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The Neuroradiology Journal logoLink to The Neuroradiology Journal
. 2020 Jan 23;33(2):118–133. doi: 10.1177/1971400919900275

Radiological predictors of hemorrhagic transformation after acute ischemic stroke: An evidence-based analysis

Nada Elsaid 1,✉, Wessam Mustafa 1, Ahmed Saied 1
PMCID: PMC7140299  PMID: 31971093

Abstract

Hemorrhagic transformation (HT) is one of the most common adverse events related to acute ischemic stroke (AIS) that affects the treatment plan and clinical outcome. Identification of a sensitive radiological marker may influence the controversial thrombolytic decision in the setting of AIS and may at a minimum indicate more intensive monitoring or further prophylactic interventions. In this article we summarize possible radiological biomarkers and the role of different radiological modalities including computed tomography (CT), magnetic resonance imaging, angiography, and ultrasound in predicting HT. Different radiological indices of early ischemic changes, large ischemic lesion volume, severe blood flow restriction, blood-brain barrier disruption, poor collaterals and high blood flow velocities have been reported to be associated with higher risk of HT. The current levels of evidence of the available studies highlight the role of the different CT perfusion parameters in predicting HT. Further large standardized studies are recommended to compare the sensitivity and specificity of the different radiological markers combined and delineate the most reliable predictor.

Keywords: Computed tomography, Digital Subtraction Angiography, hemorrhagic transformation, magnetic resonance, predictors

Introduction

Hemorrhagic transformation (HT) is one of the most common and serious challenges in management of acute ischemic stroke (AIS) that affects both the treatment plan and the clinical prognosis. It is still one of the most feared complications of thrombolysis that restricts its indications. The identification of markers for HT might be helpful in improving the risk:benefit ratio of thrombolytic therapy.1

Definition, pathology and clinical presentation of HT

HT is defined as an infarcted, hypodense area in or around which various degrees of hyperdensity appear on unenhanced computed tomography (CT) scans. According to the European Cooperative Acute Stroke Study (ECASS II), HTs are radiologically classified according to their appearance on CT as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH). HI1 is defined as small petechiae along the margins of the ischemia; HI2, as confluent petechiae within the infarcted zone but no mass effect; PH1, as blood clots in 30% or less of the ischemic zone with mild mass effect; and PH2, as blood clots in more than 30% of the ischemic area with a marked mass effect.2

The symptoms of HT vary widely from being asymptomatic to significant deterioration depending on its site and size. The ECASS II defines the intracranial hemorrhage to be symptomatic if causing an increase in the National Institutes of Health Stroke Scale (NIHSS) score of four or more points and if the hemorrhage is found to probably be the cause of clinical deterioration.2 László and Hortobágyi reported that generally HI can be considered as a sign of recanalization because it is mostly does not affect the prognosis or long-term clinical outcome; on the contrary, PH is considered a comorbidity because of its negative influence on the prognosis.3

HT pathophysiology is still not fully understood. Cerebral ischemia initiates a cascade of cellular, metabolic and inflammatory events that result in disruption of the blood-brain barrier (BBB) and the impairment of the autoregulatory capacity of the cerebral blood vessels, predisposing them to blood extravasation on reperfusion of the ischemic tissue.4 Various clinical factors have been reported to be associated with increased risk of HT, such as advancing age, pretreatment of hypertension, atrial fibrillation, cardioembolic stroke, high NIHSS, hyperglycemia, low lipid profile (total cholesterol and low-density lipoprotein), elevated globulin level, albuminuria, lower platelet count, delayed reperfusion, intravenous tissue plasminogen activator recombinant (IV rt-PA), concurrent use of antithrombotic agents or anticoagulants, fibrinolytic agents, and endovascular treatment.5,6 Massive cerebral infarction and the volume of gray-matter involvement are also among the most dangerous factors of HT development.6,7

Epidemiology and rate of HT

The appearance of HT ranges from between 10% and 40% on CT, and 40% to 70% on autopsy.5 This wide range is attributed to different individual risk factors. HIs represent 89% of the total HTs, whereas PHs account for the remainder.5 The incidence of symptomatic HT ranges from 0.6% to 20%.2,5

