**4. Anterior circulation stroke**

For this chapter anterior circulation stroke was described to show the usefulness and the role of sonological vascular imaging as a guide to treatment and to define the prognosis. Indeed the knowledge of vascular status in acute ischemic stroke have a clear prognostic relevance and it could be used also as a criterion to tailor the treatment and select the best reperfusion strategy for each patient, both in a single modality and in a sequential or

Neurosonological Evaluation of the Acute Stroke Patients 277

thrombolysis by using neuroradiological techniques or neurosonological ones (TCD or

The assumption for this imaging is the close link between the clot burden (i.e. the occlusive pattern) and the extent of brain lesion (i.e. the perfusional status), strongly suggesting the need of diagnosing presence and site of vessel occlusion in the acute phase of stroke. The advantages of neurosonology has been detailed in the previous sections, as widespread availability, easiness of use, the possibility of a repeated bedside examination and

Another main advantage of the knowledge of the occlusive pattern before treatment is the possibility of predicting the success of the reperfusion strategy in terms of recanalization rate, because it has been known from the old and recent literature that each occlusive pattern is associated with a different response to rtPA administration (Ringelstein et al. 1992; Trouillas et al. 1998). In the NINDS trial (NINDS group 1995) the subgroup of patients with combined occlusion of ICA and MCA (tandem occlusion) had lesser benefit from thrombolysis than patients with isolated MCA occlusion, particularly in case of branch occlusions, although the clinical presentation and the severity score was the same in the two groups. Another series of 139 patients shown the same results (Del Zoppo et al. 1992), and so on a small study designed for the evaluation of tandem occlusion prognosis (Rubiera et al. 2006) and several studies demonstrated a poor recanalization rate in T-type occlusion

Then there are several occlusive patterns from which it could be expected a different response to thrombolysis: "…the patients presented with similar severity of hemiplegia, but the severity of perfusion deficit and recovery were dramatically different. TCD allows early differentiation of patency and natural history of MCA thromboembolic events. This may have important implications in the decision for thrombolytic therapy…" (Alexandrov et al.

The neurosonological examination by TCD and TCCS can help in the early diagnostic workup of patients with acute ischemic stroke (Iannuzzi et al. 1995; Lee et al. 1996; Razumovsky et al. 1999; Alexandrov et al 1999; Garami et al 2003); two studies addressed the reliability of the combined application of ultrasound examination of extracranial and intracranial arteries in acute stroke patients, respectively by TCD and TCCS (Alexandrov et al. 1999; Malferrari et al 2007). This strategy allows to identify the vascular occlusive pattern eligible for treatment (accuracy near to 100%) (IMS study investigators 2004) and a fast-track ultrasound examination protocol has been proposed to diagnose the presence and site of vessel lesion bedside (Alexandrov et al. 1999; Molina et al. 2002; Feldberg et al. 2002), achieving a sensitivity, specificity, positive predictive value and negative predictive value near to 100% (Feldberg et al. 2002; Grant et al. 2003; Demchuk et al. 2001; Burgin et al. 2001; El-Mitwalli et

There are validated diagnostic criteria for occlusive pattern in acute stroke, both for TCD

Therefore TCD and TCCS are a non-invasive, rapid, reproducible, bedside, reliable tool, to provide useful data on cerebral circulation and then to select patients for reperfusion treatment. Indeed "Ultrasound and other non-invasive tests should be available for the diagnosis of carotid, vertebral artery and intracranial artery stenosis and occlusion" in the acute phase of stroke (European Perspective on Stroke Management, Kjellstrom et al 2007).

The occlusive pattern diagnosis was categorized as shown in fig. 19.

(Demchuk et al. 2000) and by TCCS (Malferrari et al. 2007) (fig. 20).

TCCS) (Malferrari and Zedde 2008), without delaying the treatment.

monitoring of recanalization, an highest reliability.

(Arnold et al. 2003).

al. 2002; Christou et al 2001).

2000).


Fig. 18. Hemodynamic changed and COGIF flow grading score (modified from Nedelmann et al 2009)

combined modality. It has been undoubtedly accepted that the occlusive pattern at the presentation is closely related to the outcome of patient, as the recanalization of the primarily occluded vessel and its time course. Another strong predictor of the outcome is the perfusional status of the brain tissue in the downstream of the occluded vessel and it is evaluable mainly by using neuroradiological techniques, MR or CT, but also ultrasound imaging by TCCS and UCA injection may provide some informations about the cerebral perfusion in the MCA territory in acute stroke patients. The combination of the two findings, the occlusive pattern and the perfusional status, could provide a reliable classification of acute stroke patients in terms of the most adequate treatment to reverse the globally poor outcome (Malferrari and Zedde 2008). The following sections are mainly focused on occlusive pattern diagnosis, monitoring of recanalization and perfusional imaging, from the point of view of ultrasound techniques application.

#### **4.1 Occlusive pattern diagnosis**

The main studies from which intravenous thrombolysis with recombinant tissue plasminogen activator (rtpA) for stroke achieved an evidence of efficacy (total amount of 2889 patients) (NINDS group 1995; Hacke et al. 1995; Hacke et al. 1998; Clark et al. 1998; Clark et al 2000) did not provide any information about the status of extra- and intracranial vessels before treatment. Therefore it could be hypothesized that a great amount of patients treated with rtPA had a situation of extracranial and intracranial patent vessels. Indeed there is a clearly demonstrated relation between the stroke subtype, according to the Oxfordshire Community Stroke Project Classification (OCSPC), and the occlusive pattern on TCD: Partial or Total Anterior Circulation Strokes (PACIs and TACIs respectively), as expected, are more frequently associated with large vessel disease, as compared with lacunar infarcts (LACIs), where only few patients had an intracranial vessel

lesion (Mead et al. 2000). This last subgroup belongs to Parent Artery Disease (PAD), with the same prognosis of patients with large artery disease.

The relation between the occlusive pattern and the outcome has been demonstrated by several studies, and then it is possible to say that "severe arterial stenosis/occlusion in the early arterial study was highly related with 90-day mortality in an unselected series of patients with stroke" (Ois et al. 2007). This is right non only for severe stroke but also for mild stroke, and it is not related to the imaging technique used. Therefore, if possible, all attempts should be made to diagnose a large-artery intracranial occlusion before

Fig. 18. Hemodynamic changed and COGIF flow grading score (modified from Nedelmann

combined modality. It has been undoubtedly accepted that the occlusive pattern at the presentation is closely related to the outcome of patient, as the recanalization of the primarily occluded vessel and its time course. Another strong predictor of the outcome is the perfusional status of the brain tissue in the downstream of the occluded vessel and it is evaluable mainly by using neuroradiological techniques, MR or CT, but also ultrasound imaging by TCCS and UCA injection may provide some informations about the cerebral perfusion in the MCA territory in acute stroke patients. The combination of the two findings, the occlusive pattern and the perfusional status, could provide a reliable classification of acute stroke patients in terms of the most adequate treatment to reverse the globally poor outcome (Malferrari and Zedde 2008). The following sections are mainly focused on occlusive pattern diagnosis, monitoring of recanalization and perfusional

