Clinical Application of Transcranial Doppler in Cerebrovascular Diseases

Abstract

Transcranial doppler (TCD) ultrasonography is a diagnostic technology for ascertaining numerous physiologic and pathologic phenomena by monitoring the direction and velocity of blood flow in intracranial vasculature. It is a noninvasive, point-of-care diagnostic tool that provides continuous and reproducible bedside data without the use of radiation or contrast agents. In this chapter, we will review principles TCD ultrasonography, and review clinical utility of TCD in aneurysmal subarachnoid hemorrhage (aSAH) and stroke as relate TCD monitoring. We will also review the advances in the clinical application of TCD in cerebrovascular diseases including robotic assisted TCD devices in PFO detection as well as clinical trials using TCD for early detection of large-vessel occlusive ischemic stroke.

1. Introduction

Transcranial doppler (TCD) is a non-invasive ultrasound technique that allows for the assessment of cerebral blood flow velocity in real-time without the use of iodine radiation commonly used in neurocritical care. It is an important bedside tool in the evaluation of cerebrovascular diseases including aneurysmal subarachnoid hemorrhage (aSAH) and ischemic stroke. In this chapter, we will review the principles of transcranial doppler, and the clinical application of TCD in aSAH for monitoring vasospasm and microemboli detection in large-vessel vasculopathy. We will also review the advances in the clinical application of TCD in cerebrovascular diseases robotic assisted TCD devices in PFO detection as well as clinical trials using TCD for early detection of large-vessel occlusive ischemic stroke.

2. Transcranial Doppler principles

The Doppler effect is the shift in frequency emitted by a source moving in relation to an observer as perceived by the observer. The shift is to higher frequencies when the distance between the source and the observer decreases and to lower frequencies when the distance increases. In TCD, the source is a red blood cell reflecting an echo, and the observer is the ultrasound probe.

TCD instruments are generally calibrated to measure blood flow velocity when blood is moving either directly toward the ultrasound probe (0°) or directly away from it (180°). This principle is important because if insonation is at an angle other than 0° or 180°, only a fraction of the true velocity is measured. Certain areas on and around the skull (windows of insonation) help the operator achieve insonation directly in line with blood flow and avoid signal attenuation from the skull and other tissue. Figure 1 shows TCD acoustic windows. The arteries that are examined at those windows are as follows:

• Transtemporal window: MCA, anterior cerebral artery (ACA), terminal portion of the internal carotid artery (ICA), and posterior cerebral artery (PCA).

• Transorbital (ophthalmic) window: ophthalmic artery and ICA at the siphon level.

• Submandibular window: distal portion of the extracranial ICA.

• Transforaminal (occipital) window: basilar artery (BA) and vertebral artery (VA).

Figure 1.

TCD acoustic windows.

Temporal window is commonly accessed as it provides optimal visualization of MCA, which is frequently involved artery in stroke. Temporal window is an areas of the skull that is located just above the zygomatic arch, approximately 1 cm posterior to the midpoint of a line connecting the lateral canthus of the eye to the auditory meatus. The ultrasound probe is positioned on the temporal bone and angled to obtain a transcranial view of the MCA. This allows for detection of emboli, stenosis, and changes in blood flow velocity that may indicate cerebral ischemia or Vasospasm.

An understanding of cerebral hemodynamics, including relevant anatomy, physiology, and pathophysiology, is critical for the accurate acquisition and interpretation of intracranial Doppler data. To this end, it is important to understand the typical vascular distributions and the manifold factors that can affect cerebral blood flow. The cerebral vasculature has autoregulatory mechanisms that compensate for changes in cardiac output and blood viscosity, thereby maintaining relatively constant cerebral blood flow (and cerebral blood flow velocity as measured with TCD). Nevertheless, extreme changes in hemostasis will affect cerebral blood flow. For example, in larger arteries, atherosclerotic plaques cause arterial stenosis alters blood flow velocity. In smaller arteries, various precipitants (e.g., arterial carbon dioxide, intracranial pressure, and mean arterial pressure) alter the flow, and the upstream effects can be inferred from TCD.

3. TCD in aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage is a life-threatening condition that can result in significant morbidity and mortality. Vasospasm and delayed cerebral ischemia (DCI) are common complication of aSAH; they contribute to substantial morbidity and mortality after aSAH [1]. TCD can detect vasospasm by measuring changes in cerebral blood flow velocity with daily monitoring. A study found that TCD had high sensitivity and specificity in detecting vasospasm in aSAH patients [2]. DCI is another common complication of aSAH that can lead to poor outcomes. DCI is thought to be caused by vasospasm from endothelial dysfunction and microthrombosis [3, 4]. TCD can detect changes in cerebral blood flow velocity and microemboli associated with DCI to determine the appropriate timing of intervention such as intraarterial or oral calcium channel blockers to treat vasospasm in aSAH [5].

