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Patient “candidate” for thrombolysis: MRI is essential
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Diagnostic and Interventional Imaging (2014) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
Patient ‘‘candidate’’ for thrombolysis: MRI is essential M. Tisserand , O. Naggara , L. Legrand , C. Mellerio , M. Edjlali , S. Lion , C. Rodriguez-Régent , R. Souillard-Scemama , C.-F. Jbanca , D. Trystram , J.-F. Méder , C. Oppenheim ∗ Centre de psychiatrie et neurosciences, Inserm S894, université Paris Descartes, Sorbonne Paris Cité, neuroimagerie, Sainte-Anne hospital, 1, rue Cabanis, 75014 Paris, France
KEYWORDS Arterial ischemic stroke; Thrombolysis; Diffusion-weighted imaging; Penumbra; Perfusion-weighted imaging
Abstract Because of its excellent sensitivity and specificity to diagnose arterial ischemic stroke (AIS) in the acute phase, MRI answers the main questions to guide treatment in ‘‘candidates’’ for thrombolysis. It lasts less than ten minutes, can confirm the diagnosis of AIS and distinguish it from hematomas and other ‘‘stroke mimics’’. It can identify the ischemic penumbra (perfusion-diffusion mismatch), determine the site of occlusion and provide prognostic information to adapt treatment in some cases in which the indications are poorly defined. In light of the most recent scientific findings, MRI can guide the treatment turning it into the investigation of choice in ‘‘candidates’’ for thrombolysis. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc
Clinical studies showing the effectiveness of intravenous (IV) rt-PA (recombinant tissue plasminogen activator) in arterial ischemic stroke (AIS) have selected patients based on brain CT. In this case the purpose of imaging was to exclude an intracranial hemorrhagic lesion. The NINDS [1] study, the princeps IV thrombolysis study, was published in 1995 and many improvements have been made in imaging since then. Currently, more sophisticated imaging is often preferred to select candidates for thrombolysis. The French National Health Authority guidelines published in May 2009 [2] on the management of AIS in the acute phase state: ‘‘patients suspected of having acute AIS must have priority access (24/24 h 7/7 d) to cerebral imaging [. . .]. MRI is the best investigation to show early signs of ischemia and visualize intracranial hemorrhage. This should be
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Corresponding author. E-mail address: [email protected] (C. Oppenheim).
http://dx.doi.org/10.1016/j.diii.2014.07.003 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
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performed as the first line examination. If MRI is available as a first line investigation it should be accessible in the emergency settings and short protocols should be preferred [. . .]. If urgent access to MRI is not available, a cerebral CT should be performed’’. These guidelines stress the importance of accessibility and speed of MRI, which are the prerequisite conditions, in order to avoid delaying intravenous thrombolytic therapy. Rapid MRI sequences (PROPELLER, Echo planar), which are of slightly poorer quality compared to the images used in other situations, can reduce the length of the investigation consistent with the adage ‘‘time is brain’’ [3]. MRI can therefore be performed without delaying patient care. The investigation protocol lasts between five and ten minutes and covers the entire brain without radiation. Patient agitation may deteriorate image quality although the information obtained is often sufficient for treatment decision (Fig. 1). Only 10—15% of patients therefore cannot access MRI (severe agitation, unstable hemodynamics or contra-indication) [4]. Some information provided by MRI are essential whereas others await validation, apart from some specific situations (> 4.5 h, age over 80 years old, unknown time of onset, etc.). The purposes of MRI are listed below: Primary objectives: • to exclude hematoma; • to confirm the positive diagnosis of AIS; • to exclude differential diagnoses. • • • • •
Secondary objectives: to characterize the infarction; to date the infarction; to assess the ‘‘core’’ of the infarction (necrosis); to establish the site of occlusion and collaterality; to assess the penumbra.
Primary objectives To exclude hematoma In order to exclude intraparenchymal hematoma, the main differential diagnosis from AIS [5—8], MRI performs as well
as CT, including during the first few hours after the onset of symptoms. The pattern of hematoma in the acute phase is: • diffusion-weighted imaging hyperintensity and reduced apparent diffusion coefficient. These can occasionally be confused with those of an AIS although a hematoma presents a more heterogeneous pattern, with magnetic susceptibility effects and a brighter diffusion-weighted hyperintensity than an acute ischemic lesion. This heterogeneous appearance is also seen on the T1-weighted image (performed as the localizing sequence) with a T1weighted hypointensity (whereas a hyperacute ischemic lesion is usually not seen on T1-weighted sequence) and a leaflike appearance in the periphery; • pronounced FLAIR hyperintensitity (the FLAIR hyperintensity is unusual in ischemic lesions before 3 hours); • peripheral T2*-weighted hypointensity consistent with the presence of deoxyhemoglobin (Fig. 2). Combined analysis of the different sequences, particularly diffusion-weighted and T2*-weighted images avoid missing the diagnosis of hematoma which is a contraindication to thrombolytic therapy. Apart from symptomatic intraparenchymal hematoma, the T2*-weighted image may show one or several chronic microbleeds (Fig. 3). These are not seen on CT and may be single or multiple, lying deeply (hypertensive origin), or peripherally (in that case they are suggestive of amyloid angiopathy [9]). In a meta-analysis of 570 patients, Fiehler et al. [10] found no additional risk of hemorrhage from thrombolysis in patients with microbleeds (it should be noted that very few patients had multiple microbleeds in this meta-analysis [10]). The issue of the risk of hemorrhagic transformation and/or cerebral hemorrhage after thrombolysis in patients with numerous microbleeds is still unanswered as this population was not represented in the study reported by Fiehler et al. A trend towards greater risk appeared in a more recent meta-analysis [11], although this did not reach statistically significance. T2*-weighted images can also assess the presence of hemorrhagic changes and is more sensitive than CT, classifying hemorrhagic changes more severely according to the ECASS classification [12] compared to CT [13] (Fig. 4).
