Neuroradiology (2014) 56:1121–1126 DOI 10.1007/s00234-014-1429-9
FUNCTIONAL NEURORADIOLOGY
Whole brain CT perfusion in acute anterior circulation ischemia: coverage size matters B. J. Emmer & M. Rijkee & J. M. Niesten & M. J. H. Wermer & B. K. Velthuis & M. A. A. van Walderveen
Received: 18 June 2014 / Accepted: 2 September 2014 / Published online: 17 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Our aim was to compare infarct core volume on whole brain CT perfusion (CTP) with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. Methods In total, 40 acute ischemic stroke patients with noncontrast CT (NCCT) and CTP imaging of anterior circulation ischemia were included. Imaging was performed using a 320multislice CT. Average volumes of infarct core of all simulated partial coverage sizes were calculated. Infarct core volume of each partial brain coverage was compared with infarct core volume of whole brain coverage and expressed using a percentage. To determine the optimal starting position for each simulated CTP coverage, the percentage of infarct coverage was calculated for every possible starting position of the simulated partial coverage in relation to Alberta Stroke Program Early CT Score in Acute Stroke Triage (ASPECTS 1) level. Results Whole brain CTP coverage further increased the percentage of infarct core volume depicted by 10 % as compared to the 8-cm coverage when the bottom slice was positioned at the ASPECTS 1 level. Optimization of the position of the B. J. Emmer (*) Department of Radiology, Erasmus Medical Centre, Postbus 2040, 3000 CA Rotterdam, The Netherlands e-mail: [email protected] M. Rijkee : M. A. A. van Walderveen Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands M. J. H. Wermer Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands J. M. Niesten : B. K. Velthuis Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands
region of interest (ROI) in 3 cm, 4 cm, and 8 cm improved the percentage of infarct depicted by 4 % for the 8-cm, 7 % for the 4-cm, and 13 % for the 3-cm coverage size. Conclusion This study shows that whole brain CTP is the optimal coverage for CTP with a substantial improvement in accuracy in quantifying infarct core size. In addition, our results suggest that the optimal position of the ROI in limited coverage depends on the size of the coverage. Keywords CT perfusion . Whole brain . Infarct core . Stroke
Introduction At this moment, intravenous treatment (IVT) and intra-arterial treatment (IAT) options for acute ischemic stroke are limited by a strict time window, being either 4.5 h (IVT) or 6–8 h (IAT). Several studies, however, suggest that IAT options for acute ischemic stroke may depend largely on the amount of tissue that has been irreversibly damaged as seen on diagnostic imaging at presentation [1–3]. Although recent studies using a multiparametric predictive model of the extent of the infarct core and the penumbra were not able to identify patients that would benefit from endovascular therapy [4, 5], Yoo et al. did show that an infarct core volume larger than 70 ml, as determined by MRI diffusion weighted imaging (DWI), does not warrant therapy because of poor outcome regardless of recanalization [6]. This result suggests that patients with an infarct core larger than 70 ml on admission imaging should probably not be exposed to the risks of intraarterial treatment, such as intracranial hemorrhage caused by reperfusion of the hypoxic brain tissue [7–9]. Another study also demonstrated that infarct core volume, as defined by DWI, is the most important predictor of outcome in patients with acute ischemic stroke [10]. Although availability of automated quantification of infarct core is still limited in most
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hospitals, automated solutions are likely to become more readily available in the near future. At the moment, clinical decisions are mostly based on qualitative analysis of infarct core volume. Nevertheless, this often involves some form of quantification like the Alberta Stroke Program Early CT Score (ASPECTS) or a cutoff value. A commonly used cutoff is one third of the MCA territory, corresponding roughly to 90 ml and thus slightly more liberal than the aforementioned 70 ml. In clinical practice, MRI is not readily available in the emergency setting in most hospitals. In addition, patient cooperation with subsequent movement artifacts is often problematic when using MRI, making this image modality less suitable in the acute diagnostic phase. Furthermore, automated measurement of infarct core volume on DWI is not possible in the acute setting at this moment [1]. Several studies have suggested that CT perfusion (CTP) might be used to triage acute ischemic patients for endovascular treatment [2, 11–13]. Reliable estimation of CTP parameters requires data acquisition in a single rotation. Most CT scanners provide 64 or 128 slice coverage in a single rotation, resulting in a coverage size of only 3 to 8 cm. Some studies suggest that coverage size as small as 4 cm suffices in the assessment of potentially treatable occlusions of the internal carotid artery (ICA) and middle cerebral artery (MCA) [11]. More recent studies show advantages of an 8-cm coverage size for detecting brain ischemia as compared to a smaller coverage size. A study comparing CTP with MRI stated that a coverage size of at least 7.5 cm would be sufficient to include the majority of the ischemic region and suggested that extended coverage size beyond 7.5 cm would probably not influence any treatment decision [14]. Nowadays, CT scanners with whole brain (16 cm) CTP coverage have become available in clinical practice. To our knowledge, no study has compared CTP results of limited coverage sizes with whole brain coverage in acute anterior cerebral circulation ischemia. Consequently, it is not known whether CTP coverage size matters with regard to clinical decision-making for IAT in patients with acute anterior circulation ischemia. The aim of this study was to compare infarct core volume on whole brain CTP with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. A secondary goal was to determine if a possible optimum exists for the placement of the region of interest (ROI) in scanners with limited coverage.