TCD measures blood flow velocity in all vessels in the circle-of-Willis, but especially for the MCA. Trends in the baseline TCD mean flow velocity (MFV) over time in patients with SAH are recommended for screening for vasospasm. MFV is most sensitive and specific for angiographic vasospasm in the MCA, whereas it is less sensitive and specific for the first segments of the ACA and PCA.

The Lindegaard ratio (or the hemispheric ratio) is the ratio of the MCA flow velocity to the ipsilateral ICA flow velocity. The ratio is often used in conjunction with MCA MFV and accounts for hemodynamic augmentation from a hyperdynamic state (e.g., from pressors or an endogenous hypersympathetic state). A Lindegaard ratio less than 3 suggests a hyperdynamic state with potential relative vasospasm as defined according to the MCA MFV (MCA MFV >120 cm/s indicates mild vasospasm; >150 cm/s, moderate; and >200 cm/s, severe). A Lindegaard ratio greater than 3 typically correlates with angiographic vasospasm seen on computed tomographic angiography (CTA) (>180 cm/s with perfusion impairment); a ratio greater than 6 indicates a high-grade angiographic spasm that may warrant an endovascular neurosurgery consultation.

With established normative data, TCD can be used to compare extracranial and intracranial flow velocities to help localize an intracranial stenosis as distinguished from a hyperdynamic state that is increasing the blood flow velocity (Lindegaard ratio = MCA flow velocity/distal extracranial ICA flow velocity; Soustiel ratio = BA flow velocity/distal extracranial VA flow velocity). Velocity trends are checked in each vessel daily and correlated with symptoms or radiographic spasm as a noninvasive means of investigating the “spasm window.” Velocities usually increase in the first 3 days after bleeding and decrease at 9–14 days. All these provide daily monitoring of cerebral and systemic hemodynamics to guide optimal aSAH treatments.

While TCD is non-invasive, bedside procedure without need for contrast or radiation, it has several limitations. First, it is operator-dependent and often limited from craniotomy wound. Second, TCD correlates well with angiographic vasospasm but not necessarily with symptomatic vasospasm (i.e., clinical deficits). Many confounders are related to the systemic illness associated with aneurysmal SAH: increased ICP, hemodynamic instability, changes in PaCO₂ or hematocrit, and collateralization. Despite these limitations, combining with other multimodal neuromonitoring for vasospasm and DCI, TCD adds tremendous value to the management of aneurysmal subarachnoid hemorrhage.

4. TCD in stroke for emboli detection

Stroke is a major cause of morbidity and mortality worldwide. Early detection and treatment are crucial for improving outcomes in stroke patients. TCD has been used as a diagnostic tool to evaluate cerebral blood flow changes or microembolic in stroke patients to guide treatments. TCD can detect the presence of distal emboli from proximal intracranial or extracranial arterial stenosis or occlusions, and it can also monitor changes in cerebral blood flow velocity and wave form patterns during and after thrombolytic therapy for response and prognosticate outcomes.

In cervical carotid stenosis, several studies have shown that TCD can detect embolic signals in the middle cerebral artery, which is the most commonly affected site in carotid artery disease [6, 7]. Markus et al. found that asymptomatic cerebral emboli signals, high-intensity transient signals (HITS), were present in 58% of patients with symptomatic carotid artery disease and in 37% of patients with asymptomatic disease [6]. Same group also demonstrated asymptomatic cerebral emboli detection over 1 h in 200 patients with >50% symptomatic carotid stenosis was associated with 4.67-fold increased risk of recurrent ipsilateral ischemic events in adjusted cox regression model [7]. TCD is also utilized in predicting risk of stroke in patients with high-risk plaque features such as intraplaque hemorrhage. Sitzer et al. reported that plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis [8]. TCD can be used during carotid endarterectomy to detect emboli in real-time and guide the surgeon to take appropriate measures to prevent embolic events. Spencer et al. demonstrated that TCD could detect middle cerebral artery emboli during carotid endarterectomy, with a sensitivity of 92% and a specificity of 100% [9]. Therefore, TCD is a useful tool in the detection of cerebral emboli in carotid stenosis, which can help guide decision for intervention and surgical approach to minimize risk of stroke.