Confirming the diagnosis of AIS MRI can confirm the positive diagnosis of acute AIS: hyperintensity on the diffusion-weighted images, distributed within an arterial territory, with a homogeneous reduction of the apparent diffusion coefficient (Fig. 5). MRI is more sensitive than CT particularly in the early phase of ischemia [14]. False negatives however can be seen with the diffusionweighted images: posterior cerebral fossa lesions, small strokes and recent lesions or transient symptoms [15]. An ‘‘optimized’’ diffusion-weighted sequence can reduce the number of false negatives [16] (Fig. 6). Figure 1. Restless patient during MRI: the diffusion-weighted image shows a hyperintensity in the superficial territory of the left middle cerebral artery (red arrows); MRA shows ipsilateral carotid and middle cerebral artery occlusion (blue arrow); the T2* image shows no hemorrhagic lesion. This information is sufficient to decide a treatment intervention.
Excluding the differential diagnoses Based on the clinical presentation or even some imaging appearances, a number of diseases may mimic AIS. These differential diagnoses (‘‘stroke mimics’’) need to be excluded to avoid inappropriate thrombolysis. Other
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Figure 2. MRI can distinguish AIS (acute ischemic stroke) from intraparenchymal hemorrhage. Case 1 is a left deep MCA (middle cerebral artery) AIS: homogenous hyperintensity on diffusion-weighted imaging with reduced ADC (apparent diffusion coefficient), hyperintensity on the Fluid Attenuated Inversion Recovery (FLAIR) image without T2* hypointensity. Case 2 is a left deep hyperacute hematoma: heterogeneous hyperintensity on diffusion-weighted imaging with a peripheral hypointense collar and a reduced ADC, peripherally hyperintense on FLAIR and hypointense on T2* (red arrows). This is confirmed by an unenhanced CT.
diseases may, for example, cause a reduction in the apparent diffusion coefficient on MRI: a recent hematoma, other causes of cytotoxic edema (reversible posterior encephalopathy, severe venous cerebral thrombosis, infectious encephalitis) [17,18] (Fig. 7), hypercellular lesions (lymphoma, medulloblastoma) [19,20] or hyperviscosity (pyogenic abscess) [21]. MRI can also correct the diagnosis in some ‘‘stroke mimics’’, which are more difficult to identify, using a combination of different sequences. These include for example, migraine aura or postictal edema [22,23].
Secondary objectives To date the infarction MRI has been shown to be able to date an AIS of unknown time of onset (for example wake-up strokes) [24]. The temporal change in the diffusion-weighted image begins with an early diffusion-weighted hyperintensity after arterial occlusion. The ADC also decreases early, reaching a nadir around 48 hours, returns to normal towards the end of the second week and then increases in the chronic phase [25]. The FLAIR
Figure 3. The T2* image is very sensitive to chronic microbleeds. Three different patients: a: a single deep right microbleed is present. b: numerous deep bilateral microbleeds (> 10) are present, in a patient with chronic hypertension. c: multiple bilateral microbleeds (> 100) located peripherally with superficial hemosiderosis: this appearance suggests amyloid angiopathy.
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Figure 4. Comparison of the T2* image with CT to assess hemorrhagic transformation (at 24 h): a punctiform hypointensity is present on the T2* image in the left lenticulate nucleus (red arrow) whereas on unenhanced CT no hemorrhagic hyperdensity is seen.
Figure 5. Positive diagnosis of AIS: diffusion-weighted hyperintensity within an arterial territory (dotted red line) with reduced apparent diffusion coefficient (not shown) and no marked Fluid Attenuated Inversion Recovery (FLAIR) hyperintensity with occlusion of the right middle cerebral artery on 3D TOF (Time-Of-Flight) and a ‘‘susceptibility vessel sign’’ on the T2* image representing the intraluminal thrombus (red arrows).
image is normal or subnormal in the initial hours and then subsequently becomes positive (Fig. 8). Two situations can be distinguished based on the ‘‘diffusion/FLAIR’’ mismatch: • a diffusion-weighted hyperintensity with no FLAIR hyperintensity, representing usually a subacute lesion (< 4.5 h) (Fig. 9);
Figure 6. Patient presenting with dizziness for 5 hours: the conventional diffusion-weighted images show no clear hyperintensity suggestive of an ischemic lesion. An optimized diffusion-weighted sequence shows multiple punctate cerebellar and brain stem hyperintensities confirming the suspected diagnosis.
Figure 7. MRI as a diagnostic tool in 3 patients suspected of having an AIS. The sequences used are: diffusion-weighted imaging with ADC (apparent diffusion coefficient) map and Fluid Attenuated Inversion Recovery (FLAIR) from left to right. a: herpes virus encephalitis: left temporal diffusion-weighted hyperintensity predominantly involving the cortex with focally cortico-subcortical heterogeneously reduced ADC FLAIR hyperintensity with a swollen appearance of the left temporal lobe. On the right, meningeal T1-weighted enhancement after gadolinium. b: glial tumor: left parietal diffusion-weighted hyperintensity predominantly involving the cortex, with increased ADC, cortico-subcortical FLAIR hyperintensity with an unusual mass effect for an acute ischemic lesion. On the right the 3D TOF sequence does not show proximal arterial conclusion. c: cerebral venous thrombosis: left fronto-parietal diffusion-weighted hyperintensity predominantly involving the cortex with a heterogeneously increased ADC, FLAIR hyperintensity in the underlying white matter. On the right the sagittal T1-weighted images after gadolinium show a defect in the superior sagittal sinus (top). On T2* (bottom) susceptibility artefact in the superior sagittal sinus and cortical veins consistent with thrombi.