Methods Patient selection We included patients 18 years or older who were scanned at our institution within 9 h after onset of the first ischemic symptoms and showing imaging signs of acute ischemia in the anterior cerebral circulation on non-contrast CT (NCCT).
Neuroradiology (2014) 56:1121–1126
Patients waking up with acute ischemic stroke symptoms were only included if they went to bed without symptoms and presented in the hospital less than 9 h before going to bed. Patients were excluded if they were known to be allergic to contrast agents and with known renal failure. Patients with other diagnosis than acute cerebral ischemia on unenhanced CT, such as cerebral hemorrhage, subarachnoid hemorrhage, and tumors, were also excluded from the study. In total, 40 acute ischemic stroke patients with NCCT and CTP imaging of anterior circulation ischemia were included in this study. Patient demographics are given in Table 1. The site of occlusion as seen on CTA was distributed as follows: no occlusion, 9; anterior cerebral artery, 1; internal carotid artery and M1 segment of middle cerebral artery, 4; middle cerebral artery M1 segment to proximal M2 segment and middle cerebral artery distal M2 segment to M3 segment, 8; and middle cerebral artery M3 segment to M4 segment, 2. Imaging Imaging was performed using a 320-multislice CT (Aquilion One Toshiba Medical Systems, Tokyo, Japan). CTP studies were performed after exclusion of brain hemorrhage or other ischemic stroke mimics on NCCT. The 0.5-mm detector array enables 16-cm z-axis coverage, from the first cervical Table 1 Patient demographics Demographics (N=40) Age (years) (mean, SD) Female sex (%) Hypertension (%) Smoking in the past 12 months (%) Family history (%) Hypercholesterolemia (%) Diabetes (%) Median admission NIHSS (range)a Median symptom onset—CT (IQR)b 6 h mRS 3 monthsb
65 (13.2) 17 (42.5) 17 (42.5) 13 (32.5) 13 (32.5) 5 (12.5) 2 (5) 8 (2–27), unknown n=10
0–1 2–5 6 Treatmentb IVT alone IVT + IAT No IVT nor IAT
11 17 7
32 0 4
28 2 7
a
One patient presented with reduced consciousness (Glasgow Coma Score E1M4V1)
b
The number does not add up to 40 because of missing data
Neuroradiology (2014) 56:1121–1126
vertebral body to the skull vertex. A contrast bolus of 50 mL Ultravist 370 was given with a flow rate of 5.0 mL/s, followed by a saline flush of 35–50 mL and a flow rate of 5.0 mL/s, using a Stellant® CT Power Injector. In the early arterial phase, 4 dynamic volumes were acquired every 2 s with 160 mA and 80 kVp; in the mid-arterial phase (the so-called full dose phase), 6 dynamic volumes were acquired every 2 s with 300 mA and 80 kVp; in the late arterial phase, 3 dynamic volumes were acquired every 2 s with 160 mA and 80 kVp; and lastly, in the venous phase, 5 dynamic volumes were acquired every 5 s with 130 mA and 80 kVp. The last 6 dynamic volumes were acquired with an interval of 30 s. This final delayed phase of the protocol was part of the scientific protocol to calculate blood-barrier permeability maps (data not presented here). In total, 24 volumes were acquired. Every rotation took 0.75 s. The total effective dose for each scan was 8.4 mSv; without the delayed phase mentioned above, the total effective dose would amount to 7.3 mSv. Data analysis Commercial CT perfusion software (Extended Brilliance Workstation, version 4.5, Philips Medical Systems) was used to make volumetric quantifications of infarct core. The Philips CTP software uses rigid registration to correct for motion artifacts and an anisotropic, edge-preserving spatial filter for noise reduction. The dynamic CTP volumes were reconstructed to contiguous 5-mm slices using Toshiba Software in order to load the data into the Philips CTP software. Infarct core was defined by pixels with a mean transit time (MTT) >145 % of the contralateral side values and a reduced cerebral blood volume (CBV) 70ml 12 10 8 ASPECTS 1
6
Opmized
4 2 0 3 cm 4 cm 6 cm 8 cm
Fig. 2 The average volume of the infarct core as depicted by the different coverage sizes before (black) and after (shaded) optimization of the starting position. Note the difference between the average infarct core volume as depicted with non-optimized 8-cm coverage and the infarct core volume as depicted with whole brain (WB) coverage
WB
Fig. 3 The number of patients with an infarct core volume larger than 70 ml before (black) and after (shaded) optimization. Note that the number of patients with an infarct core larger than 70 ml differs between 8-cm and whole brain coverage before optimization. The sensitivity improves after optimization for 8 cm but decreases by one patient for 4 cm. This decrease was due to one patient in our study population with a relatively low starting infarction
Neuroradiology (2014) 56:1121–1126
70 ml. This also holds true for a coverage size of 8 cm: in our study population, 2 patients would erroneously be depicted as having an infarct core volume smaller than 70 ml with 8-cm coverage as compared to whole brain coverage. If these scans with 8-cm coverage had been started at the optimal starting level for 8-cm coverage, i.e., 1.5 cm below ASPECTS 1 level, only 1 patient would have been misclassified as having an infarct core smaller than 70 ml.
