Multi-modal CT scanning in the evaluation of cerebrovascular disease patients

Introduction

Ischemic stroke currently represents one of the leading causes of severe disability and mortality in the western world and its early detection is extremely important (1,2). Several investigations have explored the risk factors for the development of ischemic events by confirming that the atherosclerotic disease of the carotid artery represents an important cause of the strokes (3,4).

Researchers have thus focused their attention on the diagnosis of the carotid artery pathology and on the detection of those markers that are associated with plaque vulnerability such as plaque composition, intra-plaque hemorrhage (IPH), fibrous cap rupture and plaque’s ulcerations (5-10).

In the past years digital angiography (DA) was the imaging technique most used for the detection of the carotid artery pathology. However, a fundamental limit of DA is that it is a pure luminal methodology that offers information regarding only the lumen of the vessel but no information about the carotid wall and the plaque. Ultrasound (US), magnetic resonance (MR) and computed tomography (CT) have emerged as non-invasive imaging tools. These three techniques offer a detailed overview of the lumen of the vessel and the plaque and have completely come to substitute for the DA (11-15).

In particular, CT has tremendously evolved due to the software and hardware evolution by allowing for the acquisition of isotropic analysis with a spatial resolution of 0.4 mm (16-18). Several authors consider CT the best imaging modality for quantification of carotid artery stenosis and for the detection of some elements of plaque’s vulnerability (such as ulcers). The main limitation of the CT study is the radiation dose [usually it ranges from 5 to 7 milli-Sievert (mSv)] delivered to the patients even if some methods can be used to reduce the radiation dose and multi-spectral scanner can perform a CTA of carotid arteries with 2 mSv (19).

In those patients with suspected ischemic stroke it is possible to perform CT perfusion (CTP) that offers valuable information of the brain’s vascular physiology by increasing the stroke diagnostic performance, thereby providing useful additional information. By analyzing the cerebral blood volume (CBV), the cerebral blood flow (CBF), and mean transit time (MTT), it is also possible to obtain information about the ischemic penumbra. In this review our purpose is to discuss stroke risk prediction and detection using CT.

CT protocol

CT-angiography (CTA). The acquisition protocol markedly varies according to the type of scanner available because the velocity of acquisition can be very different. In our Institution we perform un-enhanced and enhanced scans. A peripheral venous access with an 18 or 20 gauge needle is obtained and the power injector is loaded with nonionic iodinated contrast material. Usually the right antecubital vein is selected in order to avoid artifacts due to the fact that undiluted contrast material in the subclavian artery might obscure the origins of the great vessels. The amount of contrast material is usually 40-60 mL followed by a 25-mL saline bolus chaser and the injection rate should be >4 mL/sec. The acquisition should cover from the aortic arch to the circle of Willis and it can be performed in caudo-cranial or cranio-caudal directions. Patients are placed in the supine position and they are instructed not to breathe or swallow. For this type of exam the best method to deliver the contrast medium is bolus tracking. In bolus tracking, a designated vessel of interest is monitored in real-time with low-dose dynamic scanning and when the selected enhancement threshold (from 80 to 120 HU) is reach, the scan begins (Table 1).

Table 1 CTA of supra-aortic vessels technical parameters
Full table

The technical parameters can significantly change according to the different equipment. In order to obtain a good level of quality the slice thickness should be <1 mm. The use of the dose modulation can be useful to reduce the dose of radiation delivered to the patients but sometimes this approach reduces the signal-to-noise ratio. CTA is followed by the CTP, using an additional bolus of 30-40 mL of contrast material. Four adjacent 5-mm slices are analyzed on the 16 slice scanners or eight 5-mm slices on the 64-slice scanner and time density curves are then calculated for each pixel and analyzed using vendor-based software (Table 2).

