♦ Noncontrast CT can readily and reliably exclude hemorrhage, demonstrate the fresh intraluminal thrombus, and display early signs of brain ischemia (Table 3-2 and Figure 3-2).

♦ It is important to discriminate signs of brain edema, such as loss of insular ribbon (Figure 3-3), obscuration of lenticular nucleus (Figure 3-4), loss of gray–white matter differentiation, and sulcal effacement (Figure 3-5) from areas of hypoattenuation, because only the latter represents irreversible damage (established infarction).^3,4

♦ Interobserver agreement for the recognition of early ischemic changes is only fair when performed without following a formal method and without considering the clinical information.^5,6 Thus it is crucial to know the expected location of the ischemic insult on the basis of the information provided by the history and physical examination and to follow a methodical approach to maximize the yield of CT scan interpretation. Modifications of window settings may also increase the sensitivity of CT scanning to detect early ischemic changes (Figure 3-6).⁷

♦ Visual identification of early signs of ischemia (particularly hypoattenuation) involving more than one third of the estimated middle cerebral artery (MCA) territory was considered an exclusion criterion for enrollment in several thrombolysis trials, most notably those conducted by the European Acute Stroke Study (ECASS) investigators,^8,9 on the basis of a reasonable but unproved assumption that patients with early signs of extensive ischemia would have higher risk of bleeding after thrombolysis. However, this preconception was not validated by the analysis of the radiological data from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study, which did not include this radiological exclusion criterion.¹⁰ In this trial, ischemic changes on baseline CT scan were observed in 31% of patients. They correlated with greater severity of initial clinical deficits and with longer time from symptom onset but were not independently associated with functional outcome after controlling for other baseline variables. Early ischemic changes were not associated with clinical deterioration within the first 24 hours or symptomatic intracranial hemorrhage within the first 36 hours in the adjusted analysis.¹¹

♦ Moreover, although there is some evidence that extensive early ischemic changes may portend higher risk of intracerebral hemorrhage,¹² there is no proof that the extension of early ischemic changes significantly affects the chances of functional recovery after thrombolysis.^12,13

♦ Nonetheless, most current acute stroke management guidelines include extensive early signs of ischemia as a contraindication for thrombolysis. The guidelines sponsored by the American Heart Association indicate that thrombolysis should not be used if the baseline CT scan shows multilobar hypodensity involving more than one third of the cerebral hemisphere.¹ This carefully crafted recommendation appears prudent. It is important to notice that it intentionally indicates hypodensity (as opposed to other early signs that may represent only tissue swelling and are more difficult to identify) and eliminates the need to estimate the MCA territory as a parameter to define the extension of the changes. On the basis of current evidence, withholding thrombolysis in patients with early signs of tissue edema but no large hypodensities is not justified.

♦ The extension of ischemic changes in the territory of the middle cerebral artery can be quantified using the Alberta Stroke Program Early CT Score (ASPECTS) (Figures 3-7 and 3-8), a 10-point topographic scoring system that has been shown to be easy to use in real time with moderately good interrater reliability.^2,14,15 A cutoff score of less than 7 points is most useful to determine ischemia involving more than one third of the MCA territory.¹⁵ Notice that this score can only be used in cases of middle cerebral artery ischemia.

♦ CT scan may allow visualization of intraluminal thrombi in the terminal carotid, middle cerebral trunk, middle cerebral branches, and basilar arteries (Figure 3-9).

♦ The hyperdense MCA sign on baseline CT scan has been found to be associated with poor prognosis^17,18 and a higher risk of hemorrhage after thrombolysis.¹⁹ The combination of hyperdense MCA sign and extensive sulcal effacement predicts massive swelling and brain herniation.²⁰ Conversely, early resolution of the hyperdensity in the MCA indicates successful reperfusion and is associated with favorable outcome after thrombolysis.

♦ Intravenous thrombolysis can be beneficial in patients presenting with the hyperdense MCA sign.¹⁸ However, when the hyperdense signal appears to involve the carotid terminus in a patient with signs suspicious for carotid bifurcation occlusion (depressed arousal, severe leg weakness), it may be more effective to pursue intra-arterial therapy directly if this is a pragmatically feasible option.²¹

♦ Distal thrombi can sometimes be visualized generating the Sylvian fissure “dot” sign (Figure 3-9, C).²² Its sensitivity is modest (close to 40%), but when identified, it is very specific in predicting M2 or M3 branch occlusion.²³ The dot sign is associated with better outcome than more proximal hyperdense vessel signals.²²

♦ There is growing interest in the application of CT protocols using multimodal CT scanning (CT scan, CT perfusion, and CT angiogram) for the emergency diagnosis and management of ischemic stroke.^3,25 The most attractive features of CT perfusion imaging are its potential for widespread availability (it can be performed on any standard helical CT scanner) and the short time required for the acquisition of data (with adequate training, CT perfusion and CT angiogram can be acquired in 15–20 minutes, and images can be processed and interpreted in 10 minutes or less).^26,27

♦ Dynamic contrast-enhanced CT perfusion imaging (bolus tracking CT perfusion) generates maps of mean transit time (MTT; reflecting the time difference between arterial inflow and venous outflow), time to peak (TTP; representing the time to maximal concentration of contrast enhancement in a region of interest), cerebral blood flow (CBF), and cerebral blood volume (CBV) (Figure 3-10). These physiological measures can be precisely quantified, which represents an advantage over PWI MRI (Table 3-3).

