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Vascular imaging
Handbook of Clinical Neurology, Vol. 136 (3rd series) Neuroimaging, Part II J.C. Masdeu and R.G. Gonza´lez, Editors © 2016 Elsevier B.V. All rights reserved
Chapter 55
Vascular imaging: ultrasound DAVID RODRIGUEZ-LUNA* AND CARLOS A. MOLINA Stroke Unit, Department of Neurology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
Abstract The complexity of current stroke treatments requires detailed vascular imaging information. Vascular imaging using ultrasound is a safe, inexpensive, and portable technique that provides continuous real-time hemodynamic information, which allows flow changes to be monitored over prolonged time. Ultrasound imaging is in continuous development, which has led to a growing number of situations where ultrasound can be helpful, foremost in dynamic and rapidly changing clinical scenarios like acute stroke. The aim of this chapter is to review the main indications of vascular ultrasound in acute stroke, including extracranial steno-occlusive lesions diagnosis and its consequences on distal vasculature, intracranial stenosis diagnosis, acute intracranial occlusion, recanalization, and reocclusion diagnosis and monitoring, therapeutic sonothrombolysis, and vasospasm after subarachnoid hemorrhage.
INTRODUCTION The complexity of current stroke treatments requires not only accurate clinical and brain imaging data but also detailed vascular imaging information. Different vascular imaging modalities may be used in stroke diagnosis, including ultrasound, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA). However, although most times these techniques are used complementarily, sometimes they are in competition. The advantages of vascular imaging using ultrasound are well known. Ultrasound is a safe (noninvasive without ionizing radiation), relatively inexpensive, and portable technique, making it a fast bedside technique. Further and foremost, ultrasound provides continuous real-time hemodynamic information, such as quantification and direction of blood flow, which allows flow changes to be monitored over prolonged time compared with other techniques. The limitations of ultrasound include a lower spatial resolution than CTA, MRA, or DSA; the provision of a fragmented assessment of the cerebrovascular tree without direct anatomic information; and the suitability
of a bone acoustic window in transcranial ultrasound, although fixable with ultrasound contrast agents in absence of acoustic window. Ultrasound imaging, including carotid and vertebral duplex, transcranial Doppler (TCD), and transcranial color-coded duplex sonography (TCCS), is in continuous development. This has led to a growing number of situations where ultrasound can be helpful, foremost in dynamic and rapidly changing clinical scenarios like acute stroke, where it may have a direct impact on clinical decision making. Among other clinical situations, the indications of vascular ultrasound in stroke include extracranial steno-occlusive lesion diagnosis and its consequences on distal vasculature, intracranial stenosis diagnosis, acute intracranial occlusion, recanalization, and reocclusion diagnosis and monitoring, therapeutic sonothrombolysis, and vasospasm after subarachnoid hemorrhage. The aim of this chapter is to review these indications.
EXTRACRANIAL PATHOLOGY Extracranial ultrasound, in particular duplex ultrasound, can evaluate proximal segments of both carotid and
*Correspondence to: Dr. David Rodriguez-Luna, Stroke Unit, Department of Neurology, Vall d’Hebron University Hospital, Ps. Vall d’Hebron, 119, 08035, Barcelona, Spain. Tel/Fax: +34-934-894257, E-mail: [email protected]
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vertebral artery (VA) systems. Duplex ultrasound can accurately evaluate atherothrombotic changes in internal carotid artery (ICA), including characterization of the plaque, stenosis gradation, and occlusion diagnosis. Further, extracranial ultrasound can be helpful for ICA stenting and endarterectomy surveillance as well as for evaluation of VA stenosis and occlusion, subclavian steal phenomenon, and both carotid and VA dissections. One of the advantages of carotid duplex ultrasound over other vascular imaging techniques is the ability to characterize carotid atherosclerotic plaques using high-resolution B-mode imaging. Plaques may be characterized according to different parameters, including number, location, size, surface (regular, irregular), shape (eccentric, concentric), echogenicity (echolucent, echogenic), and texture (homogeneous, heterogeneous). Using some of these characteristics, different carotid plaque classifications have been developed. The most widely classification used was proposed by Geroulakos and coworkers (1993), defining five types of plaque according to echogenicity: type 1 plaques are uniformly echolucent; type 2 predominantly echolucent (Fig. 55.1); type 3 predominantly echogenic; type 4 uniformly echogenic; and type 5 plaques could not be classified owing to heavy calcification and acoustic shadows. Several studies have shown that echolucent plaques are more likely to be symptomatic (including amaurosis fugax) and more frequently associated with cerebral infarctions than echogenic ones (Geroulakos et al., 1994; Sabetai et al., 2000). Regardless of the characteristics of the plaque, the severity of the carotid stenosis is the main criterion to determine the risk of stroke in patients with both symptomatic (Barnett et al., 1998; European Carotid Surgery Trialists’ Collaborative Group, 1998) and asymptomatic (Walker et al., 1995) ICA disease. Although several criteria for ICA stenosis quantification have been proposed, the most widely used are those proposed by the Society of Radiologists in Ultrasound for duplex
ultrasound (Grant et al., 2003). Based primarily on peak systolic velocity and plaque estimation, these consensus criteria classify ICA stenosis into several degrees according to different range estimation, including normal (no stenosis), <50% stenosis, 50–69% stenosis (Fig. 55.1), 70% stenosis to near occlusion, near occlusion, and total occlusion (Fig. 55.2A and B). Further, different complementary intracranial ultrasound evaluations can be performed to better stratify the risk of ICA stenosis; such emboli monitor echolucent plaques without hemodynamically significant stenosis, vasomotor reactivity, and compensatory intracranial flow assessment through collateral channels in highgrade stenosis and occlusions (Fig. 55.2). Carotid ultrasound is the primary tool for surveillance after stenting and endarterectomy. However, in contrast to endarterectomy, the deployment of a stent alters the flow velocities and therefore standard velocity criteria should not be used for stenting restenosis diagnosis. Although ultrasound velocity criteria in stented ICAs are not well established, several velocity measurements have been proposed, including higher peak systolic velocity thresholds (AbuRahma et al., 2008) and progressively increasing both peak systolic velocity and ICA/common carotid artery ratios (Lal et al., 2008). In contrast to ICA, there are no consensus criteria for extracranial VA stenosis or occlusion diagnosis using ultrasound. Although different ultrasound diagnosis criteria have been used for VA stenosis, the sensitivity is lower than CTA and contrast-enhanced MRA (Khan et al., 2007). For extracranial VA occlusion, absence of flow signal has been proposed as a sign of occlusion in the origin of the artery, and presence of peak systolic flow, but end-diastolic flow velocity of zero as a sign of occlusion before branching into the posterior inferior cerebellar artery (Saito et al., 2004). The ultrasound evaluation of VA can also find different patterns suggestive of the presence of subclavian steal phenomenon as a surrogate of subclavian artery disease, including systolic
Fig. 55.1. Internal carotid artery stenosis on carotid duplex ultrasound. Extensive 50–69% right internal carotid artery stenosis due to a heterogeneous plaque (peak systolic velocity 223 cm/s).
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Fig. 55.2 See legend on next page.