The main studies from which intravenous thrombolysis with recombinant tissue plasminogen activator (rtpA) for stroke achieved an evidence of efficacy (total amount of 2889 patients) (NINDS group 1995; Hacke et al. 1995; Hacke et al. 1998; Clark et al. 1998; Clark et al 2000) did not provide any information about the status of extra- and intracranial vessels before treatment. Therefore it could be hypothesized that a great amount of patients treated with rtPA had a situation of extracranial and intracranial patent vessels. Indeed there is a clearly demonstrated relation between the stroke subtype, according to the Oxfordshire Community Stroke Project Classification (OCSPC), and the occlusive pattern on TCD: Partial or Total Anterior Circulation Strokes (PACIs and TACIs respectively), as expected, are more frequently associated with large vessel disease, as compared with

lesion (Mead et al. 2000). This last subgroup belongs to Parent Artery Disease (PAD), with

The relation between the occlusive pattern and the outcome has been demonstrated by several studies, and then it is possible to say that "severe arterial stenosis/occlusion in the early arterial study was highly related with 90-day mortality in an unselected series of patients with stroke" (Ois et al. 2007). This is right non only for severe stroke but also for mild stroke, and it is not related to the imaging technique used. Therefore, if possible, all attempts should be made to diagnose a large-artery intracranial occlusion before

imaging, from the point of view of ultrasound techniques application.

lacunar infarcts (LACIs), where only few patients had an intracranial vessel

the same prognosis of patients with large artery disease.

**4.1 Occlusive pattern diagnosis** 

et al 2009)

thrombolysis by using neuroradiological techniques or neurosonological ones (TCD or TCCS) (Malferrari and Zedde 2008), without delaying the treatment.

The assumption for this imaging is the close link between the clot burden (i.e. the occlusive pattern) and the extent of brain lesion (i.e. the perfusional status), strongly suggesting the need of diagnosing presence and site of vessel occlusion in the acute phase of stroke. The advantages of neurosonology has been detailed in the previous sections, as widespread availability, easiness of use, the possibility of a repeated bedside examination and monitoring of recanalization, an highest reliability.

Another main advantage of the knowledge of the occlusive pattern before treatment is the possibility of predicting the success of the reperfusion strategy in terms of recanalization rate, because it has been known from the old and recent literature that each occlusive pattern is associated with a different response to rtPA administration (Ringelstein et al. 1992; Trouillas et al. 1998). In the NINDS trial (NINDS group 1995) the subgroup of patients with combined occlusion of ICA and MCA (tandem occlusion) had lesser benefit from thrombolysis than patients with isolated MCA occlusion, particularly in case of branch occlusions, although the clinical presentation and the severity score was the same in the two groups. Another series of 139 patients shown the same results (Del Zoppo et al. 1992), and so on a small study designed for the evaluation of tandem occlusion prognosis (Rubiera et al. 2006) and several studies demonstrated a poor recanalization rate in T-type occlusion (Arnold et al. 2003).

Then there are several occlusive patterns from which it could be expected a different response to thrombolysis: "…the patients presented with similar severity of hemiplegia, but the severity of perfusion deficit and recovery were dramatically different. TCD allows early differentiation of patency and natural history of MCA thromboembolic events. This may have important implications in the decision for thrombolytic therapy…" (Alexandrov et al. 2000).

The neurosonological examination by TCD and TCCS can help in the early diagnostic workup of patients with acute ischemic stroke (Iannuzzi et al. 1995; Lee et al. 1996; Razumovsky et al. 1999; Alexandrov et al 1999; Garami et al 2003); two studies addressed the reliability of the combined application of ultrasound examination of extracranial and intracranial arteries in acute stroke patients, respectively by TCD and TCCS (Alexandrov et al. 1999; Malferrari et al 2007). This strategy allows to identify the vascular occlusive pattern eligible for treatment (accuracy near to 100%) (IMS study investigators 2004) and a fast-track ultrasound examination protocol has been proposed to diagnose the presence and site of vessel lesion bedside (Alexandrov et al. 1999; Molina et al. 2002; Feldberg et al. 2002), achieving a sensitivity, specificity, positive predictive value and negative predictive value near to 100% (Feldberg et al. 2002; Grant et al. 2003; Demchuk et al. 2001; Burgin et al. 2001; El-Mitwalli et al. 2002; Christou et al 2001).

The occlusive pattern diagnosis was categorized as shown in fig. 19.

There are validated diagnostic criteria for occlusive pattern in acute stroke, both for TCD (Demchuk et al. 2000) and by TCCS (Malferrari et al. 2007) (fig. 20).

Therefore TCD and TCCS are a non-invasive, rapid, reproducible, bedside, reliable tool, to provide useful data on cerebral circulation and then to select patients for reperfusion treatment. Indeed "Ultrasound and other non-invasive tests should be available for the diagnosis of carotid, vertebral artery and intracranial artery stenosis and occlusion" in the acute phase of stroke (European Perspective on Stroke Management, Kjellstrom et al 2007).

Neurosonological Evaluation of the Acute Stroke Patients 279

of this diagnosis is increased by the simultaneous visualization of the deep middle cerebral vein, the ipsilateral A2 ACA, or the contralateral anterior circulation (Nedelmann et al 2009).

Fig. 20. Diagnostic criteria of occlusive pattern in acute stroke patients by TCD and TCCS.

Fig. 21. An example of MCA occlusion by TCCS, compared to CT angiography.

a. TCCS from the temporal bone window in Power-mode with UCA administration: it is well visible the lack of signal in ipsilateral M1 MCA with the sparing of the other vessel of the circle of Willis; b. corresponding Doppler spectrum at MCA origin, with TIBI 2 score and COGIF 2 score; c Tridimensional reconstruction of the intracranial circulation by CT

The step following the diagnosis of occlusive pattern is the assignment of the TIBI or COGIF score, because of the need of a baseline value for monitoring the recanalization. The link between the grading score and the occlusive pattern diagnosis is globally weak, because a single score value matches several occlusive patterns.

Therefore the proposal of the COGIF score (Nedelmann et al. 2009) was associated to the careful analysis of each grade of the score, made by the same authors, both for the diagnosis of arterial occlusion and for the follow-up of recanalization, but mainly for the first one.

The grade 1 (no flow) corresponds to TIBI grade 0 and describes the main spectral finding seen in M1 MCA occlusion (comprising T-occlusion and its variants). The main diagnostic criterion of the M1 MCA occlusion is the absence of a Colour or Power-mode Doppler flow signal and its Doppler spectrum at the proximal MCA main stem (Malferrari et al 2007; Malferrari and Zedde 2008; Malferrari 2010). The absence of Doppler signals may also be caused by an insufficient acoustic bone window, and therefore for a reliable diagnosis of occlusion a sufficient visualization of the other ipsilateral arteries (A1 ACA, C1 ICA, posterior cerebral artery) is requested; sometimes the identification of contralateral arteries of the anterior circulation is also requested (Fig. 21).

