . 86
Cerebral Blood Flow Velocity . . . . . . . . . . . . . . . . . . . . . 86
Resistance Indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Cerebral Blood Flow Volume . . . . . . . . . . . . . . . . . . . . . 86
Cerebral Circulation Time . . . . . . . . . . . . . . . . . . . . . . . 87
Cerebral Blood Volume . . . . . . . . . . . . . . . . . . . . . . . . . 88
for example in hypertensive dilative vasculopathy or aneurysm formation, results in decreased fl ow velocities.
Other factors have more general eff ects. Anemia leads
to a generalized increase of fl ow velocities. Flow veloci-
ties tend to decrease with increasing age, which is mainly
attributed to brain parenchymal loss and subsequent reduction of CBF but also to vessel dilation. Under pathologic
conditions chronological aspects have to be considered. For
example, acute-phase fl ow assessment in ischemic stroke
with intracranial large-vessel occlusion often shows reduced fl ow velocities in the preocclusive vessel segments.
In the subsequent hyperemic phase after recanalization,
increased velocities can be seen. However, the fi nal or
chronic state might show a reduction of fl ow velocity and
an increase of pulsatility, depending on the extent of the
remaining parenchymal defect (“no brain, no fl ow”).
As brain tissue has virtually no energy reserves, changes
in perfusion lead to an immediate alteration in brain function. Therefore, many regulatory processes (these are listed
and discussed below) exist to ensure a continuous and constant blood supply. Probably more than any other organ system, the brain needs to be constantly perfused for optimal
function. However, the heart, which is responsible for blood
supply and blood drainage, is a pulsatile pump. The arteries are the solution to this problem: with their elastic vessel
walls they are capable of storing a considerable amount of
blood during the systolic phase that is then released into the
circulation during diastole (Windkessel function). This leads
to an almost continuous blood fl ow in the periphery.
For easier understanding of the fl ow pattern seen dur-
ing insonation of proximal arteries, we now introduce a
simple model (Fig. A3.1). A fi lled rain barrel discharges
80 3 Intracranial Hemodynamics and Functional Tests
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
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 fi lled water barrel. Opening (systole) and
closing (diastole) of the tap results in a pulsatile fl ow within the
pipe. Ultrasound analysis will detect fl ow in systole only and there
will be an absence of fl ow in diastole.
water through a rigid pipe. To imitate the pulsatile action
of the heart, a tap placed at the beginning of the pipe is
repeatedly opened and closed. Flow analysis, in analogy to ultrasound analysis of proximal arterial blood vessels, is performed in the central segment of this pipe.
The measured fl ow is pulsatile, with a high fl ow velocity
when the tap is open (systole) and no fl ow when the tap
is closed (diastole). If an elastic hose is used instead of a
rigid pipe the fl ow profi le will look diff erent, i.e., more like
the arterial blood fl ow profi le in nonparenchymal organs
(Fig. A3.2). When the tap is closed the elastic hose allows a
continuous fl ow comparable with the arterial Windkessel
function. If a second peripheral tap is added to the system,
a microcirculation (as found in parenchymal organs such
as the brain and kidneys) can be introduced into the model
(Fig. A3.3): A reduction of outfl ow (microcirculation tap
almost closed) will lead to reduced systolic fl ow velocities
but distinctly lowered diastolic fl ow velocities and subse-
quently higher pulsatility. Opening of the microcirculation
tap will lead to a reduction in peripheral resistance, resulting in slightly higher systolic fl ow velocities and distinctly
higher diastolic velocities, i.e., reduced pulsatility.
In addition to the mechanisms explained above, the
Doppler waveform and pulsatility are also modulated by
the quality of cardiac function, which can be altered by
conditions like atrial fi brillation, congestive heart failure,
aortic valve stenosis, insuffi ciency, or cardiomyopathy
(Fig. A3.4 and Fig. A3.5).
Heart Macrocirculation Microcirculation
1
closedclosed
openopenTap 1:
Fig. A3.2 Model of the pulsatile pump function of the heart.
A water hose is connected instead of the pipe, analogous to the
arteries with their elastic vessel walls. During diastole, the diameter
of the hose decreases (not shown), modeling the Windkessel function, thus leading to a detectable diastolic fl ow.
Heart
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 fl ow but to a larger extent
the diastolic fl ow, resulting in high-pulsatility signals. Opening tap 2
increases the diastolic fl ow to a larger extent than the systolic fl ow,
resulting in low-pulsatility signals.