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flow deceleration, different degrees of alternating flow (Fig. 55.2F), and total retrograde flow (Fig. 55.2P). Carotid duplex ultrasound is also helpful in the diagnosis of ICA dissection. While B-mode imaging can show direct signs of dissection such as tapering of ICA lumen, a membrane or a flap, or true and false lumens in up to two-thirds of cases, Doppler spectra can show an abnormal pattern in more than 90% of cases, with an overall sensitivity of 95% when combined with TCD examination (Sturzenegger et al., 1995). Ultrasound may also be helpful in VA dissection diagnosis, although the diagnostic yield when combined with TCD examination is lower than in ICA dissection (Sturzenegger et al., 1993).
The advantages of ultrasound compared to other vascular imaging techniques in the evaluation of intracranial collateral channels include the ability to detect the direction of the blood flow and its quantification. Ultrasound findings usually include elevation of flow on the donor system and normal or reduced flows in the recipient system. Further, data about the direction of the flow can be easily evaluated by ultrasound, such as reversal flow in both ipsilateral A1 segment of anterior cerebral artery and ophthalmic artery in proximal ICA occlusions, and in P1 segment of posterior cerebral artery in basilar artery (BA) occlusions.
INTRACRANIAL COLLATERAL CHANNELS
Despite the continuous development of ultrasound imaging and opposed to extracranial ICA stenosis, there are no internationally accepted criteria for grading intracranial arterial stenoses. According to Spencer’s (1987) description, the ultrasound imaging changes of an arterial stenosis could be classified into three categories: primary changes, consisting of intrastenotic flow velocity increase; secondary changes, including pre- and poststenotic flow velocity decrease; and tertiary changes, seen in the collateral circulation. Based on the primary change of intrastenotic flow velocity increase, several studies have evaluated the ability of ultrasound imaging for the diagnosis of intracranial stenosis compared with DSA as standard of reference. Baumgartner and coworkers (1999) correlated ultrasound data of basal cerebral arteries with DSA using TCCS. According to peak systolic velocity values, they reported cutoff values for <50% and 50% basal cerebral artery stenosis diagnosis, with a sensitivity and specificity near to 100% in <50% stenosis and of 100% in 50% stenosis. Similarly, intrastenotic flow velocity increase was used for intracranial stenosis diagnosis using TCD with DSA as standard of reference in the Stroke Outcomes
Three collateral channels can be evaluated by both TCD and TCCS: the anterior communicating artery, the posterior communicating artery, and the ophthalmic artery. These pathways are latent under normal conditions. However, one or more of them can open when a pressure gradient develops between two anastomosing arterial systems, the donor and the recipient, usually due to an occlusion or a hemodynamically significant stenosis located proximal to both the recipient arterial system and the origin of the collateral channel (Alexandrov and Neumyer, 2004). The paradigm of collateral channels opening is proximal ICA occlusion (Fig. 55.2), where these three channels may be involved to guarantee the flow supply to the ipsilateral middle cerebral artery (MCA), the recipient: the anterior communicating artery channel with contralateral A1 segment of anterior cerebral artery as donor; the posterior communicating artery channel with ipsilateral P1 segment of posterior cerebral artery as donor; and the ophthalmic artery channel with ipsilateral external carotid artery as donor.
INTRACRANIAL STENOSIS
Fig. 55.2. Right internal carotid artery occlusion with collateral flow via anterior communicating artery and right posterior communicating artery. Carotid and vertebral duplex ultrasound showing (A, B) right proximal internal carotid artery occlusion, (C) strong right V2–vertebral artery flow, (D, E) extensive 50–69% left internal carotid artery stenosis (peak systolic velocity 185.7 cm/s, internal carotid artery/common carotid artery ratio 2.8), and (F) left V2–vertebral artery alternating flow (incomplete subclavian steal phenomenon). Transcranial color-coded duplex sonography right-side insonation of circle of Willis (G): note (1) presence of right M1, middle cerebral artery; (2) reversed right A1, anterior cerebral artery; (3) left A1, anterior cerebral artery; (4) right P1, posterior cerebral artery aliasing, and (5) presence of right posterior communicating artery. Corresponding Doppler spectra show (H) reduced right M1, middle cerebral artery flow velocity and pulsatility, as compared to (J), left M1, middle cerebral artery; (I) retrograde right A1, anterior cerebral artery flow; (K) raised left A1, anterior cerebral artery flow velocity; (L) raised right P1, posterior cerebral artery flow velocity; (M) presence of right posterior communicating artery; and (N) normal right P2, posterior cerebral artery flow. Doppler spectrum analysis of vertebral and basilar arteries shows (O) strong right V4, vertebral artery flow; (P) total retrograde left V4, vertebral artery flow (complete subclavian steal phenomenon), and (Q) strong basilar artery flow.
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Fig. 55.3. Middle cerebral artery stenosis on transcranial color-coded duplex sonography. (A) Stenosis of the right M1 middle cerebral artery (arrow) visible due to the arterial narrowing and aliasing phenomenon as a focal change in the color coding in the stenosed region. (B) Intrastenotic flow velocity increase up to peak systolic velocity of 209 cm/s (nonangle-corrected) in a depth of 60 mm. Note a relative decrease of flow velocity in both (C) prestenotic (peak systolic velocity of 121.7 cm/s in a depth of 66 mm) and (D) poststenotic (peak systolic velocity of 94 cm/s in a depth of 54 mm) regions.
and Neuroimaging of Intracranial Atherosclerosis (SONIA) study (Feldmann et al., 2007), a companion study to the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial (Chimowitz et al., 2005). The mean flow velocity cutoffs on TCD used for identification of 50% stenosis were 100 cm/s for MCA and 80 cm/s for both VA and BA, with an overall negative predictive value of 83% and positive predictive value of 55% (Feldmann et al., 2007). The SONIA criteria were validated using TCD in a later study (Zhao et al., 2011) performed in a subpopulation of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (Chimowitz et al., 2011). This study also showed that, using a single velocity criterion, the most sensitive mean flow velocity threshold for 70% stenosis was >120 cm/s for MCA (sensitivity 71%), and >110 cm/s for both VA and BA (sensitivity 55%). Further, combined criteria for 70% stenosis diagnosis in MCA (mean flow velocity >120 cm/s, or stenotic/prestenotic ratio 3, or low velocity) and both
VA and BA (mean flow velocity >110 cm/s, or stenotic/prestenotic ratio 3) improved the sensitivity (91% and 60%, respectively) of TCD (Zhao et al., 2011). An advantage of TCCS intracranial stenosis evaluation over TCD is that it allows the visualization of other findings such as arterial narrowing and aliasing effect (change in the color coding). Thus, these findings may help to display the stenotic segment and guide with the evaluation of pre- and poststenotic segments (Fig. 55.3). However, despite the different suggested criteria and other complementary findings using TCCS or TCD, stenosis diagnosis by transcranial ultrasound may require a confirmatory test such as DSA to reliably identify the degree of the stenosis.
INTRACRANIAL OCCLUSION In patients with acute ischemic stroke, ultrasound image provides reliable data about the presence and location of an arterial occlusion. Performed by an experienced sonographer, within a few minutes, at bedside, and
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simultaneously with clinical assessment and blood draws, it does not result in any delay in the stroke management (Chernyshev et al., 2005). Zanette and coworkers (1995) described the presence of MCA occlusion as an absence of any flow signal from the symptomatic MCA or an asymmetry of the MCAs in patients with acute ischemic stroke using TCD. These criteria were later refined to better show the dynamic process of occlusion and recanalization in the setting of thrombolytic treatment in acute ischemic stroke (Burgin et al., 2000; Demchuk et al., 2001). Thereby, the Thrombolysis in Brain Ischemia (TIBI) six-score grading system is based on the relative relationship between the arterial segment insonated and the location of the occlusion (Demchuk et al., 2001), so that TIBI 0 and 1 refer to occlusion proximal to the insonated site, TIBI 2 and 3 to occlusion distal to insonated site, TIBI 4 to a residual stenosis, and TIBI 5 to normal flow (Fig. 55.4). In practice, these six grades are frequently separated into three major categories which have been validated by DSA (Burgin et al., 2000): complete occlusion (TIBI 0 and 1), partial occlusion (TIBI 2 and 3), and complete recanalization (TIBI 4 and 5).