The difficulties in the evaluation of MCA versus T occlusions by TCCS born from the lack of angiographically validated criteria. The mostly used diagnostic criterion of carotid T occlusion is detailed in fig. 20, i.e. the absence of colour Doppler flow signal and its Doppler spectrum in M1 MCA, intracranial ICA, and the ipsilateral A1 ACA (Fig. 22). The reliability

The step following the diagnosis of occlusive pattern is the assignment of the TIBI or COGIF score, because of the need of a baseline value for monitoring the recanalization. The link between the grading score and the occlusive pattern diagnosis is globally weak, because a

Therefore the proposal of the COGIF score (Nedelmann et al. 2009) was associated to the careful analysis of each grade of the score, made by the same authors, both for the diagnosis of arterial occlusion and for the follow-up of recanalization, but mainly for the first one. The grade 1 (no flow) corresponds to TIBI grade 0 and describes the main spectral finding seen in M1 MCA occlusion (comprising T-occlusion and its variants). The main diagnostic criterion of the M1 MCA occlusion is the absence of a Colour or Power-mode Doppler flow signal and its Doppler spectrum at the proximal MCA main stem (Malferrari et al 2007; Malferrari and Zedde 2008; Malferrari 2010). The absence of Doppler signals may also be caused by an insufficient acoustic bone window, and therefore for a reliable diagnosis of occlusion a sufficient visualization of the other ipsilateral arteries (A1 ACA, C1 ICA, posterior cerebral artery) is requested; sometimes the identification of contralateral arteries

The difficulties in the evaluation of MCA versus T occlusions by TCCS born from the lack of angiographically validated criteria. The mostly used diagnostic criterion of carotid T occlusion is detailed in fig. 20, i.e. the absence of colour Doppler flow signal and its Doppler spectrum in M1 MCA, intracranial ICA, and the ipsilateral A1 ACA (Fig. 22). The reliability

Fig. 19. Occlusive pattern in acute stroke patients.

single score value matches several occlusive patterns.

of the anterior circulation is also requested (Fig. 21).

of this diagnosis is increased by the simultaneous visualization of the deep middle cerebral vein, the ipsilateral A2 ACA, or the contralateral anterior circulation (Nedelmann et al 2009).


Fig. 20. Diagnostic criteria of occlusive pattern in acute stroke patients by TCD and TCCS.

Fig. 21. An example of MCA occlusion by TCCS, compared to CT angiography.

a. TCCS from the temporal bone window in Power-mode with UCA administration: it is well visible the lack of signal in ipsilateral M1 MCA with the sparing of the other vessel of the circle of Willis; b. corresponding Doppler spectrum at MCA origin, with TIBI 2 score and COGIF 2 score; c Tridimensional reconstruction of the intracranial circulation by CT

Neurosonological Evaluation of the Acute Stroke Patients 281

blood flow mainly in the penumbra (Alexandrov et al 2001; Molina et al. 2004). The residual blood flow signals classification TIBI was described and validated by Alexandrov and coworkers (Demchuk et al 2000b, 2001; Molina et al. 2002) (fig. 15). This classification has been demonstrated to be useful, because the degree of residual flow signals predicts the likelihood of recanalization (Labiche et al. 2003). Patients with TIBI 1 to 3 have a likelihood of recanalization twice more higher than patients with TIBI 0 grade, irrespectively to the occlusion site. This is probably due to the consideration that the detectable residual flow (TIBI 1-3) ensues a better delivery of rtPA to thrombus than the condition of no flow (TIBI 0). Furthermore, an early improvement of blood flow on TCD or TCCS, within 30 min after rt-PA bolus, is related to an higher likelihood of achieving a final complete recanalization and a better outcome (Alexandrov et al. 2001). Then it has been demonstrated that neurosonological technique may distinguish patients who will benefit from thrombolysis, from patients who probably don't. This last subgroup has a poor outcome and the early knowledge of this status could allow to select more aggressive or rescue strategies to achieve the recanalization of the occluded vessel (Saqqur et al. 2006; Sekoranja et al. 2006;

In studies defining the impact of recanalization time od an occluded MCA on outcome by TCD monitoring during rtPA treatment (Alexandrov et al. 2001), the timing of arterial


In the stepwise group the mean recanalization time of onset was after 17 min from rt-PA bolus and it was complete after 35 min. The complete recanalization was more rapid (mean 10 min) than the partial one (mean 30 min) and recanalization time positively correlated with a favourable clinical outcome. This was also demonstrated in tandem ICA and MCA occlusions (Kim et al. 2005). The slow recanalization pattern and the confimation of TIBI 3 at the end of rtPA administration were poor prognostic factors, related to the persistence of a

Another useful application of neurosonological examination in the acute stroke, combined with a perfusional approach, is the potential identification of patients treatable beyond the 3

As expected according to the previous considerations, the time of tPA-induced recanalization, monitored by TCD (Delgado-Mederos et al. 2007) is a strong predictor of the evolution of ischemic lesion at diffusion-weighted imaging (DWI)-MRI (Kidwell et al. 2000; Fiehler et al. 2004) and of the clinical outcome; slow recanalization pattern correlates with greater lesion size and poorer short- and long-term outcomes than sudden and stepwise

DIAS study (Duplex-Sonographic Assessment of the Cerebrovascular Status in Acute Stroke), a German multicentre study, was designed to evaluate the vascular status within 6 h from symptoms onset and to monitor the recanalization after thrombolysis or best medical therapy (Gerriets et al. 2000). Only one of the twelve patients with T occlusion not treated with thrombolysis shown a late spontaneous reperfusion. Also another relevant multicentre study, the NAIS (Study Project of the Neurosonology Research Group of the World Federation of Neurology) (Allendoerfer et al. 2006) had the aim of monitoring the vascular

Ribo et al. 2006).

60 s)

reopening was classified into:

distal occlusion (Demchuk et al. 2001).

patterns (Malferrari and Zedde 2008).

h time window (Ribo et al. 2005).


angiography of the same patient with the lack of M1 MCA (green arrow); d schematic drawing of the occluded artery, as in Fig. 19.

Fig. 22. An example of T occlusion by TCCS, compared to intracranial MR angiography.

a. TCCS from the temporal bone window in Power-mode with UCA administration: it is well visible the lack of signal in ipsilateral M1 MCA, C1 ICA and A1 ACA with the sparing of the posterior cerebral artery and the contralateral anterior circulation; b. MR angiography of the intracranial circulation of the same patient with the corresponding findings; c. schematic drawing of the occluded artery, as in Fig. 19; d. final cerebral infarction at MRI. In the Consensus Conference these considerations raised other two statements about the diagnostic criterion of T occlusion (Fig. 23).


