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(Stroke. 1997;28:1198-1202.)
© 1997 American Heart Association, Inc.

Articles

Predictors of Hemorrhagic Transformation Occurring Spontaneously and on Anticoagulants in Patients With Acute Ischemic Stroke

Andrei V. Alexandrov, MD; Sandra E. Black, MD, FRCPC; Lisa E. Ehrlich, MD; Curtis B. Caldwell, PhD; John W. Norris, MD

From the Divisions of Neurology (A.V.A., S.E.B., J.W.N.), Nuclear Medicine (L.E.E.), and Medical Imaging (C.B.C.), Sunnybrook Health Science Center, University of Toronto (Ontario, Canada).

Correspondence to Dr Andrei Alexandrov, Stroke Program, Department of Neurology, University of Texas at Houston, MSB 7.044 6431 Fannin St, Houston, TX 77030. E-mail avalexandrov{at}worldnet.att.net

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Hemorrhagic transformation (HT) is a common evolution of large-volume ischemic lesions, particularly of cardioembolic origin. We used transcranial Doppler ultrasound (TCD), single-photon emission computed tomography (SPECT) with ^99mTc–hexamethylpropyleneamine oxime (HMPAO), and the Toronto Embolic Scale (TES) to decide (1) whether TCD, HMPAO-SPECT, and TES can improve on clinical and CT tests to predict spontaneous HT and (2) whether SPECT can help to predict the outcome of symptomatic HT.

Methods Prognostic criteria included Canadian Neurological Scale (CNS) scores 50 on admission, early ischemic changes on CT, M1 middle cerebral artery occlusion on TCD, the focal absence of brain perfusion on SPECT, and a high risk of cardiogenic embolism on TES.

Results In part 1, 85 consecutive patients admitted within the first 6 hours were studied. No patient received thrombolysis. HT was found in 11 patients (13%) at 3 to 5 days. Admission CNS and CT were not predictive of HT: odds ratios (95% confidence intervals) were 0.49 (0.18 to 1.23) (P=.1) and 0.88 (0.23 to 3.45) (P=.8), respectively. TCD, SPECT, and TES were significant predictors of HT (P<.05), as follows: TCD, 8.67 (1.42 to 70.59); SPECT, 17.40 (2.69 to 170.89); and TES, 18.13 (2.6 to 406.86). In part 2, 490 consecutive patients were studied and 21 (4%) had symptomatic HT, of which 12 had focal hypoperfusion on SPECT at 4 days after stroke onset and 9 had focal hyperperfusion. Patients with hypoperfusion had larger CT lesions (115±97 versus 42±29 cm³; P=.04) and poorer outcome at 2 weeks (CNS, 38±45 versus 96±10; P=.001), including death (6/12 versus 0/9; P=.04), compared with those with hyperperfusion on SPECT.

Conclusions High risk of cardioembolism, M1 middle cerebral artery occlusion, and absence of collateral flow evaluated by TES, TCD, and SPECT help to identify patients at risk for spontaneous HT. Although TES was the most powerful predictor of HT, SPECT is the best single adjunct to the triage of clinical and CT tests. Patients with brain hyperperfusion on HMPAO-SPECT after symptomatic HT have better chances for recovery.

Key Words: embolism • hemorrhagic stroke • tomography, emission computed • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hemorrhagic transformation of brain infarction represents a multifocal secondary bleeding into ischemic tissue ranging from small petechiae and confluent purpura to parenchymal hematoma,^{1 2 3} with variable clinical sequelae.⁴ Some authors differentiate hemorrhagic infarction from parenchymal hematoma, implying a worse outcome of the latter,⁵ while to others, "the difference is of degree rather than of kind."⁶ Nevertheless, both events naturally arise from vascular injury, transiently increased vessel permeability, and secondary hemorrhage.^{1 2 3 4 5 6}

Several autopsy studies report that HT of any kind is most common with large-volume lesions, particularly of cardioembolic origin, with an incidence of up to 71%.^{1 2 3} Meanwhile, the incidence of HT in CT studies was variously reported over the past two decades, from few to 43% of consecutive patients.^{7 8 9} The differences depend largely on the diagnostic criteria for HT identification, evolution of in vivo scanning technologies, and patient population studied. The clinical spectrum of HT also varies from "silent" CT appearances in neurologically improving or stable patients to deterioration and death.^{3 6 8} The development and clinical sequelae of HT are related to the initial size of brain infarction and midline shift.^{9 10 11}