Table 2 CTA of brain technical parameters
Full table

Post processing is performed by the technologist at the scanner or in the 3D laboratory. Maximum intensity projection (MIP) images of the carotid bifurcations are obtained bilaterally in sagittal oblique planes and the origins of the great vessels and extracranial carotid arteries are obtained in the coronal plane.

Diagnostic flow chart and role of CTA

The selection of patients requiring surgical/interventional treatment for carotid atherosclerotic disease is based on the degree of stenosis and presence of symptoms (Flow-chart: Figure 1). However, risk of embolism is not only due to presence, location and size of carotid plaque, but also to its composition. Therefore, the detection of vulnerable plaque and IPH is fundamental when choosing the correct therapeutical approach. US is an accurate and cost-effective non-invasive method for screening patients at risk for carotid atherosclerosis, used also in asymptomatic subjects scheduled for surgery such as coronary artery bypass graft, abdominal aortic aneurysm and lower limb ischemia (20). However, the role of CTA and MRA in the detection of carotid stenosis is increasing and in our Institution, CTA is currently considered the first choice examination in patients at high risk of cerebrovascular disease, reserving US for the evaluation of patients with a lower risk (21,22) or screening program. An important advantage of the CTA versus the US is the potentiality of CTA to explore the distal ICA and intra-cranial ICA and the consequent potential detection of tandem-lesions.

Figure 1 Imaging flow-chart. US, ultrasound; CTA, CT-angiography.

In patients with stenosis greater than 50% at US or less than 50% but symptomatic, CTA or MRA are suggested to confirm the diagnosis, to accurately determine the precise degree of stenosis and to plan appropriate treatment (i.e., detection of anatomical variants in vessel course, tandem lesions, intracranial atherosclerotic disease, etc.). No definitive conclusion exists as to which is the best technique regarding CTA and MRA (23-25) but since MRA is time-consuming, costly and not as easily available as CTA, the latter is the preferred diagnostic method in most centers. CTA allows for an optimal assessment of the morphology of the carotid plaque (the “inner lumen”), and differentiating between a smooth (Figure 2), irregular or ulcerated surface (Figure 3) (26). Plaque irregularities may be associated with increased risk for stroke/TIA or previous cerebrovascular adverse events. Ulcerated plaque is characterized by the presence of an intimal defect larger than 1,000 µm in width exposing the necrotic core of the plaque (27). Previous studies comparing CTA and US-ECD demonstrated that the diagnostic accuracy of CTA is significantly higher in the detection of ulceration (93% versus 37.5%) (9). Ulcerations of plaque can be classified into four types: plaque with an ulcer that comes out perpendicular to the lumen (type 1); plaque with a narrow neck showing a “mushroom shape” or no visible neck (type 2), plaque with an ulcer neck proximal and main part of the ulcer pointing distally (type 3) and plaque with an ulcer neck that is distal and points proximally (type 4). Irregular plaque’s morphology and ulcerations are associated with IPH, lipid core, thin or ruptured fibrous cap and plaque instability (25).

Figure 2 VR, MIP and multiplanar reconstruction show an ulcerated plaque of the carotid bifurcation (A-C) (red arrow). Axial images (D,E) show degree of stenosis, ulceration and composition of the plaque (low density). Common carotid artery is indicated by white arrows whereas internal carotid artery by white arrowheads. VP, volume rendered; MIP, maximum intensity projection.

Figure 3 VR and MPR (A,B) show a non-significant stenosis caused by a smooth plaque with irregular and ulcerated surface (C-E). CTA incidentally detects the presence of two intracranial aneurysms (yellow arrow). Common carotid artery is indicated by white arrows whereas internal carotid artery by white open arrows. VR, volume rendered; MPR, maximum intensity projection; CTA, CT-angiography.

CTA allows us to classify the type of plaque as fatty (soft plaque with density value <50 HU), mixed (density value between 50 and 119 HU) and calcified (density >120 HU) (28) placing a circular or elliptical region of interest (ROI) in the predominant area of the plaque (9,10,25). An excellent inter-observer reproducibility has been reported in connection with this method and it has been demonstrated that HU values measured in the center of fibrous-rich regions and the lipid core are significantly different (29).

