Neurol Sci DOI 10.1007/s10072-015-2244-8
ORIGINAL ARTICLE
CT perfusion cerebral blood volume does not always predict infarct core in acute ischemic stroke Christopher D. d’Esterre1,2 • Gloria Roversi3 • Marina Padroni3 • Andrea Bernardoni4 Carmine Tamborino3 • Alessandro De Vito5 • Cristiano Azzini5 • Onofrio Marcello6 • Andrea Saletti6 • Stefano Ceruti6 • Ting Yim Lee1,2,7 • Enrico Fainardi6
•
Received: 21 March 2015 / Accepted: 8 May 2015 Ó Springer-Verlag Italia 2015
Abstract We investigated the practical clinical utility of the CT perfusion (CTP) cerebral blood volume (CBV) parameter for differentiating salvageable from non-salvageable tissue in acute ischemic stroke (AIS). Fifty-five patients with AIS were imaged within 6 h from onset using CTP. Admission CBV defect (CBVD) volume was outlined using previously established gray and white matter CBV thresholds for infarct core. Admission cerebral blood flow (CBF) hypoperfusion and CBF/CBV mismatch were visually evaluated. Truncation of the ischemic time–density Electronic supplementary material The online version of this article (doi:10.1007/s10072-015-2244-8) contains supplementary material, which is available to authorized users. & Enrico Fainardi [email protected] 1
Calgary Stroke Program, University of Calgary, Calgary, AB, Canada
2
Imaging Program, Lawson Health Research Institute, London, ON, Canada
3
Section of Neurology, Department of Biological, Psychiatric and Psychological Science, University of Ferrara, Ferrara, Italy
4
Section of Diagnostic Imaging, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
5
Neurology Unit, Department of Neuroscience and Rehabilitation, Azienda Ospedaliera Universitaria, Ferrara, Italy
6
Unita` Operativa di Neuroradiologia, Dipartimento di Neuroscienze, Azienda Ospedaliera Universitaria, Arcispedale S. Anna, Via Aldo Moro 8, 44124 Cona, Ferrara, Italy
7
Imaging Research Lab, Robarts Research Institute, London, ON, Canada
curve (ITDC) and hypervolemia status at admission, recanalization at 24-h CT angiography, hemorrhagic transformation (HT) at 24 h and/or 7-day non-contrast CT (NCCT), final infarct volume as indicated by 3-month NCCT defect (NCCTD) and 3-month modified Rankin Score were determined. Patients with recanalization and no truncation had the highest correlation (R = 0.81) and regression slope (0.80) between CBVD and NCCTD. Regression slopes were close to zero for patients with admission hypervolemia with/without recanalization. Hypervolemia underestimated (p = 0.02), while recanalization and ITDC truncation overestimated (p = 0.03) the NCCTD. Among patients with confirmed recanalization at 24 h, 38 % patients had an admission CBF/CBV mismatch within normal appearing areas on respective NCCT. 83 % of these patients developed infarction in admission hypervolemic CBF/CBV mismatch tissue. A reduction in CBV is a valuable predictor of infarct core when the acquisition of ITDC data is complete and hypervolemia is absent within the tissue destined to infarct. Raised or normal CBV is not always indicative of salvageable tissue, contrary to the current definition of penumbra. Keywords CT perfusion Cerebral blood volume Infarct core Penumbra Hypervolemia
Introduction Thromboembolic cerebral ischemia makes up 87 % of all stroke sub-types [1]. Early restoration of blood flow using thrombolytic therapy is the most effective way to reverse stroke symptoms, improving clinical outcome [2]. The intravenous tPA therapeutic window is 4.5 h post-stroke onset [3]. This time constraint limits its use in less than 7 % of
123
Neurol Sci
acute ischemic stroke (AIS) patients as the risk of hemorrhagic transformation (HT) outweighs the clinical benefit beyond the treatment window [4]. A patient-specific approach, based on tissue viability at the time of onset, is expected to relax the rigid temporal criterion for deciding if thrombolytic therapy is appropriate. With the use of the Alberta Stroke Program Early CT Score (ASPECTS), the non-contrast CT (NCCT) scan remains the recommended imaging modality for the selection of patients who may not be harmed from reperfusion. Nonetheless, ASPECTS provides only subtle indications of early ischemic changes (EIC) along with broad inter-subject variability, cannot differentiate between penumbra and benign oligemia, or the overall volume of severe hypoperfusion [5–7]. Consequently, there have been many attempts to standardize perfusion parameters to determine tissue viability in the acute stroke setting [8–14]. Changes in cerebral blood volume (CBV) are used to discriminate viable (penumbra) and non-viable (infarction) tissue states, the former characterized by an acute increase/preservation and the latter by a drastic reduction as a result of failed cerebrovascular autoregulation. Thus, according to this so-called ‘‘penumbral hypothesis’’, infarct core is the tissue with reduced CBF and CBV (CBF/CBV match) and the penumbra is the tissue with low CBF and high CBV (CBF/CBV mismatch) [15, 16]. Recently, several studies have suggested that CBV is unreliable in the accurate delineation of the acute infarct core since cerebral blood flow (CBF) better approximates the DWI-defined infarct core than CBV and mean transit time (MTT) [10, 13, 17]. However, the first two studies used shortened CT perfusion (CTP) acquisition times, which may miss the complete wash-out phase of ischemic tissue resulting in underestimation of CBV and MTT [10, 13]. Further, acute DWI lesions may not be truly representative of non-viable tissue, as partial/full reversal can occur [18]. Hypervolemia, indicating high CBV, is considered protective, but may mask impending infarction during the first few hours of onset [15, 17]. This response has not been investigated with respect to radiological and clinical outcomes. Herein, we sought to determine the role of hypervolemia, defined using the CBV parameter, on penumbra/infract delineation in the acute stroke setting.
(between February 2009 and July 2011). Patients were included if they had an admission CBF defect, presented at the hospital \6 h post-symptom onset, had no previous stroke and showed signs and symptoms consistent with occlusion of the anterior circulation, had a CT angiography (CTA) at baseline and at 24 h for recanalization status. Exclusion criteria were: evidence of brain stem infarct, prior stroke with residual deficit, intracranial hemorrhage, clinically significant hyperglycemia, impaired renal function and/or known allergy to contrast media; pregnancy, and age less than 18 years. Of the 64 patients enrolled, 55 contributed data for this study, while 9 were excluded because onset National Institutes of Health Stroke Scale (NIHSS) score B5. Results of the CTP studies performed at admission did not influence treatment decisions (patients and legal representatives providing informed consent were aware of this). Patients were enrolled regardless of therapy. An experienced neurologist (G.R.) assessed clinical outcome for all patients using the NIHSS at admission, 24 h and 7 days, as well as the modified Rankin scale (mRS) 3 months post-stroke onset. Imaging protocol
Methods
Patients underwent NCCT, CTA and CTP at admission, NCCT and CTA at 24 h and NCCT at 7 days and 3 months post-stroke. All imaging was conducted on a 64-slice Lightspeed VCT scanner (GE Healthcare, Waukesha, WI, USA). NCCT helical scans were performed from the skull base to the vertex using the following imaging parameters: 120 kV, 340 mA, 4 9 5 mm collimation, 1 s/rotation, and table speed of 15 mm/rotation. CTA was performed as follows: 0.7 mL/kg contrast (maximum 90 mL), 5- to 10-s delay from injection to scanning, 120 kV, 270 mA, 1 s/ rotation, 1.25-mm-thick slices, and table speed 3.75 mm/ rotation. CTA covered from the carotid bifurcation to vertex. The CTP scanning protocol consisted of a continuous 50 s scan using 80 kV, 100 mA and 1 s rotation time while the couch remained stationary. Seven-hundred ninety-two 512 9 512 images were reconstructed with a 25-cm field of view at 0.5-s intervals for each of the eight 5-mm-thick slice locations. Five seconds before the start of scanning, 40 mL bolus of iodinated contrast agent (Iomeron 300 mg/mL, Bracco Imaging SpA, Milan, Italy) was injected at a rate of 4 mL/s into an antecubital vein with an automatic injector (Medrad, Indianola, PA).
