**6. Ultrasound-assisted thrombolysis**

288 Neuroimaging for Clinicians – Combining Research and Practice

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

Some relevant aspects of intracranial large artery disease, as recently stated and



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


**5. Focus on intracranial stenosis** 

summarized (Gorelick et al. 2008), are:

embolism) (Bang et al. 2002) (Fig. 29).

Fig. 29. PAD example.

occlusive disease;



unravel enigmas related to this disorder.

white population, in patients with multiple vascular risk factors.

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 tissue and blood microbubbles (Alexandrov 2009).

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" (Tsivgoulis et al. 2010).

The limitations are certainly the small number of patients included, particularly in sonothrombolysis studies using TCCS, and other studies are needed.
