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Microembolus detection by transcranial doppler sonography
Ralf Dittrich �, Martin A. Ritter, Dirk W. Droste
Klinik und Poliklinik fur Neurologie, Universitatsklinikum Munster, Albert-Schweitzer-Str. 33, D-48129 Munster, Germany
Abstract
Microembolic signals can be detected by transcranial ultrasound as signals of high intensity and short duration.
These signals represent circulating gaseous or solid particles. To optimize the differentiation from artefacts and the
background signal and to facilitate the clinical use, several attempts have been made to automatize the detection of
microemboli. Microemboli occur spontaneously in various clinical situations but their clinical impact and possible
therapeutical implications are still under debate. This article provides a review of the actual literature concerning the
current state of technical and clinical aspects of microembolus detection.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Microembolus detection; Doppler sonography; Properties
1. Introduction
Microembolic signals (MES) appear as signals of
high intensity and short duration within the
transcranial Doppler (TCD) frequency spectrum,
resulting from thedifferent acoustic properties of the
underlying microemboli (ME) compared with the
circulating blood (Spencer et al., 1990; Markus et al.,
1993a, 1994a; Droste and Ringelstein, 1998; Droste
et al., 1998a; Markus et al., 1994b). MES have been
proven to represent solid or gaseous particles within
the blood flow (Markus et al., 1994b; Russell et al.,
1991;MarkusandBrown,1993).Sincetheywerefirst
described in humans by Spencer et al. (1990)
numerous studies had been performed to evaluate
(a) the origin and composition of ME, (b) the
occurrence in different sets of patients, (c) the
technical modalities in the detection of MES (d) and
the predictive and clinical value of MES.
This article provides an overview about the
development and current state of technical and
clinical aspects of ME detection.
2. Characteristics of MES
During TCD monitoring, MES can be detected
as an unidirectional intensity increase within the
Doppler frequency spectrum (cf. Fig. 1). MES
occur at random within the cardiac cycle and they
can be acoustically identified by a characteristic
‘chirp’, ‘click’ or ‘whistle’ sound. In-vitro andanimal models have demonstrated that MES
correspond to circulating particles because they
only occurred when a previously introduced par-
ticle passed the sample volume of the ultrasound
probe (Droste et al., 1994a; Markus et al., 1994b;
Russell et al., 1991; Markus and Brown, 1993;
� Corresponding author. Tel.: �/49-251-834-7955; fax: �/49-
251-834-8181
E-mail address: dittrir@gmx.de (R. Dittrich).
European Journal of Ultrasound 16 (2002) 21�/30
www.elsevier.com/locate/ejultrasou
0929-8266/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 9 2 9 - 8 2 6 6 ( 0 2 ) 0 0 0 4 6 - 0
Markus et al., 1993b; Molloy and Markus, 1996).
In some conditions, MES correspond to gaseous
microbubbles, e.g. due to cavitation at mechanical
heart valves (Kaps et al., 1997) or gaseous ultra-
sound contrast agents, like Echovist† (Droste et
al., 1999b). In other conditions, MES most likely
correspond to solid particles such as platelet-rich
aggregates, atheromatous material or fat. This was
shown, when ME of this composition were intro-
duced into the aorta of rabbits. Similar signals as
known from humans could be produced and were
found downstream to the introduction site (Rus-
sell et al., 1991). Histological examination of
carotid endarterectomy specimens from patients
with carotid artery occlusive disease suggest that
MES in these patients correspond to platelet- and
fibrin-rich particles originating from the athero-
sclerotic plaque (Babikian et al., 1994a).
The duration of MES within the Doppler
spectrum is between 1 and 100 ms. In general,
faster circulating ME appear visually as shorter
signals (‘vertical line’) in the Doppler spectrum
than slower ME, which have a longer horizontal
extension on the time axis due to their longer stay
within the borders of the Doppler sample volume(Droste et al., 1994b).
3. Size and composition of ME
More intense signals, e.g. originating from
prosthetic heart valves tend also to be longer in
duration compared with signals originating from
carotid occlusive disease (Droste et al., 1999a). Ithas been shown that the MES in patients with
prosthetic heart valves are mainly gaseous and
most likely correspond to nitrogen bubbles be-
cause inhalation of oxygen leads to a decline of
MES in these patients (Droste et al., 1997a; Kaps
et al., 1997). Gaseous particles have a higher
acoustic impedance than solid particles compared
with the circulating blood. Therefore, these parti-cles have a higher degree of ultrasound backscatter
and this leads to signals of higher intensity. The
gaseous particles emerge because the pressure
gradient at mechanical heart valves result in
cavitation gas bubbles. The underlying mechanism
of the reduction of MES is the higher propensity of
Fig. 1. MES within the TCD frequency spectrum of right the middle cerebral artery in a patient with carotid occlusive disease.