Another important risk factor that should be considered is the plaque volume: a moderate association between plaque volume and severity of luminal stenosis has been observed (30). Furthermore, recent studies have shown that CTA can measure carotid artery wall thickness (CAWT) and that there is a significant association between thicker CAWT (>1 mm) and stroke risk (P<0.0001).

Lastly, CTA may incidentally detect intracranial aneurysms: it has been reported an incidence of 4.1% intracranial aneurysm in presence of internal carotid artery stenosis (31), significantly higher compared to the general population, in which the prevalence is 2.3% (32); authors hypothesized that this relation may be explained by the fact that atherosclerotic diseases and intracranial aneurysms share common risk factors.

Quantification of degree of stenosis of carotid artery

The quantification of the degree of stenosis (Figure 4) is considered the leading parameter in selecting better treatment because of its correlation with risk of stroke. For this reason different multi-centric randomized trials have been performed to identify the cut-off values of stenosis degree that may benefit from carotid endarterectomy (CEA): North American Symptomatic Carotid Endarterectomy Trial (NASCET), the European Carotid Surgery Trial (ECST) and Asymptomatic Carotid Atherosclerosis Group (ACAS). The first two trials are the most frequently used: they evaluate the degree of stenosis as the percentage reduction in the linear diameter of the artery (measurements must be performed on a strictly perpendicular plane to the longitudinal axis of the vessel). The NASCET method measures the ratio between the diameter of the lumen at the point of maximum stenosis and the diameter of the lumen in the distal, healthy internal carotid artery, while the ECST method calculates the ratio between the diameter of the lumen at the stenosis site and the total carotid diameter (including the plaque). As a result, this measurement technique determines that ECST stenosis degree is larger compared to NASCET values (e.g., 83% ECST usually is a 70% NASCET). The difference in measurements has shown a wide variability (33).

Figure 4 VR (A) and axial CTA images (B,C) of a 67-year-old patient with a severe stenosis in the left ICA. According to the NASCET the degree of stenosis is calculated with the ratio between the lumen diameter at the stenosis site (C) and lumen diameter of the distal, healthy internal carotid artery (B). VR, volume rendered; CTA, CT-angiography; NASCET, North American Symptomatic Carotid Endarterectomy Trial.

The percentage-base methods are prone to inter-observer variability and errors, mostly due to incorrect detection of the arterial reference (the distal ICA for NASCET and the ICA lumen for ECST) and a new measurement method for CTA based on a direct mm measurement of carotid stenosis has been introduced by Bartlett et al. (34). This technique shows a linear relationship between the residual lumen of the internal carotid artery measured in mm on co-axial sections and NASCET stenosis, with a residual carotid diameter of 1.3 mm equivalent to 70% NASCET stenosis. This value has been proposed as the threshold for severe carotid stenosis, showing a sensitivity of 88% and a specificity of 92%.

Another important concept to consider is “near occlusion” condition (Figure 5) which indicates a presence of severe carotid bulb stenosis with homogeneous decrease of the caliber of the ICA distal to the bifurcation secondary to flow reduction: detection of near-occlusion influences treatment planning since it has been demonstrated that this condition determines a lower risk of ipsilateral stroke and that CEA/revascularization is less effective (35). In these cases, the NASCET method fails in the determination of stenosis degree due to the lack of a distal healthy arterial reference. A near occlusion is defined as a stenosis of the ICA bulb with distal ICA caliber reduction compared to the contro-lateral internal carotid artery and the ipsilateral external carotid artery (ratio between caliber of distal ICA and ipsilateral ECA >1 is diagnostic for near occlusion) (20,34).