Discussion The most important conclusion of this study is that CTP coverage determines depiction of infarct core volume in patients with acute anterior ischemic stroke, with an increase in detected infarct core volume beyond a CTP coverage of 8 cm. Our secondary finding is that the optimal starting level of the ROI in partial coverage CTP depends on the size of the coverage. Applying this optimization in our study population resulted on average in a larger percentage of the infarct core being depicted. Our results underline the importance of whole brain CTP coverage in correctly classifying the infarct core volume with regard to a suggested clinically relevant threshold of 70 ml for intra-arterial treatment [10]. In our patient group, 11 patients showed an infarct core volume of more than 70 ml; 2 of these 11 patients would erroneously be classified as having an infarct core volume below 70 ml when using 8-cm coverage. However, when using the optimized starting level for 8-cm coverage of 1.0 cm below ASPECTS 1 level, only 1 patient would be erroneously classified as having an infarct core volume below 70 ml in our study population. In clinical practice, this would imply that misclassification of patients with regard to intra-arterial treatment decisions would occur in roughly one out of five patients and with optimization of one out of ten. Obviously, this number increases with increased limitation of coverage size, as is common with available CT scanners in current clinical practice. This suggests that after optimization, 8-cm coverage might be a useful alternative if whole brain perfusion is not available. However, with 6-cm coverage, 1 out of 4 patients were misclassified as having an infarct core volume below 70 ml, even after optimization. It is therefore, probably, not recommended to make clinical decisions with regard to treatment choices based only on calculated infarct core volume on CTP studies when whole brain CTP or optimized 8-cm coverage studies are not available [15]. This requires further investigation as treatment decisions based only on infarct volume have only been tested with MRI. In addition, other possible information derived from CTP was not investigated in this study. A limitation of our study is the use of a standardized positioning of the CTP slab in the region of interest in every patient when limited CTP coverage was simulated; the starting
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point was chosen at the level of ASPECTS 1 [14–16]. In clinical practice, the CT technician might be able to place the CTP slab more optimally, based on the expected coverage, on the clinical context, and on the imaging findings on NCCT. However, signs of ischemia on NCCT are often not clearly visible in the (hyper)acute phase, and clinical symptoms may also be confusing (e.g., discriminating hemispheric from cerebellar ischemia). Some authors therefore advise localization of the CTP slab at or at least including the level of the basal ganglia (ASPECTS 1 level) and sometimes the third ventricle [16–18]. In our patient group, we showed that the optimal placement of the CTP slab actually depends on the size of the CTP coverage. Obviously, whole brain CTP coverage eliminates this problem. Accordingly, one might argue that whole brain CTP coverage has added value in posterior fossa ischemia. However, considering the relative limited spatial resolution of CTP in combination with often small size of infarcts in posterior fossa ischemia, the value of CTP in the region of the posterior fossa has yet to be determined, preferably in a comparative study including CTP and DWI MRI. Recently, concern has arisen about diagnostic accuracy of CTP imaging for detecting acute ischemic stroke. Some argue that contrast to noise ratio (CNR) of CTP studies is too limited (CNR 8). A recent meta-analysis, however, showed that CTP has high sensitivity (80 %) and very high specificity (95 %) for detecting infarcts, with false negative findings being either due to small lacunar infarcts or limited coverage [2]. Obviously, false negative CTP studies in case of lacunar infarcts will not influence clinical decision-making with regard to choice of IAT, since no arterial occlusion will be visible on CT angiography to serve as target for IAT, and whole brain CTP would solve the latter problem. In CTP, the infarct core and the penumbra are best defined by using the relative MTT and the absolute CBV [19]. This approach is, at best, proportional to the infarct core on DWI. Nonetheless, this does not change the importance of depicting the maximum amount of the parameter considered important in clinical decision-making. Reproducibility of CTP results is another subject of concern. CTP analysis is influenced by acquisition methods and software CTP analysis settings and algorithms. Different postprocessing software packages do not necessarily produce similar infarct core volumes, underscoring the importance of further standardization and validation of CTP postprocessing software [17, 18]. Finally, critics of CTP always highlight the radiation dose in CTP. However, the effective dose of our extended scientific protocol is lower than the radiation dose of an average abdominal CT scan. Further lowering of the radiation dose is feasible by limiting acquisition time to the clinically relevant time period and increase to the sampling interval [20].