• a diffusion-weighted hyperintensity with a pronounced FLAIR hyperintensity, representing an older ischemic lesion. In such case, the time from stroke onset is likely to be > 4.5 hours, although AIS < 4.5 hours may show subtle signal changes on FLAIR. Its sensitivity and specificity to detect an AIS < 4.5 h are however not perfect (55% and 60% respectively on a 3T scanner [26]). The presence of a ‘‘diffusion/FLAIR’’ mismatch is currently used as an inclusion criterion into a clinical trial on intravenous thrombolysis for wake-up strokes, when by definition the time of onset is unknown [27]. The FLAIR sequence can therefore distinguish recent from semi-recent or old ischemia [4] (Fig. 10) and assess the
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Figure 8. Temporal change in ischemia on Fluid Attenuated Inversion Recovery (FLAIR) and diffusion-weighted images and apparent diffusion coefficient (ADC) map; the pink curve shows the changes of ADC, the acute phase being characterized by an early diffusionweighted hyperintensity after arterial occlusion. The ADC decreases early to a nadir around 48 hours returning to normal towards the end of the second week and is then increased in the chronic phase. The FLAIR image is normal or subnormal in the initial hours and thereafter becomes positive.
cerebral parenchyma (lacunar stroke, leucoaraiosis, territorial ischemic strokes). These latter are occasionally better seen on T2-weighted imaging for example an Echo planar view (b = 0 s/mm2 ) from the diffusion-weighted sequence.
To assess the ‘‘core’’ of the infarction The ‘‘core’’ or ‘‘irreversible necrosis’’ is assessed as a prognostic tool. The DEFUSE [28] and EPITHET [29] studies defined a ‘‘malignant profile’’ (defined by a diffusionweighted lesion and/or perfusion volume over 100 mL). This profile is associated with poor functional prognosis at 3 months and an increased risk of bleeding after reperfusion [30].
Another MRI approach to assess the ‘‘core’’ is the DWIASPECTS score (diffusion-weighted imaging; Alberta Stroke Program Early CT score) (Fig. 11). This score can be more readily used in routine practice than volume measurement as it provides a simple semi-quantitative visual score alternative to volumetry [31]. Large ischemic stroke (low DWI-ASPECTS score) represents an increased risk of hemorrhagic transformation after thrombolysis [32]. This conclusion, however, is disputed by Olivot et al. [33] in a population of patients receiving early intra-arterial treatment, as a high diffusion volume in this study was not always synonymous of poor outcome. This concept of a cut-off volume should therefore be adjusted by the time between the onset of symptoms and MRI.
To determine the site of occlusion
Figure 9. Fluid Attenuated Inversion Recovery (FLAIR)/diffusion mismatch: no FLAIR hyperintensity and diffusion-weighted hyperintensity in the right middle cerebral artery territory. This pattern is suggestive of an ischemic lesion before 4.5 h.
The 3D Time-of-Flight MR angiography (3D TOF) is a flow image that visualizes the site of occlusion. However it should be borne in mind that failure to visualize an artery on 3D TOF can also represent severe slowing in an artery that is nevertheless patent. The occlusion site may have implications on the decision to treat for those cases that are reputed to be poorly responsive to intravenous therapy (basilar occlusion, T carotid occlusion combining occlusion of the end of the internal carotid artery and the proximal segments of the anterior and middle cerebral arteries for example) particularly in considering endovascular treatment [34]. These issues however remain to be solved. MRA is not the only vascular sequence in the protocol. A T2*-weighted sequence can be used to assess the site of occlusion through an artefact described as the ‘‘susceptibility vessel sign’’ (SVS) [35—37] (Fig. 12). This sign is extremely specific for occlusion of the internal carotid
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Figure 12. ‘‘Susceptibility Vessel Sign’’ or SVS: magnetic susceptibility artefact on the T2* images in the proximal segment of the right middle cerebral artery due to a thrombus. Figure 10. Assessment of the brain parenchyma: Fluid Attenuated Inversion Recovery (FLAIR) (a) and diffusion-weighted (b) images can distinguish a semi-recent ischemic lesion (FLAIR and diffusion-weighted hyperintensity, red arrow) from an old ischemic lesion (FLAIR hyperintensity with no diffusion-weighted hyperintensity, blue arrow) in the same patient. FLAIR image (c) and (d) showing vascular leucopathy and old lacunar infarcts.
artery or proximal segment (M1) of the MCA [35]. It is reported to be associated with cardio embolic thrombus [38]. Its relationship with thrombus composition is debated [39]. Extension of the thrombus can be scored semi quantitatively using the ‘‘clot burden score’’ [36]. Vascular occlusion can also be indirectly assessed from collaterality circulation from linear FLAIR hyperintensities
(or FLAIR vascular hyperintensities, FVH) (Fig. 13) that can be seen in the subarachnoid spaces [40]. The FVH are seen in arterial occlusion and represent hemodynamic disturbances. Their prevalence and prognostic value however are debated in the literature. According to Legrand et al., these abnormalities represent a smaller volume of infarction and larger mismatch volume [41].
To assess the penumbra The penumbra is the area of reversible ischemia [42]. It reduces gradually with time from the arterial occlusion leaving in its place irreversible ischemia if the artery is not recanalized. This progressive decrease varies depending
Figure 11. Volume assessment on diffusion-weighted images. a: DWI-ASPECTS (diffusion-weighted imaging; Alberta Stroke Program Early CT score): in each region named by a letter or a letter combined with a figure represents 1 point. One point is subtracted from 10 for each affected region: in this case 7 regions are affected: M1, M2, M3, M5, M6, L and I (DWI-ASPECTS = 3). b: volumetry: in this case the diffusion volume was 164 cm3 .
