*2.4.3 CT angiography*

CT angiography (CTA) requires administering iodinated contrast material through an 18–20 gauge needle, and it is not necessary to obtain the results of renal function prior to CTA [30]. Ehrlich et al. studied safety of CTA in evaluation of patients with acute stroke [31]. Within 24 to 48 hours after CTA, they found no statistical difference in both renal function and changes in creatinine. They drew the conclusion that CTA should not be delayed for testing for creatinine in AIS. CTA is performed immediately after the NCCT, with the aim to visualize occlusions in both extracranial and intracranial vasculature from the aortic arch to vertex [24] and may be performed as a single, delayed, or multiphase study (**Figure 2**). Evidence suggests that performing CTA is all individuals presenting within 24 hours improved detection of LVO, increased the population of AIS patients treated with endovascular thrombectomy, and was associated with better outcome [32].

Thus, CTA may reliably discover locations of stenosis and occlusions, providing clues to etiologies and allowing further assessments for the eligibility of thrombectomy. As an example, an occlusion in the internal carotid (ICA) with ipsilateral infarct may sway the etiology towards thromboembolism originated from a large vessel, while stenosis of the ICA with bilateral embolic showers is more commonly caused by an embolism from a proximal source such as the heart of aortic arch.

#### **Figure 2.**

*CT angiogram with circle of Willis reconstruction. After the region marked by the red arrow, there is no contrast filling the artery indicating an occlusion in the distal M1 branch of the left middle cerebral artery.*

Multiphase CTA (mCTA) is an imaging tool that provides three time-resolved images of pial arterial filling in the whole brain and is superior to conventional single-phase CT angiography (sCTA) [33]. After injection of contrast bolus, the first phase, also known as the peak arterial phase, scans from the aortic arch through the vertex. The second phase, the peak venous phase, scans the skull base through the vertex, and is performed 4 seconds after completion of the peak arterial phase scan. The third phase, the late venous phase, scans from the skull base through the vertex performed 4 seconds after completion of the second phase. Multiphase CTA (mCTA) is especially useful in assessing collateral vasculature. Collaterals are connections between cerebral blood vessels; when an artery is occluded, these collaterals reroute blood flow to maintain perfusion to the ischemic tissue [24]. Patients with diminished or absent collateral vessels in the symptomatic hemisphere experienced markedly higher risk for further deterioration. Compared to sCTA, mCTA improves detection of large-vessel occlusion (LVO; occlusion of large artery in brain such as terminus of the ICA, M1/M2 branch of MCA,, ACA, and basilar artery), improved characterization of collateral status, improved tolerance of patient motion and poor hemodynamics, and higher interrater reliability [34]. Therefore, the mCTA is incredibly useful in determining prognosis and guiding treatment decisions [24, 35, 36].

#### *2.4.4 The concept of the ischemic penumbra and mismatch*

In a patient presenting with AIS, there exists an ischemic "penumbra" [37]. This is the region which receives greater than 10% of its baseline blood flow but less than 30% [38]. This tissue has not irreversibly infarcted yet, but the neurons are electrically silent (i.e. not conducting action potentials) and causing the patient's acute clinical deficits. The tissue that is already infarcted and cannot be recovered, even after reperfusion is called the ischemic "core". **Figure 3** depicts a rat model of the effect of decreased blood flow on neuronal physiology. In humans, estimates of the ischemic penumbra have been best achieved using CT-perfusion (CTP) and MRI. Using imaging modalities, we can determine which tissue is being hypoperfused, the volume of tissue being hypoperfused, and the volume of tissue that is already infarcted. The ratio between the total volume of tissue being hypoperfused and the volume of tissue that is already infarcted, the core, is known as the mismatch ratio (MMR). To define the specifics of the MMR, it is important to discuss CTP parameters.