Macrocirculation Microcirculation
1
2
wide openTap 2:
circumstances the ICP at rest is ~10–15 mm Hg and the
resulting CPP is therefore only slightly lower than the ABP.
CBF = ABP/CVR (Ohm’s law of hemodynamics).
Autoregulation
In contrast to other organ systems, but analogous to
the kidney, the brain has an autoregulatory system that
e n s u r e s c o n s t a n t t i s s u e p e r f u s i o n . F a c t o r s t h a t i n fl uence
cerebral perfusion are the cerebral perfusion pressure (CPP
= mean arterial blood pressure [ABP] − intracranial pressure [ICP]) and the cerebrovascular resistance (CVR), determined by the functional status of the arteriolar vessels
of the cerebral microcirculation. Under normal physiologic
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., a dilation of the peripheral arterial vessels.
High blood pressure requires peripheral vasoconstriction.
As CBF is closely related to the blood fl ow velocities in the
main arteries supplying the brain, the above mechanism
will result in stable fl ow velocities during changes in blood
pressure (Diehl 2002). However, this mechanism only
works under physiologic conditions within a certain range
The above formula shows that CBF can be kept almost
81Autoregulation
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
ICA-L
MCA-R
Fig. A3.4 Doppler spectra selection of a patient with a high-grade
aortic valve stenosis (valve opening area 0.8 cm
systolic fl ow rise in all brain-supplying arteries, highlighted by red
bars (examples are given for the extracranial and intracranial anterior and posterior circulation).
V2-VA R
BA
2
). Note the delayed
of blood pressure (autoregulatory plateau), as changes in
the diameter of the peripheral arterial vessels only occur
over a certain range. Above and below this range the mechanism fails and blood pressure and CBF are directly coupled (Fig. A3.6). If regional autoregulation is abolished or
impaired, for example in ischemic stroke, this 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. For further
reading see also Chapter 5, “Collateral Pathways.”
CCA-L MCA-L
ECA-L
MCA-L
Fig. A3.5 Left: Doppler spectra selection (common carotid artery
[CCA], ECA, and MCA) of a patient with atrial fi brillation. Note the
diff erent fl ow velocities in each cardiac cycle caused by varying left
heart fi lling and subsequently varying left cardiac output. Right: Ex-
ample of blood fl ow in the MCA in a patient with a ventricular assist
device (VAD). Note the loss of pulsatility (68/54 cm/s) caused by the
constant fl ow of the VAD, modulated by the patient’s heartbeat.
Arteriolar
diameter
Normal
Autoregulatory
plateau
CBF
Normal
(mm Hg)15010050BP
Testing of Autoregulation
For cerebral functional and regulatory testing, the transcranial Doppler (TCD) method is preferred; ultrasound
probe holding systems are commercially available which
permit continuous 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. A3.7).
Several methods of autoregulatory testing by means of
blood pressure alteration have been proposed. Aaslid and
coworkers (1989) published a thigh-cuff method in which
sudden blood pressure drops can be induced. Two thigh
cuff s are infl ated above systolic blood pressure values for
more than 2 minutes, causing temporary leg ischemia. A
sudden cuff release results in leg hyperemia and an ~20%
systemic blood pressure drop lasting 10 seconds. In normal autoregulation, this maneuver leads to an initial reduction of blood fl ow velocity within the MCA. Compen-
satory autoregulatory fl ow increase starts after 1 second
and fl ow 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
Fig. A3.6 The relation of blood pressure (BP) and cerebral blood fl ow
(CBF) under physiologic conditions (red lines) and pathologic conditions (blue lines). Intact autoregulation leads to a constant CBF over
a wide pressure range (autoregulatory plateau) 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/small arterial diameter relation.
Fig. A3.7 Example of a holding device for continuous bilateral TCD
monitoring with two 2-MHz probes.
82 3 Intracranial Hemodynamics and Functional Tests
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
A
B
Fig. A3.8 TCD, t ranstem pora l ap proa ch, dis tal P2-PCA segment insonation. (A) Flow velocity with the subject’s eyes closed
(TAV
36 cm/s, PI 0.78). (B) Flow in the same vessel segment after
max
eye opening (TAV
56 cm/s, PI 0.5).
max
over 15 seconds, resulting in a transient blood pressure
reduction as well as a less pronounced temporary reduction of blood fl ow 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 result in
virtually direct changes of MCA fl ow velocity. Blood pres-
sure oscillations at lower frequencies led to phase-shifted
MCA velocity changes of up to 70°, i.e., an autoregulatory
response was observed (Diehl 2002, Diehl et al 1995).