Figure 5 VR (A) and axial CTA images (B-D) of a 62-year-old patient with a near occlusion of the left ICA (white open arrow) that is markedly smaller compared to the right ICA (white arrow) in the different level (panel B at C3 level, panel C at C2 level and panel D at C1 level). VR, volume rendered; CTA, CT-angiography.

Carotid artery vulnerable plaque

As previously described, the degree of luminal stenosis (usually quantified by using the NASCET method) is considered the lead parameter for choosing the therapeutical approach (carotid endarterectomy—carotid artery PTA/stenting—best medical treatment); however, in the last few years, several researchers have demonstrated that the plaque structure may increase or reduce the risk of a patient developing an ischemic stroke. In particular, in 1989 Muller introduced the concept of “vulnerable plaque” identifying plaques (also with low degree of stenosis) susceptible to rupture and embolization (36). The vulnerable plaque is histologically characterized by a large eccentric necrotic core, covered by a thin fibrous cap (<65 µm), infiltrated by macrophages, inflammatory cells, spotty calcifications and vasa vasorum proliferation. Progression of atherosclerosis determines disintegration of the foam cells, loss of smooth muscle cell, while matrix metalloproteinases produced by inflammatory cells determines formation of a destabilizing lipid core which is fragile and prone to fibrous cap ruptures. Moreover, hypoxia in the inner layer of the vessel wall causes proliferation of fragile and immature microvessels that are sensitive to rupture with secondary bleeding (37).

Vulnerable plaque causes two thirds of acute events, with the remaining events caused by erosion of the intimal surface with thrombus formation (38). First angiographic and histopathological studies were conducted in coronary artery plaque, but similar findings were also found in carotid arteries by showing that cerebrovascular events can also be triggered in carotids with plaques that determine low grade stenosis (39-42).

Different invasive and noninvasive techniques were developed to image the morphology as well as the composition of the plaque. Authors found that the embolus detection during the trans-cranial Doppler may represent a very sensitive index of plaque instability (43). Currently the carotid artery plaques are imaged using mainly US, CTA or MRA. In particular, US is considered a first-line (screening exam) (11) even if recent papers have demonstrated that US can offer excellent detail of the carotid vulnerable plaque, such as the presence and degree of neovascularization of the plaque (43). Another study (44) found that ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis.

Today, CTA is considered an accurate method when assessing vessel wall, location, extension and morphology of the plaque as well as those features associated with plaque vulnerability such as presence of ulcerations, rupture of the fibrous cap, plaque remodeling and low plaque density (<30 HU) (9,10,41,45-47). Thanks to the potential of CT to characterize the tissues, according to the HU attenuation, a classification of the type of plaque (fatty, mixed or calcified) has been proposed. The first attempt to classify the plaques according to the attenuation was performed by Schroeder et al. in 2001 assessing coronary arteries (48) (fatty plaques <50 HU, mixed plaques between 50 and 120 HU, calcified plaques >120 HU). A few years later the Rotterdam group lead by van der Lugt performed a similar analysis on the carotid artery plaques (49,50) by determining thresholds for tissue classification in carotid arteries similar to the plaques in the coronary arteries (fatty plaques <60 HU, mixed plaques between 60 and 130 HU, calcified plaques >120 HU).

Several pieces of evidence suggest that fatty plaques with low attenuation values are associated with the vulnerability of the plaque even if clinical relationship still remains debated (51). Studies show that an increased risk of cerebrovascular events is expected (4,13). This is even more evident in recent studies that have demonstrated that the IPH in the plaque shows very low attenuation values (52,53).

Recent studies also pointed out the attention to the contrast enhancement that the carotid plaques may show after the administration of contrast material and its association with cerebrovascular events (54).

Other authors showed that the carotid plaque characteristics change and therefore those determinants of vulnerability might disappear after time. In particular van Gils et al. (55) found that in some cases carotid ulcers healed even if most of carotid ulcerations persist for a long time whereas usually plaque surface morphology remains unchanged. These findings allow for the hypothesis that carotid plaque morphology and characteristics may change between patients with acute stroke and patients with chronic cerebrovascular disease.