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In conclusion, this study shows that whole brain CTP is recommended when clinical decision-making with regard to IAT is made based only on infarct core volume, an issue that has become important since infarct core volume is suggested to be a pivotal biomarker for clinical outcome in patients with acute anterior ischemic stroke. In addition, our study suggests that in partial coverage CTP, the optimal position of ROI depends on the size of the partial coverage.
Ethical standards and patient consent We declare that all human and animal studies have been approved by the Medical Ethical Committee of the Leiden University Medical Centre and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Conflict of interest We declare that we have no conflict of interest.
References 1. Balucani C, Grotta JC (2012) Selecting stroke patients for intraarterial therapy. Neurology 78(10):755–761. doi:10.1212/WNL. 0b013e318248e558 2. Biesbroek JM, Niesten JM, Dankbaar JW, Biessels GJ, Velthuis BK, Reitsma JB, van der Schaaf IC (2013) Diagnostic accuracy of CT perfusion imaging for detecting acute ischemic stroke: a systematic review and meta-analysis. Cerebrovasc Dis 35(6):493–501. doi:10. 1159/000350200 3. Fisher M, Albers GW (2013) Advanced imaging to extend the therapeutic time window of acute ischemic stroke. Ann Neurol 73(1):4–9. doi:10.1002/ana.23744 4. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL (2013) A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 368(10):914–923. doi:10.1056/ NEJMoa1212793 5. Kidwell CS, Wintermark M, De Silva DA, Schaewe TJ, Jahan R, Starkman S, Jovin T, Hom J, Jumaa M, Schreier J, Gornbein J, Liebeskind DS, Alger JR, Saver JL (2013) Multiparametric MRI and CT models of infarct core and favorable penumbral imaging patterns in acute ischemic stroke. Stroke 44(1):73–79. doi:10.1161/ STROKEAHA.112.670034 6. Yoo AJ, Verduzco LA, Schaefer PW, Hirsch JA, Rabinov JD, Gonzalez RG (2009) MRI-based selection for intra-arterial stroke therapy: value of pretreatment diffusion-weighted imaging lesion volume in selecting patients with acute stroke who will benefit from early recanalization. Stroke 40(6):2046–2054. doi:10.1161/ STROKEAHA.108.541656 7. Nguyen-Huynh MN, Johnston SC (2011) Is mechanical clot removal or disruption a cost-effective treatment for acute stroke? AJNR Am j of neuroradiol 32(2):244–249. doi:10.3174/ajnr.A2329 8. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, Lutsep HL, Rymer MM, Higashida RT, Starkman S, Gobin YP, Frei D, Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, Marks M, Nesbit G, Silverman IE (2008) Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 39(4):1205–1212. doi:10.1161/STROKEAHA.107.497115
Neuroradiology (2014) 56:1121–1126 9. Josephson SA, Saver JL, Smith WS (2009) Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II. Neurocrit Care 10(1):43–49. doi:10.1007/s12028-0089167-7 10. Yoo AJ, Chaudhry ZA, Nogueira RG, Lev MH, Schaefer PW, Schwamm LH, Hirsch JA, Gonzalez RG (2012) Infarct volume is a pivotal biomarker after intra-arterial stroke therapy. Stroke 43(5):1323–1330. doi:10.1161/STROKEAHA.111.639401 11. Rai AT, Raghuram K, Domico J, Hobbs G, Carpenter J (2012) Preintervention triage incorporating perfusion imaging improves outcomes in patients undergoing endovascular stroke therapy: a comparison with the device trials. J of neurointerventional surg. doi:10. 1136/neurintsurg-2011-010189 12. Turk AS, Magarick JA, Frei D, Fargen KM, Chaudry I, Holmstedt CA, Nicholas J, Mocco J, Turner RD, Huddle D, Loy D, Bellon R, Dooley G, Adams R, Whaley M, Fanale C, Jauch E (2012) CT perfusion-guided patient selection for endovascular recanalization in acute ischemic stroke: a multicenter study. J of neurointerventional surg. doi:10.1136/neurintsurg-2012-010491 13. Fargen KM, Chaudry I, Turner RD, Bennett JA, Turk A, Mocco J (2012) A novel clinical and imaging based score for predicting outcome prior to endovascular treatment of acute ischemic stroke. J of neurointerventional surg. doi:10.1136/neurintsurg-2012-010513 14. Schaefer PW, Barak ER, Kamalian S, Gharai LR, Schwamm L, Gonzalez RG, Lev MH (2008) Quantitative assessment of core/penumbra mismatch in acute stroke: CT and MR perfusion imaging are strongly correlated when sufficient brain volume is imaged. Stroke 39(11):2986–2992. doi:10.1161/STROKEAHA. 