All three reported methods have been shown to detect impaired autoregulation in patients with, for example, a highgrade ICA stenosis. So far, these methods are mostly used
in specialized centers either because additional continuous
blood pressure monitoring is required (thigh-cuff and Vals-
alva method) or because commercial evaluation software is
not available (spontaneous oscillation method).
Neurovascular Coupling
Coupling of activity and blood fl ow is a ubiquitous mech-
anism of all organ systems. In neurovascular coupling
of the brain, a raised metabolic demand, due to activation of particular brain regions, for example, leads to an
increase of blood fl ow and a proportional rise of blood
fl ow velocity. A typical example of this mechanism is
the use of a visual stimulus paradigm under continuous insonation of the PCA (Fig. A3.8). While the detailed
translational mechanisms from activated brain cells to
increased fl ow are still being extensively studied, the ef-
fector mechanism is a dilatation of the peripheral arteries
(resistance vessels), i.e., the microcirculation, which leads
to a fl ow 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
A
DE
Fig. A3.9 Setup and results of visual evoked Doppler studies.
(A) Goggles with integrated light emitting diodes for visual stimulation with diff erent fl ash frequencies. Holding system for two
TCD pr obes, adj usted for both P CAs . (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 (fl icker 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.
B
C
which repetitive visual stimuli are used and the fl ow
velocity in the PCA is analyzed. As a stimulus, a fl ash-
ing light or any other standardized visual stimulus
that can be applied by means of a computer screen
can be used. To improve signal-to-noise ratio, repetitive averaging, comparable to the electric visual evoked
potential, is 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. A3.9). For
evaluation, the baseline velocity is adjusted to 100%
and the fl ow increase assessed in percent over base-
line levels. From these curves, peak increase and time
to peak can be derived and used for evaluation. Diehl
and Berlit 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 studying the physiology of neurovascular coupling (Rosengarten et
al 2006) this method has also
been used to study anterior and posterior circulation
cerebral ischemia (Lin et al 2011), in diff erent states of
brain dysfunction including suspected vegetative states
(Becker et al1996), migraineurs (Thie et al 1990, Peca
et al 2013), amyloid angiopathy (Smith et al 2008), and
more recently, pre-eclampsia (Janzarik et al 2014).
Instead of the visual stimulus paradigm, diff erent
stimuli may be used for analysis and measurements of
other basal cerebral arteries. However, as the amplitude of the vascular reaction is smaller, higher numbers of averaged repetitive cycles are usually required
to separate the signal from the background noise. Studies analyzing diff erent cognitive activation tasks have
been published looking into MCA and ACA activation
patterns (Bracco et al 2011, Boban et al 2014a, 2014b).
83Metabolic Coupling
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
An example of a clinical application is the determination of language lateralization by bilateral assessment
of MCA fl ow velocities during a cued word generation
task (Knecht et al 1998).
Metabolic Coupling
Metabolic coupling is a ubiquitous mechanism whereby
changes of CO
sues lead to changes in perfusion and fl ow velocity. CO
as a waste product of cell metabolism is a strong vasodilator. Increases in pCO
CBF and velocity, whereas low pCO
to a fl ow reduction and decreased velocities (Fig. A3.10).
Again, the eff ector mechanism is the change in cross-sec-
tional area of the peripheral resistance arteries in the microcirculation (see Fig. A3.6). 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 pCO
itoring of both MCAs using fi xed probes, although a few
studies also report on CO
ity of the basilar artery or posterior circulation (Barrett
et al 2001, Hong et al 2010, Park et al 2003). Under the
assumption that the diameter of the studied vessel, i.e.,
of both M1-MCAs or of the BA, remains almost constant
during pCO
et al 1998), the hypercapnia-induced peripheral dilation
leads to a directly correlating rise of fl ow velocity in more
proximal vessel segments. Baseline levels are commonly
set as 100%, and any increase or decrease in fl ow is docu-
mented as a relative change in percent. Under physiologic
conditions, MCA fl ow velocity can be reduced to 50% be-
low baseline fl ow velocity during hypocapnia and may
partial pressure (pCO2) in the body tis-
2
(hypercapnia) will lead to raised
2
. Most reports are of the mon-
2
-modulated vasomotor reactiv-
2
changes (Huber and Handa 1967, Valdueza
2
(hypocapnia) leads
2
rise up to 200% above baseline values under hypercapnia. Similar VMR results have been shown in the posterior circulation. A linear relation exists within a range of
30–70 mm Hg pCO
The following sections briefl y describe the main pub-
(see Fig. A3.10).
2
lished CVR tests.