♦ Prolonged relative MTT and delayed relative TTP are the most sensitive physiological parameters to detect hypoperfusion.²⁸ These measures correlate well with MRI abnormalities on PWI and accurately predict final infarct volume in patients who have persistent arterial occlusions (Figure 3-10).^29,30 Meanwhile, reduced absolute CBV (or reduced relative CBV by visual inspection) is the best indicator of established infarction; it correlates well with DWI lesions on MRI and with final infarct size in patients who recanalize.^28–30 The product CBF × CBV may have greater diagnostic accuracy than CBV alone, but this requires the use of quantitative measures.³¹

♦ When quantitative measures are used, the optimal threshold to detect tissue at risk for infarction is a relative MTT of 145% (i.e., 45% longer than in the contralateral side) and the optimal threshold to define the infarction core is an absolute CBV of 2.0 ml × 100 g^−1.32 The postprocessing technique that affords these quantitative measurements has been shown to be solidly reproducible.³³ Nonetheless, qualitative visual interpretation of the MTT and CBV maps yield fast and reliable information to estimate the penumbra.²⁸

♦ Hence, the mismatch between the areas of prolonged MTT (hypoperfusion) and reduced CBV (ischemic core) constitutes the best indicator of the penumbra on CT perfusion imaging (Figure 3-11).^28,31,32

♦ Although CT angiography has not been formally tested against catheter angiography to determine its precise positive and negative predictive values, in practice it allows rapid and reliable demonstration of intracranial or extracranial vessel occlusion.³⁴ Thus this technique may be valuable to guide timely therapeutic decisions, as illustrated by the case in Figure 3-12.

♦ CT angiography has been shown to be safe.²⁷ Renal complications related to contrast administration are exceptional and almost uniformly reversible.

♦ The source images of CT angiography have been used to estimate perfusion deficits (Figure 3-12 serves as example).³⁵ The advantages of this method over dynamic CT perfusion imaging include visualization of the whole brain and use of a single bolus of contrast material.³ However, this application has not been validated, and its sensitivity is likely to be poorer than those of CT perfusion or DWI-PWI.

♦ Evidence of restricted diffusion on DWI constitutes the most sensitive indicator of hyperacute and acute cerebral ischemia, greatly exceeding the sensitivity of CT scan^37,38 and conventional MRI sequences.³⁹

♦ Areas with restricted diffusion due to cellular edema are hyperintense on the DWI sequence and hypointense on the apparent diffusion coefficient (ADC) map (Figure 3-13). The ADC value quantifies diffusion; the lower the value, the greater the restriction of motion of water molecules. Conversely, high ADC values are observed in areas of vasogenic edema and chronic infarction in which water molecules have freedom of motion.

♦ When interpreting the MRI of a patient with acute stroke, it is essential to read the DWI images, ADC map, and T2-weighted sequence in combination. A bright signal on DWI matching with a dark signal on the ADC map will be indicative of restrictive diffusion (i.e., cellular edema consistent with acute ischemia). Bright signals appearing both on DWI and ADC map are caused by the “T2 shine through” phenomenon (Figure 3-14).⁴⁰ Hence isolated review of the DWI sequence may be misleading and should always be avoided.

♦ Decreased diffusion becomes apparent within 30 minutes of stroke onset and the reduction reaches its nadir 2 to 4 days later. ADC values then begin to increase until they return to baseline between 7 and 14 days later (pseudo-normalization) before increasing in the chronic phase.^41,42 After pseudo-normalization of the ADC value, DWI may continue to show a mildly hyperintense signal generated by T2 shine through.

♦ DWI is extremely sensitive for the detection of acute ischemia. In fact, DWI lesions are often seen in patients with reversible neurological deficits classified clinically as transient ischemic attacks (Figure 3-15).^43–46 The sensitivity of DWI only decreases slightly in cases of small medullary infarctions.

♦ Table 3-4 lists the practical values of DWI in the evaluation of acute stroke patients.

♦ A TTP delay greater than 4 seconds relative to the contralateral hemisphere appears to be the best marker of the penumbra.⁴⁸ Nonetheless, this measure may overestimate the size of penumbra in some cases.⁴⁸ CBF maps most closely identify the final infarct volume.^49,50

♦ The ischemic penumbra is represented on MRI by the perfusion-diffusion (PWI-DWI) mismatch (Figures 3-11, 3-16, and 3-17). The PWI lesion corresponds to the area of hypoperfusion and the DWI lesion to the ischemic core.

♦ Unfortunately, there is no validated definition of PWI-DWI mismatch.⁵² Different definitions have been used in published studies, and visual estimates are most commonly used in practice for acute decision making.

♦ In theory, the DWI lesion can expand to reach the size of the initial PWI deficit unless reperfusion occurs. However, confirmation of this hypothesis has proved elusive at times. In fact, some studies have shown that mismatch volume may fail to correlate with DWI lesion expansion.^50,53 Possible explanations for this lack of correlation are that areas of ischemia are highly heterogeneous,⁵⁴ DWI lesions may be reversible (normalization of ADC values has been noted in some patients after thrombolysis),⁵⁵ and PWI lesions actually incorporate regions of true penumbra and regions of reversible oligemia.⁵⁶

♦ Determining whether PWI-DWI mismatch can be reliably used to identify salvageable tissue is of major practical importance. Because DWI expansion can be prevented by early reperfusion regardless of the presence of PWI-DWI mismatch,⁵³ there is no indication for MRI before administering intravenous thrombolysis within 3 hours of symptom onset (there are some data suggesting greater safety for thrombolysis within 3 hours in patients selected with MRI vs. those only evaluated with CT scan,⁵⁷ but not enough solid evidence to change current practice guidelines). However, all other acute revascularization treatments are not the standard of care, and there is considerable interest in developing imaging protocols to guide their application (penumbra-based protocols). MRI protocols have been used in research trials to select candidates for intravenous thrombolysis beyond the currently accepted therapeutic window.^58,59