Patient selection
CTP functional maps
The study was approved by the Research Ethics Board of Azienda Ospedaliero-Universitaria di Ferrara (Italy). Written informed consent was obtained from each patient. Sixty-four patients, admitted at Ferrara Hospital were enrolled from 191 consecutively screened AIS patients over a 2-year period
For consistency, each CTP imaging study was analyzed by one author (C.D.d.) using a commercially available delayinsensitive deconvolution software (CT Perfusion 4D, GE Healthcare, Waukesha, WI). For each CTP scan, time– density curves (TDC) for the arterial input function (AIF)
123
Neurol Sci
and venous output functions (VOF) were obtained from the anterior cerebral artery and superior sagittal sinus, respectively (See Supplementary material for details). The AIF was corrected for partial volume averaging using the VOF-TDC. Functional maps of CBF [mL min-1 (100 g)-1] and CBV [mL (100 g)-1] were calculated by deconvolution of tissue TDCs and the AIF. The use of delay-insensitive deconvolution algorithm ensures that the calculated CBF is independent of the difference (delay) between contrast arrival times of tissue TDC and AIF [19]. Perfusion-weighted maps were created by averaging the cine CTP images over the duration of the first pass of contrast. A functional map, defined as the ratio of the increase in Hounsfield Unit (HU) above baseline at the end of the CTP acquisition relative to that of the peak HU, was also created representing the percentage of TDC truncation (incomplete imaging of the contrast wash-out phase) for each tissue voxel. CTP, CTA, and NCCT image analysis One author (C.D.d.) analyzed all CTP maps using custom software (IDL, version 6.2, RSI, Boulder, Colorado). Perfusion-weighted maps were used to exclude cerebrospinal fluid (CSF) and cranium from analysis as well as to produce a gray and white matter anatomical mask based on HU thresholds. All CTP maps and NCCT scans were co-registered. The admission CBV defect (CBVD) was manually outlined on all CBV maps using previously established gray and white matter CBV thresholds for infarct core [1.1 and 0.75 mL (100 g)-1 for gray and white matter, respectively], derived within the author’s (T.Y.L.) lab [20]. Two neuroradiologists (E.F. and A.S.) traced freehand a region of interest (ROI) around the hypodense area in each slice of the 3-month NCCT, obtaining the NCCT defect (NCCTD). All CBVD and NCCTD areas from each involved slice were multiplied by the section thickness and summed to calculate the CBVD and the final infarct volumes in cubic centimeters. Admission CBF hypoperfusion and CBF/CBV mismatch (CBF hypoperfused area minus the CBVD) were visually assessed. In some admission CTP studies, the 50-s acquisition led to truncation of ischemic tissue time–density curves (ITDC) before the washout phase was completed underestimating the area under the ITDC. Therefore, patients were divided into ITDC positive and negative sets, based on the average (values from both gray and white matter tissue) ITDC truncation at admission. An average ITDC truncation value of 50 % or greater was deemed truncation positive. Admission hypervolemia was defined as having CBV within the superimposed final infarct ROI, greater than the average plus one standard deviation of the CBV values in the contralateral mirrored ROI. Hypervolemia status was classified as hypervolemia positive and unknown as CTP imaging represents only a snapshot in time.
Recanalization was classified using CTA at 24 h by an experienced neuroradiologist (E.F.) based on an adaptation of the thrombolysis in myocardial infarction (TIMI) criteria [21]. Complete occlusion was characterized by the absence or minimal penetration of CT contrast distal to the thrombus (TIMI score = 0–1), while full recanalization was characterized by no visible narrowing of the involved vessel seen at baseline CTA (TIMI score = 3). Partial recanalization was defined as narrowing of the vessel at the site of occlusion with contrast distal to the thrombus (TIMI score = 2). Patients with TIMI score of 2 and 3 were considered as recanalization positive, whereas patients with TIMI score of 0 and 1 were classified as recanalization negative. The 24 h and/or 7 day post-NCCT was used to categorize HT, if present, as hemorrhagic infarction (HI-1,2) or parenchymal hematoma (PH-1,2) according to the European Cooperative Acute Stroke Study II criteria [22]. Symptomatic intracerebral hemorrhage (sICH) was identified as PH1 or PH2 with worsening of neurological deficit C4 points on the NIHSS within 24 h. Statistics Statistical analysis was performed with SPSS, version 16 for Windows; SPSS, Chicago, IL, USA. All data sets were checked for normality with the Shapiro–Wilk test prior to analysis with the appropriate parametric or non-parametric tests. As all variables were normally distributed, parametric statistical analysis was performed. The agreement between CBVD and NCCTD was assessed with Bland–Altman analysis for recanalization positive and negative groups and sub-groups based on ITDC truncation and hypervolemia status at admission [23]. Pearson correlation coefficient and slope of the regression line between CBVD and NCCTD were calculated for all groups and sub-groups. The ability of acute CBVD volume to predict final infarct volume and the effect of age, initial NIHSS, time to treatment, hypertension, and diabetes mellitus on this predictive ability were examined using univariate and stepwise selection multivariate logistic regression, respectively, in all patients and sub-groups based on over- or underestimation of the final infarct volume with CBVD. Categorical variables were compared by means of Fisher’s exact test. For all variables, the mean and standard deviation were listed. Significant differences were defined as p \ 0.05.
Results Clinical and radiological data Patient demographic, clinical and radiological findings are shown in Table 1. Locations of occlusions were as follows:
123
Neurol Sci Table 1 Demographic, clinical and radiological findings in 55 acute ischemic stroke patients assessed within 6 h after symptom onset Sex: female/male
32/23
Age, years: mean ± SD
67.3 ± 11.3
NIHSS at entry: median, IQR, mean ± SD, range
11, 7–15, 11.5 ± 5.9, 2–25
NIHSS at 24 h: median, IQR, mean ± SD, range
7, 3–13, 8.6 ± 6.2, 0–22
NIHSS at 7 days: median, IQR, mean ± SD, range
4, 2–9, 6.1 ± 6.2, 0–22
mRS at 3 months: median, IQR, mean ± SD, range
1, 1–2, 1.7 ± 1.2, 0–5
Time between symptom onset and CT scan at admission (hours): median, IQR, mean ± SD, range
2, 1.3–4.1, 2.6 ± 1.6, 0.4–6.0
Time to ictus: n/total (%) \3 h
36/55 (65.5 %)
3–6 h
19/55 (34.6 %)
Treatment: n/total (%) None
20/55 (36.4 %)
i.v. rtPA
34/55 (61.8 %)
Combined i.v. and i.a. rtPA
1/55 (1.8 %)
Recanalization on CTA at 24 h: yes/no Time between symptom onset and CT scan at 24 h (hours): median, IQR, mean ± SD, range
32/23 19.5, 18.4–21.2, 19.7 ± 2.0, 15.2–23
Time between CT scan at admission and at 24 h (hours): median, IQR, mean ± SD, range
23.1, 22.2–23.5, 22.3 ± 1.8, 4.0–8.0
Time between symptom onset and CT scan at 7 days (days): median, IQR, mean ± SD, range
8.0, 6.0–7.0, 6.2 ± 0.9, 4.0–24.2
Time between symptom onset and CT scan at 3 months (days): median, IQR, mean ± SD, range
89.0, 87.0–90.0, 88.1 ± 2.0, 84.0–90.0
Hemorrhagic transformation: n/total (%) None
34/55 (61.8 %)
HI-1
10/55 (18.1 %)
HI-2
3/55 (5.5 %)
PH-1
5/55 (9.1 %)
PH-2
3/55 (5.5 %)
CBVD volume (mL) at entry: median, IQR, mean ± SD, range
27.0, 41.0–106.3, 65.5 ± 75.7, 0.0–345.8
CBVD absolute values [mL(100 g)-1] at entry: median, IQR, mean ± SD, range
1.2, 0.8–1.4, 1.1 ± 0.4, 0.0–1.6
Final infarct volume (mL) on NCCTD at 3 months: median, IQR, mean ± SD, range
13.6, 4.8–105.7, 68.4 ± 103.6, 0.0–458.2
SD standard deviation, NIHSS National Institutes of Health Stroke Scale, IQR interquartile range, mRS modified Rankin Scale, tPA tissue plasminogen activator, i.v. intravenous, i.a. intra-arterial, CTA CT angiography, HI hemorrhagic infarction, PH parenchymal hematoma, CBVD admission CBV defect, NCCTD non-contrast CT defect
