Brain Imaging in Acute Cerebral Ischemia with Computed Tomography

Rüdiger von Kummer, MD

Department of Neuroradiology, University Hospital Dresden, Germany

Abstract

Computed tomography (CT) including CT perfusion imaging and CT angiography has the capacity to assess stroke pathology on a functional and morphological level and can thus provide important information about patients with acute stroke. It excludes brain hemorrhage, assesses the extent of perfusion deficit, the extent of ischemic damage, and the site and type of arterial obstruction. In patients with transient or mild symptoms, the assessment of vascular pathology and consecutive hemodynamic impairment is most important to guide treatment that will prevent disabling stroke. In patients with completed stroke, the early assessment of ischemic damage is most important. Ischemic brain tissue below the blood flow level of structural integrity takes up water immediately that causes a decrease in x-ray attenuation. Computed tomography has thus the specific advantage to identify the brain tissue that is irreversibly injured. If CT can exclude major ischemic damage in acute stroke patients, reperfusion strategies may rescue brain function even after accepted therapeutic time windows.

Introduction

There is evidence, that computed tomography (CT) can identify patients with acute cerebral ischemia among stroke victims and thus enable effective thrombolytic therapy. 1 It is questionable, however, whether additional information, beside the exclusion of hemorrhage, provided by non-contrast CT, CT angiography (CTA) or CT perfusion imaging (CTP) can really improve patients’ clinical outcome and reduce health care costs.

In theory, CT like magnetic resonance imaging (MRI) can be clinically effective in acute stroke patients on 6 different levels 2 :  1) Brain imaging will reduce health care costs, if it prevents disability and death of stroke victims. 2) Brain imaging will improve the clinical outcome of stroke patients, if it can identify patients who will benefit from an effective treatment, e.g. thrombolysis. To prove the impact on clinical outcome, a randomized trial with 4 arms is required where the responses to treatment is measured in 2 arms in patients identified by certain image criteria and in 2 arms without the application of image criteria. 3) To identify patients who will benefit from a certain treatment, brain imaging must provide relevant information for the choice of treatment being not available from other sources (therapeutic impact). 4) This could be imaging techniques that allow excluding brain hemorrhage and other diseases that mimic ischemic stroke, and allow assessing ischemic edema and perfusion disturbance, mass effect, arterial wall pathology and obstruction. The diagnostic impact of a brain imaging modality is the accuracy and clinical value compared with existing alternatives. 5) The imaging modality should be sensitive and specific for stroke pathology early after symptom onset. 6) This requires that the imaging modality is technically capable to reliably detect the relevant stroke pathology.

The technical capacity of CT is thus the basis for its clinical effectiveness. Technical capacity of CT is its capability to reproducibly display recognizable images that demonstrate a specific pathology with good intra- and inter-observer reliability. 3 Showing that imaging can reliably display stroke pathology, does not mean, however, that imaging is clinically effective on a higher level, e.g. has a therapeutic impact and can help to reduce stroke morbidity. I will review in this article under which conditions the early detection of stroke pathology by CT may be relevant for stroke treatment and patient outcome, and whether CT has the capacity to detect this pathology early.

Detection of Ischemic Stroke Pathology by CT

The stroke syndrome represents the sudden loss of normal brain function by various causes. The causes are focal hypoperfusion in about 85% of the patients, cerebral hemorrhage in 13%, and other conditions in 2% of the patients. Focal cerebral hypoperfusion has different causes as well. Arterial obstruction will diminish cerebral blood flow (CBF) in its territory of blood supply if not compensated by the cerebro-vascular perfusion reserve, increase in perfusion pressure, or collateral blood flow. The larger the arterial territory, the better are the chances for collateral arteries to sufficiently supply the territory with blood. An occlusion of the internal carotid artery (ICA) causes ischemic stroke in only 10% of the patients, whereas the obstruction of the lenticulo-striatal arteries causes immediate basal ganglia infarction in all patients. If the arterial obstruction is not compensated, a sudden decrease in CBF will cause cerebral dysfunction, edema, and finally necrosis depending on the degree and time period of ischemia. 4 Relatively mild degrees of brain ischemia above CBF values of 25 ml per 100g and min remain clinically silent although metabolic changes are already induced. 5 At the CBF threshold of 30 ml per 100g and min, the extracellular fluid space begins to shrink causing impairment of water diffusion. 6, 7 Brain dysfunction is observed in regions with a CBF below 20 ml per 100g and min, and structural integrity is lost in regions with CBF values below 10 ml per 100g and min. 4-6, 8 Under worst conditions, severe ischemia is affecting the entire arterial territory. This type of infarction is, therefore, called “territorial”. 9 In case of partial compensation by collaterals, only patchy areas within the affected territory will become necrotic. Typically, arterial end supply areas are affected in the first place. 10, 11 These ischemic lesions are called “hemodynamic”, because the cerebral perfusion pressure directly determines their extent via the CBF in collateral arteries.