Moreover, CTA offers the possibility to directly see vulnerable plaques by using new iodinated contrast agent that selectively accumulates into macrophages (56). Automated software enables delineation of vessel walls, detection of plaque and attribution of a color to pixel with different attenuation value. In this way characterization of the plaque is possible. Despite the high accuracy, the method is affected by some limitations such as blooming artifacts in the presence of big calcification and radiation exposure (57).

The introduction of multi-energy CT scanners allows for further exploration of the carotid artery plaques by demonstrating which tissues have an increased or reduced attenuation according to the level of kiloelectron voltage applied (58,59). This approach helps to further characterize the tissue composition of the plaque by widening the CTA potentiality in the plaque assessment.

Evaluation of arterial intracranial circulation

Other than allowing for evaluation of the cervical arteries, CTA helps in defining possible intracranial arterial disease. CTA is a widely available and very accurate technique that, in the event of a stroke, allows determination of arterial occlusion and dissection and permits rapid assessment of vascular anatomy before treatment of acute stroke, giving information such as collateral circulation and intracranial atherosclerosis (60). In case of an intracranial artery occlusion, the interventional neuroradiologist will use the information provided from the CTA to predict the extent and location of the final infarction.

CTA has a high specificity and sensitivity for detecting occlusions as distal as the M2 segment of the middle cerebral artery (60,61). CTA is important for the detection of posterior circulation thrombosis, mainly for two reasons: the low sensitivity of unenhanced CT for detection of those infarctions and the fact that posterior fossa is not covered by the standard perfusion protocol (62). To evaluate the intracranial CTA, multiplanar MIP reformatting should be created. Additional views can be created in particular cases, such as a detail view, an MPR or a 3D volume rendering view (Figure 6). Unenhanced CT does not show the arterial occlusion, except in patients with a hyperdense arterial sign with high specificity but low sensitivity for an occluded cerebral artery, an often difficult to interpret sign (Figure 7) (63). The localization of the hyperdense arterial sign is considered a parameter that may predict the patient’s outcome: when M1 (or even M2) segments are involved authors described a very poor outcome, whereas when M3-4 segment is involved usually the outcome is good (64-66). Regarding the evaluation of collateral vessels, it is notable that survival of brain parenchyma in the presence of an arterial occlusion depends on the above-mentioned leptomeningeal collateral pathways (67). Leptomeningeal collateral pathways are direct arteriolar anastomoses between pial branches which contribute to retrograde filling of pial arteries distal to an occlusion. Evaluation of leptomeningeal collaterals can be made using CTA (68). As logically expected, patients with better pial collaterals have a better prognosis (69). Leptomeningeal collaterals on CTA are also a reliable marker of good outcome in ischemic stroke. In a recently published paper the role of CTA in the evaluation of collateral circulation was explored: in 196 patients with complete occlusion of the intracranial internal carotid artery and/or the middle cerebral artery (M1 or M2 segments) The leptomeningeal collateral pattern was graded as a 3-category ordinal variable (less, equal, or greater than the unaffected contralateral hemisphere) and the authors found that presence of leptomeningeal collaterals (grade 3) was identified as independent predictors of a good outcome (OR, 1.93; 95% CI, 1.06-3.34; P=0.03) (70).

Figure 6 A 59-year-old female with acute onset of left-sided weakness and clinical suspicion for stroke. CT stroke series included a non-enhanced CT (A), which demonstrates minimal gray-white matter loss of differentiation and loss of the definition of the right basal ganglia. CTA (source image on B and VR on C demonstrates abrupt termination of the contrast column in the right middle cerebral artery distal M1 segment. This is confirmed on the subsequently performed DSA (D). CT, computed tomography; CTA, CT-angiography; VR, volume rendered.

