Original Paper Received: November 18, 2015 Accepted: December 10, 2015 Published online: January 7, 2016
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
Acute Stroke Syndromes with Isolated Hypoperfusion on MRI – A Clinical and MRI Study Angelika Alonso Kristina Szabo Marc E. Wolf Anne D. Ebert Martin Griebe Michael G. Hennerici Achim Gass Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany
Abstract Background: Acute stroke syndromes with negative diffusion-weighted imaging (DWI) but extensive perfusion deficits are rare and constitute a diagnostic challenge due to different operational definitions of penumbral hypoperfusion in acute stroke patients based on MRI criteria. Methods: MR profiles of 19 patients presenting with acute stroke syndromes with negative DWI in the presence of an extensive area of hypoperfusion on time-to-peak (TTP) maps of dynamic susceptibility contrast perfusion-weighted imaging (PWI) were analysed. DWI and PWI lesions were quantified and interpreted with regard to the clinical course. Results: Despite the large area of abnormal perfusion on TTP maps, the clinical course was benign (median National Institute of Health Stroke Scale 2 at admission, 0 at discharge). The volume of hypoperfused tissue was significantly smaller on postprocessed TTP maps with a TTP delay of >4 s than on unprocessed TTP maps with manual contrast adjustment. Semiquantitatively assessed TTP lesion volume was associated with the presence of DWI lesions on follow-up. Conclu-
© 2016 S. Karger AG, Basel 0014–3022/16/0752–0027$39.50/0 E-Mail [email protected] www.karger.com/ene
sion: TTP maps are highly sensitive to demonstrate even small-scale perfusion abnormalities. The additional information from TTP delay thresholds indicates critically reduced perfusion and appears to be a good prognostic indicator in combination with MR angiography and symptomatology. © 2016 S. Karger AG, Basel
Introduction
The main goal in acute stroke therapy is the salvation of the ischemic penumbra, traditionally defined as a region with mild to moderate reduction of cerebral blood flow (CBF) but yet viable and thus salvageable neurons [1]. Several clinical imaging modalities have been evaluated to characterize this tissue-at-risk. According to the concept of a diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) magnetic resonance imaging, the DWI/PWI mismatch was assumed to be a surrogate of the ischemic penumbra [2]. In this context, DWI/PWI mismatch has widely been used to identify patients with best potential benefit from thrombolysis. However, a recent meta-analysis of clinical trials failed to show a significant benefit [3]. Rather than disproving the mismatch concept, this meta-analysis points to a major Dr. Angelika Alonso Department of Neurology, Universitätsmedizin Mannheim University of Heidelberg, Theodor-Kutzer-Ufer 1-3 DE–68167 Mannheim (Germany) E-Mail alonso @ neuro.ma.uni-heidelberg.de
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Key Words Stroke · Diffusion-weighted imaging · Perfusion-weighted imaging · Mismatch · Thrombolysis
Patients and Methods This study was approved by the local Institutional Review Board (Medizinische Ethikkommission II der Medizinischen Fakultät Mannheim, University of Heidelberg). Patient consent was not required due to the retrospective nature of the study and lack of patient interaction. From our prospectively collected Stroke Unit Database, we identified 19 patients (13 male, mean age 69.6 years, range 44–81 years) with acute stroke symptoms, a negative DWI examination and a perfusion deficit in the initial MRI evaluation during the years 2008–2012. All patients underwent initial and follow-up cranial MRI using a standardized stroke protocol with transverse, coronal and sagittal localizing sequences, followed by transverse oblique slices aligned with the inferior borders of the corpus callosum including T1 (TE 2.5 ms, TR 225 ms, in-plane resolution 320 × 320, slice thickness 5 mm), T2 (TE 78 ms, TR 4,000 ms, inplane resolution 384 × 384, slice thickness 5 mm), fluid-attenuated-inversion-recovery (TE 136 ms, TR 8,500 ms, TI 2,500 ms, inplane resolution 256 × 184, slice thickness 5 mm), T2* (TE 19.9 ms, TR 594 ms, in-plane resolution 256 × 205, slice thickness 5 mm), and DWI images (DWI, TE 68 ms, TR 5,300 ms, in-plane resolution 192 × 192, slice thickness 5 mm, b = 0/500/1,000 s/mm2). The site of arterial occlusion, if any, was assessed by time-of-flight MRangiography (MRA; TE 3.4 ms, TR 21 ms, in-plane resolution 384 × 295, slice thickness 5 mm) and verified by extra- or intracranial Doppler-/duplexsonography. Dynamic susceptibility contrast (DSC) MRI was performed with manual injection of Gadolinium (Dotarem®, 0.1 mmol/kg body weight; TE 30 ms, TR 1,350 ms, inplane resolution 128 × 128, slice thickness 4 mm). For evaluation