Breath-holding Index
The patient is asked to hold his or her breath for at least
2
30 seconds during continuous M1-MCA fl ow velocity
monitoring. Index calculation is shown in Fig. A3.11.
N o r m a l v a l u e s a r e 1 . 2 ± 0 . 6 % / s . C a p n o m e t e r r e c o r d i n g s
are not required, but the sensitivity of the test is low
(Markus and Harrison 1992).
Hyperventilation (Apnea 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 diff erence
greater than 15% argues against a relevant impairment of
CVR (Widder and Görtler 2004).
CO2 Inhalation Test
The test consists of controlled inhalation of a CO2- enriched
gas mixture, e.g., carbogen gas (5% CO
latter leads to an increase of about one volume% CO
within the air fl ow of the studied subject. Volume percent
and pCO
on the current atmospheric pressure and the height
do not directly correlate as the latter depends
2
above mean sea level. However, the above estimation is
suffi cient to be applied as follows: The reported mean
fl ow increase per volume percent is 23 ± 5% (Widder
al 1986). As a clinical cut-off we recommend using the
et
mean − 2 SD = ~10%. Flow increases below 10% should
, 95% O2). The
2
2
A
200
%
Breath-holding index (BHI)
– V
V
apnea
V
baseline
× t
baseline
apnea
×
BHI
=
100
B
100
C
50
30 70 pCO
Fig. A3.10 Left: Doppler spectra analysis of the MCA in a single
subject during (A) hypoventilation (end-tidal CO
145/85 cm/s); (B) normoventilation (end-tidal CO
115/55 cm/s); and (C) controlled hyperventilation (end-tidal CO
55 mm Hg,
2
40 mm Hg,
2
25 mm Hg, 91/30 cm/s). Right: Schematic of the relation between
end-tidal CO
and MCA blood fl ow velocity.
2
2
Fig. A3.11 Calculation of the breath-holding index (BHI) and the
cerebrovascular reactivity (CVR) according to the CO
test and acetazolamide test. V = fl ow velocity.
2
inhalation test / acetazolamide test
CO
2
CVR
V
CO2/acetazolamide
=
V
baseline
– V
baseline
×
100 (%)
inhalation
2
84 3 Intracranial Hemodynamics and Functional Tests
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
therefore be evaluated as impaired CVR. In our experience, older patients in particular might become anxious
or uncomfortable with inhalation of the gas, and we recommend using the acetazolamide test described below.
In addition, CO
with severe pulmonary disease or dyspnea.
inhalation should be avoided in patients
2
Acetazolamide Infusion Test
Acetazolamide is a carbonic anhydrase inhibitor, which
if administered intravenously, results in a local increase
. Acetazolamide 1 g (for optimal standardized test:
of CO
2
15 mg/kg body weight) is slowly injected into a peripheral
vein, and the blood fl ow velocity in the MCA is monitored
over 15 minutes. Baseline fl ow velocities are set as 100%
(Fig. A3.11). Mean fl ow increase caused by acetazolamide
is 38 ± 15% (Widder and Görtler 2004). As a clinical cutoff we recommend using the mean – 2 SD = ~10%. There-
fore a fl ow increase below 10% should be considered as
impaired CVR, which is comparable with the CO
tion test. Unwanted side eff ects of acetazolamide injec-
tion are oral dysesthesias, headaches, dizziness, nausea,
or vomiting. Younger patients tend to be more sensitive
to these side eff ects, so we recommend using the CO
inhalation test as the fi rst-line test in these 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 CVR with
both tests may result in preserved or impaired reactivity. A decrease of fl ow 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 suffi cient for reliable fl ow velocity
monitoring, i.e., an exact fi tting 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, single photon emission computed tomography (SPECT) should be considered. While
its principle—blood fl ow measurements at rest and during
acetazolamide provocation—is the same, SPECT directly
visualizes the parenchymal perfusion pattern. Usually a
radioactive tracer, such as 99 mTc, is administered intravenously, and its distribution throughout the brain assessed
by a gamma camera system. In healthy subjects, the regional CBF increases by a factor of 1.7 (Sullivan et al 1987).
In patients with extracranial or intracranial stenoses different perfusion patterns can be found:
• Type 1: normal baseline and normal acetazolamide-
activated fl ow.
• Type 2: normal baseline and impaired activated fl ow.
• Type 3: impaired baseline but normal activated fl ow.
• Type 4: impaired resting and activated fl ow.