Fig. 23. Consensus Statements 7 and 8 from Nedelmann et al. 2009

#### **4.2 Monitoring of recanalization**

As previously outlined, a main prognostic factor in acute stroke patients, treated with rtPA, is the timing of vessel patency restoration. If there have been discussions about the usefulness of vascular imaging before thrombolysis to diagnose the occlusive pattern, there is no doubt that the monitoring of recanalization is useful and widely recommended; for this purpose TCD or TCCS is the preferred technique, because of the known advantages and time resolution. These features make neurosonology a reliable and irreplaceable tool for continuous, real-time monitoring of the beginning, speed, timing and degree of arterial recanalization during thrombolysis (Alexandrov et al. 1999; Malferrari et al 2008). The relation between time of recanalization and outcome is well explained by the attempt of achieve, through the reopening of the occluded artery, the as early as possible restoration of

angiography of the same patient with the lack of M1 MCA (green arrow); d schematic

Fig. 22. An example of T occlusion by TCCS, compared to intracranial MR angiography.

a. TCCS from the temporal bone window in Power-mode with UCA administration: it is well visible the lack of signal in ipsilateral M1 MCA, C1 ICA and A1 ACA with the sparing of the posterior cerebral artery and the contralateral anterior circulation; b. MR angiography of the intracranial circulation of the same patient with the corresponding findings; c. schematic drawing of the occluded artery, as in Fig. 19; d. final cerebral infarction at MRI. In the Consensus Conference these considerations raised other two statements about the

As previously outlined, a main prognostic factor in acute stroke patients, treated with rtPA, is the timing of vessel patency restoration. If there have been discussions about the usefulness of vascular imaging before thrombolysis to diagnose the occlusive pattern, there is no doubt that the monitoring of recanalization is useful and widely recommended; for this purpose TCD or TCCS is the preferred technique, because of the known advantages and time resolution. These features make neurosonology a reliable and irreplaceable tool for continuous, real-time monitoring of the beginning, speed, timing and degree of arterial recanalization during thrombolysis (Alexandrov et al. 1999; Malferrari et al 2008). The relation between time of recanalization and outcome is well explained by the attempt of achieve, through the reopening of the occluded artery, the as early as possible restoration of

drawing of the occluded artery, as in Fig. 19.

diagnostic criterion of T occlusion (Fig. 23).

**4.2 Monitoring of recanalization** 

Fig. 23. Consensus Statements 7 and 8 from Nedelmann et al. 2009

blood flow mainly in the penumbra (Alexandrov et al 2001; Molina et al. 2004). The residual blood flow signals classification TIBI was described and validated by Alexandrov and coworkers (Demchuk et al 2000b, 2001; Molina et al. 2002) (fig. 15). This classification has been demonstrated to be useful, because the degree of residual flow signals predicts the likelihood of recanalization (Labiche et al. 2003). Patients with TIBI 1 to 3 have a likelihood of recanalization twice more higher than patients with TIBI 0 grade, irrespectively to the occlusion site. This is probably due to the consideration that the detectable residual flow (TIBI 1-3) ensues a better delivery of rtPA to thrombus than the condition of no flow (TIBI 0). Furthermore, an early improvement of blood flow on TCD or TCCS, within 30 min after rt-PA bolus, is related to an higher likelihood of achieving a final complete recanalization and a better outcome (Alexandrov et al. 2001). Then it has been demonstrated that neurosonological technique may distinguish patients who will benefit from thrombolysis, from patients who probably don't. This last subgroup has a poor outcome and the early knowledge of this status could allow to select more aggressive or rescue strategies to achieve the recanalization of the occluded vessel (Saqqur et al. 2006; Sekoranja et al. 2006; Ribo et al. 2006).

In studies defining the impact of recanalization time od an occluded MCA on outcome by TCD monitoring during rtPA treatment (Alexandrov et al. 2001), the timing of arterial reopening was classified into:


In the stepwise group the mean recanalization time of onset was after 17 min from rt-PA bolus and it was complete after 35 min. The complete recanalization was more rapid (mean 10 min) than the partial one (mean 30 min) and recanalization time positively correlated with a favourable clinical outcome. This was also demonstrated in tandem ICA and MCA occlusions (Kim et al. 2005). The slow recanalization pattern and the confimation of TIBI 3 at the end of rtPA administration were poor prognostic factors, related to the persistence of a distal occlusion (Demchuk et al. 2001).

Another useful application of neurosonological examination in the acute stroke, combined with a perfusional approach, is the potential identification of patients treatable beyond the 3 h time window (Ribo et al. 2005).

As expected according to the previous considerations, the time of tPA-induced recanalization, monitored by TCD (Delgado-Mederos et al. 2007) is a strong predictor of the evolution of ischemic lesion at diffusion-weighted imaging (DWI)-MRI (Kidwell et al. 2000; Fiehler et al. 2004) and of the clinical outcome; slow recanalization pattern correlates with greater lesion size and poorer short- and long-term outcomes than sudden and stepwise patterns (Malferrari and Zedde 2008).

DIAS study (Duplex-Sonographic Assessment of the Cerebrovascular Status in Acute Stroke), a German multicentre study, was designed to evaluate the vascular status within 6 h from symptoms onset and to monitor the recanalization after thrombolysis or best medical therapy (Gerriets et al. 2000). Only one of the twelve patients with T occlusion not treated with thrombolysis shown a late spontaneous reperfusion. Also another relevant multicentre study, the NAIS (Study Project of the Neurosonology Research Group of the World Federation of Neurology) (Allendoerfer et al. 2006) had the aim of monitoring the vascular

Neurosonological Evaluation of the Acute Stroke Patients 283


In this study patients with TIBI 0 grade had less probability of complete recanalization than

In the CLOTBUST study (Alexandrov et al. 2004 b) the continuous TCD monitoring (i.e. exposure to ultrasound) was a positive predictor for complete recanalization (ORadj: 3.02, CI95: 1.396 to 6.514, P < 0.005). NIHSS score < 2 at 24 h was achieved in 22% of patients, so

It is notable that none of the patients with T occlusion had dramatic recovery (0%) (P <

Modified Rankin Scale score <1 was achieved in 35% of patients, so categorized in terms of

The likelihood of a good long-term outcome was twice higher for patients with distal MCA occlusion than for patients with proximal MCA occlusions (OR: 2.1, CI 95: 1.1 to 4, P < .025). The authors conclude that the "clinical response to thrombolysis is influenced by the site of occlusion" and "patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term"

Also the Eligible study (Malferrari et al. 2007) shown that the clinical recovery at both 24 h

CLOTBUST (Alexandrov et al. 2004b; Saqqur et al. 2007), NAIS (Allendoerfer et al. 2006) and ELIGIBLE (Malferrari et al. 2007; Malferrari and Zedde 2008) studies demonstrated the high predictive value of neurosonology for identifying proximal MCA occlusion. The CLOTBUST authors (Alexandrov et al. 2004b; Saqqur et al. 2007) proposed TCD as a screening tool for i.v./i.a. thrombolysis. A similar proposal has been made for TCCS by an interesting but small clinical study (Sekoranja et al. 2006), where the patients with partial or complete MCA recanalization at 30 min from the onset of i.v. thrombolysis showed an higher rate of positive outcome at 24 h and at 3 months than patients with none recanalization. In this latter subgroup the subsequent i.a. thrombolysis with the residual amount of rtPA was performed and provided a substantial benefit. Therefore, 56% of patients treated with combined i.v./i.a. thrombolysis achieved a good outcome at 3 months (mRS 0-2), compared with 22% of a previous study (Labiche et al. 2003) in patients with no recanalization with i.v.