28
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
of areas with compromised blood flow, TTP maps were conducted. The unprocessed PWI hypoperfused volumes were calculated after manual contrast adjustment, allowing delineation of the maximum hypoperfused area, regardless of the grade of hypoperfusion. For semiquantitative evaluation of TTP maps, the contralateral MCA territory was used as reference tissue. A delay of the bolus arrival >4 s in the affected region compared to the reference region was considered threshold, indicating moderately to severely hypoperfused brain tissue [8]. DWI and PWI volumes were calculated by manual outline by an experienced reader unaware of the clinical data. Initial and follow-up MRIs were further analysed for the presence of intracranial hemorrhage. All technical investigations as well as demographic and clinical data, including the National Institute of Health Stroke Scale (NIHSS) score were documented for each patient. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS version 22.0.0.0; IBM, USA), implementing χ2 test for categorical and Mann–Whitney U test or Wilcoxon-test for metric variables as data were not normally distributed. A p value 4 s, cm3
Thrombolysis
Follow-up NIHSS DWI+ admission
NIHSS discharge
M, 64 M, 65 F, 77 M, 70 M, 76 F, 72 M, 75 F, 76 M, 60 F, 77 M, 65 F, 81 M, 54 M, 73 F, 81 M, 68 M, 44 M, 80 M, 63
60 285 Wake up stroke 170 Wake up stroke 515 Wake up stroke Wake up stroke 220 90 120 280 180 120 120 120 240 300 135
ACA, l MCA, l MCA, l MCA, r MCA, r MCA, r MCA/PCA, r MCA, r MCA, r MCA, r PCA, l MCA, l MCA, l MCA, l MCA, l MCA, l PCA, r PICA, l MCA, l
38.40 137.11 88.84 103.45 38.06 115.62 246.31 19.14 199.17 15.62 3.24 64.29 12.05 265.93 46.57 6.46 52.38 34.38 95.71
0.10 1.39 0.91 21.40 0.30 8.28 0 3.19 0.05 0.08 0 2.11 2.16 42.39 8.47 0.03 0.01 0.08 17.88
y y y y y n n n n n n n n n n n n n n
y n y y y y n y y n n n n y y n n n y
0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 2 0
2 9 3 2 7 5 1 2 5 0 0 5 1 12 0 0 3 3 1
ed to thrombolysis and non-treated patients (81.17 ± 42.93 cm3; median 88.84 cm3/IQR 38.23–120.28 vs. 84.06 ± 90.17 cm3; median 49.47 cm3/IQR 14.73–136.50 cm3, p = 0.559, Mann–Whitney U test). After postprocessing with implementation of a threshold for TTP delay of 4 s, 2 patients did not show hypoperfused tissue. Over all patients, the volume of hypoperfused tissue was significantly smaller than on qualitatively analysed TTP maps, with a mean volume of 5.73 ± 10.84 cm3 (median 0.91 cm3/IQR 0.05–8.28 cm3; p < 0.0001, Wilcoxon test). Three patients with acute hemispheric stroke symptoms and hypoperfusion in the MCA territory showed a proximal pathology of the corresponding ICA but with preserved flow signal at the level of the circle of Willis. Only one patient, presenting with a transient hemihypaesthesia of his right-sided limbs, had a moderate-to-severe stenosis of an intracranial artery with loss of signal of the left PCA in the time-of-flight-angiography together with a perfusion deficit projecting onto the left thalamus. In all remaining patients, no extra- or intracranial vessel pathology could be detected by MRA and Doppler-/duplexsonography. In all patients, the persisting or transient neurological deficits corresponded anatomically to the area of hypo-
perfusion. Looking at it the other way round, we did not detect additional areas of hypoperfusion, which were unrelated to the presenting symptoms. Follow-up MRI was performed in all patients at a median of 1.5 days (range 1–5 days) after the initial MRI. Ten of 19 patients (4/5 patients receiving thrombolysis and 6/14 patients without thrombolytic therapy, p = 0.303) showed newly developed DWI lesions in the formerly hypoperfused areas. In all but a single patient, the lesions were small and scattered. A representative example is given in figure 1. Patients with larger volumes of hypoperfused area on initial MR when implementing a 4 s threshold for bolus delay on TTP maps were more likely to develop DWI lesions on follow-up MRI (p = 0.010, Mann–Whitney U test), while there was no association between hypoperfusion volume on qualitatively analysed TTP maps and presence of DWI lesions on follow-up MRI (p = 0.133, Mann–Whitney U test). Again, there was no difference in DWI lesion volume between thrombolysed and non-treated patients (0.43 ± 0.60 cm3; median 0.27 cm3/IQR 0.03–0.92 vs. 0.39 ± 1.04 cm3; median 0.00 cm3/IQR 0.00–0.23 cm3, p = 0.219, Mann–Whitney U test). On T2*-weighted images, none of the patients had signs of secondary hemorrhage.