Figure 7 A 63-year-old male with acute onset of asymmetric quadriparesis, alteration in the level of consciousness and oculomotor abnormalities, suspicious for a basilar artery territory infarction. Unenhanced CT was negative. CTA (source image on A and detailed MPR on B and C) demonstrates a focal occlusion in the proximal basilar artery. This was confirmed on the subsequently performed DSA (D). CT, computed tomography; CTA, CT-angiography.

The whole brain analysis of the source images is very useful for a few reasons. Source images give direct information about flow of contrast into the tissues (71), providing a whole-brain perfusion map. Unlike CTP images, CTA source images cover the entire brain and are available immediately at completion of imaging, without requiring any form of postprocessing (72). CTA source images are more accurate than non-enhanced CT scans in the prediction of final infarct volume, as measured by using ASPECTS score.

CT imaging of the vein

Cerebral sino-venous thrombosis (CSVT) is an uncommon disorder that involves the venous sinus and cerebral veins (73). The detection of this condition is important because the clinical presentation is usually nonspecific and when it progresses rapidly it can be lethal. The CT can help in detection and characterization of the CSVT and it is possible to identify findings in the un-enhanced phase as well as in the enhanced phase. In the un-enhanced phase it is possible to identify the “dense triangular sign” whereas after administration of contrast material the “cord sign” and the “empty delta sign” is a triangular defect determined by the enhanced dura surrounding the thrombus (Figure 8).

Figure 8 MIP (A,B) of a 37-year-old female patient with normal venous intra-cerebral system. The superior sagittal sinus is visible (white arrows) as well as the straight sinus (white arrowhead). In panel C the CTA axial image of a 42-year-old patient with headache that demonstrated the presence of thrombus at the confluence of sinuses (white open arrow). MIP, maximum intensity projection; CTA, CT-angiography.

Previous investigations showed that after CSVT parenchymal changes can occur and a classification was suggested (73,74): stage I—no parenchymal change; stage II—brain swelling, sulci effacement and mass effect; stage III—reduction of the density as mild to moderate edema; stage IV—severe edema, with or without hemorrhage; and stage V—massive edema and/or hemorrhage.

According to previous studies, failure to diagnosis CSVT or underestimation of sinus involvement and venous infarcts by using CT were reported in up to 40% of patients (73,75). However, there are some conditions that can mimic venous sinus thrombosis in unenhanced CT. In particular, authors found that subarachnoid hemorrhage along the edges of the tentorium cerebelli can be mistaken for CSTV (76).

Authors found that symmetry of venous sinuses identified by CT was correlated to an impaired cerebral reserve also in chronic conditions as atherosclerotic spontaneous occlusion of internal carotid artery (77). Moreover, the venous drainage also effects brain perfusion and collateral flow as indicated by Liebeskind (78).

CTP of the brain for stroke detection

Perfusion CT is usually performed after unenhanced CT and CTA. While these two exams demonstrate the vascular anatomy, CTP is a study suited for the evaluation of brain vascular physiology. The information provided by CTP may actually prolong the reperfusion time window giving similar information compared to those provided by an MRI (79). CTP increases the stroke diagnostic performance providing useful additional information to relatively inexperienced readers compared to the information given by stroke protocols which include only unenhanced CT and CTA (80). CTP involves a continuous cine CT imaging over around 45 seconds on a slab covering the same area of brain parenchyma during the administration of a bolus of contrast at high flow rate (81). CTP is hence obtained by monitoring the first pass of the contrast through the cerebral vasculature, evaluated using a model of linear relationship between contrast agent concentration and attenuation in Hounsfield Units (82). The following evaluation includes the visualization of different derived maps: CBV, CBF, MTT, and time to peak (TTP) (Figure 9). The parameters are related according to the following equation: CBF = CBV/MTT (Figure 10) (83). To obtain those maps, the contrast time-concentration curves are generated in an arterial ROI, in a venous ROI, and for each pixel with placement of ROIs in an input artery [usually the ACA or middle cerebral artery (MCA)] and an input vein, such as the torcular herophili. The software then generates color-coded CBF, CBV, and MTT maps (84).