107.513358 15. Furtado AD, Lau BC, Vittinghoff E, Dillon WP, Smith WS, Rigby T, Boussel L, Wintermark M (2010) Optimal brain perfusion CT coverage in patients with acute middle cerebral artery stroke. AJNR Am j of neuroradiol 31(4):691–695. doi: 10.3174/ajnr.A1880 16. 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(3):818–825. doi:10.1148/ radiol.2473070551 17. Wintermark M, Smith WS, Ko NU, Quist M, Schnyder P, Dillon WP (2004) Dynamic perfusion CT: optimizing the temporal resolution and contrast volume for calculation of perfusion CT parameters in stroke patients. AJNR Am j of neuroradiol 25(5):720–729 18. Kamena A, Streitparth F, Grieser C, Lehmkuhl L, Jamil B, Wojtal K, Ricke J, Pech M (2007) Dynamic perfusion CT: optimizing the temporal resolution for the calculation of perfusion CT parameters in stroke patients. Eur J Radiol 64(1):111–118. doi:10.1016/j.ejrad. 2007.02.025 19. Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen M, Goldsher D, Pineda C, Serena J, van der Schaaf I, Waaijer A, Anderson J, Nesbit G, Gabriely I, Medina V, Quiles A, Pohlman S, Quist M, Schnyder P, Bogousslavsky J, Dillon WP, Pedraza S (2006) Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric s t r o k e . S t r o k e 3 7 ( 4 ) : 9 7 9 – 9 8 5 . d o i : 1 0 . 11 6 1 / 0 1 . S T R . 0000209238.61459.39 20. Shankar JJ, Lum C, Sharma M (2010) Whole-brain perfusion imaging with 320-MDCT scanner: reducing radiation dose by increasing sampling interval. AJR Am J Roentgenol 195(5):1183–1186. doi:10. 2214/AJR.10.4230
FUNCTIONAL NEURORADIOLOGY
Whole brain CT perfusion in acute anterior circulation ischemia: coverage size matters B. J. Emmer & M. Rijkee & J. M. Niesten & M. J. H. Wermer & B. K. Velthuis & M. A. A. van Walderveen
Received: 18 June 2014 / Accepted: 2 September 2014 / Published online: 17 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Our aim was to compare infarct core volume on whole brain CT perfusion (CTP) with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. Methods In total, 40 acute ischemic stroke patients with noncontrast CT (NCCT) and CTP imaging of anterior circulation ischemia were included. Imaging was performed using a 320multislice CT. Average volumes of infarct core of all simulated partial coverage sizes were calculated. Infarct core volume of each partial brain coverage was compared with infarct core volume of whole brain coverage and expressed using a percentage. To determine the optimal starting position for each simulated CTP coverage, the percentage of infarct coverage was calculated for every possible starting position of the simulated partial coverage in relation to Alberta Stroke Program Early CT Score in Acute Stroke Triage (ASPECTS 1) level. Results Whole brain CTP coverage further increased the percentage of infarct core volume depicted by 10 % as compared to the 8-cm coverage when the bottom slice was positioned at the ASPECTS 1 level. Optimization of the position of the B. J. Emmer (*) Department of Radiology, Erasmus Medical Centre, Postbus 2040, 3000 CA Rotterdam, The Netherlands e-mail: [email protected] M. Rijkee : M. A. A. van Walderveen Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands M. J. H. Wermer Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands J. M. Niesten : B. K. Velthuis Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands
region of interest (ROI) in 3 cm, 4 cm, and 8 cm improved the percentage of infarct depicted by 4 % for the 8-cm, 7 % for the 4-cm, and 13 % for the 3-cm coverage size. Conclusion This study shows that whole brain CTP is the optimal coverage for CTP with a substantial improvement in accuracy in quantifying infarct core size. In addition, our results suggest that the optimal position of the ROI in limited coverage depends on the size of the coverage. Keywords CT perfusion . Whole brain . Infarct core . Stroke