Impaired CVR tends to be associated with either leptomeningeal or extra-intracranial collateral pathways, such as
via the ophthalmic artery (Ozgur et al 2001, Smith et al
1994). SPECT and Doppler-derived CVRs have been shown
inhala-
2
to correlate highly, yielding similar results in patients
with ICA stenosis (Engelhardt et al 2004). Because of its
r e s t r i c t e d a v a i l a b i l i t y , h i g h e r c o s t s , a n d g r e a t e r p e r s o n n e l
requirements, SPECT is reserved for selected patients only.
More recently, MRI and CT perfusion studies, analyzing
CBF, cerebral blood volume (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 signifi cant
correlations between the techniques (Bisdas et al 2006, A.
Chen et al 2006, Endo et al 2006, Grandin et al 2005, Ma et
al 2007). As yet 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.
L-Arginine Infusion Test
L-Arginine is an amino acid which promotes cerebral endothelial cell derived nitrite oxide (NO) liberation and
subsequent vasodilatation mediated via the endothelial
smooth muscle layer. As L-arginine infusion has been reported not to aff ect CO
action is not identical. Direct comparative studies do not
2
exist, but the L-arginine reaction is supposed to provide a
concentrations, the mechanism of
2
more direct picture of endothelial cell function or dysfunction. For example, a diminished L-arginine reaction can be
seen in lacunar infarction and also in other vascular risk
factors like hypertension or diabetes. The test has also been
used to analyze medication-induced changes of endothelial
function, e.g., L-arginine reactivity is improved after statin
treatment in hypertensive patients (Pretnar-Oblak 2014).
Other Tests to Assess Diff erences Between the
Right and Left Sides as Markers of Impaired
Collateral Function
Delayed contrast fi lling of the MCA is a well-known phe-
nomenon in conventional angiography in patients with
ipsilateral extracranial ICA occlusion. It is considered to
present insuffi cient collateralization via the anterior and/
or posterior communicating arteries (Boczko and Caplan
1967, Huber 1982) (Fig. A3.12B). It has also been recently
reintroduced to measure cerebral hemodynamics in ICA
balloon occlusion test. Here a delay on the occluded side
measured between the MCA and a cortical vein was
~1.7 seconds (Sato et al 2014).
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 diff erences between
echo-contrast bolus arrivals in the MCAs. Studies have
been reported using either Levovist (Schering) or SonoVue
(Bracco). Only the latter remains currently commercially
available (as Lumason in the United States). The technical setup is the same as for the above described TCD
AB
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
85Metabolic Coupling
Right Left
Right MCA
Left MCA
Flow velocity (cm/s)
Doppler intensity (arbitrary units)
Fig. A3.12 Top: Digital subtraction angiography (DSA) of a patient
with a left-sided 95% ICA stenosis. (A) Selective left CCA fi lling, lateral
view, stenosis marked with an arrow. (B) Aortic arch fi lling, posteroan-
terior projection. Contrast fi lling on the right side has already reached
the M2-MCA branches. On the left side, only the proximal M1-MCA is
visible, fi lling via retrograde A1-ACA fl ow. 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: Offl ine data analysis. Right MCA—raw data (dark gray) and poly-
nomial fi t (black line), left MCA—raw data (light gray) and polynomial
fi t (dashed line). The two red lines indicate the turning point of the
curves. Diff erence between the right and left MCAs is 0.96 seconds.
MCA delay = 0.96 s
Time (s)
CVR method with two fi xed 2-MHz ultrasound probes
c o n t i n u o u s l y a n a l y z i n g b o t h M C A D o p p l e r s p e c t r a ( s e e
Fig. A3.7). An intravenous contrast bolus is then administered and the contrast-induced signal rise in both Doppler spectra is registered. Time–intensity curves allow
determination of the actual diff erence between the right
and left sides in milliseconds (Fig. A3.12). Healthy individuals demonstrate mean delays of 0.16 ± 0.13 seconds
(range 0–0.48) while high-grade ICA stenoses reveal
delays of 1.16 ± 0.87 seconds. Of note, occlusions reveal
shorter delays of 0.61 ± 0.41 seconds indicating superiorly established collateral pathways (Gómez-Choco et al
2015). Applying receiver operating characteristic (ROC)
curve analysis, a cut-off value of 0.27 seconds diff eren-
tiates patients from controls with a diagnostic sensitivity
of 0.79 and a specifi city of 0.87.
Magnetic Resonance Imaging—Dynamic Arterial
Spin Labeling
Dynamic arterial spin labeling is a 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. A3.13).