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Figure 15. Cerebral blood flow (CBF) and Tmax maps illustrating the homogeneous appearance of the Tmax within the white matter and the gray matter (hypoperfusion in the left middle cerebral artery territory with reduced CBF and increased Tmax).
Figure 13. Fluid Attenuated Inversion Recovery (FLAIR) vascular hyperintensities or FVH appearing as linear hyperintensities seen in the subarachnoid spaces (red arrows) indicating slowing flow in the meningeal collateral vessels.
on the occlusion site, severity of the occlusion and presence of collateral circulation. Penumbral tissue is the target for a possible revascularization intervention. Many methods are available to assess the penumbra, the most widely used being the ‘‘perfusion-diffusion mismatch’’. Schematically, the diffusion-weighted sequence shows the irreversible ischemia or ‘‘core’’ (without considering the potential reversibility of lesions on diffusion-weighted imaging [43]) and the perfusion-weighted sequence detects the hypoperfusion area. Lesions that are hypoperfused without diffusion hyperintensity represent the penumbra (Fig. 14). The aim of this approach is to increase the thrombolysis time window, offering recanalization therapy beyond 4.5 h to patients with a penumbra in placebo-controlled randomized trials. Assessment of the penumbra volume can identify patients who may benefit from treatment.
Whilst this technique is attractive, there is, however, no consensus on the best parameter to determine the severe hypoperfusion area. The most widely used parameter at present is the Tmax, which is the time to the peak of residual function. This parameter presents the advantage of homogenous mapping (there is no difference in Tmax between the white matter and gray matter as opposed to the cerebral blood flow and cerebral blood volume) (Fig. 15). This parameter can be calculated even with short acquisitions and requires an arterial input function (AIF) for deconvolution [44]. It correlates well with cerebral blood flow values calculated using PET-CT (positron emission tomography) [45]. Moreover there is no consensus about the Tmax threshold to use. Currently the threshold in the most recent studies is a Tmax > 6 s [46]. Discrepancies between studies exist on the role of this mismatch in selecting candidates with both positive results (mismatch useful to select patients to undergo revascularization) (DIAS [47], DEDAS [48], DEFUSE [28], EPITHET [29], DEFUSE 2 [49]) and negative results (DIAS 2 [50], MR RESCUE [51]). New randomized trials are therefore ongoing. The ECASS 4 study is a randomized phase 3 study comparing IV thrombolysis to placebo between 4.5 h and 9 h or in wake-up AIS. The main inclusion criterion is a perfusion-diffusion mismatch on imaging. Other mismatch techniques are proposed to assess the ischemic penumbra: diffusion/MR angiography and clinical/diffusion [52].
Conclusion MRI can be performed in the acute phase of an AIS without delaying patient management. It serves different purposes, to confirm the diagnosis of AIS and exclude a hematoma. MRI provides better characterization of the infarction and ischemic penumbra and opens the possibility of extending the treatment time window (> 4h30) and adapting treatment depending on individual patient findings. TAKE-HOME MESSAGES Figure 14. Perfusion-diffusion mismatch: minimal punctiform diffusion-weighted hyperintensity in the left superficial middle cerebral artery territory with larger abnormalities on the Tmax map. The 3D TOF image shows left proximal middle cerebral artery occlusion.
• MRI is the recommended investigation by the French National Health Authority (2009). • It should be accessible and fast.
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M. Tisserand et al. • MRI meets the primary objectives: ◦ excluding hematoma, — MRI = CT to detect intraparenchymal hematoma; ◦ confirming the positive diagnosis of ischemic cerebrovascular accident, — diffuse hyperintensity in an arterial territory with reduced apparent diffusion coefficient; ◦ excluding differential diagnoses. • MRI meets the secondary objectives (characterizing the infarction): ◦ dating the infarction with the FLAIR diffusion mismatch, ◦ assessing the ‘‘core’’ (necrosis) by DWI-ASPECTS or volumetry (prognostic role), ◦ assessing the site of occlusion/collaterality, ◦ assessing the penumbra. • MRI can guide treatment turning it into the investigation of choice in ‘‘candidates’’ for thrombolysis.
3) What does the left posterior insular T2* hypointensity represent? 4) Should thrombolysis be performed in this patient?
Answers A) Infarctions of different ages. B) The first left periventricular lesion displays a diffusionweighted hyperintensity with decreased ADC (apparent diffusion coefficient) representing cytotoxic edema within an arterial territory. This is an acute ischemic lesion probably > 4.5 h because the FLAIR hyperintensity is already clearly visible. The second cortico-subcortical right frontal lesion represents an older ischemia with moderate diffusion-weighted hyperintensity with a high ADC. C) Distal thrombus appearing as a punctate T2* hypointensity. D) No: the time of onset is unknown and the most recent ischemic lesion is already frankly hyperintense on FLAIR images suggesting a lesion > 4.5 h. In addition there are no signs of proximal vascular occlusion.
Clinical case This 50-year-old right-handed female patient developed aphasia of unknown time of onset. An MRI was performed at admission (Fig. 16).
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Questions 1) What is the diagnosis? A. Multiple hematomas. B. Infarctions of different ages. C. Metastases. D. Abscess and pre-suppurative lesion. 2) Describe the appearances of the different lesions.
Figure 16. MRI performed at admission (aphasia of unknown time of onset) from left to right and top to bottom. A diffusionweighted sequence with ADC (apparent diffusion coefficient) map, Fluid Attenuated Inversion Recovery (FLAIR), T2* and MR 3D Timeof-Flight (TOF) angiography.