Stroke Syndromes with Isolated Hypoperfusion
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
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MCA = Middle cerebral artery; PCA = posterior cerebral artery; PICA = posterior inferior cerebellar artery; l = left; r = right; y = yes; n = no.
b
Fig. 1. Example of the imaging findings in a patient. An 81-yearold woman presented with acute onset of aphasia, which was nearly completely reversible at admission. Initial MRI (upper row) did not show a DWI lesion (a) but a cuneiform perfusion deficit on TTP maps (b) in the left MCA territory, involving the Wernicke’s area and the angular gyrus. On TTP maps with a threshold for bo-
Discussion
We report clinical and MR findings in acute stroke patients presenting with isolated signs of hypoperfusion on initial DSC MRI. This rare MR profile has first been described in 2009 in 3 patients with MCA branch occlusion [9] and was somewhat ambiguously termed ‘total mismatch’. Acute stroke patients presenting with a mismatch constellation of a small DWI abnormality and a much larger area of abnormal perfusion in TTP maps are commonly regarded at high risk for an increase of the infarct area and clinical worsening. However, although one may assume a higher risk of clinical worsening, single case reports suggested a favorable outcome in patients with ‘total mismatch’ [6]. We could demonstrate that a vast majority of our patients without initial DWI abnormality had a rather large perfusion deficit on qualitatively evaluated TTP maps despite preserved flow signal on the level of the circle of Willis on MRA. This initial combination of findings had a very good outcome at discharge and patients developed only small DWI lesions on follow-up. One key element for the best possible estimation of the risk to develop stroke lesions is the interpretation of DSCderived information. DSC MRI has widely been used to stratify patients’ eligibility for thrombolysis [10, 11]. Sev30
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
c
lus delay of >4 s, the hypoperfused area was substantially smaller (c). On follow-up imaging at day 3 (lower row), 2 small DWI lesions could be detected (a, red arrows), and the perfusion deficit was completely restored on both qualitative TTP and semiquantitative TTP maps (b, c).
eral parameter maps have been investigated. Among these, maps of TTP have been shown to give a simplified but robust estimate of the transit time [9]. In clinical practice, TTP maps are widely used to qualitatively assess hypoperfusion, as they are provided by automated calculations by most MRI systems. However, TTP maps are highly sensitive and susceptible to stenoocclusive disease [12]. In patients with underlying proximal vessel pathology as described in the so-termed ‘total mismatch’ constellation, TTP maps will thus yield large areas of compromised perfusion, not necessarily associated with a decrease of absolute CBF. The optimal threshold for a time delay in perfusion maps in order to distinguish benign oligemia and critical hypoperfusion is still under discussion, especially as the interindividual variation has been shown to be considerable. A common mismatch definition comprises a relative TTP delay of >4 s together with a PWI/DWI ratio of >1.2, based on a comparative PET/MRI study by Sobesky et al. [13]. Supporting this concept, further comparative PET/MRI study in acute stroke patients defined a relative TTP threshold of 4.2 and 4.8 s, respectively, as an optimal surrogate for a penumbral flow of 4 s resulted in a considerably smaller volume of hypoperfused tissue, amounting to about 6.5% of the qualitatively TTP-generated volume in our patients. The smaller volumes of moderately to severely hypoperfused tissue very well provide an answer to the mild clinical deficit at admission in our collective with a median NIHSS score of 2. Furthermore, the presence of DWI lesions in the follow-up scan was associated with the postprocessed TTP-generated, but not the unprocessed volume of hypoperfused tissue. This finding is in line with a previous study showing an association of DWI lesion enlargement on follow-up MRI and initial TTP delay of ≥6 s in a cohort of 20 patients with acute nonlacunar stroke [8]. The PWI information should further be interpreted in awareness of the underlying vessel pathology. In the presence of small DWI lesions, MRA evidence of an intracranial vessel stenosis or occlusion may indicate a potential benefit from early reperfusion. In analogy to the DWI/ PWI-mismatch, this concept has been termed ‘MRA/ DWI-mismatch’ [16]. In our study, only one patient had a moderate-to-severe stenosis at the level of the Circle of Willis. The lack of a detectable intracranial stenosis or occlusion in the presence of preserved flow signals in the Circle