Special advantages of the technique are the dynamic approach and its noninvasiveness, as contrast agents are not
needed. Its use is limited by the small fi eld of view, which
does not permit examination of all the arteries that supply the brain, and the short analysis period, which prohibits analysis of long-duration washout kinetics. Also,
there are limitations of spatial resolution, which do not
T
1
T
1
Fig. A3.13 Dynamic spin labeling MR angiography (MRA), circle
of Willis. Top: Healthy individual with equal fi lling of carotid
s i p h o n ( T
Patient with a left extracranial ICA occlusion. Note the absent
carotid siphon fi lling, in contrast to the opposite side (arrow in
T
rior communicating artery on the aff ected side (dotted arrow).
T
) and main branches of the circle of Willis (T2). Bottom:
1
and T2), and the delayed MCA fi lling via the ipsilateral poste-
1
= time 1; T2 = time 2.
1
T
2
T
2
permit sensitive analysis of vessel pathology or grades
of stenosis. However, it seems to be an excellent tool
for dynamic analysis of collaterals through the cerebral
arterial circle (circle of Willis) and subsequent hemodynamic eff ects (Mutke et al 2014, Warmuth et al 2005).
War muth and coworke rs analyzed 35 pati ents with unilateral ICA stenosis of varying degrees. They looked at
the time diff erence of arrival of the labeled blood bolus
in the intracranial ICA at the siphon and the MCA, using
a time resolution of 25 images per second. They found a
signifi cant correlation between the degree of stenosis and
the observed delay. The cut-off separating stenoses of less
than 70% from those of more than 70% (NASCET criteria)
was an ICA delay of 0.45 seconds, yielding a sensitivity
of 96% and a specifi city of 80%. In some patients, the ob-
served ICA delay persisted up to the MCA level. Successful
surgery or stent implantation led to normalized arterial
arrival times on the previously aff ected side (Warmuth et
al 2005). A good agreement between TCCS and dynamic
arterial spin labeling MR was reported in 12 patients with
obstructive carotid artery disease (Sallustio et al 2008). A
delay was also reported in 17 patients with ICA occlusion
which was longer if an unfavorable collateral status was
present (Bokkers et al 2008) while others could demonstrate parameter normalization, e.g., of the time-to-peak
measure after carotid surgery (MacIntosh et al 2011).
Magnetic Resonance Imaging—Contrast-enhanced
Perfusion Analysis
Perfusion MRI also allows analysis of the diff erences be-
tween the two sides after gadolinium injection, when
86 3 Intracranial Hemodynamics and Functional Tests
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
looking at the mean time-to-peak contrast enhancement.
A study of 18 patients with 50–69% ICA stenosis (NASCET criteria) presented a mean MTT delay of 0.49 seconds
(range 0–1.44 seconds 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
higher values of 0.7 seconds and 1.5 seconds respectively
(Apruzzese et al 2001).
Magnetic Resonance Imaging—Phase-contrast
Measurements
Cine phase-contrast MRI is a new technique which
permits one-plane analysis of selected vessels by
d e t e r m i n i n g p a r a m e t e r s l i k e s y s t o l i c fl ow and diastol-
ic fl ow as well as derived parameters like mean fl ow,
resistance, and pulsatility index in several time points
over the cardiac circle. Liu and coworkers published a
study analyzing blood fl ow changes induced by inha-
lation of varying concentrations of CO
individuals (Liu et al 2012). They observed a relatively
in six healthy
2
higher increase in diastolic fl ow than in systolic fl ow and
subsequently reduced pulsatility with increasing CO
concentrations (3%, 5%, and 7%) in both ICAs, the BA, and
two venous sinuses. A great advantage of this approach
is the option to analyze several vessel segments simultaneously. However, the segments have to be assessed
within the same plane, so “out of plane” vessels like the
MCA, ACA, or PCA would not be accessible. Also it is not
clear if the technique can be applied to smaller vessels,
as most clinical questions regarding quality of collateral
fl ow are addressed to vessels smaller and more distally
located than the BA.
Near-Infrared Spectroscopy (NIRS)—CVR
In short, the technique measures the tissue oxygen saturation of the cerebral microcirculation by analyzing
alterations of near-infrared light applied by specially designed optodes placed over the skull and passing
through the cortical brain regions. An increase in ETCO
leads to a characteristic increase of oxyhemoglobin and
brain-tissue oxygen saturation as well as a decrease of
deoxyhemoglobin (Terborg et al 2003). Combining TCD
and NIRS in patients with carotid artery disease, a positive correlation of TCD-derived breath-holding CVR
and tissue oxygen saturation was reported (Vasdekis et
al 2012). For more detailed information about the NIRS
technique and its application the reader is referred to
the literature (Obrig 2014).