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[49] Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG, et al. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol 2012;11:860—7. [50] Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141—50. [51] Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914—23. [52] Mishra NK, Albers GW, Christensen S, Marks M, Hamilton S, Straka M, et al. Comparison of magnetic resonance imaging mismatch criteria to select patients for endovascular stroke therapy. Stroke 2014;45:1369—74.
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Diagnostic and Interventional Imaging (2014) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
Patient ‘‘candidate’’ for thrombolysis: MRI is essential M. Tisserand , O. Naggara , L. Legrand , C. Mellerio , M. Edjlali , S. Lion , C. Rodriguez-Régent , R. Souillard-Scemama , C.-F. Jbanca , D. Trystram , J.-F. Méder , C. Oppenheim ∗ Centre de psychiatrie et neurosciences, Inserm S894, université Paris Descartes, Sorbonne Paris Cité, neuroimagerie, Sainte-Anne hospital, 1, rue Cabanis, 75014 Paris, France
KEYWORDS Arterial ischemic stroke; Thrombolysis; Diffusion-weighted imaging; Penumbra; Perfusion-weighted imaging
Abstract Because of its excellent sensitivity and specificity to diagnose arterial ischemic stroke (AIS) in the acute phase, MRI answers the main questions to guide treatment in ‘‘candidates’’ for thrombolysis. It lasts less than ten minutes, can confirm the diagnosis of AIS and distinguish it from hematomas and other ‘‘stroke mimics’’. It can identify the ischemic penumbra (perfusion-diffusion mismatch), determine the site of occlusion and provide prognostic information to adapt treatment in some cases in which the indications are poorly defined. In light of the most recent scientific findings, MRI can guide the treatment turning it into the investigation of choice in ‘‘candidates’’ for thrombolysis. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc
Clinical studies showing the effectiveness of intravenous (IV) rt-PA (recombinant tissue plasminogen activator) in arterial ischemic stroke (AIS) have selected patients based on brain CT. In this case the purpose of imaging was to exclude an intracranial hemorrhagic lesion. The NINDS [1] study, the princeps IV thrombolysis study, was published in 1995 and many improvements have been made in imaging since then. Currently, more sophisticated imaging is often preferred to select candidates for thrombolysis. The French National Health Authority guidelines published in May 2009 [2] on the management of AIS in the acute phase state: ‘‘patients suspected of having acute AIS must have priority access (24/24 h 7/7 d) to cerebral imaging [. . .]. MRI is the best investigation to show early signs of ischemia and visualize intracranial hemorrhage. This should be
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Corresponding author. E-mail address: [email protected] (C. Oppenheim).
http://dx.doi.org/10.1016/j.diii.2014.07.003 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
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performed as the first line examination. If MRI is available as a first line investigation it should be accessible in the emergency settings and short protocols should be preferred [. . .]. If urgent access to MRI is not available, a cerebral CT should be performed’’. These guidelines stress the importance of accessibility and speed of MRI, which are the prerequisite conditions, in order to avoid delaying intravenous thrombolytic therapy. Rapid MRI sequences (PROPELLER, Echo planar), which are of slightly poorer quality compared to the images used in other situations, can reduce the length of the investigation consistent with the adage ‘‘time is brain’’ [3]. MRI can therefore be performed without delaying patient care. The investigation protocol lasts between five and ten minutes and covers the entire brain without radiation. Patient agitation may deteriorate image quality although the information obtained is often sufficient for treatment decision (Fig. 1). Only 10—15% of patients therefore cannot access MRI (severe agitation, unstable hemodynamics or contra-indication) [4]. Some information provided by MRI are essential whereas others await validation, apart from some specific situations (> 4.5 h, age over 80 years old, unknown time of onset, etc.). The purposes of MRI are listed below: Primary objectives: • to exclude hematoma; • to confirm the positive diagnosis of AIS; • to exclude differential diagnoses. • • • • •
Secondary objectives: to characterize the infarction; to date the infarction; to assess the ‘‘core’’ of the infarction (necrosis); to establish the site of occlusion and collaterality; to assess the penumbra.
Primary objectives To exclude hematoma In order to exclude intraparenchymal hematoma, the main differential diagnosis from AIS [5—8], MRI performs as well
as CT, including during the first few hours after the onset of symptoms. The pattern of hematoma in the acute phase is: • diffusion-weighted imaging hyperintensity and reduced apparent diffusion coefficient. These can occasionally be confused with those of an AIS although a hematoma presents a more heterogeneous pattern, with magnetic susceptibility effects and a brighter diffusion-weighted hyperintensity than an acute ischemic lesion. This heterogeneous appearance is also seen on the T1-weighted image (performed as the localizing sequence) with a T1weighted hypointensity (whereas a hyperacute ischemic lesion is usually not seen on T1-weighted sequence) and a leaflike appearance in the periphery; • pronounced FLAIR hyperintensitity (the FLAIR hyperintensity is unusual in ischemic lesions before 3 hours); • peripheral T2*-weighted hypointensity consistent with the presence of deoxyhemoglobin (Fig. 2). Combined analysis of the different sequences, particularly diffusion-weighted and T2*-weighted images avoid missing the diagnosis of hematoma which is a contraindication to thrombolytic therapy. Apart from symptomatic intraparenchymal hematoma, the T2*-weighted image may show one or several chronic microbleeds (Fig. 3). These are not seen on CT and may be single or multiple, lying deeply (hypertensive origin), or peripherally (in that case they are suggestive of amyloid angiopathy [9]). In a meta-analysis of 570 patients, Fiehler et al. [10] found no additional risk of hemorrhage from thrombolysis in patients with microbleeds (it should be noted that very few patients had multiple microbleeds in this meta-analysis [10]). The issue of the risk of hemorrhagic transformation and/or cerebral hemorrhage after thrombolysis in patients with numerous microbleeds is still unanswered as this population was not represented in the study reported by Fiehler et al. A trend towards greater risk appeared in a more recent meta-analysis [11], although this did not reach statistically significance. T2*-weighted images can also assess the presence of hemorrhagic changes and is more sensitive than CT, classifying hemorrhagic changes more severely according to the ECASS classification [12] compared to CT [13] (Fig. 4).