of Willis in 16/19 patients in our study might contribute to the observed favorable outcome. Finally, the clinical presentation is indispensable to a conclusive interpretation of the MR data. This consideration has led to the concept of a ‘clinical/DWI mismatch’: patients presenting with a score of ≥8 on the NIHSS but small DWI lesion of ≤25 ml have been shown to have a higher probability of both infarct growth and early neurologic deterioration [17]. In our cohort, no patient had initial DWI-lesions, coming close to the ‘clinical-DWI mismatch’ constellation. However, most patients showed already partial recovery at the time of MRI with a median NIHSS score of only 2 and complete recovery in 4 patients. From a functional point of view, this finding indicates the presence of a compensated perfusion abnormality. As a limitation of the study, we have to take into account that the decision for or against thrombolysis was
made according to the preferences of the treating neurologist, thus bearing the risk of a bias. Taking together, postprocessed TTP maps with implementation of a bolus delay threshold of >4 s were much better indicators of truly critical perfusion status within the brain tissue. The lack of main stem occlusions on MRA rather suggests the presence of small branch occlusions beyond the resolution of common MRA sequences. Both the lack of major branch occlusions and only a small area of moderate to severe hypoperfusion on semiquantitatively evaluated TTP maps may be seen as prognostic important indicators of a relatively small and possibly incomplete vascular pathology. It is likely that these factors were relevant for the benign outcome. In conclusion, in patients with new onset acute stroke symptoms, areas of isolated hypoperfusion in the absence of a DWI lesion can occasionally be seen. This could potentially be the starting point of a large stroke lesion due to a very early presentation after the onset of the ischemia or alternatively may be due to a minor degree of hypoperfusion. Evaluating DSC perfusion MRI critically beyond a qualitative inspection of TTP map by subtracting the bolus arrival time of contralateral unaffected tissue with a defined threshold is a simple alternative that can be derived on-site from unprocessed TTP maps. Integration of the information from bolus delay thresholds, MRA and clinical data is likely to provide better prognostic estimates.
Stroke Syndromes with Isolated Hypoperfusion
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
Disclosure Statement The authors report no conflicts of interest.
1 Heiss WD: The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. The Johann Jacob Wepfer award 2011. Cerebrovasc Dis 2011; 32:307–320. 2 Røhl L, Ostergaard L, Simonsen CZ, et al: Viability thresholds of ischemic penumbra of hyperacute stroke defined by perfusionweighted MRI and apparent diffusion coefficient. Stroke 2001;32:1140–1146. 3 Mishra NK, Albers GW, Davis SM, et al: Mismatch-based delayed thrombolysis: a metaanalysis. Stroke 2010;41:e25–e33. 4 Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J: Maps of time to maximum and time to peak for mismatch definition in clinical stroke studies validated with positron emission tomography. Stroke 2010; 41: 2817– 2821.
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References
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10 Davis SM, Donnan GA, Parsons MW, et al: Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7:299– 309. 11 Albers GW, Thijs VN, Wechsler L, et al: Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508–517. 12 Yamada K, Wu O, Gonzalez RG, et al: Magnetic resonance perfusion-weighted imaging of acute cerebral infarction: effect of the calculation methods and underlying vasculopathy. Stroke 2002;33:87–94. 13 Sobesky J, Zaro Weber O, Lehnhardt FG, et al: Which time-to-peak threshold best identifies penumbral flow? A comparison of perfusionweighted magnetic resonance imaging and positron emission tomography in acute ischemic stroke. Stroke 2004;35:2843–2847.
14 Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J: A simple positron emission tomography-based calibration for perfusionweighted magnetic resonance maps to optimize penumbral flow detection in acute stroke. Stroke 2010;41:1939–1945. 15 Takasawa M, Jones PS, Guadagno JV, et al: How reliable is perfusion MR in acute stroke? Validation and determination of the penumbra threshold against quantitative PET. Stroke 2008;39:870–877. 16 Lansberg MG, Thijs VN, Bammer R, et al: The MRA-DWI mismatch identifies patients with stroke who are likely to benefit from reperfusion. Stroke 2008;39:2491–2496. 17 Dávalos A, Blanco M, Pedraza S, et al: The clinical-DWI mismatch: a new diagnostic approach to the brain tissue at risk of infarction. Neurology 2004;62:2187–2192.