Although the TIBI classification remains the most widely known and used system, the Consensus on Grading Intracranial Flow obstruction (COGIF) score was later proposed for its application using TCCS (Nedelmann et al., 2009). In essence, the COGIF score is a modification of the TIBI classification, where COGIF 1 corresponds to TIBI 0, COGIF 2 to TIBI 1, COGIF 3 to both TIBI 2 and 3, COGIF 4a to TIBI 5, and COGIF 4b and 4c to TIBI 4. Ultrasound image, both TCD and TCCS, also provides reliable information about the location of the arterial occlusion. Location of the occlusion has been shown to be a marker of the response to intravenous thrombolytic therapy. Saqqur and coworkers (2007) reported that the rate of complete recanalization within the first 2 hours after intravenous tissue plasminogen activator (tPA) bolus varies depending on the location of the occlusion: 44.2% for distal MCA occlusions, 30% for proximal MCA occlusions, 5.9% for terminal ICA occlusions, 27.2% for tandem ICA/MCA occlusions, and 33% for BA occlusions. Further, the location of the occlusion documented by TCD combined with other factors may help to predict
Fig. 55.4. Thrombolysis in brain ischemia (TIBI) classification. Illustration and description of the six flow grades on transcranial Doppler. (Adapted from Demchuk et al., 2001.)
VASCULAR IMAGING: ULTRASOUND the absence of recanalization 1 hour after intravenous tPA bolus in patients with acute ischemic stroke, including the presence of occlusion or severe extracranial ICA stenosis in proximal MCA occlusions and absence of atrial fibrillation in both ICA bifurcation and BA occlusions (Mendonc¸a et al., 2012), as well as intravenous thrombolytic treatment beyond 270 minutes in distal MCA occlusions (Muchada et al., 2014). Therefore, ultrasound image information about the presence and location of an artery occlusion may help to improve the selection of patients with acute ischemic stroke for more aggressive rescue reperfusion strategies.
INTRACRANIAL RECANALIZATION AND REOCCLUSION Real-time TCD monitoring allows determination of the degree, timing, and speed of recanalization in acute ischemic stroke. Performed at bedside, it provides faster information about recanalization than other techniques such as CTA, MRA, and DSA, and allows these data to be correlated simultaneously with clinical changes. The degree of arterial recanalization can be assessed by means of the TIBI grading system. MCA recanalization could be defined as partial when signals in a previously demonstrated absent or minimal (TIBI 0–1) flow appear blunted or dampened (TIBI 2–3), and complete when the flow improves to a stenotic or normal (TIBI 4–5) pattern (Burgin et al., 2000; Christou et al., 2000). The timing of arterial recanalization has a great impact on early clinical outcome in acute ischemic stroke. Christou and coworkers (2000) demonstrated that the timing of recanalization inversely correlated with improvement in neurologic status at the end of intravenous tPA infusion and at 24 hours from stroke. Further, they reported a 300-minute window timing of arterial recanalization after thrombolytic treatment to achieve recovery within the first 24 hours after stroke. To evaluate the speed of clot lysis during intravenous thrombolysis with tPA in patients with acute ischemic stroke, the duration of arterial recanalization was classified by Alexandrov and coworkers (2001) as sudden, stepwise, or slow. Sudden recanalization was defined as abrupt (<1 minute) appearance of a normal or stenotic low-resistance signal, stepwise as gradual flow improvement over 1–29 minutes, and slow as flow improvement 30 minutes. Using this classification, the authors reported that faster arterial recanalization (sudden and stepwise) is correlated with better 24-hour clinical improvement (Alexandrov et al., 2001). Similarly, sudden recanalization has been associated with higher degree of neurologic improvement at 24 hours compared with stepwise, slow, and no recanalization patterns (Molina et al., 2004).
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Arterial reocclusion after recanalization has been reported to be between 12% (Rubiera et al., 2005) and 34% (Alexandrov and Grotta, 2002) depending on the reocclusion definition. Reocclusion has been defined as a worsening in the TIBI flow grading system after a previously documented recanalization of at least one grade (Alexandrov and Grotta, 2002) or in more than one grade (Rubiera et al., 2005). Irrespective of the definition used, reocclusion after recanalization detected by real-time TCD monitoring is related to poorest early and long-term outcomes after thrombolytic treatment than patients who reanalyze without subsequent reocclusion (Alexandrov and Grotta, 2002; Rubiera et al., 2005). Therefore, real-time TCD monitoring provides information not only about the presence and location of an arterial occlusion, but also about the degree, timing, and speed of recanalization, the occurrence of reocclusion, and the lack of recanalization in the setting of intravenous thrombolytic treatment in acute ischemic stroke. So, real-time TCD monitoring provides valuable data for early identification of patients who may benefit from further treatment such as intra-arterial reperfusion therapies (Saqqur et al., 2005). Further, TCD can monitor the restoration of blood flow and provide real-time hemodynamic information during intra-arterial reperfusion procedures in patients with acute ischemic stroke (Ribo et al., 2010b; Rubiera et al., 2010; Tsivgoulis et al., 2013). This information includes recanalization, reocclusion, hyperperfusion, and thromboembolism or air embolism (Rubiera et al., 2010). A recent study has validated the TCD criteria for complete recanalization (TIBI 4–5) in real time as compared with thrombolysis in myocardial infarction angiographic scores (Tsivgoulis et al., 2013). In this multicenter study, the overall accuracy of TCD criteria for complete recanalization diagnosis was 89% (80–94%) during real-time TCD monitoring of intra-arterial reperfusion procedures in acute ischemic stroke patients with proximal intracranial occlusions.