Dynamic CT Angiography (CTA)
Approaches to the analysis of side-to-side diff erences of
cerebral hemodynamics have also been reported with
CT techniques. In dynamic three-dimensional CTA, using a rough time resolution of two images per second,
Matsumoto and coworkers demonstrated a time delay of
0.5–1 seconds in a patient with an extracranial ICA occlusion (Matsumoto et al 2007). Analyzing patients with
unilateral symptomatic ICA stenosis an MTT diff erence
of 1.4 seconds was detected within the MCA territory
whereas MTT within the PCA territory was only 0.2 seconds (Waaijer et al 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 earlier, the
Doppler spectrum is a mixture of diff erent velocities. For
analysis of velocity parameters, the fastest detectable velocities are used. For this purpose all ultrasound systems
fi t an envelope curve to the spectrum, from which the peak
systolic velocity (PSV) and the end-diastolic velocity (EDV)
can be calculated (see Chapter 1, “Doppler Shift and Flow
Veloc ity ” unde r “Ult ras ound P rin ciple s,” and Fig. A1.15).
From these two parameters, the time- averaged maximum
(TAV
velocity TAV
In TCD practice TAV
2
velocity (V
ume fl ow assessments and is also provided by almost
max
). A parameter that is important for vol-
mean
all ultrasound systems is the time-averaged mean velocity (TAV
above or below the baseline over at least three complete
), i.e., the mean of all frequencies occurring
mean
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 diff erent indices. Most frequently used
are the pulsatility index (PI = (PSV- EDV)/TAV
<1.0 in brain-supplying arteries, and the resistance index
(RI = (PSV-EDV)/PSV), usually <0.75.
Cerebral Blood Flow Volume
2
If the TAV
vessel segment (A, cm
duplex ultrasound, the blood volume fl ow (BVF) can be
calculated (BVF (mL/min) = TAV
alternatively use the term volume fl ow rate for BVF
and several ultrasound techniques have been applied
to measure it (Ratanakorn and Keandaoungchan 2012).
Thus if BVF calculations are being performed in both
ICAs and both VAs, the sum of volume fl ows reveals the
global CBF (Fig. A3.14). Ultrasound-derived data has been
shown to lie well within the range of data published by
other imaging techniques like SPECT, PET, radioactively
labeled erythrocytes, perfusion CT, or MRI (Table A3.1).
CBF alterations can be observed in several cerebral
d i s e a s e s , f o r e x a m p l e i n s t r o k e , d e m e n t i a , o r b r a i n d e a t h
(X. Liu et al 2014, Scheel et al 2000, Schöning et al 2005,
Schreiber et al 2005b). Volume fl ow can also be measured
by color M-mode imaging, yielding comparable results
(Ho and Metreweli 2000).
and the cross-sectional area of a defi ned
mean
= (PSV + 2EDV)/3) can be derived.
max
is often misleadingly named mean
max
max
2
) are measured by extracranial
× A). Some authors
mean
), which is
87Parameters of Cerebral Hemodynamics
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
AB
CD
Fig. A3.14 (A–D) Extracranial duplex assessment of global CBF
by measuring blood volume fl ow (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 arterial
cross-section (A = (d/2)
270 mL/min and 260 mL/min. (C,D) BVF of the right and left VA:
80 mL/min and 180 mL/min, respectively. In this case a global CBF
of 790 mL/ min is calculated. We recommend performing the diameter measurements without using the color mode to assure better
vessel wall delineation and higher accuracy. Here, color-mode imaging was used to illustrate the concept.
2
× π). (A,B) BVF of the right and left ICA:
Cerebral Circulation Time
An innovative dynamic ultrasound technique is the analysis of cerebral circulation times, similar to the wellknown measurements in conventional angiography
A3.1). It is based on the ability to follow the
(Video
intravascular distribution of an intravenously administered echo-contrast bolus that is able to traverse the pulmonary circulation. The terminology of circulation times
in the literature 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 time
the blood needs to pass through the brain, can be 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
ultrasound approach. Doppler ultrasound-derived gCCT
can be assessed if two 2-MHz probes are fi xed 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 plotted as a time–intensity curve
(Fig. A3.15) (O. Hoff mann et al 2000, Schreiber et al 2002).