Arterial obstruction may be local or embolic. Sources for brain emboli are diseases of the heart, the aortic arch and brain supplying arteries that causes local thrombosis or allow emboli to cross from the venous into the arterial circulation. Local arterial obstruction is a result of arterial wall pathology, - mainly atherosclerosis, but also inflammation, dissection, and malformation – that causes the activation of coagulation cascades.

Depending on its location and extent, ischemic lesions can be functionally silent or eloquent. Cerebral dysfunction indicates a high risk for a permanent neurological deficit in each patient, but does not specify the risk. Imaging can assess stroke pathology on a functional and morphological level and identify and specify an increased risk for stroke even in asymptomatic patients. 

Functional CT Imaging

Computed tomography cannot identify the brain tissue that is functionally impaired, because brain function is not associated with a change in X-ray attenuation large enough to be detected. After injection of a contrast bolus, however, CT can measure time-density curves in pre-selected brain sections that represent the blood flow determined change of tissue contrast in 1 to 4 brain sections during the first pass of the contrast agent. Quantification of CBF requires either a very rapid contrast infusion into the tissue voxel under observation, if the maximum slope method is applied 12 , or the deconvolution of concentration curves by the function of arterial input into the tissue voxel. 13, 14 Although the theoretical background allows approximations only, with modern computer technology, both methods are quick and allow producing parameter images of CBF, cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) with good reliability and validity. Both methods of dynamic CT provide images with clear differences in the blood flow parameters for gray and white matter (fig. 1). With the single section method, areas of reduced CBF were detected with a sensitivity of 83% 12 , and reactivity tests showed normal and impaired vasomotor reaction. 13 In the affected hemisphere of acute stroke patients, CBF values were reduced and MTT values increased, whereas CBV values were mainly reduced, but also increased in few patients. 14 Hypoattenuating brain tissue had a significantly decreased CBF and CBV of 13.1 ml per 100g and min and 0.9 ml per 100g, respectively. 14 Measurements of the inter-observer reliability found a  coefficient of 0.73, 0.83, and 0.92 for CBV, CBF, and MTT respectively. The mean intra-observer variability for the extent of CBV, CBF, and MTT abnormalities were 10.1%, 8.9%, and 7.6%, respectively. 14 In acute stroke patients, the mean extent of regional MTT abnormalities was significantly greater than the mean extent of regional CBF abnormalities, which were significantly greater than regional CBV abnormalities. 14 Severe perfusion deficits on CBF maps were additionally characterized by marked reduction in CBV and undetectable bolus arrival times. 12

Figure 1 (A)

Figure 1 (B)

Figure 1 (C)

Figure 1 (D)

Figure 1 (E)

Figure 1. Computed tomography in a 51 year-old man 4 hours after the onset of a severe right-sided hemiparesis and global aphasia. Doppler ultrasound is highly suspicious for a dissection of the left internal carotid artery. A) shows a long thrombembolus within the middle cerebral artery (MCA) trunk (arrow). B) The unenhanced CT shows a subtle hypoattenuating left lentiform nucleus (arrowheads). C) Two sections of cerebral blood flow (CBF) CT show hypoperfusion of the entire MCA territory, most pronounced in the left lentiform nucleus (arrow). D) The reduction in CBV is restricted to the left lentiform nucleus (arrow). E) The time-to-peak image shows a more homogenous delay of the contrast peak within the left MCA territory than the perfusion impairment on the CBF image.