SONOTHROMBOLYSIS Ultrasound exposure can enhance lysis of intravascular clot (sonothrombolysis) and therefore can be used in patients with acute ischemic stroke not only for diagnosis purposes but also as a therapeutic tool. The underlying mechanism is postulated to be related to mechanical, nonthermal effects of ultrasound in liquid media (as blood), including acoustic cavitation and negative pressure. Acoustic cavitation consists of formation and collapse of microbubbles of gas by the action of a high-intensity ultrasound acoustic field that can cause direct breakdown of the clot surface and therefore increase the permeation of tPA into the thrombus. Further, ultrasound negative-pressure waves create fluid
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motion or microstreaming and radiation forces, which can promote tPA circulation and increase the uptake of tPA into the clot (Amaral-Silva et al., 2011). Experimental studies have demonstrated an enhancement effect of ultrasound on thrombolysis using different frequencies and intensities of ultrasound. However, since high intensities may be harmful due to tissue heating, clinical studies have tested ultrasoundenhanced thrombolysis at low intensity and at low- and high-frequency ultrasound insonation combined with intravenous tPA (Amaral-Silva et al., 2011). The Transcranial Low-Frequency Ultrasound-mediated Thrombolysis in Brain Ischemia (TRUMBI) trial tested low-intensity– low-frequency ultrasound (300 MHz) but was prematurely stopped due to an unexpected rate of cerebral hemorrhages, both symptomatic and asymptomatic, in the tPA plus ultrasound group (Daffertshofer et al., 2005). Conversely, the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and systemic t-PA (CLOTBUST) phase II trial demonstrated that low-intensity–high-frequency ultrasound (2 MHz, conventional continuous TCD) enhancement of tPA thrombolytic effect could be safely achieved and increase tPA-induced recanalization as compared with placebo (Alexandrov et al., 2004). Further, CLOTBUST showed also a nonsignificant trend toward complete recovery from stroke, although it was not powered enough to achieve this issue. For that purpose, a phase III trial is currently under way to evaluate the efficacy of operator-independent ultrasound-enhanced thrombolysis (CLOTBUST-ER, NCT01098981). The synergic enhancement effect of ultrasound and microbubbles on thrombolysis has also been tested in patients with acute ischemic stroke. Although acoustic cavitation cannot be achieved by low-intensity ultrasound, extrinsic administration of microbubbles (small microspheres usually used as ultrasound contrast agents) may act as cavitation nuclei lowering the ultrasound intensity threshold needed for cavitation (Holland and Apfel, 1990) and therefore enhance sonothrombolysis. Microbubbles-enhanced sonothrombolysis was tested by Molina and coworkers (2006) using galactose-based microbubbles (first-generation Levovist) combined with 2-hour continuous high-frequency– low-intensity TCD monitoring and intravenous tPA in patients with acute MCA occlusion. In this study, the microbubbles-enhanced sonothrombolysis group achieved recanalization faster and more frequently than both tPA alone and ultrasound-enhanced tPA groups, without increasing symptomatic intracranial hemorrhage rates. Similar results were obtained in a study combining continuous microbubble perfusion (second-generation SonoVue) with 1-hour continuous high-frequency–low-intensity TCCS monitoring and
intravenous tPA (Perren et al., 2008). A new generation of microspheres (lipid-coated microspheres containing perflutren) was successfully tested in a safety pilot study comparing tPA plus TCD monitoring plus microspheres with tPA with TCD monitoring (Alexandrov et al., 2008). However, the subsequent phase I–II safety dose escalation Transcranial Ultrasound in Clinical Sonothrombolysis (TUCSON) trial was prematurely stopped due to a higher symptomatic intracranial hemorrhage rate in the higher-dose tier as compared with the lower-dose and tPA-alone tiers, probably due to imbalances in baseline severity and in blood pressure management, despite showing a trend toward higher early recanalization and clinical recovery rates in both microsphere tiers as compared to tPA alone (Molina et al., 2009). A later meta-analysis showed, however, that sonothrombolysis is safe and leads to higher rates of complete recanalization, especially in combination with microbubbles, when compared with intravenous tPA alone (Tsivgoulis et al., 2010). Besides the enhancement of intravenous thrombolysis with ultrasound or microbubbles, other approaches have been reported, including sonothrombolysis alone in patients ineligible for tPA (Eggers et al., 2005) and microbubbles-enhanced sonothrombolysis during intraarterial thrombolysis (Ribo et al., 2010a). Sonothrombolysis remains a promising stroke treatment, but further research is warranted.
VASOSPASM Cerebral vasospasm after subarachnoid hemorrhage is a potentially preventable and reversible condition where an early identification can prevent or limit cerebral infarction. TCD is a useful vascular imaging modality in the diagnosis and monitoring of vasospasm. The main TCD finding in vasospasm is flow velocity increase in an arterial segment, instead of a focal increase as occurs in intracranial stenosis. Thus, Aaslid and coworkers (1984) demonstrated that segmental flow velocity increase identified by TCD is inversely correlated with arterial diameter measured by DSA. Further, they reported that MCAs classified as spastic on DSA presented a mean flow velocity between 120 and 230 cm/s on TCD. Although diagnosis of cerebral vasospasm by TCD requires flow velocity increase, it must be discriminated from hyperemia, present in patients with subarachnoid hemorrhage spontaneously or induced by the hypertensive hypervolemic hemodilution therapy. Discrimination between MCA vasospasm and hyperemia can be achieved comparing intracranial MCA with extracranial ICA. Thus, flow velocity increase in both extracranial ICA and intracranial MCA would suggest hyperemia, while
VASCULAR IMAGING: ULTRASOUND a greater increase in intracranial MCA than extracranial ICA would suggest MCA vasospasm (Lindegaard et al., 1989). TCD is useful not only in the early vasospasm diagnosis but also in the identification of progression and severity of vasospasm. Therefore, TCD could allow both early planning of therapeutic interventions as well as monitoring the effect of these interventions.
CONCLUSION Ultrasound imaging, including carotid and vertebral duplex, TCD, and TCCS, is a valuable diagnostic tool in the evaluation of acute stroke. It allows diagnosis not only of extracranial and intracranial steno-occlusive lesions but also evaluation of its consequences on distal vasculature as well as recanalization and reocclusion diagnosis and monitoring. TCD is in continuous development, with increasing diagnostic value and therapeutic potential. Future advances are likely to focus on acute ischemic stroke, including the spreading of TCD monitoring during intra-arterial reperfusion procedures as well as operator-independent ultrasound-enhanced thrombolysis.
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Holland CK, Apfel RE (1990). Thresholds for transient cavitation produced by pulsed ultrasound in a controlled nuclei environment. J Acoust Soc Am 88: 2059–2069. Khan S, Cloud GC, Kerry S et al. (2007). Imaging of vertebral artery stenosis: a systematic review. J Neurol Neurosurg Psychiatry 78: 1218–1225. Lal BK, Hobson 2nd RW, Tofighi B et al. (2008). Duplex ultrasound velocity criteria for the stented carotid artery. J Vasc Surg 47: 63–73. Lindegaard KF, Nornes H, Bakke SJ et al. (1989). Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien) 100: 12–24. Mendonc¸a N, Rodriguez-Luna D, Rubiera M et al. (2012). Predictors of tissue-type plasminogen activator nonresponders according to location of vessel occlusion. Stroke 43: 417–421. Molina CA, Montaner J, Arenillas JF et al. (2004). Differential pattern of tissue plasminogen activator-induced proximal middle cerebral artery recanalization among stroke subtypes. Stroke 35: 486–490. Molina CA, Ribo M, Rubiera M et al. (2006). Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 37: 425–429. Molina CA, Barreto AD, Tsivgoulis G et al. (2009). Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol 66: 28–38. Muchada M, Rodriguez-Luna D, Pagola J et al. (2014). Impact of time to treatment on tissue-type plasminogen activatorinduced recanalization in acute ischemic stroke. Stroke 45: 2734–2738. Nedelmann M, Stolz E, Gerriets T et al. (2009). Consensus recommendations for transcranial color-coded duplex sonography for the assessment of intracranial arteries in clinical trials on acute stroke. Stroke 40: 3238–3244. Perren F, Loulidi J, Poglia D et al. (2008). Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. J Thromb Thrombolysis 25: 219–223. Ribo M, Molina CA, Alvarez B et al. (2010a). Intra-arterial administration of microbubbles and continuous 2-MHz ultrasound insonation to enhance intra-arterial thrombolysis. J Neuroimaging 20: 224–227. Ribo M, Rubiera M, Pagola J et al. (2010b). Bringing forward reperfusion with oxygenated blood perfusion beyond arterial occlusion during endovascular procedures in patients with acute ischemic stroke. AJNR Am J Neuroradiol 31: 1899–1902. Rubiera M, Alvarez-Sabin J, Ribo M et al. (2005). Predictors of early arterial reocclusion after tissue plasminogen