As in the TCD studies (Saqqur et al. 2005), this TCCS experience (Sekoranja et al. 2006) found that TIBI classification, defined by TCCS, was reliably related with the corresponding TIMI angiographic grades. Therefore neurosonological techniques, both TCD and TCCS, can




patients with TIBI 3 (ORadj: 0.256, CI 95: 0.11 to 0.595, P < 0.002).

categorized in terms of the occlusive pattern:



(Alexandrov et al. 2004b; Saqqur et al. 2007).

and 3 months is influenced by the site of occlusion.



the occlusive pattern:


thrombolysis.

0.003).


3.1, P < 0.005)

status within 6 h from symptoms onset and differentiating the several occlusive pattern in extra- and intracranial circulation. Only 32% of the included patients shown a significant extracranial carotid disease and the conclusion of the authors was that it is unlikely that the success of thrombolysis is independent from vascular status, with a statistical significant difference in recanalization between proximal and distal MCA occlusion. Furthermore the "sudden pattern" of recanalization, isolated MCA occlusion, embolic origin of MCA occlusion, are prognostic factors for favourable outcome in patients treated with rtPA within 3 hours and monitored by TCD (Molina et al. 2004 b).

As previously mentioned, the recanalization rate is related to the occlusive pattern. In controlled angiographic trials of intravenous thrombolysis the partial or complete recanalization rate of a previously occluded MCA, is not higher than 25% (Del Zoppo et al. 1998). Trials with intra-arterial thrombolysis had a better recanalization rate (Furlan et al 1999): for example in the PROACT II trial (121 patients), the rate of complete recanalization was 20% and the rate of partial recanalization was 46%, but the median symptom to needle time was 5.3 h and the recanalization, when it occurred, was achieved at > 7 hours from stroke onset.

The sequential bridged strategy of i.v. followed by i.a. thrombolysis, is promising and could be more efficient than each of both single technique, joining the benefit of the rapid administration of i.v. rtPA with the higher recanalization rate of the i.a. treatment (Lewandowski et al. 1999; Flaherty et al. 2005; Lee et al. 2004; Zaidat et al. 2002; Sekoranja et al. 2006).

Several studies described the role of TCD and TCCS as a useful tool for the diagnosis of MCA occlusion and the monitoring of its recanalization and the prognostic value of early arterial recanalization, identified by TCD, was reaffirmed in terms of good outcome at 3 months (Labiche et al. 2003) for:


In this study 20% of patients with proximal MCA occlusion who do not recanalize within 30 min is dead at 3 months.

In the Eligible study (Malferrari et al. 2007; Malferrari and Zedde 2008) the subgroup of patients with MCA stenosis or occlusion had the highest recanalization rate and distal MCA lesions shown a better and earlier recanalization and a significantly lower mortality rate than proximal ones, being patent nearly 50% at 3–6 h, as in the NAIS study (Allendoerfer et al. 2006). The authors conclude that "in acute stroke patients the early identification of a MCA stenosis or occlusion, mainly distal MCA lesions, is a strong predictor of good functional outcome at 3 months". The known differences in the speed and rate of recanalization are probably related to the clot age and composition, because rtPA has a better penetration in fibrin-rich thrombi, likely more recent and embolic, than in plateletrich thrombi, whose lysis is often slow and partial, with clot fragments moving to the distal smaller vessels and prolonging ischemia (Molina et al. 2004 b; Malferrari and Zedde 2008).

A revision of the data from CLOTBUST study to find out the relationship among the presence and site of vessel lesion and the rate of complete recanalization and clinical recovery was recently made (Saqqur et al. 2007), and its findings were not different from the results of the ELIGIBLE study (Malferrari et al. 2007; Malferrari and Zedde 2008):


In this study patients with TIBI 0 grade had less probability of complete recanalization than patients with TIBI 3 (ORadj: 0.256, CI 95: 0.11 to 0.595, P < 0.002).

In the CLOTBUST study (Alexandrov et al. 2004 b) the continuous TCD monitoring (i.e. exposure to ultrasound) was a positive predictor for complete recanalization (ORadj: 3.02, CI95: 1.396 to 6.514, P < 0.005). NIHSS score < 2 at 24 h was achieved in 22% of patients, so categorized in terms of the occlusive pattern:


282 Neuroimaging for Clinicians – Combining Research and Practice

status within 6 h from symptoms onset and differentiating the several occlusive pattern in extra- and intracranial circulation. Only 32% of the included patients shown a significant extracranial carotid disease and the conclusion of the authors was that it is unlikely that the success of thrombolysis is independent from vascular status, with a statistical significant difference in recanalization between proximal and distal MCA occlusion. Furthermore the "sudden pattern" of recanalization, isolated MCA occlusion, embolic origin of MCA occlusion, are prognostic factors for favourable outcome in patients treated with rtPA within

As previously mentioned, the recanalization rate is related to the occlusive pattern. In controlled angiographic trials of intravenous thrombolysis the partial or complete recanalization rate of a previously occluded MCA, is not higher than 25% (Del Zoppo et al. 1998). Trials with intra-arterial thrombolysis had a better recanalization rate (Furlan et al 1999): for example in the PROACT II trial (121 patients), the rate of complete recanalization was 20% and the rate of partial recanalization was 46%, but the median symptom to needle time was 5.3 h and the recanalization, when it occurred, was achieved at > 7 hours from

The sequential bridged strategy of i.v. followed by i.a. thrombolysis, is promising and could be more efficient than each of both single technique, joining the benefit of the rapid administration of i.v. rtPA with the higher recanalization rate of the i.a. treatment (Lewandowski et al. 1999; Flaherty et al. 2005; Lee et al. 2004; Zaidat et al. 2002; Sekoranja et

Several studies described the role of TCD and TCCS as a useful tool for the diagnosis of MCA occlusion and the monitoring of its recanalization and the prognostic value of early arterial recanalization, identified by TCD, was reaffirmed in terms of good outcome at 3

In this study 20% of patients with proximal MCA occlusion who do not recanalize within 30

In the Eligible study (Malferrari et al. 2007; Malferrari and Zedde 2008) the subgroup of patients with MCA stenosis or occlusion had the highest recanalization rate and distal MCA lesions shown a better and earlier recanalization and a significantly lower mortality rate than proximal ones, being patent nearly 50% at 3–6 h, as in the NAIS study (Allendoerfer et al. 2006). The authors conclude that "in acute stroke patients the early identification of a MCA stenosis or occlusion, mainly distal MCA lesions, is a strong predictor of good functional outcome at 3 months". The known differences in the speed and rate of recanalization are probably related to the clot age and composition, because rtPA has a better penetration in fibrin-rich thrombi, likely more recent and embolic, than in plateletrich thrombi, whose lysis is often slow and partial, with clot fragments moving to the distal smaller vessels and prolonging ischemia (Molina et al. 2004 b; Malferrari and Zedde 2008). A revision of the data from CLOTBUST study to find out the relationship among the presence and site of vessel lesion and the rate of complete recanalization and clinical recovery was recently made (Saqqur et al. 2007), and its findings were not different from the

results of the ELIGIBLE study (Malferrari et al. 2007; Malferrari and Zedde 2008):

3 hours and monitored by TCD (Molina et al. 2004 b).

stroke onset.

al. 2006).

months (Labiche et al. 2003) for:

min is dead at 3 months.