27 M1 only occlusions, 6 proximal ICA ? M1 occlusions, 22 M2 only occlusions. At admission, the ITDC of 24 (43.6 %) and 31 (56.4 %) patients were truncation positive and negative, whereas 25 (45.5 %) and 30 (55.5 %) patients were hypervolemia positive and unknown, respectively. At 24 h post, 32 (58.2 %) and 23 (41.8 %) patients were recanalization positive and negative, respectively. Table 2 shows that in the recanalization positive group 15/32 (46.9 %) patients had ITDC truncation while 15/32 (46.9 %) patients had hypervolemia and in the recanalization negative group these numbers were 9/23 (39.1 %) and 10/23 (43.5 %), respectively. CBV predictive value for infarct core and penumbra in AIS patients grouped according to recanalization/ truncation status As illustrated in Table 2, the association between CBVD and NCCTD was the strongest in the recanalization
123
positive ? truncation negative patients (R = 0.81). The 95 % limits of agreement between CBVD and NCCTD were wider for the recanalization negative group and its sub-groups compared to the recanalization positive group and its sub-groups. The regression line slopes for both hypervolemia positive sub-groups were negative and close to unity (-0.04 and -0.13, respectively). Univariate logistic regression analysis revealed that acute hypervolemia (odds ratio, 0.47; 95 % CI, 0.09–0.367; p = 0.02) was significantly associated with underestimation of the final infarct volume, while recanalization (odds ratio, 0.80, 95 % CI 0.11–3.8, p = 0.03) and truncation (odds ratio, 0.92, 95 % CI 0.010–0.045, p = 0.03) were significantly associated with overestimation of the final infarct volume. Among patients with confirmed recanalization, a matched decrease in CBF and CBV at onset within areas of slightly hypodensity on corresponding NCCT was observed in 20/32 (62 %) of them. All these patients developed infarction in the same region in the 3 months post-
Neurol Sci Table 2 Bland–Altman and linear regression results for the admission cerebral blood volume (CBV) defect volume versus the final infarct volume at 3 months 95 % Limits of agreement (mean difference ± 2*SD)
Pearson correlation coefficient, R (p value)
Slope of regression line
Recanalization positive (n = 32)
[-48.3, 29.1]
0.78 (0.08)
0.64
Truncation negative (n = 17)
[-8.4, 16.0]
0.81 (0.19)
0.80
Truncation positive (n = 15) Onset hypervolemia unknown (n = 17)
[-40.5, 30.3] [-51.9, 38.2]
0.61 (0.11) 0.80 (0.04)
0.46 0.57 -0.04
Onset hypervolemia positive (n = 15)
[-37.6, 16.1]
0.22 (0.79)
Recanalization Negative (n = 23)
[-86.2, 51.1]
0.57 (0.33)
0.42
Truncation negative (n = 14)
[-85.9, 68.3]
0.15 (0.74)
0.14
Truncation positive (n = 9)
[-69.9, 36.9]
0.71 (0.04)
0.62
Onset hypervolemia unknown (n = 13)
[-96.9, 61.3]
0.68 (0.10)
0.37
Onset hypervolemia positive (n = 10)
[-56.9, 19.2]
0.39 (0.22)
-0.13
NCCT. The remaining 38 % (12/32) patients who recanalized at 24 h had an admission CBF/CBV mismatch within areas of little or no early ischemic change on respective NCCT images. 83 % (10/12) of these patients developed infarction at 3 months in admission hypervolemic CBF/CBV mismatch tissue. No association was found between patients with and without admission CBF/ CBV mismatch and mRS (data not shown). Two illustrative cases describing these two different conditions are reported in Supplementary Figure 1. No relationship was observed between patients with and without admission hypervolemia and mRS (data not shown).
Discussion We investigated the CBV predictive value for infarct/ penumbra in patients with acute ischemic stroke. In this setting, a 3-month NCCT was used to define the final infarct volume to allow for edema reduction and infarct maturation. CBV is considered to be an important parameter to distinguish viable from non-viable tissue within hours after stroke onset since a matched reduction of CBF and CBV has been shown to identify infarction, whereas a mismatch between decreased CBF and increased CBV is suggested to be a hallmark of penumbra [24]. However, there remains a lack of standardization for CBV thresholds to define tissue viability [25], and with its poor correlation with the acute DWI hyperintensity [12, 13, 17, 26], the reliability of CBV defined infarct is increasingly being questioned. Three variables are identified which affect the CBV parameter: (1) ITDC truncation, (2) hypervolemia, and (3) recanalization status. Recanalization and ITDC truncation limit the ability of admission CBVD to identify the infarct core consistently. In fact, the best correlation
between CBVD and the final infarct volume occurs in patients who recanalized and were truncation negative at admission. This makes intuitive sense, as recanalization limits expansion of infarct after admission such that CBVD volume approximates that of the final infarct core at delayed imaging. ITDC truncation also has different effects on recanalization positive versus negative groups. In patients who did not recanalize and had truncation of the ITDC, the acute CBVD volume matched the final infarct volume because truncation at admission artifactually lowered CBV, overestimating the predicted infarct core. This could lead to an inaccurate estimate of the CBV threshold for infarction in retrospective threshold derivation studies. Conversely, in patients with fast CT to recanalization times, the overestimation of the infarct core at admission from truncation of the ITDC could lead to the paradoxical reversal of infarct defined with CBV threshold [20]. The underestimation of admission CBVD volume due to hypervolemia has not been previously described. A hypervolemic response indicative of good collaterals within a hypoperfused area during the acute phase may occur in penumbral tissue [27]. This hypervolemic response can occur due to: compensatory vasodilatation due to the opening of collaterals, reperfusion due to arterial reopening, embolic migration, therapeutic dissolution, and/or release of vasolidatory and inflammatory mediators [15]. Irrespective of recanalization, CBVD volume had the poorest correlation with final infarct volume in patients with admission hypervolemia. This result invalidates the ‘‘penumbral hypothesis’’ for discriminating between tissue that recovers and tissue that infarcts with early recanalization. Supplementary Figure 1 shows a patient with a CBF/CBV mismatch at admission with little evidence of early ischemic change on the corresponding NCCT. Even with confirmed recanalization/reperfusion from CTP, portions of the supposedly viable hypervolemic tissue at
123
Neurol Sci
admission still progressed to infarction. Hypervolemia can mask non-viable tissue and therefore be potentially malignant, non-nutritional, providing a blood flow in excess of metabolic demand [28]. This study is not without its limitations. First, use of the 3-month NCCT to determine final infarction volume could be affected by infarct shrinkage and secondary vascular injury, potentially causing under- and overestimation of admission infarct volume, respectively. Second, only a 2-cm slab of tissue was imaged during the CTP acquisition, which could have missed part of the infarct volume and hypervolemia outside of the scanned volume. Third, recanalization was defined using CTA at 24-h post instead of contemporaneous of the admission CTP study. Fourth, our sample size is relatively small compared to other AIS studies. In summary, in this study, we showed that the reliability of the admission CBV defect to define infarct is overestimated with recanalization and ITDC truncation, and underestimated with hypervolemia, whereas the risk of HT is associated with both low CBV values and hypervolemia. From a practical clinical standpoint, reduced CBV values, or a matched decrease in CBF/CBV, is a valuable predictor of infarct core when the acquisition of ITDC data is complete and hypervolemia is absent within the tissue destined to infarct. In retrospective studies, to determine an optimum admission CBV threshold for defining infarcts from delayed CT or MR scans, patients should be dichotomized into recanalization positive and negative groups in the intervening period due to potential differences in infarct expansion. Acknowledgments This work has been supported by Italian National Health System- Research Program entitled ‘‘Nuove conoscenze e problematiche assistenziali nell’ictus cerebrale: un Programma Strategico di Ricerca e Sviluppo’’ ex art. 12-12bis/D.Lgs n. 502/92, PG/2007/0293184. The authors would also like to thank the Canadian Stroke Network and European Stroke Network, Canadian Institutes of Health Research, Ontario Research Fund and GE Healthcare for partial support of this study. Conflict of interest Ting-Yim Lee licenses CT Perfusion software to and receives funding from GE Healthcare.