R. Dittrich et al. / European Journal of Ultrasound 16 (2002) 21�/3022
oxygen to remain in solution than nitrogen. Afteroxygen inhalation, oxygen replaces nitrogen in the
blood and it is supposed that less microbubbles
emerge and the microbubbles redissolve more
rapidly.
When comparing solid emboli consisting of
different materials, platelet aggregates give weaker
MES as atheroma particles of identical size
(Markus and Brown, 1993). Due to the differencesin the backscattering properties, no reliable con-
clusion as to the composition and the size of an
embolus can be drawn from the embolus’ signal.
The size of ME that results in detectable MES is
dependant on the material. Artificial particles
made of thrombotic material, platelet aggregates,
atheroma or fat with a diameter of 400�/1800 mm
introduced into the blood circulation of a rabbitcould be detected (Russell et al., 1991). In a sheep
model, ME with a diameter of 200 mm could be
visualized (Markus et al., 1994b). Ultrasound
contrast agents like Levovist† and Echovist†
composed of gas bubbles with a standardized size
of about 3 mm also appear as MES. Therefore, the
size of ME occurring in humans is supposed to be
in the range of 0.1�/500 mm.A recently marketed approach to differentiate
gaseous from solid ME using emission of two
different ultrasound frequencies (DWL, Sipplin-
gen, Germany) requires further verification in
clinical settings before it can be recommended
for routine clinical use.
4. Technical parameters and instrumentationsettings
Various technical parameters influence record-
ing and MES detection quality. In order to
standardize the technique and to make results
from different research groups comparable, the
International Consensus Group on Microembolus
Detection published guidelines and recommenda-tions for the necessary clarification of the protocol
used in each individual study.
In particular, the authors suggested that studies
report the following parameters: (1) ultrasound
device, (2) transducer type and size, (3) insonated
artery, (4) insonation depth, (5) algorithms for
signal intensity measurement, (6) scale settings, (7)detection threshold, (8) axial extension of sample
volume, (9) fast Fourier transform (FFT) size
(number of points used), (10) FFT length (time),
(11) FFT overlap, (12) transmitted ultrasound
frequency, (13) high-pass filter settings, and (14)
recording time.
5. Relative intensity increase or embolus-to-blood-ratio (EBR)
In the detection of MES, the relative intensity
increase or embolus-to-blood-ratio (EBR), is a
crucial parameter to differentiate MES from
spontaneous fluctuations of intensity in the back-
ground spectrum. The relative intensity increase is
the difference in dB between the acoustic powerbackscattered from the embolus and that of the
moving blood surrounding the embolus (Moehring
and Klepper, 1994). It is usually measured in dB.
The relative intensity increase is influenced by the
transmitted ultrasound frequency (Cullinane and
Markus, 2001), embolus size and composition, and
the volume amount of blood in the Doppler
sample volume. Several attempts have been madeto define a dB threshold for MES detection but
there are technical difficulties for the correct
assessment of the dB value. To calculate the dB
value of the relative intensity increase, different
background and embolic signal intensity measure-
ments can be used. This leads to different results of
the dB value and, therefore, the utilised technique
has to be specified in order to achieve comparableresults (Markus and Molloy, 1997). With respect
to the above, considerably differing dB-thresholds
ranging from 3 to 12 dB have been recommended
for the discrimination of MES from the physiolo-
gical Doppler flow signal (Markus and Molloy,
1997; Markus et al., 1995; Siebler et al., 1993;
Consensus Committee, 1995; Ringelstein et al.,
1998; Droste et al., 1997b, 1996) and thesetechnical aspects may be responsible for the
inconsistency in the prevalence of MES in various
clinical settings (Markus et al., 1995; Babikian et
al., 1994b; Grosset et al., 1994a; Braekken et al.,
1995; Grosset et al., 1994b). In spite of the
technical difficulties, inter-observer reproducibility
R. Dittrich et al. / European Journal of Ultrasound 16 (2002) 21�/30 23
studies revealed a high level of agreement in theidentification of MES (Markus et al., 1996, 1997).