It is notable that none of the patients with T occlusion had dramatic recovery (0%) (P < 0.003).

Modified Rankin Scale score <1 was achieved in 35% of patients, so categorized in terms of the occlusive pattern:


The likelihood of a good long-term outcome was twice higher for patients with distal MCA occlusion than for patients with proximal MCA occlusions (OR: 2.1, CI 95: 1.1 to 4, P < .025). The authors conclude that the "clinical response to thrombolysis is influenced by the site of occlusion" and "patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term" (Alexandrov et al. 2004b; Saqqur et al. 2007).

Also the Eligible study (Malferrari et al. 2007) shown that the clinical recovery at both 24 h and 3 months is influenced by the site of occlusion.

CLOTBUST (Alexandrov et al. 2004b; Saqqur et al. 2007), NAIS (Allendoerfer et al. 2006) and ELIGIBLE (Malferrari et al. 2007; Malferrari and Zedde 2008) studies demonstrated the high predictive value of neurosonology for identifying proximal MCA occlusion. The CLOTBUST authors (Alexandrov et al. 2004b; Saqqur et al. 2007) proposed TCD as a screening tool for i.v./i.a. thrombolysis. A similar proposal has been made for TCCS by an interesting but small clinical study (Sekoranja et al. 2006), where the patients with partial or complete MCA recanalization at 30 min from the onset of i.v. thrombolysis showed an higher rate of positive outcome at 24 h and at 3 months than patients with none recanalization. In this latter subgroup the subsequent i.a. thrombolysis with the residual amount of rtPA was performed and provided a substantial benefit. Therefore, 56% of patients treated with combined i.v./i.a. thrombolysis achieved a good outcome at 3 months (mRS 0-2), compared with 22% of a previous study (Labiche et al. 2003) in patients with no recanalization with i.v. thrombolysis.

As in the TCD studies (Saqqur et al. 2005), this TCCS experience (Sekoranja et al. 2006) found that TIBI classification, defined by TCCS, was reliably related with the corresponding TIMI angiographic grades. Therefore neurosonological techniques, both TCD and TCCS, can

Neurosonological Evaluation of the Acute Stroke Patients 285

al. 2006). T occlusions have similar, if not poorer, mortality and disability rates and a recanalization rate of 31% at 3 days with i.v. thrombolysis (almost all were late or slow recanalizations) (Linfante et al. 2002). This is because of the broader clot burden with lesser

After the literature review about clinical practice, it is useful to consider the TCCS score, COGIF (Nedelmann et al. 2009) for the potential pitfalls of the recanalization monitoring in

Grades 2 and 3 define the low flow situation and it may be determined by different pathological conditions. Low-flow phenomena in the M1 MCA are a main feature of a partial recanalization or T occlusion or tandem pattern, because of an upstream or downstream obstruction (i.e., distal main stem or MCA branch occlusions). The differentiation of these conditions from partial recanalization is well addressed by the

Fig. 25. The influence of upstream and downstream occlusions on low-flow status in COGIF

In the COGIF score, low-flow velocities without diastolic flow (grade 2: residual flow), are distinguished from complete obstruction (grade 1: no flow), because residual flow signals are associated with improved results of thrombolysis (Labiche et al. 2003; Saqqur et al. 2008). The grade 4 (established perfusion) comprises different hemodynamic situations: normal flow (4a), stenotic flow (4b), and high-flow velocities in hyperperfusion (4c). This grouping was determined by the thought that distinguishing high-flow velocities from normal-flow velocities is not so relevant for defining a reestablishment of sufficient hemispheric

About the differentiation between grade 4 b and 4 c the statement 9 is well explicative

collateral circle (Jansen et al. 1995; von Kummer et al. 1995; Christou et al. 2002).

An example of a slow recanalization process is in Fig. shown in Fig. 24.

clinical trials, i.e. for grade > 2.

Consensus Conference, as summarized in Fig. 25.

score (modified, from Nedelmann et al. 2009)

perfusion.

(fig. 26).

be "a suitable noninvasive tool for selecting patient with persistent arterial occlusions despite initial i.v. rtPA treatment with an i.v. /i.a. protocol" (Saqqur et al. 2005).

Fig. 24. From top to bottom a sequential TCCS examination of a patient with MCA occlusion and contraindication to thrombolysis. In the right side the corresponding drawings (adapted from Malferrari 2010) and TIBI flow grades.

This is mainly true for vascular occlusive patterns known and accepted for being prognostically poor, i.e. tandem occlusions of ICA and proximal MCA and T occlusions (Fig. 14). It has been known that tandem occlusions of ICA and proximal MCA have a poorest response to i.v. thrombolysis and are associated with an early (within 7 days) mortality rate, as high as 18%, but also 80% of the survivors have a severe disability (mRS > 2) (Rubiera et al. 2006). T occlusions have similar, if not poorer, mortality and disability rates and a recanalization rate of 31% at 3 days with i.v. thrombolysis (almost all were late or slow recanalizations) (Linfante et al. 2002). This is because of the broader clot burden with lesser collateral circle (Jansen et al. 1995; von Kummer et al. 1995; Christou et al. 2002).

An example of a slow recanalization process is in Fig. shown in Fig. 24.

After the literature review about clinical practice, it is useful to consider the TCCS score, COGIF (Nedelmann et al. 2009) for the potential pitfalls of the recanalization monitoring in clinical trials, i.e. for grade > 2.

Grades 2 and 3 define the low flow situation and it may be determined by different pathological conditions. Low-flow phenomena in the M1 MCA are a main feature of a partial recanalization or T occlusion or tandem pattern, because of an upstream or downstream obstruction (i.e., distal main stem or MCA branch occlusions). The differentiation of these conditions from partial recanalization is well addressed by the Consensus Conference, as summarized in Fig. 25.