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5 Forkert ND, Kaesemann P, Treszl A, et al: Comparison of 10 TTP and Tmax estimation techniques for MR perfusion-diffusion mismatch quantification in acute stroke. AJNR Am J Neuroradiol 2013;34:1697–1703. 6 Kim JT, Park MS, Kim MK, Cho KH: Minor stroke with total mismatch after acute MCA occlusion. J Neuroimaging 2011;21:399–402. 7 Fustier A, Naggara O, Tisserand M, et al: Total mismatch in anterior circulation stroke patients before thrombolysis. J Neuroradiol 2013;40:158–163. 8 Neumann-Haefelin T, Wittsack HJ, Wenserski F, et al: Diffusion- and perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke. Stroke 1999;30:1591–1597. 9 Cho TH, Hermier M, Alawneh JA, et al: Total mismatch: negative diffusion-weighted imaging but extensive perfusion defect in acute stroke. Stroke 2009;40:3400–3402.
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
Acute Stroke Syndromes with Isolated Hypoperfusion on MRI – A Clinical and MRI Study Angelika Alonso Kristina Szabo Marc E. Wolf Anne D. Ebert Martin Griebe Michael G. Hennerici Achim Gass Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany
Abstract Background: Acute stroke syndromes with negative diffusion-weighted imaging (DWI) but extensive perfusion deficits are rare and constitute a diagnostic challenge due to different operational definitions of penumbral hypoperfusion in acute stroke patients based on MRI criteria. Methods: MR profiles of 19 patients presenting with acute stroke syndromes with negative DWI in the presence of an extensive area of hypoperfusion on time-to-peak (TTP) maps of dynamic susceptibility contrast perfusion-weighted imaging (PWI) were analysed. DWI and PWI lesions were quantified and interpreted with regard to the clinical course. Results: Despite the large area of abnormal perfusion on TTP maps, the clinical course was benign (median National Institute of Health Stroke Scale 2 at admission, 0 at discharge). The volume of hypoperfused tissue was significantly smaller on postprocessed TTP maps with a TTP delay of >4 s than on unprocessed TTP maps with manual contrast adjustment. Semiquantitatively assessed TTP lesion volume was associated with the presence of DWI lesions on follow-up. Conclu-
© 2016 S. Karger AG, Basel 0014–3022/16/0752–0027$39.50/0 E-Mail [email protected] www.karger.com/ene
sion: TTP maps are highly sensitive to demonstrate even small-scale perfusion abnormalities. The additional information from TTP delay thresholds indicates critically reduced perfusion and appears to be a good prognostic indicator in combination with MR angiography and symptomatology. © 2016 S. Karger AG, Basel
Introduction
The main goal in acute stroke therapy is the salvation of the ischemic penumbra, traditionally defined as a region with mild to moderate reduction of cerebral blood flow (CBF) but yet viable and thus salvageable neurons [1]. Several clinical imaging modalities have been evaluated to characterize this tissue-at-risk. According to the concept of a diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) magnetic resonance imaging, the DWI/PWI mismatch was assumed to be a surrogate of the ischemic penumbra [2]. In this context, DWI/PWI mismatch has widely been used to identify patients with best potential benefit from thrombolysis. However, a recent meta-analysis of clinical trials failed to show a significant benefit [3]. Rather than disproving the mismatch concept, this meta-analysis points to a major Dr. Angelika Alonso Department of Neurology, Universitätsmedizin Mannheim University of Heidelberg, Theodor-Kutzer-Ufer 1-3 DE–68167 Mannheim (Germany) E-Mail alonso @ neuro.ma.uni-heidelberg.de
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/26/2016 4:53:29 AM
Key Words Stroke · Diffusion-weighted imaging · Perfusion-weighted imaging · Mismatch · Thrombolysis