Confirming the diagnosis of AIS MRI can confirm the positive diagnosis of acute AIS: hyperintensity on the diffusion-weighted images, distributed within an arterial territory, with a homogeneous reduction of the apparent diffusion coefficient (Fig. 5). MRI is more sensitive than CT particularly in the early phase of ischemia [14]. False negatives however can be seen with the diffusionweighted images: posterior cerebral fossa lesions, small strokes and recent lesions or transient symptoms [15]. An ‘‘optimized’’ diffusion-weighted sequence can reduce the number of false negatives [16] (Fig. 6). Figure 1. Restless patient during MRI: the diffusion-weighted image shows a hyperintensity in the superficial territory of the left middle cerebral artery (red arrows); MRA shows ipsilateral carotid and middle cerebral artery occlusion (blue arrow); the T2* image shows no hemorrhagic lesion. This information is sufficient to decide a treatment intervention.
Excluding the differential diagnoses Based on the clinical presentation or even some imaging appearances, a number of diseases may mimic AIS. These differential diagnoses (‘‘stroke mimics’’) need to be excluded to avoid inappropriate thrombolysis. Other
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Figure 2. MRI can distinguish AIS (acute ischemic stroke) from intraparenchymal hemorrhage. Case 1 is a left deep MCA (middle cerebral artery) AIS: homogenous hyperintensity on diffusion-weighted imaging with reduced ADC (apparent diffusion coefficient), hyperintensity on the Fluid Attenuated Inversion Recovery (FLAIR) image without T2* hypointensity. Case 2 is a left deep hyperacute hematoma: heterogeneous hyperintensity on diffusion-weighted imaging with a peripheral hypointense collar and a reduced ADC, peripherally hyperintense on FLAIR and hypointense on T2* (red arrows). This is confirmed by an unenhanced CT.
diseases may, for example, cause a reduction in the apparent diffusion coefficient on MRI: a recent hematoma, other causes of cytotoxic edema (reversible posterior encephalopathy, severe venous cerebral thrombosis, infectious encephalitis) [17,18] (Fig. 7), hypercellular lesions (lymphoma, medulloblastoma) [19,20] or hyperviscosity (pyogenic abscess) [21]. MRI can also correct the diagnosis in some ‘‘stroke mimics’’, which are more difficult to identify, using a combination of different sequences. These include for example, migraine aura or postictal edema [22,23].
Secondary objectives To date the infarction MRI has been shown to be able to date an AIS of unknown time of onset (for example wake-up strokes) [24]. The temporal change in the diffusion-weighted image begins with an early diffusion-weighted hyperintensity after arterial occlusion. The ADC also decreases early, reaching a nadir around 48 hours, returns to normal towards the end of the second week and then increases in the chronic phase [25]. The FLAIR
Figure 3. The T2* image is very sensitive to chronic microbleeds. Three different patients: a: a single deep right microbleed is present. b: numerous deep bilateral microbleeds (> 10) are present, in a patient with chronic hypertension. c: multiple bilateral microbleeds (> 100) located peripherally with superficial hemosiderosis: this appearance suggests amyloid angiopathy.
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Figure 4. Comparison of the T2* image with CT to assess hemorrhagic transformation (at 24 h): a punctiform hypointensity is present on the T2* image in the left lenticulate nucleus (red arrow) whereas on unenhanced CT no hemorrhagic hyperdensity is seen.
Figure 5. Positive diagnosis of AIS: diffusion-weighted hyperintensity within an arterial territory (dotted red line) with reduced apparent diffusion coefficient (not shown) and no marked Fluid Attenuated Inversion Recovery (FLAIR) hyperintensity with occlusion of the right middle cerebral artery on 3D TOF (Time-Of-Flight) and a ‘‘susceptibility vessel sign’’ on the T2* image representing the intraluminal thrombus (red arrows).
image is normal or subnormal in the initial hours and then subsequently becomes positive (Fig. 8). Two situations can be distinguished based on the ‘‘diffusion/FLAIR’’ mismatch: • a diffusion-weighted hyperintensity with no FLAIR hyperintensity, representing usually a subacute lesion (< 4.5 h) (Fig. 9);
Figure 6. Patient presenting with dizziness for 5 hours: the conventional diffusion-weighted images show no clear hyperintensity suggestive of an ischemic lesion. An optimized diffusion-weighted sequence shows multiple punctate cerebellar and brain stem hyperintensities confirming the suspected diagnosis.
Figure 7. MRI as a diagnostic tool in 3 patients suspected of having an AIS. The sequences used are: diffusion-weighted imaging with ADC (apparent diffusion coefficient) map and Fluid Attenuated Inversion Recovery (FLAIR) from left to right. a: herpes virus encephalitis: left temporal diffusion-weighted hyperintensity predominantly involving the cortex with focally cortico-subcortical heterogeneously reduced ADC FLAIR hyperintensity with a swollen appearance of the left temporal lobe. On the right, meningeal T1-weighted enhancement after gadolinium. b: glial tumor: left parietal diffusion-weighted hyperintensity predominantly involving the cortex, with increased ADC, cortico-subcortical FLAIR hyperintensity with an unusual mass effect for an acute ischemic lesion. On the right the 3D TOF sequence does not show proximal arterial conclusion. c: cerebral venous thrombosis: left fronto-parietal diffusion-weighted hyperintensity predominantly involving the cortex with a heterogeneously increased ADC, FLAIR hyperintensity in the underlying white matter. On the right the sagittal T1-weighted images after gadolinium show a defect in the superior sagittal sinus (top). On T2* (bottom) susceptibility artefact in the superior sagittal sinus and cortical veins consistent with thrombi.
