6th Newsletter – Update in Cerebral Hemodynamics and Neurosonology

In the first article “Transcranial Doppler assessment of cerebral vasospasm” R. Aaslid summarises the use of transcranial Doppler (TCD) for assessment of cerebral vasospasm. The basic hemodynamic principles are presented, and used as a basis for discussing findings and interpretation methods. The need for additional information and measurements to correctly interpret TCD velocities is analysed, and the use of a special extracranial Doppler technique is recommended. The advantages and limitations of the ‘Lindegaard Index’ (LI) are discussed. The recent advances in the use of TCD for cerebral autoregulation testing are opening up a new and promising avenue in diagnosis, monitoring and treatment of cerebral vasospasm.

Fig. Spectral outline flow velocity (Vmax) and volume flow are plotted as functions of the diameter in a realistic model of MCA vasospasm. ABP levels of 100 mmHg (normotension) and 140 mmHg (induced hypertension) are represented. The vertical line at 1.32 mm lumen diameter is used in an example discussed in the text. Roman numerals indicate the three regimes of the velocity-diameter relationship. Note: the velocity scale has been converted from cross-sectional mean velocity in the original article to Vmax as measured by most TCD instruments.

G.P. Anzola reviews the “Clinical impact of patent foramen ovale diagnosis with transcranial Doppler”. In his opinion the role of patent foramen ovale (PFO) in cryptogenic stroke is still debated, but from recent follow-up studies it seems that the amount of right-to-left shunt (RLS) and the association with atrial septal aneurysm (ASA) are major determinants of stroke recurrence. PFO and RLS through the atrial chambers have been recently studied in a number of conditions not or marginally related to cerebrovascular disease. Historically the first studies addressed the presence of RLS in scuba divers as a possible abnormality related to decompression sickness (DS) of unknown aetiology. Despite initial debate there is now robust evidence to claim that patency of foramen ovale increases the risk of developing DS by two and a half to four times. Patients with PFO-related DS tend to have early occurrence of symptoms after surfacing and a clinical presentation that indicates brain or upper cervical spinal cord involvement. Recent reports suggest that divers with hemodynamically significant RLS may have an increased risk of developing clinically asymptomatic multiple brain lesions. PFO has been found in patients suffering from migraine with aura with approximately the same frequency as that encountered in cryptogenic stroke patients. This finding has prompted speculations on the possible role of RLS in increasing the stroke risk in migraineurs and in the pathophysiology of the aura. Recent reports showing that migraine with aura is dramatically improved after transcatheter closure of PFO suggest that migraine with aura may indeed be triggered by humoral factors that reach the brain by escaping the pulmonary filter. A RLS is involved in a rare condition known as platypnea-orthodeoxia and perhaps underlies an increased risk of cerebral complications after major orthopedic surgery. Valsalva-like activities often precede the occurrence of attacks of transient global amnesia (TGA) and abnormalities consistent with hypoperfusion of deep limbic structures have been reported during a typical TGA episode. This had raised the hypothesis that TGA may be triggered by paradoxical embolism of platelets aggregates in the posterior circulation, but the search for an increased frequency of PFO in TGA patients has yielded conflicting results. Conditions that determine an increase in pulmonary pressure may facilitate the opening of the virtual interatrial valve and thus promoting shunting of blood to the left heart chambers which in turn might contribute to further desaturation of arterial blood. It is therefore not surprising that RLS has been found in 70% of patients with chronic obstructive pulmonary disease and increased pulmonary pressure and in the same proportion of patients with obstructive sleep apnoea, a condition that ultimately may result in pulmonary hypertension. In conclusion, from the evidence gathered so far the picture is emerging of an important role of PFO in a number of non-stroke conditions, either as causative factor or as associated condition predisposing to complications. The availability of simple diagnostic techniques such as transcranial Doppler (TCD) to assess RLS will undoubtedly contribute a great deal of knowledge on the relevance in medicine of this hitherto neglected condition.

The authors R. Dittrich, M.A. Ritter and D.W. Droste describe “Microembolus detection by transcranial doppler sonography”. Microembolic signals can be detected by transcranial ultrasound as signals of high intensity and short duration. These signals represent circulating gaseous or solid particles. To optimise the differentiation from artefacts and the background signal and to facilitate the clinical use, several attempts have been made to automatise the detection of microemboli. Microemboli occur spontaneously in various clinical situations but their clinical impact and possible therapeutical implications are still under debate. This article provides a review of the actual literature concerning the current state of technical and clinical aspects of microembolus detection.