The comparison between early perfusion abnormalities and the extent of the final infarct showed that MTT- or TTP-maps have the best sensitivity and CBV-maps the best specificity for brain tissue at risk to be injured by ischemia. 14, 15 Among the 22 acute stroke patients reported by Schramm et al., all 6 patients with normal TTP maps did not develop brain infarcts. These patients had normal CBV- and CBF-maps as well. In contrast, all 16 patients with TTP prolongation (> 4 sec) developed infarcts with the exception of 3 patients who were treated with thrombolysis. There were 2 patients with CBV and CBF abnormalities who did not develop brain infarcts after IV thrombolysis. 15 Based on this experience one may conclude that the high sensitivity of TTP-maps can be used to identify acute stroke patients without perfusion abnormalities who do not need treatment with thrombolytics, if the selected CT section covers the affected brain region. We have no proof so far, that perfusion thresholds detected by dynamic CT can identify an increased risk for thrombolysis associated brain hemorrhage as it was shown for Single Photon Emission CT. 16, 17

Morphological CT Imaging

Vascular Pathology

Besides embolic occlusions, arterial wall pathologies as atherosclerosis, dissection, angiospasms, or inflammation of brain supplying arteries are the main causes for cerebral hypoperfusion and ischemic stroke. The assessment of the type of arterial obstruction will guide secondary prophylaxis like anticoagulation or platelet inhibition and stent-protected angioplasty. The assessment of the site of arterial obstruction helps to estimate the territory of impaired perfusion, the risk of irreversible brain tissue injury, and the chances of reperfusion strategies. 18 In the case series of Schramm et al., all 11 patients with arterial occlusions on CT angiography (CTA) had a perfusion deficit on CTP with the exception of one patient with basilar artery occlusion where the CTP section did not cover the basilar artery territory. These authors, however, observed 3 out of 11 patients without arterial occlusions on CTA, but perfusion deficits and resulting infarcts on CT. 15 From this experience, arterial occlusion on CTA is always associated with perfusion impairment. A normal CTA does not exclude perfusion impairment, however. One may conclude then, that CTP is more important than CTA when considering reperfusion strategies in acute stroke patients.

Non -contrast CT can detect thromboembolic occlusions of major cerebral arteries with high specificity, but low sensitivity. 19 Arterial thrombi may appear as hyperattenuating segments or spots compared to other segments of the same artery. The attenuation of a thrombus depends on its hematocrit. 20 Red thrombi are better visible on CT than white thrombi. The inter-observer agreement on such ”hyperdense artery signs” varied between poor and moderate (k = 0.20 and 0.63). 21-23

Without doubt, the assessment of cervical and cranial artery obstruction is more reliable and accurate with CTA than with unenhanced CT. 24, 25 For CTA, the brain is imaged during the arterial passage of a contrast bolus. The CTA source images provide information about brain-tissue enhancement and may identify regions with low CBV. 26 Cervical and cranial arteries can be reconstructed by various computer programs and segmented from the bones if required. 27 Plaque calcifications are nicely demonstrated (fig. 2).

Figure 2 (A)

Figure 2 (B)

Figure 2. (A) CT angiography (CTA) in a 68 year-old man shows calcifications at the origin of the left internal carotid artery (ICA) with tight stenosis. (B) Contrast enhanced MR angiography obtained 5 days later shows the ICA stenosis like CTA, but not the calcifications.

Brain-Tissue Pathology

Severe acute brain ischemia with CBF values below 10 ml per 100g and min causes immediate net uptake of water in gray matter and consecutively a decrease in X-ray attenuation. 6, 28-33 Under experimental conditions, X-ray attenuation decreased by 1.06 Hounsfield Units (HU) per hour, reflecting a tissue water uptake of 0.62% per hour after occlusion of the middle cerebral artery. 33 Hypoattenuating gray matter loses its contrast to white matter and consequently its anatomical information. Such ischemic edema was, therefore, first characterized as “obscuration of lentiform nucleus” 34 or “loss of the insular ribbon” (fig. 1b). 35 The CBF threshold for this type of ischemic edema is the same as for ischemic tissue damage. Others confirmed that hypoattenuating brain tissue is associated with very low CBF on CTP 14 or on positron emission tomography. 36 The detection of hypoattenuating brain tissue by CT in acute stroke patients has thus a high predictive value and specificity for irreversible tissue injury. 37

Computed tomography cannot reliably detect other ischemic changes that do not influence brain-tissue water content and consequently brain-tissue attenuation.