Introduction At this moment, intravenous treatment (IVT) and intra-arterial treatment (IAT) options for acute ischemic stroke are limited by a strict time window, being either 4.5 h (IVT) or 6–8 h (IAT). Several studies, however, suggest that IAT options for acute ischemic stroke may depend largely on the amount of tissue that has been irreversibly damaged as seen on diagnostic imaging at presentation [1–3]. Although recent studies using a multiparametric predictive model of the extent of the infarct core and the penumbra were not able to identify patients that would benefit from endovascular therapy [4, 5], Yoo et al. did show that an infarct core volume larger than 70 ml, as determined by MRI diffusion weighted imaging (DWI), does not warrant therapy because of poor outcome regardless of recanalization [6]. This result suggests that patients with an infarct core larger than 70 ml on admission imaging should probably not be exposed to the risks of intraarterial treatment, such as intracranial hemorrhage caused by reperfusion of the hypoxic brain tissue [7–9]. Another study also demonstrated that infarct core volume, as defined by DWI, is the most important predictor of outcome in patients with acute ischemic stroke [10]. Although availability of automated quantification of infarct core is still limited in most
1122
hospitals, automated solutions are likely to become more readily available in the near future. At the moment, clinical decisions are mostly based on qualitative analysis of infarct core volume. Nevertheless, this often involves some form of quantification like the Alberta Stroke Program Early CT Score (ASPECTS) or a cutoff value. A commonly used cutoff is one third of the MCA territory, corresponding roughly to 90 ml and thus slightly more liberal than the aforementioned 70 ml. In clinical practice, MRI is not readily available in the emergency setting in most hospitals. In addition, patient cooperation with subsequent movement artifacts is often problematic when using MRI, making this image modality less suitable in the acute diagnostic phase. Furthermore, automated measurement of infarct core volume on DWI is not possible in the acute setting at this moment [1]. Several studies have suggested that CT perfusion (CTP) might be used to triage acute ischemic patients for endovascular treatment [2, 11–13]. Reliable estimation of CTP parameters requires data acquisition in a single rotation. Most CT scanners provide 64 or 128 slice coverage in a single rotation, resulting in a coverage size of only 3 to 8 cm. Some studies suggest that coverage size as small as 4 cm suffices in the assessment of potentially treatable occlusions of the internal carotid artery (ICA) and middle cerebral artery (MCA) [11]. More recent studies show advantages of an 8-cm coverage size for detecting brain ischemia as compared to a smaller coverage size. A study comparing CTP with MRI stated that a coverage size of at least 7.5 cm would be sufficient to include the majority of the ischemic region and suggested that extended coverage size beyond 7.5 cm would probably not influence any treatment decision [14]. Nowadays, CT scanners with whole brain (16 cm) CTP coverage have become available in clinical practice. To our knowledge, no study has compared CTP results of limited coverage sizes with whole brain coverage in acute anterior cerebral circulation ischemia. Consequently, it is not known whether CTP coverage size matters with regard to clinical decision-making for IAT in patients with acute anterior circulation ischemia. The aim of this study was to compare infarct core volume on whole brain CTP with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. A secondary goal was to determine if a possible optimum exists for the placement of the region of interest (ROI) in scanners with limited coverage.
Methods Patient selection We included patients 18 years or older who were scanned at our institution within 9 h after onset of the first ischemic symptoms and showing imaging signs of acute ischemia in the anterior cerebral circulation on non-contrast CT (NCCT).