284 Neuroimaging for Clinicians – Combining Research and Practice

be "a suitable noninvasive tool for selecting patient with persistent arterial occlusions

Fig. 24. From top to bottom a sequential TCCS examination of a patient with MCA occlusion and contraindication to thrombolysis. In the right side the corresponding drawings (adapted

This is mainly true for vascular occlusive patterns known and accepted for being prognostically poor, i.e. tandem occlusions of ICA and proximal MCA and T occlusions (Fig. 14). It has been known that tandem occlusions of ICA and proximal MCA have a poorest response to i.v. thrombolysis and are associated with an early (within 7 days) mortality rate, as high as 18%, but also 80% of the survivors have a severe disability (mRS > 2) (Rubiera et

from Malferrari 2010) and TIBI flow grades.

despite initial i.v. rtPA treatment with an i.v. /i.a. protocol" (Saqqur et al. 2005).

Fig. 25. The influence of upstream and downstream occlusions on low-flow status in COGIF score (modified, from Nedelmann et al. 2009)

In the COGIF score, low-flow velocities without diastolic flow (grade 2: residual flow), are distinguished from complete obstruction (grade 1: no flow), because residual flow signals are associated with improved results of thrombolysis (Labiche et al. 2003; Saqqur et al. 2008). The grade 4 (established perfusion) comprises different hemodynamic situations: normal flow (4a), stenotic flow (4b), and high-flow velocities in hyperperfusion (4c). This grouping was determined by the thought that distinguishing high-flow velocities from normal-flow velocities is not so relevant for defining a reestablishment of sufficient hemispheric perfusion.

About the differentiation between grade 4 b and 4 c the statement 9 is well explicative (fig. 26).

Neurosonological Evaluation of the Acute Stroke Patients 287

out curves into selected areas of cerebral parenchyma or ROIs (Region of Interest)

a. unenhanced brain CT at the baseline; b. TCCS from the right temporal window with a diagnosis of a T occlusion; c. ultrasound perfusional curves (normal hemisphere in the upper half and flattened curves of the affected hemisphere in the lower half); d. tridimensional perfusional map with a broad area of hypoperfusion (blue); e. 90° rotated bidimensional map to make easier to compare it with the CT; f. 24 hours unenhanced brain

Another recent application of TCCS is the monitoring of the hemorrhagic transformation after thrombolysis for acute stroke of the anterior circulation (Seidel et al. 2009). An example

a. TCCS from the left temporal window, showing the rounded hyperechoic hemorrhagic

lesion in the contralateral hemisphere; b. corresponding unenhanced brain CT.

(Malferrari and Zedde 2008) (Fig. 27).

Fig. 27. An example of Ultrasound Perfusional Imaging.

CT with a perfectly corresponding ischemic lesion.

Fig. 28. Parenchymal haemorrhage after thrombolysis.

of this application is showed in Fig. 28.


Fig. 26. Consensus Statement 9 (from Nedelmann et al. 2009)

#### **4.3 Perfusional ultrasound imaging**

As previously mentioned at the beginning of this section, both vascular and perfusional informations are relevant to define the prognosis of acute stroke patients and the success of treatment, because the reopening of the occluded vessel is not equal to the reperfusion of the affected brain tissue. Neuroradiological imaging, with the concept of core/penumbra mismatch, raised some questions about the reliability and the usefulness of these data before thrombolysis, but there are several logistic limitation to the wide use of this techniques, besides some contraindications (to the technique, as for patients with pacemakers in MRI, or to the contrast medium, as for CT). Ultrasound techniques, namely TCCS with UCA administration and harmonic imaging, are safe and bedside executable, but their reliability for evaluating the brain perfusional status has not been demonstrated and there are not validated thresholds for core (brain tissue irreversibly harmed and not salvageable by any treatment) and penumbra (brain tissue surrounding the core and hypoperfused, likely not irreversibly harmed, and therefore potentially salvageable by reperfusion). Although these limitations, TCCS can help the clinician to decide in the acute stroke setting, where other techniques are not available or reliable (as for patients with severe arterial disease on both sides).

The purpose of this imaging strategy is the selection of patients for reperfusion treatment, i.v. or i.a., in order to improve its safety and efficacy, decreasing the hemorrhagic complications. This strategy could theoretically lead to overcome the concept of a fixed time window.

In clinical practice, there are two established imaging techniques to distinguish core from penumbra, MRI and contrast CT. The first technique diagnoses the core by using DWI and the penumbra by using perfusion-weighted imaging (PWI); the second one uses CT cerebral blood volume imaging for the core and PWI for the penumbra.

Also ultrasound techniques allow to perform a perfusional study of the brain parenchyma, depicting the blood flow in the microcirculation (Malferrari and Zedde 2008). This noninvasive tool can assess the perfusion deficits in acute stroke patients, although the lack of validated threshold in comparison with conventional neuroradiological methods.

The optimization of this concept was achieved by routine use of second generation UCA (for European countries, because UCA are not approved for neurosonological application in the USA) and harmonic imaging, that allow a real time dynamic study of cerebral circulation. It is possible to achieve an early visualization of the estimated size of the ischemic area in the acute phase, with minimal or no signs at the basal unenhanced CT (Seidel et al. 2004; Wiesman et al. 2004; Meyer-Wiethe et al. 2007). Ultrasound perfusion, like perfusional studies by CT and MRI, is based on dilution theory and allows to obtain wash-in and wash-

As previously mentioned at the beginning of this section, both vascular and perfusional informations are relevant to define the prognosis of acute stroke patients and the success of treatment, because the reopening of the occluded vessel is not equal to the reperfusion of the affected brain tissue. Neuroradiological imaging, with the concept of core/penumbra mismatch, raised some questions about the reliability and the usefulness of these data before thrombolysis, but there are several logistic limitation to the wide use of this techniques, besides some contraindications (to the technique, as for patients with pacemakers in MRI, or to the contrast medium, as for CT). Ultrasound techniques, namely TCCS with UCA administration and harmonic imaging, are safe and bedside executable, but their reliability for evaluating the brain perfusional status has not been demonstrated and there are not validated thresholds for core (brain tissue irreversibly harmed and not salvageable by any treatment) and penumbra (brain tissue surrounding the core and hypoperfused, likely not irreversibly harmed, and therefore potentially salvageable by reperfusion). Although these limitations, TCCS can help the clinician to decide in the acute stroke setting, where other techniques are not available or reliable (as for patients with severe arterial disease on both

The purpose of this imaging strategy is the selection of patients for reperfusion treatment, i.v. or i.a., in order to improve its safety and efficacy, decreasing the hemorrhagic complications. This strategy could theoretically lead to overcome the concept of a fixed time

In clinical practice, there are two established imaging techniques to distinguish core from penumbra, MRI and contrast CT. The first technique diagnoses the core by using DWI and the penumbra by using perfusion-weighted imaging (PWI); the second one uses CT cerebral

Also ultrasound techniques allow to perform a perfusional study of the brain parenchyma, depicting the blood flow in the microcirculation (Malferrari and Zedde 2008). This noninvasive tool can assess the perfusion deficits in acute stroke patients, although the lack of

The optimization of this concept was achieved by routine use of second generation UCA (for European countries, because UCA are not approved for neurosonological application in the USA) and harmonic imaging, that allow a real time dynamic study of cerebral circulation. It is possible to achieve an early visualization of the estimated size of the ischemic area in the acute phase, with minimal or no signs at the basal unenhanced CT (Seidel et al. 2004; Wiesman et al. 2004; Meyer-Wiethe et al. 2007). Ultrasound perfusion, like perfusional studies by CT and MRI, is based on dilution theory and allows to obtain wash-in and wash-

validated threshold in comparison with conventional neuroradiological methods.