“Cerebral autoregulation studies in clinical practice” are reviewed by R.R.Diehl. During the past 15 years several paradigms to study dynamic cerebral autoregulation (CA) were developed by measuring cerebral blood flow (CBF) velocity with transcranial Doppler (TCD) in response to blood pressure changes. As a more indirect approach to measure autoregulation, vasomotor reactivity (VMR) can be determined by the use of vasodilatory stimuli. CA or VMR are often severely disturbed in occlusive carotid artery disease. Several prospective studies have shown that reduced VMR is an important risk factor for stroke or TIA in patients with symptomatic and asymptomatic carotid artery stenosis or occlusion. Future randomised intervention studies will show whether asymptomatic patients with carotid artery stenosis and pathological autoregulation or VMR will benefit from revascularization therapy.

The authors B.Schmidt, M.Czosnyka and J.Klingelhöfer describe in their article “Clinical applications of a non-invasive ICP monitoring method”. Until now the assessment of intracranial pressure (ICP) requires invasive methods. A previously introduced mathematical model allowed the non-invasive estimation of ICP (nICP) from arterial blood pressure (ABP) and blood flow velocity (FV). In various studies they have investigated the accuracy of this method and possible clinical applications. Selected hemodynamic parameters, calculated from the cerebral blood FV and the ABP curves, were used to express the relationship between ABP input and ICP output by linear transformation rules. In several clinical studies the accuracy assess and possible benefits of this method of non-invasive ICP (nICP) assessment were investigated. In 17 severely injured patients this model was verified by comparison of nICP and measured ICP during generation of plateau waves, recorded in seven of these patients. In all simulations plateau elevations of ICP were well replicated. The correlation coefficient between increase of nICP and real ICP was R=0.98; P<0.001. Twenty one hydrocephalic patients were studied. Parallel increases in real ICP and nICP during lumbar infusion tests were evidently visible. Resistance of cerebrospinal fluid outflow (Rcsf) was computed using nICP and compared with Rcsf computed from real ICP. The mean error between real and non-invasive Rcsf was 4.1 ± 2.2 mmHg min/ml. One hundred and forty five patients were studied after severe head injuries. The state of autoregulation was assessed by moving correlation of cerebral perfusion pressure (CPP=ABP-ICP) and FV (Mx index). nICP instead of ICP was used to continuously estimate the state of autoregulation and to dynamically adapt the nICP procedure to this state. A median error between ICP and nICP of 6.0 mmHg was observed. Directly and non-invasively assessed Mx indices correlated highly significantly (R=0.9; P<0.001). In conclusion the results demonstrate that the nICP assessment model constitutes a reliable method to monitor ICP and may therefore provide various useful clinical applications.
Fig. ICP plateau waves – measured ICP and nICP calculated from FV and ABP. Parallel increase and decrease in ICP and nICP may be observed.

Eva Bartels deals with the question “The axial imaging plane – the main domain of the transcranial colour-coded duplex ultrasonography?” Transcranial colour-coded duplex ultrasonography (TCCS) makes possible the visualization of basal cerebral arteries through colour-coding the flow velocity information. This method is well established in the clinical routine for the diagnostics of pathological processes in cerebrovascular disease. The present review describes the examination technique, normal and pathological findings, such as stenosis and occlusion of intracranial arteries, as well as intracranial vascular malformations focussing on the advantages of examination in the axial imaging planes.

“Transcranial ultrasonography of cerebral veins and sinuses” is summarised by S.J. Schreiber, E. Stolz, J.M. Valdueza. Transcranial ultrasonography has become a valuable diagnostic tool for the bed-side evaluation of cerebral hemodynamics. While the assessment of arterial blood flow is well established, analysis of venous hemodynamics by transcranial ultrasonography is a new application of the method. The present review summarises the current state of transcranial venous ultrasound in adults by means of transcranial Doppler (TCD) and transcranial colour-coded duplex sonography (TCCS). It gives a critical overview regarding current and possible future clinical applications of the techniques.