Neuroradiology (2014) 56:1121–1126
Patients waking up with acute ischemic stroke symptoms were only included if they went to bed without symptoms and presented in the hospital less than 9 h before going to bed. Patients were excluded if they were known to be allergic to contrast agents and with known renal failure. Patients with other diagnosis than acute cerebral ischemia on unenhanced CT, such as cerebral hemorrhage, subarachnoid hemorrhage, and tumors, were also excluded from the study. In total, 40 acute ischemic stroke patients with NCCT and CTP imaging of anterior circulation ischemia were included in this study. Patient demographics are given in Table 1. The site of occlusion as seen on CTA was distributed as follows: no occlusion, 9; anterior cerebral artery, 1; internal carotid artery and M1 segment of middle cerebral artery, 4; middle cerebral artery M1 segment to proximal M2 segment and middle cerebral artery distal M2 segment to M3 segment, 8; and middle cerebral artery M3 segment to M4 segment, 2. Imaging Imaging was performed using a 320-multislice CT (Aquilion One Toshiba Medical Systems, Tokyo, Japan). CTP studies were performed after exclusion of brain hemorrhage or other ischemic stroke mimics on NCCT. The 0.5-mm detector array enables 16-cm z-axis coverage, from the first cervical Table 1 Patient demographics Demographics (N=40) Age (years) (mean, SD) Female sex (%) Hypertension (%) Smoking in the past 12 months (%) Family history (%) Hypercholesterolemia (%) Diabetes (%) Median admission NIHSS (range)a Median symptom onset—CT (IQR)b 6 h mRS 3 monthsb
65 (13.2) 17 (42.5) 17 (42.5) 13 (32.5) 13 (32.5) 5 (12.5) 2 (5) 8 (2–27), unknown n=10
0–1 2–5 6 Treatmentb IVT alone IVT + IAT No IVT nor IAT
11 17 7
32 0 4
28 2 7
a
One patient presented with reduced consciousness (Glasgow Coma Score E1M4V1)
b
The number does not add up to 40 because of missing data
Neuroradiology (2014) 56:1121–1126
vertebral body to the skull vertex. A contrast bolus of 50 mL Ultravist 370 was given with a flow rate of 5.0 mL/s, followed by a saline flush of 35–50 mL and a flow rate of 5.0 mL/s, using a Stellant® CT Power Injector. In the early arterial phase, 4 dynamic volumes were acquired every 2 s with 160 mA and 80 kVp; in the mid-arterial phase (the so-called full dose phase), 6 dynamic volumes were acquired every 2 s with 300 mA and 80 kVp; in the late arterial phase, 3 dynamic volumes were acquired every 2 s with 160 mA and 80 kVp; and lastly, in the venous phase, 5 dynamic volumes were acquired every 5 s with 130 mA and 80 kVp. The last 6 dynamic volumes were acquired with an interval of 30 s. This final delayed phase of the protocol was part of the scientific protocol to calculate blood-barrier permeability maps (data not presented here). In total, 24 volumes were acquired. Every rotation took 0.75 s. The total effective dose for each scan was 8.4 mSv; without the delayed phase mentioned above, the total effective dose would amount to 7.3 mSv. Data analysis Commercial CT perfusion software (Extended Brilliance Workstation, version 4.5, Philips Medical Systems) was used to make volumetric quantifications of infarct core. The Philips CTP software uses rigid registration to correct for motion artifacts and an anisotropic, edge-preserving spatial filter for noise reduction. The dynamic CTP volumes were reconstructed to contiguous 5-mm slices using Toshiba Software in order to load the data into the Philips CTP software. Infarct core was defined by pixels with a mean transit time (MTT) >145 % of the contralateral side values and a reduced cerebral blood volume (CBV) 70ml 12 10 8 ASPECTS 1
6
Opmized
4 2 0 3 cm 4 cm 6 cm 8 cm
Fig. 2 The average volume of the infarct core as depicted by the different coverage sizes before (black) and after (shaded) optimization of the starting position. Note the difference between the average infarct core volume as depicted with non-optimized 8-cm coverage and the infarct core volume as depicted with whole brain (WB) coverage
WB
Fig. 3 The number of patients with an infarct core volume larger than 70 ml before (black) and after (shaded) optimization. Note that the number of patients with an infarct core larger than 70 ml differs between 8-cm and whole brain coverage before optimization. The sensitivity improves after optimization for 8 cm but decreases by one patient for 4 cm. This decrease was due to one patient in our study population with a relatively low starting infarction
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70 ml. This also holds true for a coverage size of 8 cm: in our study population, 2 patients would erroneously be depicted as having an infarct core volume smaller than 70 ml with 8-cm coverage as compared to whole brain coverage. If these scans with 8-cm coverage had been started at the optimal starting level for 8-cm coverage, i.e., 1.5 cm below ASPECTS 1 level, only 1 patient would have been misclassified as having an infarct core smaller than 70 ml.