Management of patients with ischemic stroke and HT

HT represents the most feared complication and main limitation facing the use of thrombolytic therapy.1 History of intracranial hemorrhage (ICH), severe uncontrolled hypertension, serious head trauma or stroke in the previous three months, recent use of anticoagulation, thrombocytopenia and coagulopathy are considered as absolute contraindications for IV rt-PA use for treatment of AIS because of the associated high risk of HT.1 Multiple clinically based risk-predictive scores have been proposed to predict the risk of symptomatic HT.8–13 Despite the high sensitivity of these scores to symptomatic HT, high risk scores are not enough to withhold thrombolytic therapy because these patients are still likely to benefit from alteplase.14 These cases require close monitoring and follow-up. The general guidelines of treatment of HT are quite similar to the treatment of spontaneous ICH but increase the risk of worsening ischemia.14 The risk:benefit ratio of treatment has to be weighed; the use of reversal agents such as cryoprecipitate, platelets, fresh-frozen plasma, prothrombin complex concentrate, vitamin K, recombinant factor VIIa and antifibrinolytic agents are indicated in treatment of symptomatic ICH or asymptomatic cases with evidence of coagulopathy. Neurosurgical evacuation of the hematoma may be warranted in some cases.14 Moreover, HT also represents a challenge against initiating a secondary prophylactic antiplatelet or anticoagulants.15

Endovascular treatment was reported to be associated with higher risk of HT than thrombolytic therapy. The incidence of PH after endovascular treatment was recently reported to be 6.0%.16

Economic burden of HT

HT-induced increase in morbidity and mortality subsequently carries a higher economic and social burden than that already reported with ischemic stroke.17 The increased health-care cost including treatment, duration and quality of care and repeated imaging required for follow-up, and the non–health-care cost associated with decreased productivity, warrant further efforts to predict and prevent hemorrhagic adverse events.17,18

Aim of the work

The identification of markers for HT might be helpful in improving the risk:benefit ratio of thrombolytic therapy. Besides being a diagnostic and classifying tool, neuroimaging may also predict the occurrence of HT. In this article we review the possible radiological biomarkers and the role of different radiological modalities including CT, magnetic resonance imaging (MRI), digital subtraction angiography (DSA) and ultrasound (US) in predicting HT in light of administrated treatment, including intravenous (IV) thrombolysis and/or thrombolytic or mechanical intra-arterial (IA) therapy.

Methodology and search strategy

We conducted a systematic review of the literature using a database search of MEDLINE (Bethesda, MD), PubMed, Scopus, and Web of Science (Clarivate Analytics, PA) to identify studies addressing 1) AIS, 2) HT and 3) relevant neuroimaging methods. The search covered January 1990 to November 2019 using the following key terms: 1) “Hemorrhagic transformation” AND/ OR 2) “Predictors”, AND one of the following from 3): “CT or MR, or DSA, or US.” We expanded our retrieval to also include clinical trials, cohort studies, multicenter studies, comparative studies, case-control studies, and case reports having more than five participants for key questions regarding HT. Letters, hospital bulletins and single case reports were excluded.

The level of evidence (LOE) was adopted from Ackley et al. as follows: level 1: systematic review or meta-analysis, level II: randomized controlled trial, level III: nonrandomized controlled trials, level IV: case control studies, cohort studies, level V: meta-synthesis, and level VI: single descriptive or qualitative study.19

Discussion

Impact of CT imaging on the prediction of HT after AIS

Noncontrast CT

The availability, speed and accessibility of noncontrast CT of the brain are the main reasons that this examination remains the diagnostic procedure of choice in patients presenting with acute ischemic stroke (AIS) to exclude pretreatment intracranial hemorrhage.20

Despite being nonsensitive to early infarctions, some early subtle CT findings strongly predict HT, including the loss of differentiation of the lentiform nucleus and insular ribbon, and effacement of the sulci, either alone or with a hyperdense middle cerebral artery sign (HMCAS) (Figure 1).20 HMCAS is a common sign in the anterior circulation infarction and is independently predictive of HT after thrombolytic therapy; it is also associated with increased severity and more frequent early ischemic changes on the baseline CT scan than those without HMCAS (LOE: IV).21

Figure 1.

Figure 1.

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Noncontrast computed tomography (CT) of the brain showing (a) early sign of cerebral ischemia, (b) hyperdense middle cerebral artery sign and (c) Alberta Stroke Program Early CT Score 5 with evidence of hemorrhagic transformation.

Alberta Stroke Program Early CT Score (ASPECTS) is used as a quantitative CT score of acute anterior-circulation ischemic stroke (Figure 1). Low ASPECTS (<7) indicating large infarctions are associated with increased stroke severity and increased risk of HT (LOE: IV, II and IV, respectively).22–24

CT angiography

CT angiography (CTA) is available in most emergency departments and stroke centers, providing reliable, rapid and safe diagnosis of occlusion of major intracranial arteries.25

Several CTA imaging parameters related to ischemic lesions have been associated with an increased risk of HT such as proximal large-vessel occlusion and the extent of collaterals.