Patients and Methods This study was approved by the local Institutional Review Board (Medizinische Ethikkommission II der Medizinischen Fakultät Mannheim, University of Heidelberg). Patient consent was not required due to the retrospective nature of the study and lack of patient interaction. From our prospectively collected Stroke Unit Database, we identified 19 patients (13 male, mean age 69.6 years, range 44–81 years) with acute stroke symptoms, a negative DWI examination and a perfusion deficit in the initial MRI evaluation during the years 2008–2012. All patients underwent initial and follow-up cranial MRI using a standardized stroke protocol with transverse, coronal and sagittal localizing sequences, followed by transverse oblique slices aligned with the inferior borders of the corpus callosum including T1 (TE 2.5 ms, TR 225 ms, in-plane resolution 320 × 320, slice thickness 5 mm), T2 (TE 78 ms, TR 4,000 ms, inplane resolution 384 × 384, slice thickness 5 mm), fluid-attenuated-inversion-recovery (TE 136 ms, TR 8,500 ms, TI 2,500 ms, inplane resolution 256 × 184, slice thickness 5 mm), T2* (TE 19.9 ms, TR 594 ms, in-plane resolution 256 × 205, slice thickness 5 mm), and DWI images (DWI, TE 68 ms, TR 5,300 ms, in-plane resolution 192 × 192, slice thickness 5 mm, b = 0/500/1,000 s/mm2). The site of arterial occlusion, if any, was assessed by time-of-flight MRangiography (MRA; TE 3.4 ms, TR 21 ms, in-plane resolution 384 × 295, slice thickness 5 mm) and verified by extra- or intracranial Doppler-/duplexsonography. Dynamic susceptibility contrast (DSC) MRI was performed with manual injection of Gadolinium (Dotarem®, 0.1 mmol/kg body weight; TE 30 ms, TR 1,350 ms, inplane resolution 128 × 128, slice thickness 4 mm). For evaluation
28
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
of areas with compromised blood flow, TTP maps were conducted. The unprocessed PWI hypoperfused volumes were calculated after manual contrast adjustment, allowing delineation of the maximum hypoperfused area, regardless of the grade of hypoperfusion. For semiquantitative evaluation of TTP maps, the contralateral MCA territory was used as reference tissue. A delay of the bolus arrival >4 s in the affected region compared to the reference region was considered threshold, indicating moderately to severely hypoperfused brain tissue [8]. DWI and PWI volumes were calculated by manual outline by an experienced reader unaware of the clinical data. Initial and follow-up MRIs were further analysed for the presence of intracranial hemorrhage. All technical investigations as well as demographic and clinical data, including the National Institute of Health Stroke Scale (NIHSS) score were documented for each patient. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS version 22.0.0.0; IBM, USA), implementing χ2 test for categorical and Mann–Whitney U test or Wilcoxon-test for metric variables as data were not normally distributed. A p value 4 s, cm3
Thrombolysis
Follow-up NIHSS DWI+ admission
NIHSS discharge
M, 64 M, 65 F, 77 M, 70 M, 76 F, 72 M, 75 F, 76 M, 60 F, 77 M, 65 F, 81 M, 54 M, 73 F, 81 M, 68 M, 44 M, 80 M, 63
60 285 Wake up stroke 170 Wake up stroke 515 Wake up stroke Wake up stroke 220 90 120 280 180 120 120 120 240 300 135
ACA, l MCA, l MCA, l MCA, r MCA, r MCA, r MCA/PCA, r MCA, r MCA, r MCA, r PCA, l MCA, l MCA, l MCA, l MCA, l MCA, l PCA, r PICA, l MCA, l
38.40 137.11 88.84 103.45 38.06 115.62 246.31 19.14 199.17 15.62 3.24 64.29 12.05 265.93 46.57 6.46 52.38 34.38 95.71
0.10 1.39 0.91 21.40 0.30 8.28 0 3.19 0.05 0.08 0 2.11 2.16 42.39 8.47 0.03 0.01 0.08 17.88
y y y y y n n n n n n n n n n n n n n
y n y y y y n y y n n n n y y n n n y
0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 2 0
2 9 3 2 7 5 1 2 5 0 0 5 1 12 0 0 3 3 1
ed to thrombolysis and non-treated patients (81.17 ± 42.93 cm3; median 88.84 cm3/IQR 38.23–120.28 vs. 84.06 ± 90.17 cm3; median 49.47 cm3/IQR 14.73–136.50 cm3, p = 0.559, Mann–Whitney U test). After postprocessing with implementation of a threshold for TTP delay of 4 s, 2 patients did not show hypoperfused tissue. Over all patients, the volume of hypoperfused tissue was significantly smaller than on qualitatively analysed TTP maps, with a mean volume of 5.73 ± 10.84 cm3 (median 0.91 cm3/IQR 0.05–8.28 cm3; p < 0.0001, Wilcoxon test). Three patients with acute hemispheric stroke symptoms and hypoperfusion in the MCA territory showed a proximal pathology of the corresponding ICA but with preserved flow signal at the level of the circle of Willis. Only one patient, presenting with a transient hemihypaesthesia of his right-sided limbs, had a moderate-to-severe stenosis of an intracranial artery with loss of signal of the left PCA in the time-of-flight-angiography together with a perfusion deficit projecting onto the left thalamus. In all remaining patients, no extra- or intracranial vessel pathology could be detected by MRA and Doppler-/duplexsonography. In all patients, the persisting or transient neurological deficits corresponded anatomically to the area of hypo-