The enlargement of the cerebral cortex and the effacement of cerebral spinal fluid (CSF) spaces suggest brain tissue swelling. CT may detect brain tissue swelling without hypoattenuation for a short period early after arterial or venous obstruction. Compensatory arterial dilatation due to low perfusion pressure 38 or passive arterial dilatation due to high venous pressure 39 cause this type of swelling. Six neuroradiologists agreed on tissue swelling in 45 CT of acute stroke patients with a k = 0.56 – 0.59. 22 Cytotoxic edema with a shift of extracellular water into the neurons with consecutive cells swelling and decrease in the extracellular fluid space in regions with CBF values of 30 ml per 100g and min and lower is not detected by CT because it does not change tissue attenuation.

In summary, brain-tissue imaging by CT ignores the changes above the CBF threshold of irreversible injury with the exception of the very subtle findings of brain tissue swelling due to other causes than ischemic edema.  Unenhanced CT has a rather low sensitivity for brain ischemia, but a high specificity for irreversible ischemic injury. The advantage of this constellation is that CT can tell us to which extent brain regions are already damaged when the patient presents with symptoms of acute ischemic stroke. One may conclude that mainly patients will benefit from reperfusion therapy who have no or only small volumes of hypoattenuating brain tissue on CT, but severe symptoms or extended perfusion deficits on CTP. Several studies showed that the response to thrombolytic therapy is associated with the extent of hypoattenuation on early CT. 40-42

Brain-tissue CT imaging can easily be combined with CTA and CTP adding only a few minutes of extra examination time to the unenhanced CT. The doses and costs of contrast agent and additional X-ray radiation should be considered, however. One may question, therefore, whether all information that can be provided by CT is necessary in each stroke patient. We will here consider patients with findings or symptoms indicating an increased risk for stroke, patients with basilar artery symptoms, and patients with completed hemispheric stroke.

Pending Ischemic Stroke

Ischemic attacks, a mild central neurological deficit, or the incidental finding of cervical or cerebral arterial stenosis or occlusion is associated with an increased risk of disabling ischemic stroke. 43 In this group of patients, CTP and CTA provide the most important information. A hemodynamic deficit increases the risk for stroke and should be treated by vessel reconstruction as soon as possible. 43 In patients without perfusion impairment, cerebral embolism is more likely. The source of embolism should be identified and treated. Unenhanced CT may provide additional information about a pattern of old ischemic lesions. In summary, in patients with pending ischemic stroke, the information about brain perfusion and cerebral arteries is more important that the information about brain tissue.

Posterior Circulation Ischemia

In patients with progressive dizziness, ataxia, tetraparesis, and impaired consciousness, obstruction of vertebral or basilar arteries should be considered. Because of its high mortality 44 , basilar artery occlusion or tight stenosis should be excluded by CTA in the first place. Thrombolysis may be insufficient if the stenosis is not treated. In this group of patients, CTA provides the most valuable information. Perfusion CT is unnecessary for a decision about thrombolysis, and CT tissue imaging is insensitive to assess the amount of brain-stem damage early.

Major Hemispheric Stroke

In patients with a full hemispheric stroke syndrome, the risk of permanent brain dysfunction and death is immediate and increasing with time. 1 The chances of brain functions to recover are associated with the amount of brain-tissue that can be rescued from ischemic damage. In this group of patients, brain-tissue imaging with CT provides the most valuable information because it detects the volume of brain-tissue that is lost for reperfusion strategies. Patients with normal CT or only small amounts of hypoattenuating brain tissue (ischemic edema) may benefit most from reperfusion, whereas patients with an extended volume of ischemic edema may further deteriorate with reperfusion 33, 40-42 . Because stroke severity already indicates the extent of brain perfusion disturbance, it is questionable whether CTP adds any important information. CTA could be useful to decide about the type of reperfusion strategy.