In 2008 Peutz and colleagues introduced the clot burden score (CBS), which scores major anterior circulation arteries at 10 points for presence of contrast opacification on CTA. Two points are subtracted for each thrombus preventing contrast opacification in the proximal M1, distal M1 or supraclinoid internal carotid artery (ICA) and one point each for M2 branches, A1 and infraclinoid ICA (Figure 2). Lower CBS were associated with lower follow-up ASPECTS and higher parenchymal hematoma rates (LOE: IV). The quantification of the extent of intracranial thrombus with the CBS acutely predicts the prognosis, final infarct volume and HT risk (LOE: IV).25 Similar results were reported by further studies (LOE: IV).26,27

Figure 2.

Figure 2.

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Assessment of clot burden score: Two points are subtracted for each thrombus preventing contrast opacification in the proximal M1, distal M1 or supraclinoid internal carotid artery (ICA) and one point each for M2 branches, A1 and infraclinoid ICA.

Large-vessel obliteration and poor collateral state on CTA have been shown to be associated with higher risk of HT (LOE: IV).24,26,28 In 2012 Lin et al. reviewed three variables in CTA: (1) distal ICA and/or M1 segment of the MCA, (2) ASPECTS and (3) collateral score.24 The collaterals were scored on reviewing the source images using a four-point scale from 0 to 3 as previously introduced by Kim and colleagues:29 “0”—absent collateral supply; “1”—collaterals filling between 0% and 50%; “2”—collateral supply filling from 50% to 100%; and “3”—collateral supply filling 100% of the occluded MCA territory in comparison to the other side (Figure 3). HT univariate predictors were proximal vessel occlusion (p = 0.049), low collateral score (p = 0.017) and low ASPECTS (p = 0.001). Multivariable analysis found ASPECTS to be the only independent predictor.24 More recent studies reported the low collateral score as an significant predictor of hemorrhagic transformation.26,30

Figure 3.

Figure 3.

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Computed tomography brain angiography showing M1 occlusion with (a) absent collaterals, collateral score 0; (b) collateral filling less than 50% (collateral score: 1); (c) collateral filling greater than 50% (collateral score: 2) and (d) collateral filling 100% (collateral score: 3).

CT perfusion

Computed tomography perfusion (CTP) can distinguish between the potentially salvageable “penumbra” and irreversibly damaged brain tissue “infarct core” via quantitative assessments of cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) (Figure 4). CBV is defined as the total blood volume in a given region of the brain. MTT is defined as the average transit time of blood through a given brain region. CBF is defined as the CBV per a specific amount of time (CBF = CBV/MTT).31 Absolute CTP parameters are values of a certain brain region, whereas the relative parameters are the values measured in the pathological hemisphere expressed as a percentage of the values measured in the contralateral normal hemisphere.31

Figure 4.

Figure 4.

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(a) Noncontrast computed tomography; computed tomography perfusion maps including (b) cerebral blood volume, (c) cerebral blood flow, (d) mean transit time and (e) Tmax showing a large area of matched deficit indicative of core infarct in the right middle cerebral artery territory.

There is no agreement on which CTP parameter is the most predictive of HT. Some studies have shown that CTP parameters of the whole infarct area involving the penumbra and infarct core could be used to predict HT, finding a relative CBV (rCBV) less than or equal to 1.09 and Tmax greater than 14 seconds, respectively, to be the most predictive of HT, with a relative CBF (rCBF) less than 30% also being of considerable utility in predicting HT (LOE: IV).5,32 Others found rCBF to have the highest HT predictive value (LOE: IV).33 One study found neither absolute CBF nor CBV to be significantly correlated to HT; relative CTP parameters were not examined.19 Another study focused on the absolute CTP parameters of the infarction core, finding a CBV of less than or equal to 0.5 ml/100 g to be predictive of HT, but not investigating relative CTP parameters (LOE: IV).34 The infarcted region volume derived from MTT maps and rCBV values at admission have been reported to be strongly associated with HT (LOE: IV).35,36

CTP also can assess the permeability surface product (PS). PS measures the rate by which the contrast material extravasates from the intravascular to the extravascular space through a disrupted BBB, reflecting the permeability of the BBB involved in the pathophysiology of HT of ischemic stroke. High PS has increased risk of occurrence of HT after AIS (LOE: IV).27,34,37,38

A recently published high LOE (I) systematic review found the CTP imaging appearance suggestive of high BBB permeability, and acute severe hypoperfusion (i.e. CBV < 0.5 ml/100 g; rCBV = 1.09; rCBF < 0.48; Tmax > 14 s; rMTT.1.3; TTP 0.27 s) are highly sensitive and predictive for the risk of HT.39

Single-photon emission computed tomography

Single-photon emission computed tomography (SPECT) is a nuclear medicine tomographic imaging technique using gamma rays that is able to create three-dimensional images. SPECT is used in cases of AIS to assess the ischemic defect along with residual blood flow.40,41 The CBF reduction severity in SPECT has also been reported to be associated with a higher risk of HT (LOE: IV).40–43

Brief conclusion

The reviewed LOE of the role of the different CT imaging modalities in the prediction of HT after AIS (summarized in Table 1) highlights the superiority of the different CT perfusion parameters in the prediction of HT after IV thrombolysis and/or thrombolytic or mechanical IA therapy (LOE: I).