References 1. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623 2. Wahlgren N, Ahmed N, Da´valos A, Hacke W, Milla´n M, Muir K, Roine RO, Toni D, Lees KR, SITS investigators (2008) Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITSISTR): an observational study. Lancet 372:1303–1309 3. Hacke W, Kaste M, Bluhmki E, Brozman M, Da´valos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, Investigators ECASS (2008)
123
4.
5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317–1329 Schumacher HC, Bateman BT, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, Pile-Spellman J (2007) Use of thrombolysis in acute ischemic stroke: analysis of the nationwide inpatient sample 1999 to 2004. Ann Emerg Med 50:99–107 Bivard A, Parsons M (2012) ASPECTaSaurus (a dinosaur)? Int J Stroke 7:564 Wardlaw J, Dorman P, Lewis S, Sandercock PA (1999) Can stroke physicians and neuroradiologists identify signs of early cerebral infarction on CT? J Neurol Neurosurg Psychiatry 67:651–653 Puetz V, Dzialowski I, Hill MD, Demchuk AM (2009) The Alberta Stroke Program Early CT Score in clinical practice: what have we learned? Int J Stroke 4:354–364 Turk AS, Nyberg EM, Chaudry MI, Turner RD, Magarik JA, Nicholas JS, Holmstedt CA, Chalela JA, Hays A, Lazaridis C, Chimowitz MI, Turan TN, Adams RJ, Jauch EC (2013) Utilization of CT perfusion patient selection for mechanical thrombectomy irrespective of time: a comparison of functional outcomes and complications. J Neurointerv Surg 5:518–522 Turk A, Magarik JA, Chaudry I, Turner RD, Nicholas J, Holmstedt CA, Chalela J, Hays A, Lazaridis C, Jauch E, Chimowitz M, Turan T, Adams R (2012) CT perfusion-guided patient selection for endovascular treatment of acute ischemic stroke is safe and effective. J Neurointerv Surg 4:261–265 Kamalian S, Kamalian S, Konstas AA, Maas MB, Payabvash S, Pomerantz SR, Schaefer PW, Furie KL, Gonza´lez RG, Lev MH (2012) CT perfusion mean transit time maps optimally distinguish benign oligemia from true ‘‘at-risk’’ ischemic penumbra, but thresholds vary by postprocessing technique. Am J Neuroradiol 33:545–549 Garcı´a-Bermejo P, Calleja AI, Pe´rez-Ferna´ndez S, Cortijo E, del Monte JM, Garcı´a-Porrero M, Fe Mun˜oz M, Ferna´ndez-Herranz R, Arenillas JF (2012) Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours: a case-control study. Cerebrovasc Dis 34:31–37 Kamalian S, Kamalian S, Maas MB, Goldmacher GV, Payabvash S, Akbar A, Schaefer PW, Furie KL, Gonzalez RG, Lev MH (2011) CT cerebral blood flow maps optimally correlate with admission diffusion-weighted imaging in acute stroke but thresholds vary by postprocessing platform. Stroke 42:1923–1928 Campbell BC, Christensen S, Levi CR, Desmond PM, Donnan GA, Davis SM, Parsons MW (2011) Cerebral blood flow is the optimal CT perfusion parameter for assessing infarct core. Stroke 42:3435–3440 Murphy BD, Fox AJ, Lee DH, Sahlas DJ, Black SE, Hogan MJ, Coutts SB, Demchuk AM, Goyal M, Aviv RI, Symons S, Gulka IB, Beletsky V, Pelz D, Chan RK, Lee TY (2008) White matter thresholds for ischemic penumbra and infarct core in patients with acute stroke: CT perfusion study. Radiology 247:818–825 Hatazawa J, Shimosegawa E, Toyoshima H, Ardekani BA, Suzuki A, Okudera T, Miura Y (1999) Cerebral blood volume in acute brain infarction: a combined study with dynamic susceptibility contrast MRI and 99mTc-HMPAO-SPECT. Stroke 30:800–806 Murphy BD, Fox AJ, Lee DH, Sahlas DJ, Black SE, Hogan MJ, Coutts SB, Demchuk AM, Goyal M, Aviv RI, Symons S, Gulka IB, Beletsky V, Pelz D, Hachinski V, Chan R, Lee TY (2006) Identification of penumbra and infarct in acute ischemic stroke using computed tomography perfusion-derived blood flow and blood volume measurements. Stroke 37:1771–1777 Deipolyi AR, Wu O, Macklin EA, Schaefer PW, Schwamm LH, Gilberto Gonzalez R, Copen WA (2012) Reliability of cerebral blood volume maps as a substitute for diffusion-weighted imaging in acute ischemic stroke. J Magn Reson Imaging 36:1083–1087
Neurol Sci 18. Labeyrie MA, Turc G, Hess A, Hervo P, Mas JL, Meder JF, Baron JC, Touze´ E, Oppenheim C (2012) Diffusion lesion reversal after thrombolysis: a MR correlate of early neurological improvement. Stroke 43:2986–2991 19. d’Esterre CD, Fainardi E, Aviv RI, Lee TY (2012) Improving acute stroke management with computed tomography perfusion: a review of imaging basics and applications. Transl Stroke Res 3:205–220 20. d’Esterre CD, Aviv RI, Lee TY (2012) The evolution of the cerebral blood volume abnormality in patients with ischemic stroke: a CT perfusion study. Acta Radiol 53:461–467 21. TIMI Study Group (1985) The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 312:932–936 22. Larrue V, von Kummer RR, Mu¨ller A, Bluhmki E (2001) Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke 32:438–441 23. Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8:135–160 24. Konstas AA, Goldmakher GV, Lee TY, Lev MH (2009) Theoretic basis and technical implementations of CT perfusion in
25.
26.
27.