References

1.             The ATLANTIS E, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: Pooled analysis of atlantis, ecass, and ninds rt-pa stroke trials. Lancet. 2004;363:768-774

2.             Fryback D, Thornbury J. The efficacy of diagnostic imaging. Med Decis Making. 1991:88-94

3.             Powers W. Testing a test. A report card for dwi in acute stroke. Neurology. 2000;54:1549-1551

4.             Jones T, Morawetz R, Crowell R, Marcoux F, FitzGibbon S, DeGirolami R, Ojemann R. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54:773-782

5.             Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36:557-565

6.             Schuier FJ, Hossmann KA. Experimental brain infarcts in cats. Ii. Ischemic brain edema. Stroke. 1980;11:593-601

7.             Wang Y, Hu W, Perez-Trepichio A, Ng T, Furlan A, Majors A, Jones S. Brain tissue sodium is a ticking clock telling time after arterial occlusion in rat focal cerebral ischemia. Stroke. 2000;31:1386-1392

8.             Heiss W, Rosner G. Fuctional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol. 1983;14:294-301

9.             Ringelstein E, Zeumer H, Schneider R. Der beitrag der zerebralen computertomographie zur differentialtypologie und differentialtherapie des ischämischen großhirninfarkts. Fortschr Neurol Psychiat. 1985;53:315-336

10.           Ringelstein E, Biniek R, Weiller C, Ammeling B, Nolte P, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology. 1992;42:289-298

11.           Zülch KJ. Cerebrovascular pathology and pathogenesis as a basis of neuroradiological diagnosis. In: Diethelm L, Heuck F, Olsson O, Strnad F, Vieten H, Zuppinger A, eds. Encyclopedia of Medical Radiology. Berlin, Heidelberg, New York: Springer; 1981:1-192.

12.           Koenig M, Klotz E, Luka B, Venderink D, Spittler J, Heuser L. Perfusion ct of the brain: Diagnostic approach for early detection of ischemic stroke. Radiology. 1998;209:85-93

13.           Nabavi D, Cenic A, Craen R, Gelb A, Bennett J, Kozak R, Lee T. Ct assessment of cerebral perfusion: Experimental and initial clinical experience. Radiology. 1999;213:141-149

14.           Eastwood J, Lev M, Azhari T, Lee T, Barboriak D, Delong D, Fitzek C, et al. Ct perfusion scanning with deconvolution analysis: Pilot study in patients with acute middle cerebral artery stroke. Radiology. 2002;222:227-236

15.           Schramm P, Schellinger P, Klotz E, Kallenberg K, Fiebach J, Külkens S, Heiland S, et al. Comparison of perfusion ct and cta source images with pwi and dwi in patients with acute stroke < 6 h. Stroke. 2004;35:1562-1568

16.           Ueda T, Hatakeyama T, Kumon Y, Sakaki S, Uraoka T. Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis in acute ischemic stroke by initial spect. Stroke. 1994;25:298 - 303

17.           Ueda T, Sakaki A, Yuh W, Nochide I, Ohta S. Outcome in acute stroke with successful intra-arterial thrombolysis and predictive value of initial single-photon-emission-computed tomography. J Cereb Blood Flow Metab. 1999;19:99-108

18.           Wildermuth S, Knauth M, Brandt T, Winter R, Sartor K, Hacke W. Role of ct angiography in patient selection for thrombolytic therapy in acute hemispheric stroke. Stroke. 1998;29:935-938

19.           von Kummer R, Meyding-Lamadé U, Forsting M, Rosin L, Rieke K, Hacke W, Sartor K. Sensitivity and prognostic value of early computed tomography in middle cerebral artery trunk occlusion. AJNR Am J Neuroradiol. 1994;15:9-15

20.           Kirchhof K, Welzel T, Mecke C, Zoubaa S, Sartor K. Differentiation of white, mixed, and red thrombi: Value of ct in estimation of the prognosis of thrombolysis-phantom study. Radiology. 2003;228:126-130

21.           Tomsick T, Brott T, Chambers A, Fox A, Gaskill M, Lukin R, Pleatman C, et al. Hyperdense middle artery sign on ct: Efficacy in detecting middle cerebral artery thrombosis. AJNR Am J Neuroradiol. 1990;11:473-477

22.           von Kummer R, Holle R, Grzyska U, Hofmann E, Jansen O, Petersen D, Schumacher M, et al. Interobserver agreement in assessing early ct signs of middle cerebral artery infarction. AJNR Am J Neuroradiol. 1996;17:1743-1748

23.           Marks M, Holmgren E, Fox A, Patel S, von Kummer R, Froehlich J. Evaluation of early computed tomographic findings in acute ischemic stroke. Stroke. 1999;30:389-392