The authors S. Behnke and G. Becker report on “Sonographic imaging of the brain parenchyma”. Using B-mode transcranial sonography (TCS), makes it possible to image the brain parenchyma through the intact skull with conventional low-frequency probes. Several brain disorders can be depicted by TCS such as bleedings, brain tumors, or enlargement of the ventricular system. More recently there is evidence that TCS findings can complement information from other neuroimaging techniques in neurodegenerative disorders leading to new insights and pathophysiological concepts.

G.Seidel and K.Meyer review the “Impact of ultrasound contrast agents in cerebrovascular diagnostics”. They give a summary on current ultrasound contrast agents and their composition. Methods of brain imaging using UCA, like harmonic imaging and acoustic emission, are also described. Besides contrast-enhanced conventional colour duplexsonography of the extracranial brain supplying arteries, transcranial contrast investigation of the basal cerebral arteries and visualization of cerebral microcirculation are also discussed in this paper. Another main topic are the interactions between UCA, human tissue and the ultrasound system.

Fig. (A) Mean time-intensity curves of SonoVueTM continuos infusion (1.2 and 0.6 ml/min, respectively) in five dogs. (B) Mean time-intensity curves of SonoVueTM (0.03 ml/kg, 5 mg/ml) and LevovistTM (0.1 ml/kg, 400 mg/ml) bolus injection in six beagles. Notice the peak intensity increased at the beginning of the contrast enhancement leading to the “blooming” artifact in color duplexsonography.

In their article the authors J. Eyding, W. Wilkening and T. Postert describe “Brain perfusion and ultrasonic imaging techniques”. Advances in neurosonology have generated several techniques of ultrasonic perfusion imaging employing ultrasound echo contrast agents (ECAs). Doppler imaging techniques cannot measure the low flow velocities that are associated with parenchymal perfusion. Ultrasonic perfusion imaging, therefore, is a combination of a contrast agent-specific ultrasound imaging technique (CAI) mode and a data acquisition and processing (DAP) technique that is suited to observe and evaluate the perfusion kinetics. The intensity in CAI images is a measure of ECA concentration but also depends on various other parameters, e.g. depth of examination. Moreover, ECAs can be destroyed by ultrasound, which is an artifact but can also be a feature. Thus, many different DAPs have been developed for certain CAI techniques, ECAs and target organs. Although substantial progress in ECA and CAI technology can be foreseen, ultrasound contrast imaging has yet to reliably differentiate between normal and pathological perfusion conditions. Destructive imaging techniques, such as contrast burst imaging (CBI) or time variance imaging (TVI), in combination with new DAP techniques provide sufficient signal-to-noise ratio (SNR) for transcranial applications, and consider contrast agent kinetics and destruction to eliminate depth dependency and to calculate semi-quantitative parameters. Since ultrasound machines are widely accessible and cost-effective, ultrasonic perfusion imaging techniques should become supplementary standard perfusion imaging techniques in acute stroke diagnosis and monitoring. This paper gives an overview on different CAI and DAP techniques with special focus on recent innovations and their clinical potential.

The “Clinical impact of intima media measurement” is presented by P.-J. Toubol.

In the following article M. Goertler, J. Allendoerfer and G.-M. v. Reutern report on the “Design of a multicentre study on neurosonology in acute ischaemic stroke”. The authors belong to the Neurosonology in Acute Ischaemic Stroke (NAIS) Study Group which summarises the design and the organisation of a multicentre study on neurosonology in acute ischaemic stroke. The Neurosonology in Acute Ischaemic Stroke Study will determine whether extracranial and transcranial Doppler and duplex sonography performed within 6h after onset of stroke improves prediction of functional outcome if applied in addition to routine diagnostic admission investigations, i.e. medical history, standardised neurological examination, brain imaging by computed or magnetic resonance tomography, electrocardiography and baseline laboratory examination. The primary hypothesis is that there is a consistent and persuasive difference between patients with an occluded middle cerebral artery and those with an open artery in terms of the functional deficit after 3 months. Power calculations are based on the assumption of a=0.05 (two-sided test) and a probability of a maximally mild functional deficit of 0.4. Detection of a 20% difference with a power of 0.8 resulted in a calculated sample of 400 patients to be observed. Calculation took into consideration that only 50% admitted patients would have a moderate to severe neurological deficit of whom only 30% will have an occlusion of the corresponding middle cerebral artery. Furthermore, the study is designed to evaluate a difference of the functional outcome in relation to occurrence and time of recanalisation in patients presenting with an initially occluded middle cerebral cerebral artery.