Table 1.

Review of LOE of the role of CT imaging in the prediction of hemorrhagic transformation.

Study LOEa No of Study Participants Treatment Modality (%) OR 95% CI, p
Noncontrast CT
 Early ischemia sign Jaillard et al.20 IV 237 IV streptokinase 2.6 (1.5–4.4), p = 0.002
 Hyperdense middle cerebral artery sign Zou et al.21 IV 182 IV thrombolysis (100) 2.691 (1.231–5.882), p = 0.013
 Low Alberta Stroke Program Early CT Score Barber et al.22 IV 203 IV thrombolysis (100) 14 (18–117), p = 0·012
Dzialowski et al.23 II 800 IV thrombolysis (100) 18.9 (2.6–138)
Lin et al.24 IV 83 IV thrombolysis and/or thrombolytic or mechanical IA therapy (52.4) 0.731 (0.561–0.953), p = 0.021
CTA
 Clot burden score Puetz et al.25 IV 263 IV thrombolysis and/or thrombolytic or mechanical IA therapy (49.8) p = 0.003
Fanou et al.26 IV 395 IV thrombolysis (69.1) 0.46 (0.23–0.90), p = 0.0253
Horsch et al.27 IV 545 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) 1.28, (1.16–1.41)
 Large-vessel occlusions Sims et al.28 IV 47 IV thrombolysis (100) p = 0.04
Lin et al.24 IV 83 IV thrombolysis and/or thrombolytic or mechanical IA therapy (46.9) p = 0.049
Fanou et al.26 IV 395 IV thrombolysis (69.1) 2.22 (1.21–4.12), p = 0.0102
 Poor collateral vessels Lin et al.24 IV 83 IV thrombolysis and/or thrombolytic or mechanical IA therapy (46.9) p = 0.017
Fanou et al.26 IV 395 IV thrombolysis (69.1) 0.36 (0.14–0.88), p = 0.0284
van Kranendonk et al.30 IV 478 IV thrombolysis and/or thrombolytic or mechanical IA therapy 1.90 (1.05–3.42)
CTP
 Decreased rCBF Yassi et al.5 IV 132 IV thrombolysis (53) p = 0.021
Langel and Popovic33 IV 75 IV thrombolysis (100) p < 0.001
 Decreased CBV Jain et al.32 IV 83 IV thrombolysis (27.7) 1.14 (1.05–1.25), p = 0.009
 Increased MTT Yassi et al.5 IV 132 IV thrombolysis (53) p = 0.002
Souza et al.35 IV 96 IV thrombolysis and/or thrombolytic or mechanical IA therapy 3.7, p = 0.007
 Increased permeability surface product Horsch et al.27 IV 545 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) 2.22 (1.46–3.37), p = 0.001
Aviv et al.34 IV 41 IV thrombolysis and/or thrombolytic or mechanical IA therapy (54) 3.5 (1.69, 7.06) p = 0.0007
Hom et al.37 IV 32 IV thrombolysis and/or thrombolytic or mechanical IA therapy 1.71, p = 0.01
Ozkul-Wermester et al.38 IV 86 IV thrombolysis (36) 28 (1.75–452.98), p = 0.02
High BBB permeability and acute severe hypoperfusion (i.e. CBV < 0.5 ml/100 g; rCBV = 1.09; rCBF < 0.48; Tmax > 14 s; rMTT .1.3; TTP 0.27 s) Adebayo and Culpan39 I 808 IV thrombolysis and/or thrombolytic or mechanical IA therapy (95% CI; 65%–97%)
SPECT
 CBF reduction Hanson et al.40 IV 15 NA p < 0.005
Ueda et al.41 IV 34 IA thrombolysis p < 0.05
Alexandrov et al.42 IV 185 None 17.40 (2.69–170.89) p < 0.05
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BBB: blood-brain barrier; CBF: cerebral blood flow; CBV: cerebral blood volume; CI: confidence interval; CT: computed tomography; CTA: computed tomography angiography; CTP: computed tomography perfusion; IA: intra-arterial; IV: intravenous; LOE: level of evidence; MTT: mean transit time; NA: not available; OR: odds ratio; rCBF: relative cerebral blood flow; rCBV: relative cerebral blood volume; rMTT: relative mean transit time; SPECT: single-photon emission computed tomography; TTP: time to peak. aLOE adopted from Ackley et al. as follows: level 1: systematic review or meta-analysis, level II: randomized controlled trial, level III: nonrandomized controlled trials, level IV: case-control studies, cohort studies, level V: meta-synthesis, and level VI: single descriptive or qualitative study.20