• a diffusion-weighted hyperintensity with a pronounced FLAIR hyperintensity, representing an older ischemic lesion. In such case, the time from stroke onset is likely to be > 4.5 hours, although AIS < 4.5 hours may show subtle signal changes on FLAIR. Its sensitivity and specificity to detect an AIS < 4.5 h are however not perfect (55% and 60% respectively on a 3T scanner [26]). The presence of a ‘‘diffusion/FLAIR’’ mismatch is currently used as an inclusion criterion into a clinical trial on intravenous thrombolysis for wake-up strokes, when by definition the time of onset is unknown [27]. The FLAIR sequence can therefore distinguish recent from semi-recent or old ischemia [4] (Fig. 10) and assess the
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Figure 8. Temporal change in ischemia on Fluid Attenuated Inversion Recovery (FLAIR) and diffusion-weighted images and apparent diffusion coefficient (ADC) map; the pink curve shows the changes of ADC, the acute phase being characterized by an early diffusionweighted hyperintensity after arterial occlusion. The ADC decreases early to a nadir around 48 hours returning to normal towards the end of the second week and is then increased in the chronic phase. The FLAIR image is normal or subnormal in the initial hours and thereafter becomes positive.
cerebral parenchyma (lacunar stroke, leucoaraiosis, territorial ischemic strokes). These latter are occasionally better seen on T2-weighted imaging for example an Echo planar view (b = 0 s/mm2 ) from the diffusion-weighted sequence.
To assess the ‘‘core’’ of the infarction The ‘‘core’’ or ‘‘irreversible necrosis’’ is assessed as a prognostic tool. The DEFUSE [28] and EPITHET [29] studies defined a ‘‘malignant profile’’ (defined by a diffusionweighted lesion and/or perfusion volume over 100 mL). This profile is associated with poor functional prognosis at 3 months and an increased risk of bleeding after reperfusion [30].
Another MRI approach to assess the ‘‘core’’ is the DWIASPECTS score (diffusion-weighted imaging; Alberta Stroke Program Early CT score) (Fig. 11). This score can be more readily used in routine practice than volume measurement as it provides a simple semi-quantitative visual score alternative to volumetry [31]. Large ischemic stroke (low DWI-ASPECTS score) represents an increased risk of hemorrhagic transformation after thrombolysis [32]. This conclusion, however, is disputed by Olivot et al. [33] in a population of patients receiving early intra-arterial treatment, as a high diffusion volume in this study was not always synonymous of poor outcome. This concept of a cut-off volume should therefore be adjusted by the time between the onset of symptoms and MRI.
To determine the site of occlusion
Figure 9. Fluid Attenuated Inversion Recovery (FLAIR)/diffusion mismatch: no FLAIR hyperintensity and diffusion-weighted hyperintensity in the right middle cerebral artery territory. This pattern is suggestive of an ischemic lesion before 4.5 h.
The 3D Time-of-Flight MR angiography (3D TOF) is a flow image that visualizes the site of occlusion. However it should be borne in mind that failure to visualize an artery on 3D TOF can also represent severe slowing in an artery that is nevertheless patent. The occlusion site may have implications on the decision to treat for those cases that are reputed to be poorly responsive to intravenous therapy (basilar occlusion, T carotid occlusion combining occlusion of the end of the internal carotid artery and the proximal segments of the anterior and middle cerebral arteries for example) particularly in considering endovascular treatment [34]. These issues however remain to be solved. MRA is not the only vascular sequence in the protocol. A T2*-weighted sequence can be used to assess the site of occlusion through an artefact described as the ‘‘susceptibility vessel sign’’ (SVS) [35—37] (Fig. 12). This sign is extremely specific for occlusion of the internal carotid
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Figure 12. ‘‘Susceptibility Vessel Sign’’ or SVS: magnetic susceptibility artefact on the T2* images in the proximal segment of the right middle cerebral artery due to a thrombus. Figure 10. Assessment of the brain parenchyma: Fluid Attenuated Inversion Recovery (FLAIR) (a) and diffusion-weighted (b) images can distinguish a semi-recent ischemic lesion (FLAIR and diffusion-weighted hyperintensity, red arrow) from an old ischemic lesion (FLAIR hyperintensity with no diffusion-weighted hyperintensity, blue arrow) in the same patient. FLAIR image (c) and (d) showing vascular leucopathy and old lacunar infarcts.
artery or proximal segment (M1) of the MCA [35]. It is reported to be associated with cardio embolic thrombus [38]. Its relationship with thrombus composition is debated [39]. Extension of the thrombus can be scored semi quantitatively using the ‘‘clot burden score’’ [36]. Vascular occlusion can also be indirectly assessed from collaterality circulation from linear FLAIR hyperintensities
(or FLAIR vascular hyperintensities, FVH) (Fig. 13) that can be seen in the subarachnoid spaces [40]. The FVH are seen in arterial occlusion and represent hemodynamic disturbances. Their prevalence and prognostic value however are debated in the literature. According to Legrand et al., these abnormalities represent a smaller volume of infarction and larger mismatch volume [41].
To assess the penumbra The penumbra is the area of reversible ischemia [42]. It reduces gradually with time from the arterial occlusion leaving in its place irreversible ischemia if the artery is not recanalized. This progressive decrease varies depending
Figure 11. Volume assessment on diffusion-weighted images. a: DWI-ASPECTS (diffusion-weighted imaging; Alberta Stroke Program Early CT score): in each region named by a letter or a letter combined with a figure represents 1 point. One point is subtracted from 10 for each affected region: in this case 7 regions are affected: M1, M2, M3, M5, M6, L and I (DWI-ASPECTS = 3). b: volumetry: in this case the diffusion volume was 164 cm3 .