Fig. 26. Consensus Statement 9 (from Nedelmann et al. 2009)

blood volume imaging for the core and PWI for the penumbra.

**4.3 Perfusional ultrasound imaging** 

sides).

window.

out curves into selected areas of cerebral parenchyma or ROIs (Region of Interest) (Malferrari and Zedde 2008) (Fig. 27).

Fig. 27. An example of Ultrasound Perfusional Imaging.

a. unenhanced brain CT at the baseline; b. TCCS from the right temporal window with a diagnosis of a T occlusion; c. ultrasound perfusional curves (normal hemisphere in the upper half and flattened curves of the affected hemisphere in the lower half); d. tridimensional perfusional map with a broad area of hypoperfusion (blue); e. 90° rotated bidimensional map to make easier to compare it with the CT; f. 24 hours unenhanced brain CT with a perfectly corresponding ischemic lesion.

Another recent application of TCCS is the monitoring of the hemorrhagic transformation after thrombolysis for acute stroke of the anterior circulation (Seidel et al. 2009). An example of this application is showed in Fig. 28.

Fig. 28. Parenchymal haemorrhage after thrombolysis.

a. TCCS from the left temporal window, showing the rounded hyperechoic hemorrhagic lesion in the contralateral hemisphere; b. corresponding unenhanced brain CT.

Neurosonological Evaluation of the Acute Stroke Patients 289

a. schematic drawing of proximal and distal atherosclerosis of M1 MCA; b. corresponding TCCS from the right temporal window, with the Doppler spectrum and a clear increase of the flow velocity; c. MRI with ischemic lesions in the centrum semiovale of lacunar size.

In the last decade a considerable amount of experimental and pilot clinical studies on stroke patients addressed the matter of ultrasound-assisted thrombolysis. The in vitro experience and the studies on animal models demonstrated that ultrasounds at frequencies in the 20 KHz -1 MHz range, lower than the ones usually available for diagnostic purposes, can potentiate the action of endogenous or exogenous tPA (Malferrari and Zedde 2008), leading to design a human study with a specific therapeutic ultrasound machine (Daffershofer et al. 2005) with the premature stop of the enrolment because of the increased rate of hemorrhage. This study caused a mild slowdown in the TCCS application on this field, although the good results of the above-mentioned CLOTBUST study with TCD (Alexandorv et al. 2004b). The phenomena by which ultrasounds enhance thrombolysis is the increased delivery of rtPA into the fibrin clot and the breaking of the tight binding of fibrin itself, therefore providing a greater surface for thrombolytic drugs action, by cavitation, starting from the

The association of the UCA administration provides a great amount of right-sized microbubbles and then makes easier the clot fragmentation by the cavitation and thermal effects of ultrasound waves. This process happens by using the same ultrasound machines available for clinical purposes and the frequencies of the diagnostic transcranial doppler (1-2 MHz) (Malferrari and Zedde 2008). Microbubbles lower the ultrasound-induced cavitation threshold and dramatically increase the lytic action of ultrasounds. Several microbubbles has been used in experimental studies and some kind of not commercially available microbubbles also for human studies (Molina et al. 2009). The CLOTBUST study (Alexandrov et al. 2004b) evaluated the combined effect of rtPA administration within 3 h from symptom onset and TCD continuous monitoring at 2 MHz (diagnostic parameters), achieving a recanalization rate of 36% and an hemorrhagic transformation rate of 9%, not significantly different in comparison with the hemorrhagic rate of non-monitored patients. Other authors used TCCS for the same purposes with a diagnostic setting, with or without

rtPA administration, confirming these findings (Cintas et al. 2002; Eggers et al. 2008). The data about ultrasound-enhanced thrombolysis has been recently analysed in a metaanalysis (Tsivgoulis et al. 2010) and the results were comforting, regarding the safety of sonothrombolysis with high frequency ultrasounds, with or without UCA. This modality of sonothrombolysis "is associated with a nearly 3-fold increased likelihood of complete recanalization and 2-fold higher likelihood of functional independence at 3 months"

The limitations are certainly the small number of patients included, particularly in

Neurosonology is a safe, reliable and useful technique for evaluate acute stroke patients It may provide relevant information about the prognosis and guide the selection of the most adequate treatment for each patient. The recent development of intrinsic therapeutic

sonothrombolysis studies using TCCS, and other studies are needed.

**6. Ultrasound-assisted thrombolysis** 

tissue and blood microbubbles (Alexandrov 2009).

(Tsivgoulis et al. 2010).

**7. Conclusion** 

### **5. Focus on intracranial stenosis**

Intracranial atherosclerosis is an often neglected cause of stroke but it represents the first cause of ischemic stroke in the world (Gorelick et al. 2008). Not only atherosclerosis may cause an intracranial stenosis, but it is certainly the most frequent cause and also in the white population, in patients with multiple vascular risk factors.

Some relevant aspects of intracranial large artery disease, as recently stated and summarized (Gorelick et al. 2008), are:


The evaluation of the intracranial atherosclerosis and stenosis has addressed in the literature mainly in the setting of the post-acute phase and the diagnostic criteria for all techniques are not directly applicable in the acute phase; for example the TCCS criteria (Baumgartner et al. 1999) were selected and validated in a stable situation, because of the frequent presence of a transient intracranial stenosis (TIBI grade 4 and COGIF grade 4b) during the recanalization process of an occluded intracranial artery; therefore it is not possible to define criteria for a dynamically changing situation and the persistence of the stenosis days and weeks after the acute phase may more reliably indicate the intracranial atherosclerosis as the cause of the cerebrovascular event (Nedelmann et al. 2009; Malferrari et al. 2007; Malferrari et al. 2008).

Because of these considerations, the diagnosis of intracranial stenosis is not a main item in the ultrasound monitoring of the acute phase of ischemic stroke. Nevertheless it is useful to outline a neglected aspect of intracranial stenosis, as previously mentioned, i.e. the PAD subgroup (patients with clinical and radiological manifestations of lacunar infarction as a result of intracranial large artery atherosclerosis, mainly in MCA, located near the origin of perforating branches and therefore occluding them by direct clot growth of artery-to-artery embolism) (Bang et al. 2002) (Fig. 29).

Fig. 29. PAD example.

a. schematic drawing of proximal and distal atherosclerosis of M1 MCA; b. corresponding TCCS from the right temporal window, with the Doppler spectrum and a clear increase of the flow velocity; c. MRI with ischemic lesions in the centrum semiovale of lacunar size.