28.
acute ischemic stroke, part 1: theoretic basis. Am J Neuroradiol 30:662–668 Dani KA, Thomas RG, Chappell FM, Shuler K, MacLeod MJ, Muir KW, Wardlaw JM, Translational Medicine Research Collaboration Multicentre Acute Stroke Imaging Study (2011) Computed tomography and magnetic resonance perfusion imaging in ischemic stroke: definitions and thresholds. Ann Neurol 70:384–401 Bivard A, Spratt N, Levi C, Parsons M (2011) Perfusion computer tomography: imaging and clinical validation in acute ischaemic stroke. Brain 134:3408–3416 Cortijo E, Calleja AI, Garcı´a-Bermejo P, Mulero P, Pe´rezFerna´ndez S, Reyes J, Mun˜oz MF, Martı´nez-Galda´mez M, Arenillas JF (2014) Relative cerebral blood volume as a marker of durable tissue-at-risk viability in hyperacute ischemic stroke. Stroke 45:113–118 Marchal G, Furlan M, Beaudouin V, Rioux P, Hauttement JL, Serrati C, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC (1996) Early spontaneous hyperperfusion after stroke. A marker of favourable tissue outcome? Brain 119:409–419
123
ORIGINAL ARTICLE
CT perfusion cerebral blood volume does not always predict infarct core in acute ischemic stroke Christopher D. d’Esterre1,2 • Gloria Roversi3 • Marina Padroni3 • Andrea Bernardoni4 Carmine Tamborino3 • Alessandro De Vito5 • Cristiano Azzini5 • Onofrio Marcello6 • Andrea Saletti6 • Stefano Ceruti6 • Ting Yim Lee1,2,7 • Enrico Fainardi6
•
Received: 21 March 2015 / Accepted: 8 May 2015 Ó Springer-Verlag Italia 2015
Abstract We investigated the practical clinical utility of the CT perfusion (CTP) cerebral blood volume (CBV) parameter for differentiating salvageable from non-salvageable tissue in acute ischemic stroke (AIS). Fifty-five patients with AIS were imaged within 6 h from onset using CTP. Admission CBV defect (CBVD) volume was outlined using previously established gray and white matter CBV thresholds for infarct core. Admission cerebral blood flow (CBF) hypoperfusion and CBF/CBV mismatch were visually evaluated. Truncation of the ischemic time–density Electronic supplementary material The online version of this article (doi:10.1007/s10072-015-2244-8) contains supplementary material, which is available to authorized users. & Enrico Fainardi [email protected] 1
Calgary Stroke Program, University of Calgary, Calgary, AB, Canada
2
Imaging Program, Lawson Health Research Institute, London, ON, Canada
3
Section of Neurology, Department of Biological, Psychiatric and Psychological Science, University of Ferrara, Ferrara, Italy
4
Section of Diagnostic Imaging, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
5
Neurology Unit, Department of Neuroscience and Rehabilitation, Azienda Ospedaliera Universitaria, Ferrara, Italy
6
Unita` Operativa di Neuroradiologia, Dipartimento di Neuroscienze, Azienda Ospedaliera Universitaria, Arcispedale S. Anna, Via Aldo Moro 8, 44124 Cona, Ferrara, Italy
7
Imaging Research Lab, Robarts Research Institute, London, ON, Canada
curve (ITDC) and hypervolemia status at admission, recanalization at 24-h CT angiography, hemorrhagic transformation (HT) at 24 h and/or 7-day non-contrast CT (NCCT), final infarct volume as indicated by 3-month NCCT defect (NCCTD) and 3-month modified Rankin Score were determined. Patients with recanalization and no truncation had the highest correlation (R = 0.81) and regression slope (0.80) between CBVD and NCCTD. Regression slopes were close to zero for patients with admission hypervolemia with/without recanalization. Hypervolemia underestimated (p = 0.02), while recanalization and ITDC truncation overestimated (p = 0.03) the NCCTD. Among patients with confirmed recanalization at 24 h, 38 % patients had an admission CBF/CBV mismatch within normal appearing areas on respective NCCT. 83 % of these patients developed infarction in admission hypervolemic CBF/CBV mismatch tissue. A reduction in CBV is a valuable predictor of infarct core when the acquisition of ITDC data is complete and hypervolemia is absent within the tissue destined to infarct. Raised or normal CBV is not always indicative of salvageable tissue, contrary to the current definition of penumbra. Keywords CT perfusion Cerebral blood volume Infarct core Penumbra Hypervolemia
Introduction Thromboembolic cerebral ischemia makes up 87 % of all stroke sub-types [1]. Early restoration of blood flow using thrombolytic therapy is the most effective way to reverse stroke symptoms, improving clinical outcome [2]. The intravenous tPA therapeutic window is 4.5 h post-stroke onset [3]. This time constraint limits its use in less than 7 % of
123
Neurol Sci
acute ischemic stroke (AIS) patients as the risk of hemorrhagic transformation (HT) outweighs the clinical benefit beyond the treatment window [4]. A patient-specific approach, based on tissue viability at the time of onset, is expected to relax the rigid temporal criterion for deciding if thrombolytic therapy is appropriate. With the use of the Alberta Stroke Program Early CT Score (ASPECTS), the non-contrast CT (NCCT) scan remains the recommended imaging modality for the selection of patients who may not be harmed from reperfusion. Nonetheless, ASPECTS provides only subtle indications of early ischemic changes (EIC) along with broad inter-subject variability, cannot differentiate between penumbra and benign oligemia, or the overall volume of severe hypoperfusion [5–7]. Consequently, there have been many attempts to standardize perfusion parameters to determine tissue viability in the acute stroke setting [8–14]. Changes in cerebral blood volume (CBV) are used to discriminate viable (penumbra) and non-viable (infarction) tissue states, the former characterized by an acute increase/preservation and the latter by a drastic reduction as a result of failed cerebrovascular autoregulation. Thus, according to this so-called ‘‘penumbral hypothesis’’, infarct core is the tissue with reduced CBF and CBV (CBF/CBV match) and the penumbra is the tissue with low CBF and high CBV (CBF/CBV mismatch) [15, 16]. Recently, several studies have suggested that CBV is unreliable in the accurate delineation of the acute infarct core since cerebral blood flow (CBF) better approximates the DWI-defined infarct core than CBV and mean transit time (MTT) [10, 13, 17]. However, the first two studies used shortened CT perfusion (CTP) acquisition times, which may miss the complete wash-out phase of ischemic tissue resulting in underestimation of CBV and MTT [10, 13]. Further, acute DWI lesions may not be truly representative of non-viable tissue, as partial/full reversal can occur [18]. Hypervolemia, indicating high CBV, is considered protective, but may mask impending infarction during the first few hours of onset [15, 17]. This response has not been investigated with respect to radiological and clinical outcomes. Herein, we sought to determine the role of hypervolemia, defined using the CBV parameter, on penumbra/infract delineation in the acute stroke setting.
(between February 2009 and July 2011). Patients were included if they had an admission CBF defect, presented at the hospital \6 h post-symptom onset, had no previous stroke and showed signs and symptoms consistent with occlusion of the anterior circulation, had a CT angiography (CTA) at baseline and at 24 h for recanalization status. Exclusion criteria were: evidence of brain stem infarct, prior stroke with residual deficit, intracranial hemorrhage, clinically significant hyperglycemia, impaired renal function and/or known allergy to contrast media; pregnancy, and age less than 18 years. Of the 64 patients enrolled, 55 contributed data for this study, while 9 were excluded because onset National Institutes of Health Stroke Scale (NIHSS) score B5. Results of the CTP studies performed at admission did not influence treatment decisions (patients and legal representatives providing informed consent were aware of this). Patients were enrolled regardless of therapy. An experienced neurologist (G.R.) assessed clinical outcome for all patients using the NIHSS at admission, 24 h and 7 days, as well as the modified Rankin scale (mRS) 3 months post-stroke onset. Imaging protocol
Methods
Patients underwent NCCT, CTA and CTP at admission, NCCT and CTA at 24 h and NCCT at 7 days and 3 months post-stroke. All imaging was conducted on a 64-slice Lightspeed VCT scanner (GE Healthcare, Waukesha, WI, USA). NCCT helical scans were performed from the skull base to the vertex using the following imaging parameters: 120 kV, 340 mA, 4 9 5 mm collimation, 1 s/rotation, and table speed of 15 mm/rotation. CTA was performed as follows: 0.7 mL/kg contrast (maximum 90 mL), 5- to 10-s delay from injection to scanning, 120 kV, 270 mA, 1 s/ rotation, 1.25-mm-thick slices, and table speed 3.75 mm/ rotation. CTA covered from the carotid bifurcation to vertex. The CTP scanning protocol consisted of a continuous 50 s scan using 80 kV, 100 mA and 1 s rotation time while the couch remained stationary. Seven-hundred ninety-two 512 9 512 images were reconstructed with a 25-cm field of view at 0.5-s intervals for each of the eight 5-mm-thick slice locations. Five seconds before the start of scanning, 40 mL bolus of iodinated contrast agent (Iomeron 300 mg/mL, Bracco Imaging SpA, Milan, Italy) was injected at a rate of 4 mL/s into an antecubital vein with an automatic injector (Medrad, Indianola, PA).