A duplex ultrasound-derived gCCT can be assessed by unilateral longitudinal or cross-sectional imaging of the ICA
and IJV (see Fig. A3.16 and Video
A3.1) (Schreiber et al
2003c). Normal values in healthy individuals are reported
to be between 5.3 and 10.1 seconds. A reduction in gCCT
can be observed in patients with arteriovenous malformations (AVMs) or occipital dural fi stulas (Schreiber et al
2002, 2004). Similar results have recently been obtained
by others who analyzed bilateral ICAs and IJVs using a duplex sonographic gray-scale analysis of gCCT (X. Liu et al
2014). They found a shorter gCCT of 3 ± 0.6 seconds (range
2.2–4 seconds) in patients with AVM and a value of 6.2 ±
1.4 seconds (range 4.2–10.8 seconds) in healthy individuals. Prolongation of gCCT has been shown in patients with
vascular and Alzheimer’s dementia (Schreiber et al 2005b),
in patients with multiple sclerosis (Mancini et al 2012),
and in patients with idiopathic intracranial hypertension
(Sander et al 2011). Regional duplex ultrasound-derived
circulation times, defi ned as the contrast bolus arrival
Table A3.1 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 1,400 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
S
hirahata et al 1985 SPECT 784 mL/min 56 ± 7 mL/min
Waldemar et al 1991 SPECT 756 mL/min 54 ± 9 mL/min
Huang et al 1983 PET 588 mL/min 42 ± 8 mL/min
Steiger et al 1993 CT 700 mL/min 50 ± 13 mL/min
Nylin et al 1961
Schöning et al 1994 Ultrasound 701 ± 104 mL/min 50 mL/min
Dörfl er 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 2005b Ultrasound 733 ± 54 mL/min 52 mL/min
X. Liu et al 2014 Ultrasound 760 ± 159 mL/min 54 mL/min
32
P erythrocytes 879 ± 55 mL/min 63 mL/min
88 3 Intracranial Hemodynamics and Functional Tests
Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers
All rights reserved. Usage subject to terms and conditions of license.
A
B
Fig. A3.15 Extracranial Doppler ultrasound-derived measurement of the global cerebral circulation time, same subject as in
Fig. A3.14. (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 diff erence between the turning
points of both curves, is 5.4 seconds. The global cerebral blood volume (CBV) can be derived from Fig. A3.14: global CBF (790 mL/
min = 13.2 mL/s) × global cerebral circulation time (5.4 seconds) =
global CBV (71.3 mL).
Table A3.2 Published data on cerebral circulation time
Authors Method CCT defi nition CCT
32
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
Toennis and Scheifer 1959 Angiography C3-ICA to venous drainage 4–8 s
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 ± 0–1 s
O. Hoff mann et al 2000 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
X. Liu et al 2014 Ultrasound ICA to IJV 6.2 ± 1.4 s
P erythrocytes ICA to IJV
131
I erythrocytes ICA to IJV 7–10 s
131
I erythrocytes ICA to IJV 8.6 ± 0.3 s
Fig. A3.16 Extracranial duplex ultrasound-derived measurement
of the global cerebral circulation time using power-mode imaging in two diff erent subjects. Top: Longitudinal imaging plane.
Bottom: Cross-sectional imaging plane. ICA = internal carotid
artery; ECA = external carotid artery; IJV = internal jugular vein.
(A,D) Baseline images. (B,E) Arterial contrast fi lling. (C,F) Venous
contrast fi lling. Note the delayed signal increase in the IJV ~6 seconds
after arterial fi lling.
A
IJV
ICA
DE
IJV
ECA
ICA
BC
F
time between the PCA and the great cerebral vein (vein of
Galen), were shown to be prolonged in patients with vascular dementia and CADASIL, as well as in patients with
CBV can be calculated as a simple bedside parameter if
the central volume principle is applied (Celsis et al 1985,
Hedlund et al 1966):
acute stroke (Liebetrau et al 2002, Puls et al 1999a, 1999b,
Ruprecht-Dörfl er et al 2002). Despite these interesting
CBV (mL) = CCT (s) × CBF (mL/min) (Figs. A3.14 and A3.15).
clinical applications, the discriminatory power of the
method is currently too low for routine clinical application
outside of study settings.
CBV is the total amount of blood in the skull at a giv-
en time. Normal values determined by ultrasound in
healthy subjects were 77 ± 13 mL in our case series
Cerebral Blood Volume
Provided that the above two parameters, global CCT and
global CBF, are known in an individual subject, the global
(Doepp et al 2003) and 74 ± 19 mL in a recent publica-
tion by Liu and coworkers (X. Liu et al 2014). Both find-
ings are congruent with the results of other radiologic
modalities (Table A3.3). Controlled hyperventilation
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