#### *2.4.4.1 The parameters of CTP*

CTP is the accepted modality for selecting patients with AIS within 6 to 24 hours of LKNT, as it is can determine how much salvageable tissue remains [24]. There are four primary parameters that CTP uses to determine if tissue is hypoperfused and if so, if can be saved. Cerebral blood flow (CBF) is the volume of blood flowing in a unit (100 g) of brain tissue during a unit of time (1 minute). Time-to-maximum (Tmax) is the time delay between the contrast arriving in the large vessels to when it arrives in brain tissue. Cerebral blood volume (CBV) is the volume of blood/contrast in mL per 100 g of brain tissue. Finally, mean-transit-time (MTT) is the average time required for the blood/contrast to traverse the 100 g of brain tissue. Automated software computes these qualitative and quantitative maps of ischemic lesion tissue [39]. **Table 2** presents a visual comparison of CTP parameters distinguishing core from penumbra.

#### **Figure 3.**

*A rat model of the effect of decreased cerebral blood flow (CBF; measured in mL/100 g/min) on neuronal physiology and brain tissue. Below 15 mL/100 g/min, ATP is depleted, Na/K pumps fail, and cells die, forming the ischemic core. Below 35 mL/100 g/min, there is a change in neuronal metabolism and the neuron is not conducting action potentials. The tissue is non-functional but has not infarcted yet. This is the ischemic penumbra, the region that is still salvageable by intervention and "doomed to die" without it. Below 55 mL/100 g/min, the tissue is "at risk" but will not necessarily die, even without intervention. Adapted from lieu et al. 2020.*

#### **Table 2.**

*CT perfusion measurements for core and penumbra. In both the core and the penumbra, due to blockage of the artery, there is less flow of blood to the tissue, leading to decreased CBF. The blood is also taking longer to fill and to leave the tissue and therefore, MTT and T max are increased. In the core infarct, cerebral blood volume is decreased as blood is no longer filling the dead tissue.*

The penumbra can be determined by subtracting the ischemic core from the tissue at risk There have been multiple methods of estimating the tissue-at-risk or the perfusion deficit as well as estimating the ischemic core. Visually, comparing MTT maps to CBV maps gives a qualitative estimate of the penumbra (**Figure 4**). The most useful quantitative measurements are Tmax>6 s, which best estimates tissue-at-risk and CBF < 30 ml/100 g/min, which best estimates core [40]. One can also calculate the MMR, which is the ratio between the core volume and perfusion deficit volume. These numbers are crucial as they determine eligibility for endovascular thrombectomy. To be eligible for the intervention, the MMR must be greater than 1.8, the penumbra must be greater than 15 mL, and the Tmax >10 seconds [41].

There are caveats pertaining to potential inaccuracy of the above parameters. CTP parameters may be affected by reduced cardiac output, carotid artery stenosis, and injection rate. Technical factors such as motion artifacts, and erroneous CTP protocol, for example wrong contrast injection rate, can also bias the computation of ischemic core and penumbra [39]. A perfusion protocol shorter than 60 seconds, as a further example, is known to overestimate the infarct core volume [30]. Occasionally CTP results can be entirely misleading when a non-stroke hemisphere is labeled as ischemic due to recanalization and luxury hyperperfusion of the stroked hemisphere [42]. Stroke mimics causing vascular dysregulation, such as seizures, hypertensive encephalopathy, hemiplegic migraines, may produce false images of penumbra, and so can vascular anatomical variations [39]. Although CTP has become standard in assessing anterior circulation stroke, there is to date insufficient evidence for its application in posterior circulation strokes. In particular, the CBF cut off of 30%, a defining feature of the ischemic core, can only be applied to anterior circulation strokes. MRI on the other hand is considered the gold standard for assessing posterior circulation infarcts [43].

#### **Figure 4.**

*CT perfusion map of a patient with acute left MCA occlusion with mean transit time map (MTT; left) and cerebral blood volume map (CBV; right) demonstrating acute occlusion of left MCA. In the MTT map, increased time is indicated by a color higher on the spectrum with the longest time being red. It can be seen that the region marked by the white arrow has a prolonged MTT versus the right hemisphere. On the CBV map, the color lower on the spectrum demonstrates lower CBV.*