The clinical significance of HT relates to whether a high risk of bleeding should preclude acute anticoagulation or thrombolytic therapy.^{4 5 6} The Cerebral Embolism Study Group and the McMaster University trialists attempted to resolve this issue and recommended that hypertensive patients with large-volume lesions should not be anticoagulated.^{12 13} However, it is still controversial whether anticoagulation produces HT or accentuates the degree of HT, often with clinical worsening.⁶ Several natural history studies failed to show anticoagulation as a significant risk factor for HT, while the results of the International Stroke Trial await publication. Further studies are warranted with a view of potential effectiveness of low-molecular-weight heparinoids.¹⁴

However, no firm prognostic criteria were established to predict the risk of clinically relevant HT. Toni et al¹¹ recently showed that focal hypodensity on CT during the first 5 hours had a sensitivity of 77% and specificity of 94% to predict subsequent HT. However, 89% of repeated CT scans in this study showed petechial HTs that likely produced no change in clinical status, thus decreasing the clinical value of this prediction.

Furthermore, the recent randomized clinical trials of intravenous thrombolysis enrolled patients based on severity of neurological deficit and admission CT scanning. The trials of streptokinase were prematurely terminated because of excessive rates of hemorrhagic events and deaths in the treatment groups compared with placebo.^{15 16 17} In the ECASS, the benefit from recombinant tissue plasminogen activator was also outweighed by the risks of bleeding with clinical worsening.¹⁸ In the National Institute of Neurological Disorders and Stroke–sponsored trial of recombinant tissue plasminogen activator, intravenous thrombolysis was superior to placebo but still associated with an almost 11 times greater risk of symptomatic HT,¹⁹ implying that some form of additional vascular imaging would be helpful in patient selection for safe thrombolysis.²⁰

However, it is unclear which noninvasive test can improve on the predictive value of the clinical and CT examinations. Before any vascular test could be included into future clinical trials, a look at the data on spontaneous HT during the "prethrombolytic era" may help to identify potential predictive factors. In our prospective series we used TCD, SPECT, and the TES,²¹ which rates the risk of cardiogenic embolism according to clinical and laboratory data. Our goals were to decide (1) whether TCD, SPECT, and TES (alone or in combination) can improve on clinical and CT tests to predict spontaneous HT and (2) whether SPECT can help to predict the outcome of symptomatic spontaneous HT.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Consecutive patients with hemispheric ischemic stroke were studied. Patients were evaluated by a neurologist on admission and at 2 weeks after stroke. The severity of the neurological deficit was scored with the use of the CNS²² by the same neurologist, who was unaware of the purposes of the study. Anticoagulation was administered in patients with hemispheric stroke who showed progression or fluctuation of the initial neurological deficit and no evidence of large-volume lesions on CT scan.²³ Since there are no conclusive data on the role of anticoagulants in the development of HT, we combined spontaneous HT with HT occurring on anticoagulation. No patients received intravenous or intra-arterial thrombolysis in this series.

CT scanning was performed on admission and again at 3 to 5 days and was used for lesion volume measurements and HT diagnosis. Admission CT scan was carefully evaluated for any early signs of cerebral ischemia, including focal hypodensities in the affected area, effacement of cerebral sulci, hyperdense MCA sign, and swelling. The volume of brain damage was measured planimetrically with a computerized program (Sigma Scan, Jandel Scientific). HT was diagnosed by a radiologist who was unaware of the purposes of the study. Scans were later reviewed to exclude petechial hemorrhages, following criteria adopted by ECASS trialists.¹⁸ The outcome events (HT) included type II HT and type I or II parenchymal hematoma. Type I HT was excluded from the analysis since it represents small petechiae along the margins of the infarct. Type II HT is confluent petechiae with heterogeneous density but without space-occupying effect. Type I parenchymal hematoma represents a clot 30% of the infarcted area with or without space-occupying effect. Type II parenchymal hematoma is present when a blood clot is >30% of the infarcted area and is usually accompanied by a space-occupying effect. Symptomatic HT was judged by deterioration of 10 points (the CNS scores) during the first 2 weeks after stroke.