The detection of MES by human experts rely more
on the typical audible sound and on the visual
appearance within the Doppler flow spectrum
than on calculated dB values. These studies have
also demonstrated that the use of a higher dB
threshold results in a higher specificity at the
expense of a lower sensitivity. We recommendindividual calibration of each setting and the use
of a threshold where only about 2% of sponta-
neous fluctuations of the Doppler spectrum (so-
called ‘speckles’) occur above this threshold
(Droste et al., 1999a).
6. Recording time
Embolization shows marked variation over time
(Markus et al., 1997) and there is no consensus
concerning the recording time required. In patients
with carotid artery occlusive disease or atrial
fibrillation the frequency is relatively low and,
therefore, recordings of at least 1 h are recom-
mended. In patients with mechanical heart valvesor during monitoring of invasive procedures the
frequency of MES is higher so that a shorter
recording time may suffice.
7. Automatic embolus detection
The current gold standard for the MES analysis
is the storage of the signal and the analysis of thewhole investigation by an experienced human
observer at a later date, blinded to the diagnosis.
But this proceeding is very time-consuming and
hampers the clinical application. To simplify the
clinical use, several attempts were made to facil-
itate the evaluation and to develop a reliable
automated detection system with both high sensi-
tivity and specificity. The use of the relativeintensity increase alone is not very helpful, because
also artefacts also produce a relative intensity
increase, which leads to huge overlap with MES.
For a better differentiation between MES and
artefacts, the semi-automated multigate-technique
was introduced. It operates with sample volumes
in several depths within the same artery. Thisdetects the movement of an embolus as a result of
the time delay when passing the sample volumes
arranged in sequence, whereas an artefact occurs
in all channels simultaneously (Droste et al.,
1997b; Notzold et al., 1997; Droste et al., 1999a;
Molloy and Markus, 1996; Georgiadis et al., 1996;
Moehring and Spencer, 2002). The technique
detects almost all cases of embolus, but thespecificity of the system is low because the soft-
ware detection of the signals depends on their
relative intensity increase. Hence, the analyzers
have to inspect regions of interest in great quan-
tities. The use of a neural network achieved
improved specificity but still inadequate sensitivity
(Siebler et al., 1994b; Kemeny et al., 1999). The
design of a novel frequency filtering approach bythe group of Markus et al. was a further step to
improve the automated detection of MES (Markus
and Reid, 1999; Markus et al., 1999; Cullinane et
al., 2000). The technique is also based on FFT
relative intensity increase of embolic and artefact
signals but it takes into account that the intensity
increase of embolic signals is focused at a specific,
narrow frequency range, whereas artefacts usuallyhave an intensity increase at a low frequency. It
operates with the use of a band-pass frequency
filter and the application of a Hanning windowing
function leading to a rise of the relative intensity
increase of MES up to 3 dB (Markus and Reid,
1999; Markus et al., 1999; Aydin and Markus,
2000) and providing a better distinction between
MES and artefacts. The implementation of an on-line version exhibited promising results, better
than previous systems (Droste et al., 1999a; van
Zuilen et al., 1996) and its comparison with a panel
of international experts showed a performance
only slightly below the results of human analysers
(Cullinane et al., 2000). The software was tested
with the data from patients with carotid stenosis
and from patients in the period after carotidendarterectomy. In the patients with carotid
stenosis, the software reached a sensitivity of
85.7% and a specificity of 88.9%. For the patient
group studied after carotid endarterectomy sensi-
tivity was 95.4% and specificity 97.5% (Cullinane
et al., 2000). A different development of auto-
mated detection systems is the application of a
R. Dittrich et al. / European Journal of Ultrasound 16 (2002) 21�/3024
wavelet transform instead of using the FFT basedspectral analysis (Aydin et al., 1999; Brucher and
Russell, 1999; Devuyst et al., 2000, 2001). Auto-
mated systems have been developed and the
studies are focussed on the differentiation between
gaseous and solid emboli (Brucher and Russell,
1999; Devuyst et al., 2000). The combination of
the wavelet transformation with dual-gate TCD
(Devuyst et al. 2001) led to an off-line detectionsystem, which can reliably differentiate between
artifacts versus emboli and gaseous emboli versus
solid emboli. In the distinction, between artifacts
and emboli, the software reached a sensitivity of
97% and a specificity of 98%. The corresponding
values for the differentiation between gaseous and
solid emboli were 89% (sensitivity), and 86%
(specificity) (Devuyst et al., 2001). Another soft-ware algorithm approach combined the emission
of two different ultrasound frequencies with wave-
let transform to differentiate between solid and
gaseous ME (Brucher and Russell, 1999). It is now
on the market but needs, to be validated in large
clinical trials. The solution of this issue would be
very helpful, e.g. in the monitoring of carotid
angioplasties and carotid endarterectomies as wellas during cardiac surgery.