perfusion. Looking at it the other way round, we did not detect additional areas of hypoperfusion, which were unrelated to the presenting symptoms. Follow-up MRI was performed in all patients at a median of 1.5 days (range 1–5 days) after the initial MRI. Ten of 19 patients (4/5 patients receiving thrombolysis and 6/14 patients without thrombolytic therapy, p = 0.303) showed newly developed DWI lesions in the formerly hypoperfused areas. In all but a single patient, the lesions were small and scattered. A representative example is given in figure 1. Patients with larger volumes of hypoperfused area on initial MR when implementing a 4 s threshold for bolus delay on TTP maps were more likely to develop DWI lesions on follow-up MRI (p = 0.010, Mann–Whitney U test), while there was no association between hypoperfusion volume on qualitatively analysed TTP maps and presence of DWI lesions on follow-up MRI (p = 0.133, Mann–Whitney U test). Again, there was no difference in DWI lesion volume between thrombolysed and non-treated patients (0.43 ± 0.60 cm3; median 0.27 cm3/IQR 0.03–0.92 vs. 0.39 ± 1.04 cm3; median 0.00 cm3/IQR 0.00–0.23 cm3, p = 0.219, Mann–Whitney U test). On T2*-weighted images, none of the patients had signs of secondary hemorrhage.
Stroke Syndromes with Isolated Hypoperfusion
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
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MCA = Middle cerebral artery; PCA = posterior cerebral artery; PICA = posterior inferior cerebellar artery; l = left; r = right; y = yes; n = no.
b
Fig. 1. Example of the imaging findings in a patient. An 81-yearold woman presented with acute onset of aphasia, which was nearly completely reversible at admission. Initial MRI (upper row) did not show a DWI lesion (a) but a cuneiform perfusion deficit on TTP maps (b) in the left MCA territory, involving the Wernicke’s area and the angular gyrus. On TTP maps with a threshold for bo-
Discussion
We report clinical and MR findings in acute stroke patients presenting with isolated signs of hypoperfusion on initial DSC MRI. This rare MR profile has first been described in 2009 in 3 patients with MCA branch occlusion [9] and was somewhat ambiguously termed ‘total mismatch’. Acute stroke patients presenting with a mismatch constellation of a small DWI abnormality and a much larger area of abnormal perfusion in TTP maps are commonly regarded at high risk for an increase of the infarct area and clinical worsening. However, although one may assume a higher risk of clinical worsening, single case reports suggested a favorable outcome in patients with ‘total mismatch’ [6]. We could demonstrate that a vast majority of our patients without initial DWI abnormality had a rather large perfusion deficit on qualitatively evaluated TTP maps despite preserved flow signal on the level of the circle of Willis on MRA. This initial combination of findings had a very good outcome at discharge and patients developed only small DWI lesions on follow-up. One key element for the best possible estimation of the risk to develop stroke lesions is the interpretation of DSCderived information. DSC MRI has widely been used to stratify patients’ eligibility for thrombolysis [10, 11]. Sev30
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
c
lus delay of >4 s, the hypoperfused area was substantially smaller (c). On follow-up imaging at day 3 (lower row), 2 small DWI lesions could be detected (a, red arrows), and the perfusion deficit was completely restored on both qualitative TTP and semiquantitative TTP maps (b, c).
