Microembolus detection by transcranial doppler sonography

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: [email protected] (R. Dittrich).

European Journal of Ultrasound 16 (2002) 21�/30

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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


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).


. 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


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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Microembolus detection by transcranial doppler sonography