Discussion The most important conclusion of this study is that CTP coverage determines depiction of infarct core volume in patients with acute anterior ischemic stroke, with an increase in detected infarct core volume beyond a CTP coverage of 8 cm. Our secondary finding is that the optimal starting level of the ROI in partial coverage CTP depends on the size of the coverage. Applying this optimization in our study population resulted on average in a larger percentage of the infarct core being depicted. Our results underline the importance of whole brain CTP coverage in correctly classifying the infarct core volume with regard to a suggested clinically relevant threshold of 70 ml for intra-arterial treatment [10]. In our patient group, 11 patients showed an infarct core volume of more than 70 ml; 2 of these 11 patients would erroneously be classified as having an infarct core volume below 70 ml when using 8-cm coverage. However, when using the optimized starting level for 8-cm coverage of 1.0 cm below ASPECTS 1 level, only 1 patient would be erroneously classified as having an infarct core volume below 70 ml in our study population. In clinical practice, this would imply that misclassification of patients with regard to intra-arterial treatment decisions would occur in roughly one out of five patients and with optimization of one out of ten. Obviously, this number increases with increased limitation of coverage size, as is common with available CT scanners in current clinical practice. This suggests that after optimization, 8-cm coverage might be a useful alternative if whole brain perfusion is not available. However, with 6-cm coverage, 1 out of 4 patients were misclassified as having an infarct core volume below 70 ml, even after optimization. It is therefore, probably, not recommended to make clinical decisions with regard to treatment choices based only on calculated infarct core volume on CTP studies when whole brain CTP or optimized 8-cm coverage studies are not available [15]. This requires further investigation as treatment decisions based only on infarct volume have only been tested with MRI. In addition, other possible information derived from CTP was not investigated in this study. A limitation of our study is the use of a standardized positioning of the CTP slab in the region of interest in every patient when limited CTP coverage was simulated; the starting
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point was chosen at the level of ASPECTS 1 [14–16]. In clinical practice, the CT technician might be able to place the CTP slab more optimally, based on the expected coverage, on the clinical context, and on the imaging findings on NCCT. However, signs of ischemia on NCCT are often not clearly visible in the (hyper)acute phase, and clinical symptoms may also be confusing (e.g., discriminating hemispheric from cerebellar ischemia). Some authors therefore advise localization of the CTP slab at or at least including the level of the basal ganglia (ASPECTS 1 level) and sometimes the third ventricle [16–18]. In our patient group, we showed that the optimal placement of the CTP slab actually depends on the size of the CTP coverage. Obviously, whole brain CTP coverage eliminates this problem. Accordingly, one might argue that whole brain CTP coverage has added value in posterior fossa ischemia. However, considering the relative limited spatial resolution of CTP in combination with often small size of infarcts in posterior fossa ischemia, the value of CTP in the region of the posterior fossa has yet to be determined, preferably in a comparative study including CTP and DWI MRI. Recently, concern has arisen about diagnostic accuracy of CTP imaging for detecting acute ischemic stroke. Some argue that contrast to noise ratio (CNR) of CTP studies is too limited (CNR 8). A recent meta-analysis, however, showed that CTP has high sensitivity (80 %) and very high specificity (95 %) for detecting infarcts, with false negative findings being either due to small lacunar infarcts or limited coverage [2]. Obviously, false negative CTP studies in case of lacunar infarcts will not influence clinical decision-making with regard to choice of IAT, since no arterial occlusion will be visible on CT angiography to serve as target for IAT, and whole brain CTP would solve the latter problem. In CTP, the infarct core and the penumbra are best defined by using the relative MTT and the absolute CBV [19]. This approach is, at best, proportional to the infarct core on DWI. Nonetheless, this does not change the importance of depicting the maximum amount of the parameter considered important in clinical decision-making. Reproducibility of CTP results is another subject of concern. CTP analysis is influenced by acquisition methods and software CTP analysis settings and algorithms. Different postprocessing software packages do not necessarily produce similar infarct core volumes, underscoring the importance of further standardization and validation of CTP postprocessing software [17, 18]. Finally, critics of CTP always highlight the radiation dose in CTP. However, the effective dose of our extended scientific protocol is lower than the radiation dose of an average abdominal CT scan. Further lowering of the radiation dose is feasible by limiting acquisition time to the clinically relevant time period and increase to the sampling interval [20].
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In conclusion, this study shows that whole brain CTP is recommended when clinical decision-making with regard to IAT is made based only on infarct core volume, an issue that has become important since infarct core volume is suggested to be a pivotal biomarker for clinical outcome in patients with acute anterior ischemic stroke. In addition, our study suggests that in partial coverage CTP, the optimal position of ROI depends on the size of the partial coverage.
Ethical standards and patient consent We declare that all human and animal studies have been approved by the Medical Ethical Committee of the Leiden University Medical Centre and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Conflict of interest We declare that we have no conflict of interest.
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