5. TCD for cerebrovascular reactivity

Cerebrovascular reserve (CVR) is the ability of brain to autoregulate cerebral blood flow in response to physiologic changes such as arterial occlusion as in stroke. Impaired CV in patients with steno-occlusive disease is associated with increased risk of stroke [10, 11, 12]. CVR quantified change in cerebral blood flow in response to vasodilatory stimuli such as carbon dioxide (CO2). Several multiple modalities for measuring CVR, including Blood Oxygen Level Dependent (BOLD) or arterial spin labeling (ASL) MR imaging with CO2 challenge, CT perfusion with acetazolamide. Among these noninvasive modalities, TCD is the most commonly used modality for assessing CVR and guiding decisions for revascularization. A systematic review involving 754 patients with asympatomic severe carotid stenosis and impaired CVR on TCD had 3.69 fold increased risk of ipsilateral ischemic stroke (HR 3.69, 95% CI 2.01–6.77, P < 0.001) [11].

CVR measured by TCD appears to be a useful tool for predicting outcomes after revascularization in patients with carotid stenosis or ICAD. However, due to the dynamic and time-variant nature of CVR, the influence of aging (normal or pathologic aging), exposure to common vasoactive agents such as caffefine or medications, and diurnal variation on CVR in relationship to cerebrovascular diseases is not yet well understood.

A recent study involving 185 healthy adults between the age of 21 and 80 years, who underwent TCD and multimodal MRI, revealed that blood flow velocity decreases with age while the caliber of large vessels remains similar among age groups. These findings suggest that age-related decreases in CBFV and impaired CVR likely reflect small vessel diseases [13]. Another study further demonstrated that the speed of CVR of MCA response to induced vasodilation with CO₂ slowed with age [14]. Further research is needed to gain a deeper understanding of the implications of CVR on treatment decisions and to determine optimal threshold values for CVR across all age groups, enabling informed therapeutic decisions.

6. TCD for PFO detection

Right to left shunt from patent foramen ovale (PFO) is a common anatomical variation in which there is an opening between the right and left atria, and it can be a potential risk factor for cryptogenic stroke [15]. Several randomized clinical trials support closure of PFO in patients between age 16 and 60 years who suffer from cryptogenic stroke from paradoxical embolism through PFO. TCD can detect microbubbles that cross from the right to the left atrium during a Valsalva maneuver, indicating the presence of a PFO. A meta-analysis by Mojadidi et al. showed that TCD has a sensitivity of 97% and a specificity of 93% for the detection of PFO compared to transesophageal echocardiography, which is the gold standard imaging modality for PFO detection [16]. However, TCD is less invasive and less expensive than TEE, making it an attractive alternative for PFO detection in certain patient populations. In addition, TCD can be performed at the bedside, allowing for real-time evaluation of PFO during a Valsalva maneuver, which can provide valuable information about the hemodynamic significance of the PFO in stroke pathogenesis. Overall, TCD is a reliable and cost-effective tool for the detection of PFO in patients with cryptogenic stroke.

While TCD is very sensitivity and specific for the detection of PFO, it relies heavily on the operator’s technical skills and availability of trained technicians. Recently, a robotic-assistant TCD (ra-TCD) system with artificial intelligence (AI)-enhanced signal detection algorithms has been tested in clinical research to mitigate the variability in TCD acquisition. The BUBL study is a multicenter, prospective trial comparing raTCD to TTE for PFO detection (NCT04604015) [17]. The study found that raTCD detecting all and large RLS at approximately three times the rate of TTE (primary outcome, any RLS: raTCD 64% vs. TTE 20% [absolute difference 43.4% (95% CI 34.3–52.5%), p < 0.001]) [18]. Ongoing studies are testing whether these results are generalizable in routine practice.

7. Conclusion

TCD is a non-invasive ultrasound technique that allows for the assessment of cerebral blood flow velocity in real-time. It has emerged as an important diagnostic tool in the evaluation of cerebrovascular diseases such as aSAH and ischemic stroke. TCD can detect cerebral blood flow changes that can help guide clinical management and improve patient outcomes. TCD has been used to diagnose and monitor changes in cerebral blood flow velocity in stroke patients, and to detect vasospasm and DCI in aSAH patients. TCD can also guide treatment decisions in these patients. Further research is needed to determine the full extent of the utility of TCD in these conditions.

Goals

• Review the principles of transcranial Doppler (TCD) ultrasonography.

• Review the clinical utility of TCD in monitoring vasospasm after aneurysmal subarachnoid hemorrhage.

• Review the clinical utility of TCD in ischemic stroke including microemboli and PFO detections, and cerebrovascular reactivity quantification.