The authors M. Daffertshofer and M. Fatar report on a new and fascinating therapeutical application of ultrasound: “Therapeutic ultrasound in ischemic stroke treatment: experimental evidence”.Re-opening of the occluded artery is the primary therapeutic goal in hyper-acute ischemic stroke. Systemic treatment with IV rt-PA has been shown to be beneficial at least in a 3h ‘door to needle’ window and is approved within that interval in many countries.Trials of thrombolytic therapy with rt-PA demonstrated a small, but significant improvement in neurological outcome in selected patients. As recently shown, intra-arterial application of rt-PA is effective and opens the therapeutical window to 6h, but requires invasive intra-arterial angiographic intervention in a high number of patients, who do not finally achieve thrombolysis. Ultrasound (US) is known to have several biological effects depending on the emission characteristics. At higher energy levels US alone has a thromolytic effect. That effect is already used for clinical purposes in interventional therapy using US catheters. Recently, there is growing evidence that US at a lower energy level (<2W/cm²) facilitates enzymatic mediated thrombolysis, most probably by breaking molecular linkages of fibrin polymers and therefore, increasing the working surface for the thrombolytic drug. Different in-vitro and in-vivo experiments have shown increased clot lysis as well as accelerated recanalization of occluded peripherals, coronary vessels and most recently also intracerebral arteries. Sonothrombolysis at low energy levels, however, is of great interest because of the low risk for collateral tissue damage, enabling external insonation without the need for local catheterization. Whereas little or no attenuation of US can be expected through skin and chest, intensity will be significantly attenuated if penetration of bones, particularly the skull, is required. That effect, however, is frequency dependent. Whereas >90% of intracerebral US intensity is lost (of the output power) in frequencies currently used for diagnostic purposes (mostly 2MHz and up), that ratio is nearly reversed in the lower KHz range (< 300kHz). US at these low frequencies, however, is efficient for accelerating enzymatic thrombolysis in-vitro as well as in vivo within a wide range of intensities, from 0.5 W/cm² (MI~0.3) to several W/cm². Since the emitted beam widens with decreasing frequency, low frequency US can insonate the entire intracerebral vasculature. That may overcome the limitation of US in the MHz range being restricted to insonation of the MCA mainstem. There are no reports in the preclinical literature about intracerebral bleeding or relevant cerebral cellular damage (either signs of necrosis or apoptosis) for US energy levels up to 1W/cm². Moreover, recent investigations showed no break-down of the blood brain barrier. Safety of US exposure of the brain for therapeutic purposes has to address heating. Heating depends critically on the characteristics of the US. The most significant heating of the brain tissue itself is >1°C/h using a continuous wave (CW) 2W/cm² probe, whereas no significant heating could be found when using an intermittent (pulsed) emission protocol. The experimental data so far help to characterize the optimal US settings for sonothrombolysis and support the hypothesis that this combined treatment is a prospective advance in optimizing thrombolytic therapy in acute stroke.
Fig. Thrombolytic activity: spontaneously after 1h in a control groups, and after 1h treatment with transcranial US (33 kHz, CW, 0.5 W/cm²) insonation only, after 1h treatment with rt-PA only, and 1h treatment with combined US + rt-PA.

Finally A. V. Alexandrov also describes the therapeutical use of ultrasound in his article “Ultrasound-enhanced thrombolysis for stroke: clinical significance”. In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy for ischemic stroke, a low rate of early arterial recanalization was suspected due to the small numbers of patients who had early dramatic clinical improvement. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD can identify residual signals around the thrombus with the thrombolysis in brain ischemia (TIBI) flow grading system and therefore expose more thrombus surface to circulating TPA. A phase I clinical study, monitoring TPA infusion with diagnostic ultrasound resulted in an unexpectedly high rate of complete recanalization (36% of proximal middle cerebral artery (MCA) occlusions) and associated early dramatic clinical recovery (24%) among treated patients. The external application of diagnostic ultrasound in our studies raised the possibility that a synergistic TPA and ultrasound action accelerated flow improvement and achieved faster and more complete thrombus dissolution as predicted from experimental models. The CLOTBUST (combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic TPA) trial is testing this hypothesis in a phase II clinical randomised multi-center setting. Dramatic clinical recovery from stroke and complete recanalization shortly after TPA bolus are feasible goals for thrombolysis assisted with TCT monitoring.