TCD was performed in the emergency department as soon as possible with a portable TC-2-64 EME unit. Based on previously reported criteria,²⁴ patients were classified as having normal, stenosed, or occluded M1 MCA segment. As pertinent to this report, M1 MCA occlusion was diagnosed when no signal was detected from MCA in the presence of signals (usually elevated) from unilateral ICA, ACA, or PCA through temporal windows (Fig 1). In a multicenter study, these diagnostic criteria had a 100% specificity and a good correlation with angiography, and SPECT was demonstrated by several authors.²⁴ All TCDs were performed by the same examiner and reported without any knowledge of the purposes of the study.

View larger version (17K): [in this window] [in a new window]   Figure 1. TCD criteria for M1 MCA occlusion: (1) clear temporal "windows," ie, detection of signals originating from the ICA, ACA, or PCA; (2) asonic M1 MCA segment; (3) detection of signals from contralateral M1 MCA segment; and possibly (4) increased velocity values in ACA or ICA (diversion of flow).

SPECT scanning was performed as a part of ongoing clinical protocol on a single-head gamma camera (General Electric 400 AT) 30 minutes after intravenous injection of 740 MBq (20 mCi) HMPAO (Ceretec, Amersham Ltd) according to a standard imaging protocol.^{25 26} Sixty-four frames were acquired, each for 25 seconds in step and shoot mode. A low-energy, high-resolution collimator was used, and images were reconstructed with attenuation correction. The reconstructed full-width, half-maximum resolution of the system was 1.5 cm. Images were tilt- and flow-corrected for nonlinear uptake of HMPAO to improve contrast resolution in high-flow regions and to ensure optimal intraobserver and interobserver agreement.²⁶ SPECT images were interpreted by the same nuclear medicine physician without knowledge of the purposes of the study using a semiquantitative visual analysis and classified into five patterns: normal, high, mixed, low, and absent, as previously reported.²⁵ Absent and low perfusion patterns are further referred to as hypoperfusion, while high and mixed patterns are termed hyperperfusion. Both TCD and SPECT were performed as part of an ongoing research project, and the attending physicians were different from the research personnel involved in this study.

To assess the likelihood of cardioembolic stroke, the patients' clinical and laboratory data were prospectively analyzed by a neurologist who was unaware of the purpose of this study. As part of an ongoing research project, patient status and the results of ancillary tests were reviewed on days 1, 3, 7, and 14 after admission to identify stroke pathogenic mechanism. A cardiovascular diagnostic workup included electrocardiography, echocardiography, and Holter monitor when indicated. At our hospital most stroke patients undergo transthoracic echocardiography first, followed by a transesophageal study if necessary. The risk of cardioembolic stroke was assessed with the TES (Table 1), which arbitrarily combines clinical and laboratory criteria, suggesting a cardiac origin of the cerebral ischemic event. It is important to note that since there is no gold standard for the diagnosis of cardioembolic stroke, we do not have data on the accuracy of this scale nor on its comparison with other scales and its interrater/intrarater validity. A high risk of cardioembolism is present when one or more major criteria exist, such as atrial fibrillation and evidence of systemic embolization. Other pathogenic mechanisms were diagnosed with the use of clinical and CT criteria for lacunar stroke and carotid duplex for extracranial atherosclerosis.

View this table: [in this window] [in a new window]   Table 1. TES: Clinical and Laboratory Criteria for Cardiogenic Brain Embolism1

The data obtained from CNS, CT, TCD, SPECT, and TES tests were used to predict the CT appearance of type II HT and type I or II parenchymal hematoma. Prognostic criteria included CNS scores 50 on admission, early ischemic changes on CT, M1 MCA occlusion on TCD, the focal absence of brain perfusion on HMPAO-SPECT, and a high risk of cardiogenic embolism on TES. Logistic regression, ORs, and receiver operating characteristic curves were used to analyze the data.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Part 1
In the first part of this study, we evaluated 85 consecutive patients admitted within the first 6 hours of stroke onset. In these patients CNS scores were obtained at 4±2 hours, CT was performed at 4.5±2 hours, TCD was performed at 9±6 hours (median, 8 hours), and SPECT was performed at 34±24 hours (median, 24 hours). CT scanning was repeated at days 3 to 5, and HT was found in 11 patients or 13% of the total number of patients. Anticoagulation was started on admission in 4 of 11 patients with HT (36%) compared with 23 of the 74 remaining patients (31%). In the HT group (n=11), deterioration of neurological deficit during the first 2 weeks after stroke onset was found in 4 patients (36%) and improvement or no change in neurological status in the remaining 7 patients (64%).