In summary, automated detection systems can-
not replace the experienced human observer so far,
but the technical advances in this field give reason
to suggest that it is possible to develop a sufficient
and reliable detection system in the near future. The
recently developed algorithms need further clinical
investigation before they can enter routine clinicaluse without verification by a human observer.
8. Clinical value and future applications
Clinical applications of MES detection by TCD
revealed that the vast majority of MES occur in
patients with an embolic source or during opening
of the vasculature allowing air to enter the bloodcirculation. Removal of the embolic source (e.g.
endarterectomy) reduces or abolishes MES (Mar-
kus et al., 1995; van Zuilen et al., 1995; Siebler et
al., 1993). The following list shows different sets of
patients in which MES could be found sponta-
neously:
. Extracranial carotid artery stenosis (Markus et
al., 1993a; Babikian et al., 1994b; Siebler et al.,
1994a, 1993, 1992, 1995; Georgiadis et al., 1994;
Ries et al., 1998; van Zuilen et al., 1995; Eicke et
al., 1995; Markus et al., 1995; Droste et al.,
1999a; Molloy and Markus, 1999; Droste et al.,
1999e; Valton et al., 1995).
. Intracranial carotid artery and middle cerebral
artery stenosis (Nabavi et al., 1996a; Sliwka et
al., 1997; Droste et al., 2002a; Segura et al.,
1998, 2001).. Aneurysmal subarachnoid hemorrhage (Ro-
mano et al., 2002).
. Carotid or vertebral artery dissection (Droste et
al., 2001; Molina et al., 2000; Babikian et al.,
1996; Scrinivasan et al., 1996; Oliveira et al.,
2001).
. Mechanical heart valves (Braekken et al., 1995;
Muller et al., 1994; Markus et al., 1994a;
Grosset et al., 1993; Georgiadis et al., 1997;
Droste et al., 1997a,b).. Heart valve bioprosthesis (Markus et al., 1994a;
Georgiadis et al., 1997).
. Following Ross operation (Notzold et al.,
1997).
. Atrial fibrillation (Sliwka et al., 1995; Tong et
al., 1994; Georgiadis et al., 1997; Infeld et al.,
1996; Cullinane et al., 1998; Nabavi et al.,
1998).
. Mitral valve prolapse (Tong et al., 1994; Droste
et al., 1998b).. Dilatative cardiomyopathy (Georgiadis et al.,
1997; Sliwka et al., 1995).
. Left ventricular assist device (Nabavi et al.,
1996b; Schmid et al., 1998).
. Bacterial endocarditis (Eicke et al., 1997).
. During cerebral arteriography (Markus et al.,
1993c).
. During carotid angioplasty (Markus et al.,
1994c).. Extracorporal circulation, especially during
coronary bypass surgery (Barbut et al., 1994;
Harrison et al., 1990; Pugsley et al., 1994).
. During and after carotid endarterectomy (Spen-
cer, 1997; Siebler et al., 1994b; Molloy et al.,
1998; Kaposzta et al., 2001; Jansen et al., 1994).
. Sneddon Syndrome (Sitzer et al., 1995).
R. Dittrich et al. / European Journal of Ultrasound 16 (2002) 21�/30 25
. Antiphospholipid syndrome (APS) (Specker etal., 1998, 1997).
. Eisenmenger’s syndrome (Droste et al., 1999d).
. Polycythemia rubra vera (Segura et al., 2000).
. Behcet’s disease (Kumral et al., 1999).
. Patients with bone fractures after trauma with
risk of fat emboli (Forteza et al., 1999, 2002).
Another clinical application of induced MES is
the detection of right-to-left-shunts (Droste et al.,
1998b; Tong et al., 1994; Sliwka et al., 1995;
Droste et al., 1999b,c, 2000; Forteza et al., 2002;
Droste et al., 2002b), where ultrasound contrast
agents like Echovist† are injected intravenously.