activator-induced recanalization in acute ischemic stroke. Stroke 36: 1452–1456. Rubiera M, Cava L, Tsivgoulis G et al. (2010). Diagnostic criteria and yield of real-time transcranial Doppler monitoring of intra-arterial reperfusion procedures. Stroke 41: 695–699. Sabetai MM, Tegos TJ, Nicolaides AN et al. (2000). Hemispheric symptoms and carotid plaque echomorphology. J Vasc Surg 31: 39–49. Saito K, Kimura K, Nagatsuka K et al. (2004). Vertebral artery occlusion in duplex color-coded ultrasonography. Stroke 35: 1068–1072. Saqqur M, Shuaib A, Alexandrov AV et al. (2005). Derivation of transcranial Doppler criteria for rescue intraarterial thrombolysis: multicenter experience from the Interventional Management of Stroke study. Stroke 36: 865–868. Saqqur M, Uchino K, Demchuk AM et al. (2007). Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 38: 948–954. Spencer MP (1987). Hemodynamics of arterial stenosis. In: MP Spencer (Ed.), Ultrasonic Diagnosis of Cerebrovascular Disease, Springer Netherlands, Dordrecht. Sturzenegger M, Mattle HP, Rivoir A et al. (1993). Ultrasound findings in spontaneous extracranial vertebral artery dissection. Stroke 24: 1910–1921. Sturzenegger M, Mattle HP, Rivoir A et al. (1995). Ultrasound findings in carotid artery dissection: analysis of 43 patients. Neurology 45: 691–698. Tsivgoulis G, Eggers J, Ribo M et al. (2010). Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke 41: 280–287. Tsivgoulis G, Ribo M, Rubiera M et al. (2013). Real-time validation of transcranial Doppler criteria in assessing recanalization during intra-arterial procedures for acute ischemic stroke: an international, multicenter study. Stroke 44: 394–400. Walker MD, Marler JR, Goldstein M et al. (1995). Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 273: 1421–1428. Zanette EM, Roberti C, Mancini G et al. (1995). Spontaneous middle cerebral artery reperfusion in ischemic stroke. A follow-up study with transcranial Doppler. Stroke 26: 430–433. Zhao L, Barlinn K, Sharma VK et al. (2011). Velocity criteria for intracranial stenosis revisited: an international multicenter study of transcranial Doppler and digital subtraction angiography. Stroke 42: 3429–3434.
Chapter 55
Vascular imaging: ultrasound DAVID RODRIGUEZ-LUNA* AND CARLOS A. MOLINA Stroke Unit, Department of Neurology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
Abstract The complexity of current stroke treatments requires detailed vascular imaging information. Vascular imaging using ultrasound is a safe, inexpensive, and portable technique that provides continuous real-time hemodynamic information, which allows flow changes to be monitored over prolonged time. Ultrasound imaging is in continuous development, which has led to a growing number of situations where ultrasound can be helpful, foremost in dynamic and rapidly changing clinical scenarios like acute stroke. The aim of this chapter is to review the main indications of vascular ultrasound in acute stroke, including extracranial steno-occlusive lesions diagnosis and its consequences on distal vasculature, intracranial stenosis diagnosis, acute intracranial occlusion, recanalization, and reocclusion diagnosis and monitoring, therapeutic sonothrombolysis, and vasospasm after subarachnoid hemorrhage.
INTRODUCTION The complexity of current stroke treatments requires not only accurate clinical and brain imaging data but also detailed vascular imaging information. Different vascular imaging modalities may be used in stroke diagnosis, including ultrasound, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA). However, although most times these techniques are used complementarily, sometimes they are in competition. The advantages of vascular imaging using ultrasound are well known. Ultrasound is a safe (noninvasive without ionizing radiation), relatively inexpensive, and portable technique, making it a fast bedside technique. Further and foremost, ultrasound provides continuous real-time hemodynamic information, such as quantification and direction of blood flow, which allows flow changes to be monitored over prolonged time compared with other techniques. The limitations of ultrasound include a lower spatial resolution than CTA, MRA, or DSA; the provision of a fragmented assessment of the cerebrovascular tree without direct anatomic information; and the suitability
of a bone acoustic window in transcranial ultrasound, although fixable with ultrasound contrast agents in absence of acoustic window. Ultrasound imaging, including carotid and vertebral duplex, transcranial Doppler (TCD), and transcranial color-coded duplex sonography (TCCS), is in continuous development. This has led to a growing number of situations where ultrasound can be helpful, foremost in dynamic and rapidly changing clinical scenarios like acute stroke, where it may have a direct impact on clinical decision making. Among other clinical situations, the indications of vascular ultrasound in stroke include extracranial steno-occlusive lesion diagnosis and its consequences on distal vasculature, intracranial stenosis diagnosis, acute intracranial occlusion, recanalization, and reocclusion diagnosis and monitoring, therapeutic sonothrombolysis, and vasospasm after subarachnoid hemorrhage. The aim of this chapter is to review these indications.
EXTRACRANIAL PATHOLOGY Extracranial ultrasound, in particular duplex ultrasound, can evaluate proximal segments of both carotid and
*Correspondence to: Dr. David Rodriguez-Luna, Stroke Unit, Department of Neurology, Vall d’Hebron University Hospital, Ps. Vall d’Hebron, 119, 08035, Barcelona, Spain. Tel/Fax: +34-934-894257, E-mail: [email protected]
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vertebral artery (VA) systems. Duplex ultrasound can accurately evaluate atherothrombotic changes in internal carotid artery (ICA), including characterization of the plaque, stenosis gradation, and occlusion diagnosis. Further, extracranial ultrasound can be helpful for ICA stenting and endarterectomy surveillance as well as for evaluation of VA stenosis and occlusion, subclavian steal phenomenon, and both carotid and VA dissections. One of the advantages of carotid duplex ultrasound over other vascular imaging techniques is the ability to characterize carotid atherosclerotic plaques using high-resolution B-mode imaging. Plaques may be characterized according to different parameters, including number, location, size, surface (regular, irregular), shape (eccentric, concentric), echogenicity (echolucent, echogenic), and texture (homogeneous, heterogeneous). Using some of these characteristics, different carotid plaque classifications have been developed. The most widely classification used was proposed by Geroulakos and coworkers (1993), defining five types of plaque according to echogenicity: type 1 plaques are uniformly echolucent; type 2 predominantly echolucent (Fig. 55.1); type 3 predominantly echogenic; type 4 uniformly echogenic; and type 5 plaques could not be classified owing to heavy calcification and acoustic shadows. Several studies have shown that echolucent plaques are more likely to be symptomatic (including amaurosis fugax) and more frequently associated with cerebral infarctions than echogenic ones (Geroulakos et al., 1994; Sabetai et al., 2000). Regardless of the characteristics of the plaque, the severity of the carotid stenosis is the main criterion to determine the risk of stroke in patients with both symptomatic (Barnett et al., 1998; European Carotid Surgery Trialists’ Collaborative Group, 1998) and asymptomatic (Walker et al., 1995) ICA disease. Although several criteria for ICA stenosis quantification have been proposed, the most widely used are those proposed by the Society of Radiologists in Ultrasound for duplex
ultrasound (Grant et al., 2003). Based primarily on peak systolic velocity and plaque estimation, these consensus criteria classify ICA stenosis into several degrees according to different range estimation, including normal (no stenosis), <50% stenosis, 50–69% stenosis (Fig. 55.1), 70% stenosis to near occlusion, near occlusion, and total occlusion (Fig. 55.2A and B). Further, different complementary intracranial ultrasound evaluations can be performed to better stratify the risk of ICA stenosis; such emboli monitor echolucent plaques without hemodynamically significant stenosis, vasomotor reactivity, and compensatory intracranial flow assessment through collateral channels in highgrade stenosis and occlusions (Fig. 55.2). Carotid ultrasound is the primary tool for surveillance after stenting and endarterectomy. However, in contrast to endarterectomy, the deployment of a stent alters the flow velocities and therefore standard velocity criteria should not be used for stenting restenosis diagnosis. Although ultrasound velocity criteria in stented ICAs are not well established, several velocity measurements have been proposed, including higher peak systolic velocity thresholds (AbuRahma et al., 2008) and progressively increasing both peak systolic velocity and ICA/common carotid artery ratios (Lal et al., 2008). In contrast to ICA, there are no consensus criteria for extracranial VA stenosis or occlusion diagnosis using ultrasound. Although different ultrasound diagnosis criteria have been used for VA stenosis, the sensitivity is lower than CTA and contrast-enhanced MRA (Khan et al., 2007). For extracranial VA occlusion, absence of flow signal has been proposed as a sign of occlusion in the origin of the artery, and presence of peak systolic flow, but end-diastolic flow velocity of zero as a sign of occlusion before branching into the posterior inferior cerebellar artery (Saito et al., 2004). The ultrasound evaluation of VA can also find different patterns suggestive of the presence of subclavian steal phenomenon as a surrogate of subclavian artery disease, including systolic
Fig. 55.1. Internal carotid artery stenosis on carotid duplex ultrasound. Extensive 50–69% right internal carotid artery stenosis due to a heterogeneous plaque (peak systolic velocity 223 cm/s).