Impact of MRI on prediction of HT after AIS

Noncontrast MRI

Leukoaraiosis (LA) is defined as a diffuse, confluent white-matter abnormality (with hyperintensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI sequences) (Figure 5). LA of the deep white matter is an independent risk factor for HT after thrombolytic treatment for acute stroke (LOE: IV).44,45 Yang et al. could not find an association between LA and risk of symptomatic ICH.46

Figure 5.

Figure 5.

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Noncontrast magnetic resonance imaging showing evidence of leukoaraiosis in the form of hyperintensity both in T2 and fluid-attenuated inversion recovery sequences.

Contrast-enhanced MRI

Contrast enhancement at T1 after contrast media administration, which is indicative of a BBB leak, may be another important tool in assessing the risk of HT. Early parenchymal enhancement was observed in mice subjected to temporary MCA occlusion that subsequently developed petechial hemorrhage (LOE: IV).44,47,48 In ischemic stroke patients treated with thrombolysis, parenchymal enhancement shown on immediate post-treatment CT scans is well correlated with subsequent HT (LOE: IV).49–52

Another reported sign of BBB defect is extravasation of contrast agent into cerebrospinal fluid (CSF) resulting in poor fluid suppression on FLAIR MRI, and hyperintensity of the CSF space termed hyperintense acute reperfusion marker (HARM).53 Latour et al. retrospectively identified HARM in 53% of tPA-treated patients, 46% of whom developed HT, and found a correlation between HARM and reperfusion within one week (LOE: IV).54 Another study could not find enough evidence of HARM as a predictor of HT.52

Sulcal hyperintensity (cortical gadolinium enhancement) on FLAIR is another pattern attributed to BBB disruption. Cho et al. reported that such FLAIR hyperintensity was predictive of symptomatic hemorrhage after thrombolysis (LOE: IV).55 Sulcal hyperintensity on FLAIR was also documented to be significantly associated with HT after IA thrombolysis (LOE: IV).56

Diffusion-weighted MRI

Recently, the use of diffusion-weighted MRI (DWI) has increased to guide therapeutic decisions regarding thrombolysis, especially for patients outside the three-hour window (Figure 6).57 Several studies suggest that DWI findings may help to identify patients who are at increased risk for HT after IV rt-PA. The size of infarction on DWI was reported as a predictive parameter of symptomatic HT by Singer et al., who applied the ASPECTS score to DWI images in a study that predicted HT risk after IV rt-PA (LOE: IV).58

Figure 6.

Figure 6.

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Magnetic resonance (a) diffusion and (b) perfusion showing evidence of restricted blood flow in the left middle cerebral artery territory.

Assessment of the water apparent diffusion coefficient (ADC) in the DWI lesions shows that significantly lower ADC values are found more in DWI lesion regions that develop ICH than in viable or necrotic regions after rt-PA. ADC values less than or equal to 550 × 10–6 mm2 per second were found to be a predictor of HT (LOE: IV).59,60 Another study reported that the volume of initial DWI lesion and ADC values both predict HT, but only ADC values less than or equal to 550 × 10–6 mm2 per second persisted as an independent predictor after multivariable analysis (LOE: IV).61

Very low CBV (VLCBV), defined as CBV less than the 2.5th percentile of normal contralateral brain, was reported to predict HT after thrombolysis better than did DWI or ADC volume (LOE: IV).62 Both baseline DWI lesion volume and VLCBV were more predictive of HT when compared to sulcal hyperintensity on FLAIR (LOE: IV).63

Perfusion-weighted MRI

Similar to diffusion-weighted (DWI), perfusion-weighted MRI (PWI) can detect tissue ischemia earlier than other conventional neuroimaging modalities in experimental and clinical settings (Figure 6). Prolonged perfusion deficit at three to six hours after the initial MRI scan was identified in significantly more of the area of subsequent HT (LOE: IV).60

PWI was also used to assess BBB integrity. Bang and colleagues initially reported that BBB derangements as shown by decreased signal intensity at later time points in T2* PWI can identify patients at risk for HT after recanalization therapy (LOE: IV).64 However, they later reported that the permeability of the BBB is a dynamic process and that HT types may differ to the extent that, in some patients, permeability abnormalities may not be associated with HT.65 In a prospective study, percentage recovery and the relative recirculation of the contrast agent as another BBB permeability marker, derived from T2* PWI, were shown to be significantly higher in patients with subsequent HT when compared to those without (LOE: IV).66 Kim et al. compared the degree of contribution of pretreatment perfusion status vs tissue status (as measured by size of DWI lesions) to the development of HT (LOE: IV).67 A large area of severe perfusion delay was found to be an independent predictor of HT irrespective of DWI lesion volume or CT changes. Thus, PWI can identify patients at risk even if the CT or DWI seems promising.67