The contrast agent cannot pass the pulmonary
circulation, therefore, it can be only detected in the
arterial system in the case of a right-to-left-shunt
where the contrast microbubbles appear as MES
in the cerebral circulation. Studies have shown
that the sensitivity of the method is comparable
with transesophageal echocardiography, the cur-
rent gold-standard. In addition, it allows the
detection of extra-cardiac right-to-left-shunts.
In normal persons, MES are absent (Daffert-
shofer et al., 1996; Droste et al., 1997b; Markus et
al., 1994a, 1995; Droste et al., 1997a; Braekken et
al., 1995; Eicke et al., 1995; Siebler et al., 1994a)
except for very rare cases (Infeld et al., 1996;
Georgiadis et al., 1997) of unknown cause where
possible embolic sources are present, however, not
systematically looked for.
Spontaneous detectable ME do not produce
stroke but they may be a possible parameter for
the risk of stroke. It is known that there are similar
mechanisms for the formation of ME which are
clinically silent, and for the formation of macro-
emboli which can cause strokes. Moreover, studies
have shown a higher prevalence of MES in
patients with an increased risk of stroke (Acker-
staff et al., 1995; Spencer, 1997; Babikian et al.,
1997; Levi et al., 1997; Valton et al., 1998; Molloy
and Markus, 1999; Droste et al., 1999e). The
potential clinical applications thus are the identi-
fication of patients at high risk of stroke, the
assessment of the activity of an embolic source,
and the monitoring of the effectiveness of therapy.
A further issue is the localization of the active
embolic source in case of competing embolic
sources. For instance, the bilateral occurrence ofMES points to a cardiac embolic source, whereas
their unilateral occurrence would favor a carotid
source. Carotid artery occlusive disease is a well
investigated example. The degree of stenosis,
presence of symptoms and a short latency after
occurrence of symptoms are associated with a
higher risk of stroke (European Carotid Surgery
Trialists Collaborative Group, 1991; North Amer-ican Symptomatic Carotid Endarterectomy Trial
Collaborators, 1991; Executive Committee, 1995;
Barnett, 1998; Farrell et al., 1998; Rothwell et al.,
2000). The prevalence of these factors is also
associated with a higher prevalence of MES
(Siebler et al., 1995; Markus et al., 1995; Ries et
al., 1998; Eicke et al., 1995; Molloy and Markus,
1999; Droste et al., 1999e; Valton et al., 1995). Theimportant question, whether the detection of MES
is an independent risk factor for the occurrence of
stroke has not yet been answered definitely.
Follow-up investigations in small sets of patients
(73 and 111, respectively) revealed a trend in this
direction (Valton et al., 1998; Molloy and Markus,
1999) because patients with MES have a signifi-
cantly higher risk for the occurrence of stroke ortransient ischaemic attack. Investigations with
large patient cohorts are currently being per-
formed to clarify this question.
Further support for the clinical importance of
MES are the results of the study by Pugsley et al.
(1994). His group demonstrated that a higher rate
of MES during cardiopulmonary bypass operation
is correlated with a higher degree of neuropsycho-logical deficits 8 days and 8 weeks after the
surgical procedure. It can be assumed that ME
may not always be clinically ‘silent’, but can lead
to small brain infarcts which may be responsible
for the poorer neuropsychological outcome. This
hypothesis is supported by in-vivo investigations
where atheroemboli with a size ranging 200�/500
mm introduced into the blood circulation causeddisseminated neuronal cell death in rats (Rapp et
al., 2000).
Another potential field of general application of
MES detection is the monitoring of the efficacy of
antithrombotic treatment. Recent studies per-
formed by the group of Goertler examined the
influence of antithrombotic treatment on the
R. Dittrich et al. / European Journal of Ultrasound 16 (2002) 21�/3026
occurrence of MES (Goertler et al., 1999, 2001,2002). Either intravenous or oral application of
acetylsalicylic acid in patients with symptomatic
carotid stenosis lead to a decline of MES (Goertler
et al., 1999, 2001). Follow-up studies of patients
with symptomatic carotid artery stenosis receiving
antiplatelet treatment also demonstrated that the
occurrence of MES is related to a higher risk of
stroke and transient ischaemic attack (Goertler etal., 2002). These results suggest that patients who
do show MES despite being treated possibly need
more aggressive therapy to prevent further cere-
bral ischaemic events.
In conclusion, there is increasing evidence that
ME detection by TCD is a promising technique to
enter clinical routine, but so far, therapeutic
decisions should not be made based only on thisinvestigation as long as definitive findings concern-
ing the significance of the technique are missing.
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