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Fig. 55.2 See legend on next page.
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flow deceleration, different degrees of alternating flow (Fig. 55.2F), and total retrograde flow (Fig. 55.2P). Carotid duplex ultrasound is also helpful in the diagnosis of ICA dissection. While B-mode imaging can show direct signs of dissection such as tapering of ICA lumen, a membrane or a flap, or true and false lumens in up to two-thirds of cases, Doppler spectra can show an abnormal pattern in more than 90% of cases, with an overall sensitivity of 95% when combined with TCD examination (Sturzenegger et al., 1995). Ultrasound may also be helpful in VA dissection diagnosis, although the diagnostic yield when combined with TCD examination is lower than in ICA dissection (Sturzenegger et al., 1993).
The advantages of ultrasound compared to other vascular imaging techniques in the evaluation of intracranial collateral channels include the ability to detect the direction of the blood flow and its quantification. Ultrasound findings usually include elevation of flow on the donor system and normal or reduced flows in the recipient system. Further, data about the direction of the flow can be easily evaluated by ultrasound, such as reversal flow in both ipsilateral A1 segment of anterior cerebral artery and ophthalmic artery in proximal ICA occlusions, and in P1 segment of posterior cerebral artery in basilar artery (BA) occlusions.
INTRACRANIAL COLLATERAL CHANNELS
Despite the continuous development of ultrasound imaging and opposed to extracranial ICA stenosis, there are no internationally accepted criteria for grading intracranial arterial stenoses. According to Spencer’s (1987) description, the ultrasound imaging changes of an arterial stenosis could be classified into three categories: primary changes, consisting of intrastenotic flow velocity increase; secondary changes, including pre- and poststenotic flow velocity decrease; and tertiary changes, seen in the collateral circulation. Based on the primary change of intrastenotic flow velocity increase, several studies have evaluated the ability of ultrasound imaging for the diagnosis of intracranial stenosis compared with DSA as standard of reference. Baumgartner and coworkers (1999) correlated ultrasound data of basal cerebral arteries with DSA using TCCS. According to peak systolic velocity values, they reported cutoff values for <50% and 50% basal cerebral artery stenosis diagnosis, with a sensitivity and specificity near to 100% in <50% stenosis and of 100% in 50% stenosis. Similarly, intrastenotic flow velocity increase was used for intracranial stenosis diagnosis using TCD with DSA as standard of reference in the Stroke Outcomes
Three collateral channels can be evaluated by both TCD and TCCS: the anterior communicating artery, the posterior communicating artery, and the ophthalmic artery. These pathways are latent under normal conditions. However, one or more of them can open when a pressure gradient develops between two anastomosing arterial systems, the donor and the recipient, usually due to an occlusion or a hemodynamically significant stenosis located proximal to both the recipient arterial system and the origin of the collateral channel (Alexandrov and Neumyer, 2004). The paradigm of collateral channels opening is proximal ICA occlusion (Fig. 55.2), where these three channels may be involved to guarantee the flow supply to the ipsilateral middle cerebral artery (MCA), the recipient: the anterior communicating artery channel with contralateral A1 segment of anterior cerebral artery as donor; the posterior communicating artery channel with ipsilateral P1 segment of posterior cerebral artery as donor; and the ophthalmic artery channel with ipsilateral external carotid artery as donor.
INTRACRANIAL STENOSIS
Fig. 55.2. Right internal carotid artery occlusion with collateral flow via anterior communicating artery and right posterior communicating artery. Carotid and vertebral duplex ultrasound showing (A, B) right proximal internal carotid artery occlusion, (C) strong right V2–vertebral artery flow, (D, E) extensive 50–69% left internal carotid artery stenosis (peak systolic velocity 185.7 cm/s, internal carotid artery/common carotid artery ratio 2.8), and (F) left V2–vertebral artery alternating flow (incomplete subclavian steal phenomenon). Transcranial color-coded duplex sonography right-side insonation of circle of Willis (G): note (1) presence of right M1, middle cerebral artery; (2) reversed right A1, anterior cerebral artery; (3) left A1, anterior cerebral artery; (4) right P1, posterior cerebral artery aliasing, and (5) presence of right posterior communicating artery. Corresponding Doppler spectra show (H) reduced right M1, middle cerebral artery flow velocity and pulsatility, as compared to (J), left M1, middle cerebral artery; (I) retrograde right A1, anterior cerebral artery flow; (K) raised left A1, anterior cerebral artery flow velocity; (L) raised right P1, posterior cerebral artery flow velocity; (M) presence of right posterior communicating artery; and (N) normal right P2, posterior cerebral artery flow. Doppler spectrum analysis of vertebral and basilar arteries shows (O) strong right V4, vertebral artery flow; (P) total retrograde left V4, vertebral artery flow (complete subclavian steal phenomenon), and (Q) strong basilar artery flow.