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Figure 15. Cerebral blood flow (CBF) and Tmax maps illustrating the homogeneous appearance of the Tmax within the white matter and the gray matter (hypoperfusion in the left middle cerebral artery territory with reduced CBF and increased Tmax).
Figure 13. Fluid Attenuated Inversion Recovery (FLAIR) vascular hyperintensities or FVH appearing as linear hyperintensities seen in the subarachnoid spaces (red arrows) indicating slowing flow in the meningeal collateral vessels.
on the occlusion site, severity of the occlusion and presence of collateral circulation. Penumbral tissue is the target for a possible revascularization intervention. Many methods are available to assess the penumbra, the most widely used being the ‘‘perfusion-diffusion mismatch’’. Schematically, the diffusion-weighted sequence shows the irreversible ischemia or ‘‘core’’ (without considering the potential reversibility of lesions on diffusion-weighted imaging [43]) and the perfusion-weighted sequence detects the hypoperfusion area. Lesions that are hypoperfused without diffusion hyperintensity represent the penumbra (Fig. 14). The aim of this approach is to increase the thrombolysis time window, offering recanalization therapy beyond 4.5 h to patients with a penumbra in placebo-controlled randomized trials. Assessment of the penumbra volume can identify patients who may benefit from treatment.
Whilst this technique is attractive, there is, however, no consensus on the best parameter to determine the severe hypoperfusion area. The most widely used parameter at present is the Tmax, which is the time to the peak of residual function. This parameter presents the advantage of homogenous mapping (there is no difference in Tmax between the white matter and gray matter as opposed to the cerebral blood flow and cerebral blood volume) (Fig. 15). This parameter can be calculated even with short acquisitions and requires an arterial input function (AIF) for deconvolution [44]. It correlates well with cerebral blood flow values calculated using PET-CT (positron emission tomography) [45]. Moreover there is no consensus about the Tmax threshold to use. Currently the threshold in the most recent studies is a Tmax > 6 s [46]. Discrepancies between studies exist on the role of this mismatch in selecting candidates with both positive results (mismatch useful to select patients to undergo revascularization) (DIAS [47], DEDAS [48], DEFUSE [28], EPITHET [29], DEFUSE 2 [49]) and negative results (DIAS 2 [50], MR RESCUE [51]). New randomized trials are therefore ongoing. The ECASS 4 study is a randomized phase 3 study comparing IV thrombolysis to placebo between 4.5 h and 9 h or in wake-up AIS. The main inclusion criterion is a perfusion-diffusion mismatch on imaging. Other mismatch techniques are proposed to assess the ischemic penumbra: diffusion/MR angiography and clinical/diffusion [52].
Conclusion MRI can be performed in the acute phase of an AIS without delaying patient management. It serves different purposes, to confirm the diagnosis of AIS and exclude a hematoma. MRI provides better characterization of the infarction and ischemic penumbra and opens the possibility of extending the treatment time window (> 4h30) and adapting treatment depending on individual patient findings. TAKE-HOME MESSAGES Figure 14. Perfusion-diffusion mismatch: minimal punctiform diffusion-weighted hyperintensity in the left superficial middle cerebral artery territory with larger abnormalities on the Tmax map. The 3D TOF image shows left proximal middle cerebral artery occlusion.
• MRI is the recommended investigation by the French National Health Authority (2009). • It should be accessible and fast.
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M. Tisserand et al. • MRI meets the primary objectives: ◦ excluding hematoma, — MRI = CT to detect intraparenchymal hematoma; ◦ confirming the positive diagnosis of ischemic cerebrovascular accident, — diffuse hyperintensity in an arterial territory with reduced apparent diffusion coefficient; ◦ excluding differential diagnoses. • MRI meets the secondary objectives (characterizing the infarction): ◦ dating the infarction with the FLAIR diffusion mismatch, ◦ assessing the ‘‘core’’ (necrosis) by DWI-ASPECTS or volumetry (prognostic role), ◦ assessing the site of occlusion/collaterality, ◦ assessing the penumbra. • MRI can guide treatment turning it into the investigation of choice in ‘‘candidates’’ for thrombolysis.
3) What does the left posterior insular T2* hypointensity represent? 4) Should thrombolysis be performed in this patient?
Answers A) Infarctions of different ages. B) The first left periventricular lesion displays a diffusionweighted hyperintensity with decreased ADC (apparent diffusion coefficient) representing cytotoxic edema within an arterial territory. This is an acute ischemic lesion probably > 4.5 h because the FLAIR hyperintensity is already clearly visible. The second cortico-subcortical right frontal lesion represents an older ischemia with moderate diffusion-weighted hyperintensity with a high ADC. C) Distal thrombus appearing as a punctate T2* hypointensity. D) No: the time of onset is unknown and the most recent ischemic lesion is already frankly hyperintense on FLAIR images suggesting a lesion > 4.5 h. In addition there are no signs of proximal vascular occlusion.
Clinical case This 50-year-old right-handed female patient developed aphasia of unknown time of onset. An MRI was performed at admission (Fig. 16).
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Questions 1) What is the diagnosis? A. Multiple hematomas. B. Infarctions of different ages. C. Metastases. D. Abscess and pre-suppurative lesion. 2) Describe the appearances of the different lesions.
Figure 16. MRI performed at admission (aphasia of unknown time of onset) from left to right and top to bottom. A diffusionweighted sequence with ADC (apparent diffusion coefficient) map, Fluid Attenuated Inversion Recovery (FLAIR), T2* and MR 3D Timeof-Flight (TOF) angiography.
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