Two prospective multicenter studies termed Diffusion and Perfusion Imaging for Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) used MRI to predict hemorrhage after TPA administration. The DEFUSE trial looked at severity of perfusion delay and DWI lesion volume in an attempt to identify risk factors for HT after recanalization therapy. “Malignant profile” was characterized by a large DWI lesion volume (100 ml or more) and/or a large PWI lesion volume (100 ml or more) with long delays on the Tmax (eight seconds or longer) map. Early reperfusion was associated with fatal intracranial hemorrhage in patients with a malignant profile.68 Although EPITHET used the same mismatch definitions as the DEFUSE study, it showed that patients with a malignant profile were not found to have an increased risk for HT when it is limited to parenchymal type of ICH.69

T2*-weighted gradient-echo sequences and susceptibility-weighted imaging MRI

Cerebromicrobleeds (CMBs) are small, perivascular hemosiderin deposits (usually with macrophages) from leakage through cerebral small vessels, reflective of impaired small-vessel integrity. Radiologically, CMBs are visualized as small, rounded, homogeneous, and hypointense lesions on T2*-weighed gradient-recalled echo (GRE) or susceptibility-weighted imaging MRI (SWI) (Figure 7). Some studies that explored the association between CMBs and the risk of HT following IV rt-PA in patients of ischemic stroke have indicated possible links (LOE: IV).70,71

Figure 7.

Figure 7.

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Susceptibility-weighted imaging magnetic resonance imaging showing evidence of small, rounded, homogeneous, and hypointense lesions suggestive of cerebral microbleeds.

A drop of signal within transcerebral veins detected in T2*-GRE imaging during the early stage of cerebral ischemia was observed within the affected hemisphere in some patients with acute ICA territory ischemia. The abnormal visibility of transcerebral veins reflects severe hemodynamic impairment and was linked to higher risk of HT (LOE: IV).72

Brief conclusion

The reviewed LOE of the role of the different MRI modalities in the prediction of HT after AIS (summarized in Table 2) does not favor a certain MRI biomarker over the other.

Table 2.

Review of LOE of the role of MRI in the prediction of hemorrhagic transformation.

Study LOEa No of Study Participants Treatment Modality (%) OR 95% CI, p
Noncontrast MRI
 Leukoaraiosis (hyperintensity on T2 or FLAIR Shi et al.45 IV 105 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) 3.4 (1.23–9.57), p = 0.019
Contrast-enhanced MRI
 Contrast enhancement at T1-weighted Yokogami et al.49 IV 35 IA urokinase p < 0.01
Vo et al.50 IV 22 IV thrombolysis (27.2) p = 0.013
Kim et al.51 IV 55 IV thrombolysis (27.2) p = 0.003
Hjort et al.52 IV 33 IV thrombolysis (100) p = 0.043
 Hyperintensity of CSF space termed hyperintense acute reperfusion marker on FLAIR Latour et al.54 IV 144 IV thrombolysis and/or thrombolytic or mechanical IA therapy (28.4) 8.11 (2.85–23.1) p < 0.001
 Sulcal hyperintensity on FLAIR Cho et al.55 IV 88 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) 13.64 (1.51–123.28)
Kim et al.56 IV 14 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p = 0.031
DWI
 Large-sized lesion on DWI Singer et al.58 IV 217 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p = 0.004
Selim et al.61 IV 29 IV thrombolysis (100) p = 0.032
Campbell et al.63 IV 49 IV thrombolysis and/or thrombolytic or mechanical IA therapy p = 0.003
 ADC values ≤550 × 10−6 mm2/s Tong et al.59 IV 17 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p < 0.001
Tong et al.60 IV 27 IV thrombolysis and/or thrombolytic or mechanical IA therapy (59.2) p = 0.02
Selim et al. 61 IV 29 IV thrombolysis (100) 1.176; p = 0.042
 Very low CBV Campbell et al. 62 IV 91 IV thrombolysis (39.5) 0.727 p = 0.0002
Campbell et al.63 IV 49 IV thrombolysis and/or thrombolytic or mechanical IA therapy p = 0.002
PWI
 Prolonged perfusion deficit Tong et al.60 IV 27 IV thrombolysis and/or thrombolytic or mechanical IA therapy (59.2) p = 0.03
 Decreased signal intensity at later time points in perfusion MRI acquisition Bang et al.64 IV 32 IV thrombolysis and/or thrombolytic or mechanical IA therapy p < 0.001
 Increased relative recirculation of the contrast agent in T2* PWI Thornhill et al.66 IV 18 IV thrombolysis (44.4) p = 0.006
 Large area of severe perfusion delay Kim et al.67 IV 183 IV thrombolysis and/or thrombolytic or mechanical IA therapy 12.91 (3.69–45.17), p < 0.001
T2*-weighted GRE sequences and SWI
 Cerebromicrobleeds: small, rounded, homogeneous, hypointense lesions Nighoghossian et al.70 IV 100 IV thrombolysis (27) p < 0.001
Kidwell et al.71 IV 41 p < 0.05
 Abnormal visibility of transcerebral veins Hermier et al.72 IV 49 IV thrombolysis (100) p = 0.001
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ADC: apparent diffusion coefficient; CBV: cerebral blood volume; CSF: cerebrospinal fluid; DWI: diffusion-weighted MRI; FLAIR: fluid-attenuated inversion recovery; GRE: gradient-echo sequences; IA: intra-arterial; IV: intravenous; LOE: level of evidence; MRI: magnetic resonance imaging; PWI: perfusion-weighted MRI; SWI: susceptibility-weighted imaging.