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Fig. 55.3. Middle cerebral artery stenosis on transcranial color-coded duplex sonography. (A) Stenosis of the right M1 middle cerebral artery (arrow) visible due to the arterial narrowing and aliasing phenomenon as a focal change in the color coding in the stenosed region. (B) Intrastenotic flow velocity increase up to peak systolic velocity of 209 cm/s (nonangle-corrected) in a depth of 60 mm. Note a relative decrease of flow velocity in both (C) prestenotic (peak systolic velocity of 121.7 cm/s in a depth of 66 mm) and (D) poststenotic (peak systolic velocity of 94 cm/s in a depth of 54 mm) regions.
and Neuroimaging of Intracranial Atherosclerosis (SONIA) study (Feldmann et al., 2007), a companion study to the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial (Chimowitz et al., 2005). The mean flow velocity cutoffs on TCD used for identification of 50% stenosis were 100 cm/s for MCA and 80 cm/s for both VA and BA, with an overall negative predictive value of 83% and positive predictive value of 55% (Feldmann et al., 2007). The SONIA criteria were validated using TCD in a later study (Zhao et al., 2011) performed in a subpopulation of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (Chimowitz et al., 2011). This study also showed that, using a single velocity criterion, the most sensitive mean flow velocity threshold for 70% stenosis was >120 cm/s for MCA (sensitivity 71%), and >110 cm/s for both VA and BA (sensitivity 55%). Further, combined criteria for 70% stenosis diagnosis in MCA (mean flow velocity >120 cm/s, or stenotic/prestenotic ratio 3, or low velocity) and both
VA and BA (mean flow velocity >110 cm/s, or stenotic/prestenotic ratio 3) improved the sensitivity (91% and 60%, respectively) of TCD (Zhao et al., 2011). An advantage of TCCS intracranial stenosis evaluation over TCD is that it allows the visualization of other findings such as arterial narrowing and aliasing effect (change in the color coding). Thus, these findings may help to display the stenotic segment and guide with the evaluation of pre- and poststenotic segments (Fig. 55.3). However, despite the different suggested criteria and other complementary findings using TCCS or TCD, stenosis diagnosis by transcranial ultrasound may require a confirmatory test such as DSA to reliably identify the degree of the stenosis.
INTRACRANIAL OCCLUSION In patients with acute ischemic stroke, ultrasound image provides reliable data about the presence and location of an arterial occlusion. Performed by an experienced sonographer, within a few minutes, at bedside, and
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simultaneously with clinical assessment and blood draws, it does not result in any delay in the stroke management (Chernyshev et al., 2005). Zanette and coworkers (1995) described the presence of MCA occlusion as an absence of any flow signal from the symptomatic MCA or an asymmetry of the MCAs in patients with acute ischemic stroke using TCD. These criteria were later refined to better show the dynamic process of occlusion and recanalization in the setting of thrombolytic treatment in acute ischemic stroke (Burgin et al., 2000; Demchuk et al., 2001). Thereby, the Thrombolysis in Brain Ischemia (TIBI) six-score grading system is based on the relative relationship between the arterial segment insonated and the location of the occlusion (Demchuk et al., 2001), so that TIBI 0 and 1 refer to occlusion proximal to the insonated site, TIBI 2 and 3 to occlusion distal to insonated site, TIBI 4 to a residual stenosis, and TIBI 5 to normal flow (Fig. 55.4). In practice, these six grades are frequently separated into three major categories which have been validated by DSA (Burgin et al., 2000): complete occlusion (TIBI 0 and 1), partial occlusion (TIBI 2 and 3), and complete recanalization (TIBI 4 and 5).
Although the TIBI classification remains the most widely known and used system, the Consensus on Grading Intracranial Flow obstruction (COGIF) score was later proposed for its application using TCCS (Nedelmann et al., 2009). In essence, the COGIF score is a modification of the TIBI classification, where COGIF 1 corresponds to TIBI 0, COGIF 2 to TIBI 1, COGIF 3 to both TIBI 2 and 3, COGIF 4a to TIBI 5, and COGIF 4b and 4c to TIBI 4. Ultrasound image, both TCD and TCCS, also provides reliable information about the location of the arterial occlusion. Location of the occlusion has been shown to be a marker of the response to intravenous thrombolytic therapy. Saqqur and coworkers (2007) reported that the rate of complete recanalization within the first 2 hours after intravenous tissue plasminogen activator (tPA) bolus varies depending on the location of the occlusion: 44.2% for distal MCA occlusions, 30% for proximal MCA occlusions, 5.9% for terminal ICA occlusions, 27.2% for tandem ICA/MCA occlusions, and 33% for BA occlusions. Further, the location of the occlusion documented by TCD combined with other factors may help to predict
Fig. 55.4. Thrombolysis in brain ischemia (TIBI) classification. Illustration and description of the six flow grades on transcranial Doppler. (Adapted from Demchuk et al., 2001.)
VASCULAR IMAGING: ULTRASOUND the absence of recanalization 1 hour after intravenous tPA bolus in patients with acute ischemic stroke, including the presence of occlusion or severe extracranial ICA stenosis in proximal MCA occlusions and absence of atrial fibrillation in both ICA bifurcation and BA occlusions (Mendonc¸a et al., 2012), as well as intravenous thrombolytic treatment beyond 270 minutes in distal MCA occlusions (Muchada et al., 2014). Therefore, ultrasound image information about the presence and location of an artery occlusion may help to improve the selection of patients with acute ischemic stroke for more aggressive rescue reperfusion strategies.
INTRACRANIAL RECANALIZATION AND REOCCLUSION Real-time TCD monitoring allows determination of the degree, timing, and speed of recanalization in acute ischemic stroke. Performed at bedside, it provides faster information about recanalization than other techniques such as CTA, MRA, and DSA, and allows these data to be correlated simultaneously with clinical changes. The degree of arterial recanalization can be assessed by means of the TIBI grading system. MCA recanalization could be defined as partial when signals in a previously demonstrated absent or minimal (TIBI 0–1) flow appear blunted or dampened (TIBI 2–3), and complete when the flow improves to a stenotic or normal (TIBI 4–5) pattern (Burgin et al., 2000; Christou et al., 2000). The timing of arterial recanalization has a great impact on early clinical outcome in acute ischemic stroke. Christou and coworkers (2000) demonstrated that the timing of recanalization inversely correlated with improvement in neurologic status at the end of intravenous tPA infusion and at 24 hours from stroke. Further, they reported a 300-minute window timing of arterial recanalization after thrombolytic treatment to achieve recovery within the first 24 hours after stroke. To evaluate the speed of clot lysis during intravenous thrombolysis with tPA in patients with acute ischemic stroke, the duration of arterial recanalization was classified by Alexandrov and coworkers (2001) as sudden, stepwise, or slow. Sudden recanalization was defined as abrupt (<1 minute) appearance of a normal or stenotic low-resistance signal, stepwise as gradual flow improvement over 1–29 minutes, and slow as flow improvement 30 minutes. Using this classification, the authors reported that faster arterial recanalization (sudden and stepwise) is correlated with better 24-hour clinical improvement (Alexandrov et al., 2001). Similarly, sudden recanalization has been associated with higher degree of neurologic improvement at 24 hours compared with stepwise, slow, and no recanalization patterns (Molina et al., 2004).