24.           Knauth M, Jansen O, von Kummer R, Wildermuth S, Forsting M, Sartor K. Sensitivität, interrater-reliabilität und prognostischer wert der ct-angiographie in der diagnostik akuter intrakranieller gefäßverschlüsse. RöFo. 1996;164:S 21

25.           Knauth M, von Kummer R, Jansen O, Hähnel S, Dörfler A, Sartor K. Potential of ct angiography in acute ischemic stroke. AJNR Am J Neuroradiol. 1997;18:1001-1010

26.           Schramm P, Schellinger P, Fiebach J, Heiland S, Jansen O, Knauth M, Hacke W, et al. Comparison of ct and ct angiography source images with diffusion-weighted imaging in patients with acute stroke within 6 hours after onset. Stroke. 2002;33:2426-2432

27.           Tomandl B, Kostner N, Schempershofe M, Huk W, Strauss C, Anker L, Hastreiter P. Ct angiography of intracranial aneurysms: A focus on postprocessing. Radiographics. 2004;24:637

28.           Hossmann KA, Schuier FJ. Experimental brain infarcts in cats. I. Pathophysiological observations. Stroke. 1980;11:583-592

29.           Watanabe, West C, Bremer A. Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 2: Effects on brain water and electrolytes in the early phase of mca stroke. Stroke. 1977;8:71-76

30.           Gotoh O, Asano T, Koide T, Takakura K. Ischemic brain edema following occlusion of the middle cerebral artery in the rat. I: The time courses of the brain water, sodium, and potassium contents and blood-brain-barrier permeability to 125i-albumin. Stroke. 1985;16:101-109

31.           Todd N, Picozzi P, Crockard A, Ross Russel R. Duration of ischemia influences the development and resolution of ischemic brain edema. Stroke. 1986;17:466-471

32.           Todd N, Picozzi P, Crockard A, Ross Russel R. Reperfusion after cerebral ischemia: Influence of duration of ischemia. Stroke. 1986;17:460-465

33.           Dzialowski I, Weber J, Doerfler A, Forsting M, von Kummer R. Brain tissue water uptake after middle cerebral artery occlusion assessed with ct. J Neuroimaging. 2004;14:42-48

34.           Tomura N, Uemura K, Inugami A, Fujita H, Higano S, Shishido F. Early ct finding in cerebral infarction. Radiology. 1988;168:463-467

35.           Truwit C, Barkovich A, Gean-Marton A, Hibri N, Norman D. Loss of the insular ribbon: Another early ct sign of acute middle cerebral artery infarction. Radiology. 1990;176:801 - 806

36.           Grond M, von Kummer R, Sobesky J, Schmülling S, Heiss W-D. Early computed-tomography abnormalities in acute stroke. Lancet. 1997;350:1595-1596

37.           von Kummer R, Bourquain H, Bastianello S, Bozzao L, Manelfe C, Meier D, Hacke W. Early prediction of irreversible brain damage after ischemic stroke by computed tomography. Radiology. 2001;219:95-100

38.           Gibbs J, Wise R, Leenders K, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet. 1984;8372:310-314

39.           Yuh W, Simonson T, Wang A, Koci T, Tali E, Fisher D, Simon J, et al. Venous sinus occlusive disease: Mr findings. AJNR Am J Neuroradiol. 1994;15:309-316

40.           von Kummer R, Allen K, Holle R, Bozzao L, Bastianello S, Manelfe C, Bluhmki E, et al. Acute stroke: Usefulness of early ct findings before thrombolytic therapy. Radiology. 1997;205:327-333

41.           Barber P, Demchuk A, Zhang J, Buchan A. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet. 2000;355:1670-1674

42.           Hill M, Rowley H, Adler F, Eliasziew M, Furlan A, Higashida R, Wechsler L, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using aspects. Stroke. 2003;34:1925-1931

43.           Blaser T, Hofmann K, Buerger T, Effenberger O, Wallesch C, Goertler M. Risk of stroke, transient ischemic attack, and vessel occlusion before endarteriectomy in patients with symptomatic severe carotid stenosis. Stroke. 2002;33:1057-1062

44.           Brandt T, von Kummer R, Müller-Küppers M, Hacke W. Thrombolytic therapy of acute basilar occlusion: Variables affecting recanalization and outcome. Stroke. 1996;27:875-881