Patient selection
CTP functional maps
The study was approved by the Research Ethics Board of Azienda Ospedaliero-Universitaria di Ferrara (Italy). Written informed consent was obtained from each patient. Sixty-four patients, admitted at Ferrara Hospital were enrolled from 191 consecutively screened AIS patients over a 2-year period
For consistency, each CTP imaging study was analyzed by one author (C.D.d.) using a commercially available delayinsensitive deconvolution software (CT Perfusion 4D, GE Healthcare, Waukesha, WI). For each CTP scan, time– density curves (TDC) for the arterial input function (AIF)
123
Neurol Sci
and venous output functions (VOF) were obtained from the anterior cerebral artery and superior sagittal sinus, respectively (See Supplementary material for details). The AIF was corrected for partial volume averaging using the VOF-TDC. Functional maps of CBF [mL min-1 (100 g)-1] and CBV [mL (100 g)-1] were calculated by deconvolution of tissue TDCs and the AIF. The use of delay-insensitive deconvolution algorithm ensures that the calculated CBF is independent of the difference (delay) between contrast arrival times of tissue TDC and AIF [19]. Perfusion-weighted maps were created by averaging the cine CTP images over the duration of the first pass of contrast. A functional map, defined as the ratio of the increase in Hounsfield Unit (HU) above baseline at the end of the CTP acquisition relative to that of the peak HU, was also created representing the percentage of TDC truncation (incomplete imaging of the contrast wash-out phase) for each tissue voxel. CTP, CTA, and NCCT image analysis One author (C.D.d.) analyzed all CTP maps using custom software (IDL, version 6.2, RSI, Boulder, Colorado). Perfusion-weighted maps were used to exclude cerebrospinal fluid (CSF) and cranium from analysis as well as to produce a gray and white matter anatomical mask based on HU thresholds. All CTP maps and NCCT scans were co-registered. The admission CBV defect (CBVD) was manually outlined on all CBV maps using previously established gray and white matter CBV thresholds for infarct core [1.1 and 0.75 mL (100 g)-1 for gray and white matter, respectively], derived within the author’s (T.Y.L.) lab [20]. Two neuroradiologists (E.F. and A.S.) traced freehand a region of interest (ROI) around the hypodense area in each slice of the 3-month NCCT, obtaining the NCCT defect (NCCTD). All CBVD and NCCTD areas from each involved slice were multiplied by the section thickness and summed to calculate the CBVD and the final infarct volumes in cubic centimeters. Admission CBF hypoperfusion and CBF/CBV mismatch (CBF hypoperfused area minus the CBVD) were visually assessed. In some admission CTP studies, the 50-s acquisition led to truncation of ischemic tissue time–density curves (ITDC) before the washout phase was completed underestimating the area under the ITDC. Therefore, patients were divided into ITDC positive and negative sets, based on the average (values from both gray and white matter tissue) ITDC truncation at admission. An average ITDC truncation value of 50 % or greater was deemed truncation positive. Admission hypervolemia was defined as having CBV within the superimposed final infarct ROI, greater than the average plus one standard deviation of the CBV values in the contralateral mirrored ROI. Hypervolemia status was classified as hypervolemia positive and unknown as CTP imaging represents only a snapshot in time.
Recanalization was classified using CTA at 24 h by an experienced neuroradiologist (E.F.) based on an adaptation of the thrombolysis in myocardial infarction (TIMI) criteria [21]. Complete occlusion was characterized by the absence or minimal penetration of CT contrast distal to the thrombus (TIMI score = 0–1), while full recanalization was characterized by no visible narrowing of the involved vessel seen at baseline CTA (TIMI score = 3). Partial recanalization was defined as narrowing of the vessel at the site of occlusion with contrast distal to the thrombus (TIMI score = 2). Patients with TIMI score of 2 and 3 were considered as recanalization positive, whereas patients with TIMI score of 0 and 1 were classified as recanalization negative. The 24 h and/or 7 day post-NCCT was used to categorize HT, if present, as hemorrhagic infarction (HI-1,2) or parenchymal hematoma (PH-1,2) according to the European Cooperative Acute Stroke Study II criteria [22]. Symptomatic intracerebral hemorrhage (sICH) was identified as PH1 or PH2 with worsening of neurological deficit C4 points on the NIHSS within 24 h. Statistics Statistical analysis was performed with SPSS, version 16 for Windows; SPSS, Chicago, IL, USA. All data sets were checked for normality with the Shapiro–Wilk test prior to analysis with the appropriate parametric or non-parametric tests. As all variables were normally distributed, parametric statistical analysis was performed. The agreement between CBVD and NCCTD was assessed with Bland–Altman analysis for recanalization positive and negative groups and sub-groups based on ITDC truncation and hypervolemia status at admission [23]. Pearson correlation coefficient and slope of the regression line between CBVD and NCCTD were calculated for all groups and sub-groups. The ability of acute CBVD volume to predict final infarct volume and the effect of age, initial NIHSS, time to treatment, hypertension, and diabetes mellitus on this predictive ability were examined using univariate and stepwise selection multivariate logistic regression, respectively, in all patients and sub-groups based on over- or underestimation of the final infarct volume with CBVD. Categorical variables were compared by means of Fisher’s exact test. For all variables, the mean and standard deviation were listed. Significant differences were defined as p \ 0.05.
Results Clinical and radiological data Patient demographic, clinical and radiological findings are shown in Table 1. Locations of occlusions were as follows:
123
Neurol Sci Table 1 Demographic, clinical and radiological findings in 55 acute ischemic stroke patients assessed within 6 h after symptom onset Sex: female/male
32/23
Age, years: mean ± SD
67.3 ± 11.3
NIHSS at entry: median, IQR, mean ± SD, range
11, 7–15, 11.5 ± 5.9, 2–25
NIHSS at 24 h: median, IQR, mean ± SD, range
7, 3–13, 8.6 ± 6.2, 0–22
NIHSS at 7 days: median, IQR, mean ± SD, range
4, 2–9, 6.1 ± 6.2, 0–22
mRS at 3 months: median, IQR, mean ± SD, range
1, 1–2, 1.7 ± 1.2, 0–5
Time between symptom onset and CT scan at admission (hours): median, IQR, mean ± SD, range
2, 1.3–4.1, 2.6 ± 1.6, 0.4–6.0
Time to ictus: n/total (%) \3 h
36/55 (65.5 %)
3–6 h
19/55 (34.6 %)
Treatment: n/total (%) None
20/55 (36.4 %)
i.v. rtPA
34/55 (61.8 %)
Combined i.v. and i.a. rtPA
1/55 (1.8 %)
Recanalization on CTA at 24 h: yes/no Time between symptom onset and CT scan at 24 h (hours): median, IQR, mean ± SD, range
32/23 19.5, 18.4–21.2, 19.7 ± 2.0, 15.2–23
Time between CT scan at admission and at 24 h (hours): median, IQR, mean ± SD, range
23.1, 22.2–23.5, 22.3 ± 1.8, 4.0–8.0
Time between symptom onset and CT scan at 7 days (days): median, IQR, mean ± SD, range
8.0, 6.0–7.0, 6.2 ± 0.9, 4.0–24.2
Time between symptom onset and CT scan at 3 months (days): median, IQR, mean ± SD, range
89.0, 87.0–90.0, 88.1 ± 2.0, 84.0–90.0
Hemorrhagic transformation: n/total (%) None
34/55 (61.8 %)
HI-1
10/55 (18.1 %)
HI-2
3/55 (5.5 %)
PH-1
5/55 (9.1 %)
PH-2
3/55 (5.5 %)
CBVD volume (mL) at entry: median, IQR, mean ± SD, range
27.0, 41.0–106.3, 65.5 ± 75.7, 0.0–345.8
CBVD absolute values [mL(100 g)-1] at entry: median, IQR, mean ± SD, range
1.2, 0.8–1.4, 1.1 ± 0.4, 0.0–1.6
Final infarct volume (mL) on NCCTD at 3 months: median, IQR, mean ± SD, range
13.6, 4.8–105.7, 68.4 ± 103.6, 0.0–458.2
SD standard deviation, NIHSS National Institutes of Health Stroke Scale, IQR interquartile range, mRS modified Rankin Scale, tPA tissue plasminogen activator, i.v. intravenous, i.a. intra-arterial, CTA CT angiography, HI hemorrhagic infarction, PH parenchymal hematoma, CBVD admission CBV defect, NCCTD non-contrast CT defect