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Arterial reocclusion after recanalization has been reported to be between 12% (Rubiera et al., 2005) and 34% (Alexandrov and Grotta, 2002) depending on the reocclusion definition. Reocclusion has been defined as a worsening in the TIBI flow grading system after a previously documented recanalization of at least one grade (Alexandrov and Grotta, 2002) or in more than one grade (Rubiera et al., 2005). Irrespective of the definition used, reocclusion after recanalization detected by real-time TCD monitoring is related to poorest early and long-term outcomes after thrombolytic treatment than patients who reanalyze without subsequent reocclusion (Alexandrov and Grotta, 2002; Rubiera et al., 2005). Therefore, real-time TCD monitoring provides information not only about the presence and location of an arterial occlusion, but also about the degree, timing, and speed of recanalization, the occurrence of reocclusion, and the lack of recanalization in the setting of intravenous thrombolytic treatment in acute ischemic stroke. So, real-time TCD monitoring provides valuable data for early identification of patients who may benefit from further treatment such as intra-arterial reperfusion therapies (Saqqur et al., 2005). Further, TCD can monitor the restoration of blood flow and provide real-time hemodynamic information during intra-arterial reperfusion procedures in patients with acute ischemic stroke (Ribo et al., 2010b; Rubiera et al., 2010; Tsivgoulis et al., 2013). This information includes recanalization, reocclusion, hyperperfusion, and thromboembolism or air embolism (Rubiera et al., 2010). A recent study has validated the TCD criteria for complete recanalization (TIBI 4–5) in real time as compared with thrombolysis in myocardial infarction angiographic scores (Tsivgoulis et al., 2013). In this multicenter study, the overall accuracy of TCD criteria for complete recanalization diagnosis was 89% (80–94%) during real-time TCD monitoring of intra-arterial reperfusion procedures in acute ischemic stroke patients with proximal intracranial occlusions.
SONOTHROMBOLYSIS Ultrasound exposure can enhance lysis of intravascular clot (sonothrombolysis) and therefore can be used in patients with acute ischemic stroke not only for diagnosis purposes but also as a therapeutic tool. The underlying mechanism is postulated to be related to mechanical, nonthermal effects of ultrasound in liquid media (as blood), including acoustic cavitation and negative pressure. Acoustic cavitation consists of formation and collapse of microbubbles of gas by the action of a high-intensity ultrasound acoustic field that can cause direct breakdown of the clot surface and therefore increase the permeation of tPA into the thrombus. Further, ultrasound negative-pressure waves create fluid
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motion or microstreaming and radiation forces, which can promote tPA circulation and increase the uptake of tPA into the clot (Amaral-Silva et al., 2011). Experimental studies have demonstrated an enhancement effect of ultrasound on thrombolysis using different frequencies and intensities of ultrasound. However, since high intensities may be harmful due to tissue heating, clinical studies have tested ultrasoundenhanced thrombolysis at low intensity and at low- and high-frequency ultrasound insonation combined with intravenous tPA (Amaral-Silva et al., 2011). The Transcranial Low-Frequency Ultrasound-mediated Thrombolysis in Brain Ischemia (TRUMBI) trial tested low-intensity– low-frequency ultrasound (300 MHz) but was prematurely stopped due to an unexpected rate of cerebral hemorrhages, both symptomatic and asymptomatic, in the tPA plus ultrasound group (Daffertshofer et al., 2005). Conversely, the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and systemic t-PA (CLOTBUST) phase II trial demonstrated that low-intensity–high-frequency ultrasound (2 MHz, conventional continuous TCD) enhancement of tPA thrombolytic effect could be safely achieved and increase tPA-induced recanalization as compared with placebo (Alexandrov et al., 2004). Further, CLOTBUST showed also a nonsignificant trend toward complete recovery from stroke, although it was not powered enough to achieve this issue. For that purpose, a phase III trial is currently under way to evaluate the efficacy of operator-independent ultrasound-enhanced thrombolysis (CLOTBUST-ER, NCT01098981). The synergic enhancement effect of ultrasound and microbubbles on thrombolysis has also been tested in patients with acute ischemic stroke. Although acoustic cavitation cannot be achieved by low-intensity ultrasound, extrinsic administration of microbubbles (small microspheres usually used as ultrasound contrast agents) may act as cavitation nuclei lowering the ultrasound intensity threshold needed for cavitation (Holland and Apfel, 1990) and therefore enhance sonothrombolysis. Microbubbles-enhanced sonothrombolysis was tested by Molina and coworkers (2006) using galactose-based microbubbles (first-generation Levovist) combined with 2-hour continuous high-frequency– low-intensity TCD monitoring and intravenous tPA in patients with acute MCA occlusion. In this study, the microbubbles-enhanced sonothrombolysis group achieved recanalization faster and more frequently than both tPA alone and ultrasound-enhanced tPA groups, without increasing symptomatic intracranial hemorrhage rates. Similar results were obtained in a study combining continuous microbubble perfusion (second-generation SonoVue) with 1-hour continuous high-frequency–low-intensity TCCS monitoring and
intravenous tPA (Perren et al., 2008). A new generation of microspheres (lipid-coated microspheres containing perflutren) was successfully tested in a safety pilot study comparing tPA plus TCD monitoring plus microspheres with tPA with TCD monitoring (Alexandrov et al., 2008). However, the subsequent phase I–II safety dose escalation Transcranial Ultrasound in Clinical Sonothrombolysis (TUCSON) trial was prematurely stopped due to a higher symptomatic intracranial hemorrhage rate in the higher-dose tier as compared with the lower-dose and tPA-alone tiers, probably due to imbalances in baseline severity and in blood pressure management, despite showing a trend toward higher early recanalization and clinical recovery rates in both microsphere tiers as compared to tPA alone (Molina et al., 2009). A later meta-analysis showed, however, that sonothrombolysis is safe and leads to higher rates of complete recanalization, especially in combination with microbubbles, when compared with intravenous tPA alone (Tsivgoulis et al., 2010). Besides the enhancement of intravenous thrombolysis with ultrasound or microbubbles, other approaches have been reported, including sonothrombolysis alone in patients ineligible for tPA (Eggers et al., 2005) and microbubbles-enhanced sonothrombolysis during intraarterial thrombolysis (Ribo et al., 2010a). Sonothrombolysis remains a promising stroke treatment, but further research is warranted.
VASOSPASM Cerebral vasospasm after subarachnoid hemorrhage is a potentially preventable and reversible condition where an early identification can prevent or limit cerebral infarction. TCD is a useful vascular imaging modality in the diagnosis and monitoring of vasospasm. The main TCD finding in vasospasm is flow velocity increase in an arterial segment, instead of a focal increase as occurs in intracranial stenosis. Thus, Aaslid and coworkers (1984) demonstrated that segmental flow velocity increase identified by TCD is inversely correlated with arterial diameter measured by DSA. Further, they reported that MCAs classified as spastic on DSA presented a mean flow velocity between 120 and 230 cm/s on TCD. Although diagnosis of cerebral vasospasm by TCD requires flow velocity increase, it must be discriminated from hyperemia, present in patients with subarachnoid hemorrhage spontaneously or induced by the hypertensive hypervolemic hemodilution therapy. Discrimination between MCA vasospasm and hyperemia can be achieved comparing intracranial MCA with extracranial ICA. Thus, flow velocity increase in both extracranial ICA and intracranial MCA would suggest hyperemia, while
VASCULAR IMAGING: ULTRASOUND a greater increase in intracranial MCA than extracranial ICA would suggest MCA vasospasm (Lindegaard et al., 1989). TCD is useful not only in the early vasospasm diagnosis but also in the identification of progression and severity of vasospasm. Therefore, TCD could allow both early planning of therapeutic interventions as well as monitoring the effect of these interventions.
CONCLUSION Ultrasound imaging, including carotid and vertebral duplex, TCD, and TCCS, is a valuable diagnostic tool in the evaluation of acute stroke. It allows diagnosis not only of extracranial and intracranial steno-occlusive lesions but also evaluation of its consequences on distal vasculature as well as recanalization and reocclusion diagnosis and monitoring. TCD is in continuous development, with increasing diagnostic value and therapeutic potential. Future advances are likely to focus on acute ischemic stroke, including the spreading of TCD monitoring during intra-arterial reperfusion procedures as well as operator-independent ultrasound-enhanced thrombolysis.
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