LOE adopted from Ackley et al. as follows: level 1: systematic review or meta-analysis, level II: randomized controlled trial (RCT), level III: nonrandomized controlled trials, level IV: case control studies, cohort studies, level V: meta-synthesis, and level VI: single descriptive or qualitative study.20

Impact of DSA on the prediction of HT after AIS

Diagnostic DSA and intervention at admission

There are limited data on angiographic markers of HT. Based on the baseline angiography, the collateral grade is evaluated with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System. This angiographic scale assigns patients to: “Grade 0 (no collaterals visible to the ischemic site), 1 (slow collaterals to the periphery of the ischemic site with persistence of some of the defect), 2 (rapid collaterals to the periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory), 3 (collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase) and 4 (complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion).” Lower angiographic collateral flow grades strongly influence the rate of HT after therapeutic recanalization for AIS (LOE: IV).73

Follow-up DSA after recanalization

Prominent brain vascularity in the form of capillary blush with or without arteriovenous shunting and early venous drainage (so called angiographic blush) can be seen on angiography after acute recanalization of cerebral artery occlusion with mechanical thrombectomy (Figure 8). Presence of angiographic blush after mechanical thrombectomy was independently associated with the volume of HT (LOE: IV).74

Figure 8.

Figure 8.

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Angiography of the right internal carotid artery showing evidence of capillary blush.

We previously reported on two-dimensional parametric parenchymal blood flow analysis software that could potentially act as an indicator for post-thrombectomy ICH. The software allows the separation of these two signals using band-pass and band-reject filtering to allow for greater visibility of the parenchyma. Elevated parametric parenchymal blood flow wash-in rates after thrombectomy may be associated with increased risk of HT (Figure 9) (LOE: IV).16

Figure 9.

Figure 9.

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(a) Pretherapeutic parametric blood flow wash-in rate color-coded images showing restricted diffusion in the middle cerebral artery territory, (b) post-therapeutic parametric blood flow wash-in rate color-coded images showing middle cerebral artery recanalization after treatment, and (c) noncontrast computed tomography showing evidence of hemorrhagic transformation.

Brief conclusion

The reviewed LOE of the role of the diagnostic, interventional or follow-up DSA in the prediction of HT after AIS (summarized in Table 3) does not favor one certain angiographic biomarker over another.

Table 3.

Review of LOE of the role of DSA in the prediction of hemorrhagic transformation.

Study LOEa No of Study Participants Treatment Modality (%) OR 95% CI, p
Poor collaterals Bang et al.73 IV 222 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) 2.666 (1.163–6.113), p = 0.048
Angiographic blush Omran et al.74 IV 48 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p = 0.01
Elevated parametric parenchymal blood flow wash-in rates Elsaid et al.16 IV 30 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p = 0.024
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CI: confidence interval; DSA: digital subtraction angiography; IA: intra-arterial; IV: intravenous; LOE: level of evidence; OR: odds ratio. aLOE adopted from Ackley et al. as follows: level 1: systematic review or meta-analysis, level II: randomized controlled trial (RCT), level III: nonrandomized controlled trials, level IV: case control studies, cohort studies, level V: meta-synthesis, and level VI: single descriptive or qualitative study.20

Impact of US imaging on prediction of HT after AIC

Among the diagnostic tools that can investigate the cerebral hemodynamic, transcranial Doppler (TCD) and transcranial color-coded sonography (TCCS) is a noninvasive technique that can be repeated bedside during the disease course.