In a logistic regression model, CNS and CT were not significant predictors of all HTs: ORs and 95% CIs were 0.49 (0.18 to 1.23) for CNS (P=.1) and 0.88 (0.23 to 3.45) for CT (P=.8, NS) (Fig 2). As predictors of HT, TCD, SPECT, and TES were found at the significance level (P<.05) with ORs and 95% CIs >1 (Fig 2), ranging from 8.67 (1.42 to 70.59) for TCD (P=.027) to 17.40 (2.69 to 170.89) for SPECT (P=.006) and 18.13 (2.60 to 406.86) for TES (P=.01).

View larger version (14K): [in this window] [in a new window]   Figure 2. Severity of stroke and risk of HT. Severe neurological deficit (CNS scores 50) and early ischemic changes on CT during the first 6 hours after stroke are not significant predictors of HT. The risk of HT is significantly increased in the presence of either M1 MCA occlusion on TCD, focal absence of perfusion on SPECT, or high risk of cardiogenic embolism on TES. ORs and 95% CIs >1 were found for TCD, SPECT, and TES at the significance level (P.05).

When evaluated separately, these prognostic criteria had positive predictive values ranging from 36% for CNS, 55% for CT, 64% for TCD, and 73% for SPECT to 91% for TES (Table 2). However, when combined, the accuracy of CNS and CT criteria to predict the risk of HT was 63%, as indicated by the c value or the area under the receiver operating characteristic curve (Table 3). A combination of CNS, CT, and TCD had an accuracy of 72%, while a combination of CNS, CT, and SPECT had an accuracy of 78%. A combination of CNS, CT, TCD, SPECT, and TES yielded the highest accuracy of 89%, with significant predictors being only TES and SPECT. Thus, the addition of SPECT alone to triage of the clinical (CNS) and CT examinations improved the accuracy of predicting HT by 15% (Table 3).

View this table: [in this window] [in a new window]   Table 2. Individual Predictive Values

View this table: [in this window] [in a new window]   Table 3. Accuracy of Combined Prognostic Criteria to Predict HT

Part 2
In the second part of the study, all consecutive patients were evaluated prospectively with CNS, CT, SPECT, and TES tests. A total of 490 consecutive patients were analyzed, and 21 (4%) had HT with worsening of neurological deficit during the first 2 weeks after stroke. Anticoagulation was started on admission in 8 of 21 patients who later developed symptomatic HT (38%) compared with 141 patients in the remaining group (29%). Large-volume lesions and cardioembolic stroke were more frequent in the HT group than in the remaining patients: mean±SD CT volume was 84±81 cm³ in the HT group versus 39±58 cm³ in the remaining patients (P=.0008), and a high risk of cardioembolism was present in 57% of patients with symptomatic HT versus 46% of the remaining patients (P=.02).

Within the symptomatic HT group (n=21), HMPAO-SPECT was performed 4 days after stroke. Of these, 12 patients (57%) had focal hypoperfusion and 9 (43%) had focal hyperperfusion. Patients with focal brain hypoperfusion had larger CT lesions: 115±97 versus 42±29 cm³ (P=.04). These patients also had poorer outcome at 2 weeks: CNS scores of 38±45 versus 96±10 (P=.001). Within the symptomatic HT group, all deaths occurred in patients with focal hypoperfusion, with a death rate of 50% (6/12) compared with 0% (0/9) in those with hyperperfusion on HMPAO-SPECT (P=.04) (Table 4).

View this table: [in this window] [in a new window]   Table 4. Brain Perfusion and Outcome of Symptomatic HT

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study confirms that the cardioembolic mechanism of ischemic stroke has a special propensity for HT,^{1 6} particularly when embolism results in major arterial occlusion and failure of collateral flow. Our data also show that noninvasive vascular tests considerably improve on clinical and CT examinations in predicting the risk of HT.

This study, however, has certain limitations. First, anticoagulation as well as blood pressure may play a significant role in the development of HT, and their effects are difficult to elucidate outside of a controlled trial. Second, the diagnosis of cardiogenic embolism has no gold standard and is often based on a variety of tests that cannot be completed sooner than a few days after admission (see below). Finally, the time delays between admission and noninvasive tests may attenuate their prognostic value.