Figure 9 A 67-year-old male with a frontal lobe. The first video—CBF and CBV (Cerebral blood flow and cerebral blood volume), the second with the CBF and the third with the CBV demonstrate a left frontal cortical-subcortical area of decreased CBF and decreased CBV without mismatch are noted in the same location. All maps are color-coded red blue for low values and red for high values. CBF, cerebral blood flow; CBV, cerebral blood volume.

Figure 10 A healthy 42-year-old man. CT perfusion maps showing cerebral blood flow (A), cerebral blood volume (B), time to peak (C), demonstrates normal symmetric brain parenchyma perfusion. All maps are color-coded red blue for low values and red for high values. CT, computed tomography.

The evaluation of acute stroke is the main indication for CTP, with which we can distinguishing infarcted non-vitalized tissue from the penumbra (Figures 11,12) (85), the penumbra being the tissue salvageable with thrombolytic agents, while infarcted non-vitalized tissue is irreversibly damaged with no benefit from reperfusion and at increased risk of hemorrhage after thrombolysis. Notably, this evaluation transcends an arbitrary clock time (86), possibly demonstrating that the reperfusion time window should be based on the single patient due to the highly variable regional ischemic vulnerability. Ischemic core has a decrease in both CBF and CBV, whereas the penumbra demonstrates a reduction in CBF with a relatively maintained CBV. The CBV is maintained in the penumbra because the decreased perfusion pressure causes dilation of pre-capillary arterioles and engorgement of veins (87), while in the ischemic core, the reduction of CBF and CBV is related to the failure of autoregulation with consequent hypoperfusion. Tissue at risk of infarction will also have elevated MTT. Hence, patients with large CBV-MTT mismatch are the best candidates for reperfusion therapy, even after the first 3 hours after stroke onset (Figure 13) (88). After the stroke, postischemic hyperperfusion is another entity that can take advantage of CTP. Postischemic hyperperfusion represents the restoration of perfusion pressure close to normal values in the vascular territory previously affected by severe ischemia (89,90). Notably, areas of hyperperfusion within the brain parenchyma in the setting of stroke should not be abnormally interpreted as contralateral areas of hypoperfusion and acute infarction (91).

Figure 11 A 55-year-old male with acute onset of slurred speech, suspicious for a left frontal infarction. CTP maps showing CBF (A), CBV (B), TTP (C), demonstrates a left frontal cortical-subcortical area of decreased CBF and decreased CBV without mismatch are noted in the same location. There is, however, a very small mismatch between the TTP and the CBF and CBV maps. Notably, the unenhanced CT (D) performed right before the CTP was negative. CT, computed tomography; CBF, cerebral blood flow; CBV, cerebral blood volume; TTP, time to peak; CTP, CT perfusion.

Figure 12 A 63-year-old female with acute onset of left-sided weakness, profound left neglect and right gaze preference. Unenhanced CT (A) demonstrates very mild symmetric density within the right middle cerebral artery territory. CTP maps showing CBF (B), CBV (C), MTT (D), demonstrates a right large area of decreased CBF (B) and a relative maintained CBV (C). There is elevated MTT (D), suggesting a large penumbra. CT, computed tomography; CTP, CT perfusion; CBF, cerebral blood flow; CBV, cerebral blood volume; TTP, time to peak; MTT, mean transit time.

Figure 13 A 63-year-old female with acute stroke, same patient of Figure 8. Cerebral angiogram (A) demonstrates a fully occluding thromboembolus within the proximal M1 segment of the right middle cerebral artery, with evidence of some collateral to superior convexity and temporal regions, the former via anterior cerebral artery leptomeningeal branches. Same view demonstrates recanalization of multiple middle cerebral artery branches (B) after intra-arterial thrombolysis and thrombectomy performed with administration of t-PA and penumbra device reperfusion and direct mechanical thrombectomy. Internal carotid artery is indicated by white arrows whereas middle cerebral artery by white open arrow.