27 M1 only occlusions, 6 proximal ICA ? M1 occlusions, 22 M2 only occlusions. At admission, the ITDC of 24 (43.6 %) and 31 (56.4 %) patients were truncation positive and negative, whereas 25 (45.5 %) and 30 (55.5 %) patients were hypervolemia positive and unknown, respectively. At 24 h post, 32 (58.2 %) and 23 (41.8 %) patients were recanalization positive and negative, respectively. Table 2 shows that in the recanalization positive group 15/32 (46.9 %) patients had ITDC truncation while 15/32 (46.9 %) patients had hypervolemia and in the recanalization negative group these numbers were 9/23 (39.1 %) and 10/23 (43.5 %), respectively. CBV predictive value for infarct core and penumbra in AIS patients grouped according to recanalization/ truncation status As illustrated in Table 2, the association between CBVD and NCCTD was the strongest in the recanalization
123
positive ? truncation negative patients (R = 0.81). The 95 % limits of agreement between CBVD and NCCTD were wider for the recanalization negative group and its sub-groups compared to the recanalization positive group and its sub-groups. The regression line slopes for both hypervolemia positive sub-groups were negative and close to unity (-0.04 and -0.13, respectively). Univariate logistic regression analysis revealed that acute hypervolemia (odds ratio, 0.47; 95 % CI, 0.09–0.367; p = 0.02) was significantly associated with underestimation of the final infarct volume, while recanalization (odds ratio, 0.80, 95 % CI 0.11–3.8, p = 0.03) and truncation (odds ratio, 0.92, 95 % CI 0.010–0.045, p = 0.03) were significantly associated with overestimation of the final infarct volume. Among patients with confirmed recanalization, a matched decrease in CBF and CBV at onset within areas of slightly hypodensity on corresponding NCCT was observed in 20/32 (62 %) of them. All these patients developed infarction in the same region in the 3 months post-
Neurol Sci Table 2 Bland–Altman and linear regression results for the admission cerebral blood volume (CBV) defect volume versus the final infarct volume at 3 months 95 % Limits of agreement (mean difference ± 2*SD)
Pearson correlation coefficient, R (p value)
Slope of regression line
Recanalization positive (n = 32)
[-48.3, 29.1]
0.78 (0.08)
0.64
Truncation negative (n = 17)
[-8.4, 16.0]
0.81 (0.19)
0.80
Truncation positive (n = 15) Onset hypervolemia unknown (n = 17)
[-40.5, 30.3] [-51.9, 38.2]
0.61 (0.11) 0.80 (0.04)
0.46 0.57 -0.04
Onset hypervolemia positive (n = 15)
[-37.6, 16.1]
0.22 (0.79)
Recanalization Negative (n = 23)
[-86.2, 51.1]
0.57 (0.33)
0.42
Truncation negative (n = 14)
[-85.9, 68.3]
0.15 (0.74)
0.14
Truncation positive (n = 9)
[-69.9, 36.9]
0.71 (0.04)
0.62
Onset hypervolemia unknown (n = 13)
[-96.9, 61.3]
0.68 (0.10)
0.37
Onset hypervolemia positive (n = 10)
[-56.9, 19.2]
0.39 (0.22)
-0.13
NCCT. The remaining 38 % (12/32) patients who recanalized at 24 h had an admission CBF/CBV mismatch within areas of little or no early ischemic change on respective NCCT images. 83 % (10/12) of these patients developed infarction at 3 months in admission hypervolemic CBF/CBV mismatch tissue. No association was found between patients with and without admission CBF/ CBV mismatch and mRS (data not shown). Two illustrative cases describing these two different conditions are reported in Supplementary Figure 1. No relationship was observed between patients with and without admission hypervolemia and mRS (data not shown).
Discussion We investigated the CBV predictive value for infarct/ penumbra in patients with acute ischemic stroke. In this setting, a 3-month NCCT was used to define the final infarct volume to allow for edema reduction and infarct maturation. CBV is considered to be an important parameter to distinguish viable from non-viable tissue within hours after stroke onset since a matched reduction of CBF and CBV has been shown to identify infarction, whereas a mismatch between decreased CBF and increased CBV is suggested to be a hallmark of penumbra [24]. However, there remains a lack of standardization for CBV thresholds to define tissue viability [25], and with its poor correlation with the acute DWI hyperintensity [12, 13, 17, 26], the reliability of CBV defined infarct is increasingly being questioned. Three variables are identified which affect the CBV parameter: (1) ITDC truncation, (2) hypervolemia, and (3) recanalization status. Recanalization and ITDC truncation limit the ability of admission CBVD to identify the infarct core consistently. In fact, the best correlation
between CBVD and the final infarct volume occurs in patients who recanalized and were truncation negative at admission. This makes intuitive sense, as recanalization limits expansion of infarct after admission such that CBVD volume approximates that of the final infarct core at delayed imaging. ITDC truncation also has different effects on recanalization positive versus negative groups. In patients who did not recanalize and had truncation of the ITDC, the acute CBVD volume matched the final infarct volume because truncation at admission artifactually lowered CBV, overestimating the predicted infarct core. This could lead to an inaccurate estimate of the CBV threshold for infarction in retrospective threshold derivation studies. Conversely, in patients with fast CT to recanalization times, the overestimation of the infarct core at admission from truncation of the ITDC could lead to the paradoxical reversal of infarct defined with CBV threshold [20]. The underestimation of admission CBVD volume due to hypervolemia has not been previously described. A hypervolemic response indicative of good collaterals within a hypoperfused area during the acute phase may occur in penumbral tissue [27]. This hypervolemic response can occur due to: compensatory vasodilatation due to the opening of collaterals, reperfusion due to arterial reopening, embolic migration, therapeutic dissolution, and/or release of vasolidatory and inflammatory mediators [15]. Irrespective of recanalization, CBVD volume had the poorest correlation with final infarct volume in patients with admission hypervolemia. This result invalidates the ‘‘penumbral hypothesis’’ for discriminating between tissue that recovers and tissue that infarcts with early recanalization. Supplementary Figure 1 shows a patient with a CBF/CBV mismatch at admission with little evidence of early ischemic change on the corresponding NCCT. Even with confirmed recanalization/reperfusion from CTP, portions of the supposedly viable hypervolemic tissue at
123
Neurol Sci
admission still progressed to infarction. Hypervolemia can mask non-viable tissue and therefore be potentially malignant, non-nutritional, providing a blood flow in excess of metabolic demand [28]. This study is not without its limitations. First, use of the 3-month NCCT to determine final infarction volume could be affected by infarct shrinkage and secondary vascular injury, potentially causing under- and overestimation of admission infarct volume, respectively. Second, only a 2-cm slab of tissue was imaged during the CTP acquisition, which could have missed part of the infarct volume and hypervolemia outside of the scanned volume. Third, recanalization was defined using CTA at 24-h post instead of contemporaneous of the admission CTP study. Fourth, our sample size is relatively small compared to other AIS studies. In summary, in this study, we showed that the reliability of the admission CBV defect to define infarct is overestimated with recanalization and ITDC truncation, and underestimated with hypervolemia, whereas the risk of HT is associated with both low CBV values and hypervolemia. From a practical clinical standpoint, reduced CBV values, or a matched decrease in CBF/CBV, is a valuable predictor of infarct core when the acquisition of ITDC data is complete and hypervolemia is absent within the tissue destined to infarct. In retrospective studies, to determine an optimum admission CBV threshold for defining infarcts from delayed CT or MR scans, patients should be dichotomized into recanalization positive and negative groups in the intervening period due to potential differences in infarct expansion. Acknowledgments This work has been supported by Italian National Health System- Research Program entitled ‘‘Nuove conoscenze e problematiche assistenziali nell’ictus cerebrale: un Programma Strategico di Ricerca e Sviluppo’’ ex art. 12-12bis/D.Lgs n. 502/92, PG/2007/0293184. The authors would also like to thank the Canadian Stroke Network and European Stroke Network, Canadian Institutes of Health Research, Ontario Research Fund and GE Healthcare for partial support of this study. Conflict of interest Ting-Yim Lee licenses CT Perfusion software to and receives funding from GE Healthcare.