eral parameter maps have been investigated. Among these, maps of TTP have been shown to give a simplified but robust estimate of the transit time [9]. In clinical practice, TTP maps are widely used to qualitatively assess hypoperfusion, as they are provided by automated calculations by most MRI systems. However, TTP maps are highly sensitive and susceptible to stenoocclusive disease [12]. In patients with underlying proximal vessel pathology as described in the so-termed ‘total mismatch’ constellation, TTP maps will thus yield large areas of compromised perfusion, not necessarily associated with a decrease of absolute CBF. The optimal threshold for a time delay in perfusion maps in order to distinguish benign oligemia and critical hypoperfusion is still under discussion, especially as the interindividual variation has been shown to be considerable. A common mismatch definition comprises a relative TTP delay of >4 s together with a PWI/DWI ratio of >1.2, based on a comparative PET/MRI study by Sobesky et al. [13]. Supporting this concept, further comparative PET/MRI study in acute stroke patients defined a relative TTP threshold of 4.2 and 4.8 s, respectively, as an optimal surrogate for a penumbral flow of 4 s resulted in a considerably smaller volume of hypoperfused tissue, amounting to about 6.5% of the qualitatively TTP-generated volume in our patients. The smaller volumes of moderately to severely hypoperfused tissue very well provide an answer to the mild clinical deficit at admission in our collective with a median NIHSS score of 2. Furthermore, the presence of DWI lesions in the follow-up scan was associated with the postprocessed TTP-generated, but not the unprocessed volume of hypoperfused tissue. This finding is in line with a previous study showing an association of DWI lesion enlargement on follow-up MRI and initial TTP delay of ≥6 s in a cohort of 20 patients with acute nonlacunar stroke [8]. The PWI information should further be interpreted in awareness of the underlying vessel pathology. In the presence of small DWI lesions, MRA evidence of an intracranial vessel stenosis or occlusion may indicate a potential benefit from early reperfusion. In analogy to the DWI/ PWI-mismatch, this concept has been termed ‘MRA/ DWI-mismatch’ [16]. In our study, only one patient had a moderate-to-severe stenosis at the level of the Circle of Willis. The lack of a detectable intracranial stenosis or occlusion in the presence of preserved flow signals in the Circle of Willis in 16/19 patients in our study might contribute to the observed favorable outcome. Finally, the clinical presentation is indispensable to a conclusive interpretation of the MR data. This consideration has led to the concept of a ‘clinical/DWI mismatch’: patients presenting with a score of ≥8 on the NIHSS but small DWI lesion of ≤25 ml have been shown to have a higher probability of both infarct growth and early neurologic deterioration [17]. In our cohort, no patient had initial DWI-lesions, coming close to the ‘clinical-DWI mismatch’ constellation. However, most patients showed already partial recovery at the time of MRI with a median NIHSS score of only 2 and complete recovery in 4 patients. From a functional point of view, this finding indicates the presence of a compensated perfusion abnormality. As a limitation of the study, we have to take into account that the decision for or against thrombolysis was
made according to the preferences of the treating neurologist, thus bearing the risk of a bias. Taking together, postprocessed TTP maps with implementation of a bolus delay threshold of >4 s were much better indicators of truly critical perfusion status within the brain tissue. The lack of main stem occlusions on MRA rather suggests the presence of small branch occlusions beyond the resolution of common MRA sequences. Both the lack of major branch occlusions and only a small area of moderate to severe hypoperfusion on semiquantitatively evaluated TTP maps may be seen as prognostic important indicators of a relatively small and possibly incomplete vascular pathology. It is likely that these factors were relevant for the benign outcome. In conclusion, in patients with new onset acute stroke symptoms, areas of isolated hypoperfusion in the absence of a DWI lesion can occasionally be seen. This could potentially be the starting point of a large stroke lesion due to a very early presentation after the onset of the ischemia or alternatively may be due to a minor degree of hypoperfusion. Evaluating DSC perfusion MRI critically beyond a qualitative inspection of TTP map by subtracting the bolus arrival time of contralateral unaffected tissue with a defined threshold is a simple alternative that can be derived on-site from unprocessed TTP maps. Integration of the information from bolus delay thresholds, MRA and clinical data is likely to provide better prognostic estimates.
Stroke Syndromes with Isolated Hypoperfusion
Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
Disclosure Statement The authors report no conflicts of interest.
1 Heiss WD: The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. The Johann Jacob Wepfer award 2011. Cerebrovasc Dis 2011; 32:307–320. 2 Røhl L, Ostergaard L, Simonsen CZ, et al: Viability thresholds of ischemic penumbra of hyperacute stroke defined by perfusionweighted MRI and apparent diffusion coefficient. Stroke 2001;32:1140–1146. 3 Mishra NK, Albers GW, Davis SM, et al: Mismatch-based delayed thrombolysis: a metaanalysis. Stroke 2010;41:e25–e33. 4 Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J: Maps of time to maximum and time to peak for mismatch definition in clinical stroke studies validated with positron emission tomography. Stroke 2010; 41: 2817– 2821.
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Eur Neurol 2016;75:27–32 DOI: 10.1159/000443305
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