Clinical relevance of CTA-CTP

The clinical relevance of CTA and CTP has recently been demonstrated. Coutts et al. (92,93) have investigated in the prospective CATCH trial the predictive value of CTA in recurrent stroke in a population of 510 patients and they found that the early assessment of the intracranial and extracranial vasculature using CT/CTA predicts recurrent stroke and clinical outcome in patients with transient ischemic attack and minor stroke (hazard ratio, 4.0; 95% CI, 2.0-8.5). In patients with intracerebral haemorrhage (ICH), early haemorrhage expansion affects clinical outcome and investigators from the PREDICT study found that the CTA can predict the haematoma expansion (93,94).

The CTP value was underlined in the paper by Parsons et al. (95) where the authors used this technique to define the ischemic penumbra and the infarct core in order to select patients that underwent tenecteplase treatment.

CTA-CTP drawbacks

The main limitation of CTA is the delivered radiation dose (usually it ranges from 5 to 7 mSv). These values may represent a high level of delivered radiation, particularly in female patients of reproductive age, and the use of CTA in young-med-aged patients should be critically reviewed. However, it is important to underline that various methods can be used to reduce the radiation dose and that multi-spectral scanners can perform a CTA analysis in 2 mSv (19). The main drawback of the radiation is the increased stochastic risk of developing cancer (96).

Another potential limitation is the possible contrast toxicity because of the potential detrimental interaction of iodinated contrast with thrombolytic drugs (97,98).

CTP has some drawbacks that should be noted. First, as with CTP, the radiation dose presents a problem. In late 2009, excessive radiation dose during CTP was covered by the media after learning about 206 patients exposed to excess radiation at Cedars-Sinai Medical Center in Los Angeles over an 18-month period. This was followed by reports of excess radiation in >50 additional patients from other states, prompting an investigation by the FDA which issued an initial safety notification (99). The protocols that led to safety concerns in some US sites deviated from normal use and certainly from use in stroke, however it is important to underline that the typical exposure from a single CTP examination is around 2-10 mSv, similar to head CT alone and much lower than that from a full length CTA. Notably, the newest scanners have optimized protocols, allowing for stroke imaging with CTP to be done with an acceptable amount of radiation (100). In the CTA/CTP analysis it is mandatory to adopt some dose reduction strategies. The first one is to fix the tube current by taking patient size into account when selecting the parameters that affect radiation dose (in particular the mAs) (101,102). The second option is to use the tube-current (mA) modulation because it is demonstrated that extremely large variations in patient absorption occur according to the anatomic area explored and this parameter is not considered when using a fixed tube current. Therefore, information acquired through body parts having less attenuation can be obtained with substantially less radiation. More advanced modalities for obtaining dose reduction are the automatic exposure control (AEC) and the iterative reconstruction. With the AEC, the CT systems adjusts the X-ray tube current in real time in response to variations in X-ray intensity at the detectors; with the iterative reconstruction the dose reduction is obtained through a significant reduction in the number of required projection views (and therefore of the necessary X-rays), while still producing acceptable image quality (101).

A second drawback is the volume-of-interest in TCP because it usually only covers a portion of the brain, which varies according to the manufacturing characteristics of the CT scanner.

Conclusions

In this review we aimed to discuss stroke risk prediction and detection using CT Angiography. Rapid improvement in the hardware and software has resulted in CT scanners that can detect and characterize the stroke and its cause (atherosclerotic pathology of supra-aortic vessels) with an exquisite level of detail. CTP offers valuable information about the brain vascular physiology thus increasing the stroke diagnostic performance.

Acknowledgements

The authors are deeply grated to Mrs Lia Tsarnas for her precious help in revising the manuscript.

Disclosure: The authors declare no conflict of interest.

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