References 1. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623 2. Wahlgren N, Ahmed N, Da´valos A, Hacke W, Milla´n M, Muir K, Roine RO, Toni D, Lees KR, SITS investigators (2008) Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITSISTR): an observational study. Lancet 372:1303–1309 3. Hacke W, Kaste M, Bluhmki E, Brozman M, Da´valos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, Investigators ECASS (2008)
123
4.
5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317–1329 Schumacher HC, Bateman BT, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, Pile-Spellman J (2007) Use of thrombolysis in acute ischemic stroke: analysis of the nationwide inpatient sample 1999 to 2004. Ann Emerg Med 50:99–107 Bivard A, Parsons M (2012) ASPECTaSaurus (a dinosaur)? Int J Stroke 7:564 Wardlaw J, Dorman P, Lewis S, Sandercock PA (1999) Can stroke physicians and neuroradiologists identify signs of early cerebral infarction on CT? J Neurol Neurosurg Psychiatry 67:651–653 Puetz V, Dzialowski I, Hill MD, Demchuk AM (2009) The Alberta Stroke Program Early CT Score in clinical practice: what have we learned? Int J Stroke 4:354–364 Turk AS, Nyberg EM, Chaudry MI, Turner RD, Magarik JA, Nicholas JS, Holmstedt CA, Chalela JA, Hays A, Lazaridis C, Chimowitz MI, Turan TN, Adams RJ, Jauch EC (2013) Utilization of CT perfusion patient selection for mechanical thrombectomy irrespective of time: a comparison of functional outcomes and complications. J Neurointerv Surg 5:518–522 Turk A, Magarik JA, Chaudry I, Turner RD, Nicholas J, Holmstedt CA, Chalela J, Hays A, Lazaridis C, Jauch E, Chimowitz M, Turan T, Adams R (2012) CT perfusion-guided patient selection for endovascular treatment of acute ischemic stroke is safe and effective. J Neurointerv Surg 4:261–265 Kamalian S, Kamalian S, Konstas AA, Maas MB, Payabvash S, Pomerantz SR, Schaefer PW, Furie KL, Gonza´lez RG, Lev MH (2012) CT perfusion mean transit time maps optimally distinguish benign oligemia from true ‘‘at-risk’’ ischemic penumbra, but thresholds vary by postprocessing technique. Am J Neuroradiol 33:545–549 Garcı´a-Bermejo P, Calleja AI, Pe´rez-Ferna´ndez S, Cortijo E, del Monte JM, Garcı´a-Porrero M, Fe Mun˜oz M, Ferna´ndez-Herranz R, Arenillas JF (2012) Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours: a case-control study. Cerebrovasc Dis 34:31–37 Kamalian S, Kamalian S, Maas MB, Goldmacher GV, Payabvash S, Akbar A, Schaefer PW, Furie KL, Gonzalez RG, Lev MH (2011) CT cerebral blood flow maps optimally correlate with admission diffusion-weighted imaging in acute stroke but thresholds vary by postprocessing platform. Stroke 42:1923–1928 Campbell BC, Christensen S, Levi CR, Desmond PM, Donnan GA, Davis SM, Parsons MW (2011) Cerebral blood flow is the optimal CT perfusion parameter for assessing infarct core. Stroke 42:3435–3440 Murphy BD, Fox AJ, Lee DH, Sahlas DJ, Black SE, Hogan MJ, Coutts SB, Demchuk AM, Goyal M, Aviv RI, Symons S, Gulka IB, Beletsky V, Pelz D, Chan RK, Lee TY (2008) White matter thresholds for ischemic penumbra and infarct core in patients with acute stroke: CT perfusion study. Radiology 247:818–825 Hatazawa J, Shimosegawa E, Toyoshima H, Ardekani BA, Suzuki A, Okudera T, Miura Y (1999) Cerebral blood volume in acute brain infarction: a combined study with dynamic susceptibility contrast MRI and 99mTc-HMPAO-SPECT. Stroke 30:800–806 Murphy BD, Fox AJ, Lee DH, Sahlas DJ, Black SE, Hogan MJ, Coutts SB, Demchuk AM, Goyal M, Aviv RI, Symons S, Gulka IB, Beletsky V, Pelz D, Hachinski V, Chan R, Lee TY (2006) Identification of penumbra and infarct in acute ischemic stroke using computed tomography perfusion-derived blood flow and blood volume measurements. Stroke 37:1771–1777 Deipolyi AR, Wu O, Macklin EA, Schaefer PW, Schwamm LH, Gilberto Gonzalez R, Copen WA (2012) Reliability of cerebral blood volume maps as a substitute for diffusion-weighted imaging in acute ischemic stroke. J Magn Reson Imaging 36:1083–1087
Neurol Sci 18. Labeyrie MA, Turc G, Hess A, Hervo P, Mas JL, Meder JF, Baron JC, Touze´ E, Oppenheim C (2012) Diffusion lesion reversal after thrombolysis: a MR correlate of early neurological improvement. Stroke 43:2986–2991 19. d’Esterre CD, Fainardi E, Aviv RI, Lee TY (2012) Improving acute stroke management with computed tomography perfusion: a review of imaging basics and applications. Transl Stroke Res 3:205–220 20. d’Esterre CD, Aviv RI, Lee TY (2012) The evolution of the cerebral blood volume abnormality in patients with ischemic stroke: a CT perfusion study. Acta Radiol 53:461–467 21. TIMI Study Group (1985) The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 312:932–936 22. Larrue V, von Kummer RR, Mu¨ller A, Bluhmki E (2001) Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke 32:438–441 23. Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8:135–160 24. Konstas AA, Goldmakher GV, Lee TY, Lev MH (2009) Theoretic basis and technical implementations of CT perfusion in
25.
26.
27.
28.
acute ischemic stroke, part 1: theoretic basis. Am J Neuroradiol 30:662–668 Dani KA, Thomas RG, Chappell FM, Shuler K, MacLeod MJ, Muir KW, Wardlaw JM, Translational Medicine Research Collaboration Multicentre Acute Stroke Imaging Study (2011) Computed tomography and magnetic resonance perfusion imaging in ischemic stroke: definitions and thresholds. Ann Neurol 70:384–401 Bivard A, Spratt N, Levi C, Parsons M (2011) Perfusion computer tomography: imaging and clinical validation in acute ischaemic stroke. Brain 134:3408–3416 Cortijo E, Calleja AI, Garcı´a-Bermejo P, Mulero P, Pe´rezFerna´ndez S, Reyes J, Mun˜oz MF, Martı´nez-Galda´mez M, Arenillas JF (2014) Relative cerebral blood volume as a marker of durable tissue-at-risk viability in hyperacute ischemic stroke. Stroke 45:113–118 Marchal G, Furlan M, Beaudouin V, Rioux P, Hauttement JL, Serrati C, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC (1996) Early spontaneous hyperperfusion after stroke. A marker of favourable tissue outcome? Brain 119:409–419
123