Conventional TCD

Gaseous or solid microemboli within the MCA can be detected by TCD as high-intensity transient signals, also called microembolic signals (MES). They are characterized by: (1) having a duration, 300 ms; (2) an amplitude that is three dB higher than the background blood flow signal; (3) are typically unidirectional and occur randomly within the cardiac cycle; and (4) produce a characteristic sound like a “moan” or “chirp” on audio signal. Higher prevalence rates of MES have been reported in strokes caused by large-vessel disease and in cardioembolic strokes, which are in turn the major risk factors of HT (LOE: V).75

Color-coded Doppler TCD

TCCS provides complementary information to periprocedural radiologic data and might help to gain more insight into the complex changes occurring not only after artery occlusion but also after successful recanalization. Changes of the flow velocities of TCCD in symptomatic MCA occlusive disease may be related to the occurrence of further vascular events after stroke (Figure 10).76 Early TCCS detection of a high peak systolic velocity (PSV) MCA ratio (recanalized MCA PSV/contralateral MCA PSV) in successfully recanalized stroke patients indicates an increased risk of ICH (LOE: IV).77 These results are consistent with a previous TCD study that reported high MCA mean blood flow velocity index after successful recanalization therapy for anterior circulation stroke as a risk for postinterventional ICH (LOE: IV).78

Figure 10.

Figure 10.

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Transtemporal transcranial color-coded duplex (TCCD) insonation of the left middle cerebral artery showing elevated peak systolic velocity. LT MCA: left middle cerebral artery, SV: sample volume, PSV: peak systolic velocity, EDV: end diastolic velocity, TCD: transcranial doppler, PI: Pulsatility Index.

Brief conclusion

The reviewed LOE of the role of the transcranial ultrasonography in the prediction of HT after AIS (summarized in Table 4) does not favor one certain sonographic biomarker over another.

Table 4.

Review of LOE of the role of ultrasound imaging in the prediction of hemorrhagic transformation.

Study LOEa No of Study Participants Treatment Modality (%) OR 95% CI, p
Microembolic signals Sarkar et al. 75 V NS NS NS
High PSV:MCA ratio (recanalized MCA PSV/ contralateral MCA PSV) Baracchini et al. 77 IV 226 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p < 0.0001
High MCA mean blood flow velocity index Kneihsl et al. 78 IV 123 IV thrombolysis and/or thrombolytic or mechanical IA therapy (100) p < 0.001
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CI: confidence interval; IA: intra-arterial; IV: intravenous; LOE: level of evidence; MCA: middle cerebral artery; NS: not stated; OR: odds ratio; PSV: peak systolic velocity. aLOE adopted from Ackley et al. as follows: level 1: systematic review or meta-analysis, level II: randomized controlled trial, level III: nonrandomized controlled trials, level IV: case control studies, cohort studies, level V: meta-synthesis, and level VI: single descriptive or qualitative study.20

Current imaging protocols and future research

Revision of the LOE of the previously reported possible biomarkers for HT shows that there are no current guidelines for imaging protocols for prediction of the risk of HT. Most of the studies were either retrospective or prospective cohort or case-control studies that did not provide the required LOE, but they do deserve a considerable degree of attention. The highest LOEs provided by a meta-analysis review article highlight the sensitivity, specificity and accuracy of the different CT perfusion parameters in predicting HT.39 Identification of a sensitive radiological marker may serve influence the controversial thrombolytic decision in the setting of AIS and may at a minimum indicate more intensive monitoring or further prophylactic interventions. Further large standardized studies are recommended to compare the sensitivity and specificity of these radiological markers and delineate the most reliable predictor.

Being the standard initial tool of assessment of any stroke patient, the availability, the relative low cost and short scan duration, from our point of view, gives the CT with its different modalities an advantage over the other tools, especially in the absence of a superior LOE in favor of the others. In addition to the fact that the most used imaging protocol in the setting of AIS is noncontrast CT of the brain, CTA, and CTP, we propose that a combination of the HT radiological biomarkers in these modalities (Figure 11) may provide a more sensitive and predictive value of the risk of HT than a single biomarker. A combination of different biomarkers has already proved to be promising, as shown by Adebayo and Culpan.39 Analysis of the risk of HT in patients with multiple radiological biomarkers is warranted.

Figure 11.

Figure 11.

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Summary of the hemorrhagic transformation radiological biomarkers in noncontrast computed tomography (CT) brain, computed tomography angiography, and computed tomography perfusion. ASPECTS: Alberta Stroke Program Early CT Score; CBF: cerebral blood flow; CBV: cerebral blood volume; MTT: mean transit time.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Nada Elsaid https://orcid.org/0000-0002-2476-5652

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