Patients with large-volume lesions and mass effect are at risk of HT,^{1 2 3} but in this study a cardioembolic mechanism of M1 MCA occlusion with focal absence of perfusion was a stronger predictor of HT than clinical and CT tests. An overlap exists between the two groups, but vascular tests ascertain the stroke mechanism and depth of cerebral ischemia more definitely. Although TCD and SPECT improved the predictive value of CNS and CT, no single test was accurate enough to solely identify patients at risk for HT. Unlike Toni et al,¹¹ we found lower positive predictive values for early CT scanning as a result of petechial hemorrhages being excluded because they were clinically irrelevant.^{5 6}

Our results are comparable to previous reports. For instance, Hornig et al⁹ reported a 17% incidence of both symptomatic and asymptomatic HT during the first week. The incidence was 13% in our study when CT scans were done at 3 to 5 days. Further similarities include the mean volume of HT of 103 cm³, which was close to the 115 cm³ reported here, and the rate of cardioembolism among patients with HT of 64%⁹ compared with 56% in our series. In addition, cardioembolism was the cause of 63% of HTs in the autopsy series by Lodder et al.³ In a study by Ott et al,⁸ 37% of patients with HT worsened clinically, which is similar to 36% in the first part of our study. Finally, the 4% incidence of symptomatic HT in our series of 490 consecutive patients is equal to the 4.7% incidence reported by Toni et al¹¹ in a group of 150 consecutive patients.

Arterial occlusion is commonplace in patients with HT.^{27 28 29} Okada et al²⁷ performed angiography in patients with HT and found an 82% incidence of intracranial arterial occlusion, of which 95% reopened subsequently. These data support our findings that an M1 MCA segment occlusion is an independent risk factor for HT, and TCD improves on the predictive value of the clinical and CT examinations. However, HT can occur without a reopening of occluded arteries, as demonstrated by Ogata et al²⁸ in an autopsy report of 14 brains with cardioembolic infarctions. Therefore, the arterial occlusion itself is an important but not decisive factor that points to the importance of collateral circulation in the pathogenesis of HT.²⁸

It was postulated that for HT to occur there must be an ischemic insult of sufficient degree to induce disruption of the vessel wall followed by reperfusion of the injured vascular bed.^{1 28 29} In a study by Giubilei et al,³⁰ patients with arterial occlusions, failure of collateral flow, and poor outcome had severe hypoperfusion on early SPECT scans, similar to the results of our previous report²⁵ and this series. Focal absence of brain perfusion was associated with large-volume ischemic lesions, poor outcome, and a high risk of death after stroke.²⁵ According to our present study, this pattern is also useful in predicting the risk of HT.

HT can occur with or without reopening of the occluded arteries^{2 28 31 32} when reperfusion occurs through leptomeningeal anastomoses.^{28 29} The continuing hypoperfusion on SPECT was seen in patients who died, had poor outcome, or had intraparenchymal hematomas with clinical worsening²⁵ and was also associated with poor outcome in patients with symptomatic HT in this series. Brain hyperperfusion on HMPAO-SPECT, however, was seen in patients with smaller lesions and better outcome after symptomatic HT. These observations suggest that the amount of transcortical flow and timing of reperfusion are also important factors in determining HT and its outcome, while increased deposition of HMPAO may be a marker of cardioembolic stroke and indicator of better prognosis compared with other SPECT perfusion patterns.²⁵

In regard to the mechanism of cerebral ischemia, TES estimates probability of cardioembolism. The scale improved on the clinical and CT examinations in prediction of HT and in combination with TCD and SPECT had an 89% accuracy. However, TES scores often can only be obtained a few days after stroke, and therefore TES may not be suitable for urgent evaluation of acute stroke patients since these tests could not be performed together with TCD and SPECT during the first 6 hours. Thus, applicability during this time window and a 15% improvement in the predictive value of clinical and CT examinations point to SPECT as the best single adjunct to routine diagnostic workup of stroke patients. These advantages of noninvasive vascular testing could be helpful in future trials of interventional treatment in the acute phase of stroke. Furthermore, vascular imaging protocol should be included in the new generation of stroke data banks³³ to understand the clinical significance of HT³⁴ and other "hidden shoals of stroke management"³⁵ through an integrated approach to patient evaluation. It would be important to see whether our findings can be validated in an independent data set from stroke registries utilizing noninvasive vascular testing.

In summary, we found that high risk of cardioembolism, M1 MCA occlusion, and absence of collateral flow as evaluated by TES, TCD, and SPECT help to identify patients at risk of spontaneous HT. Although TES was the most powerful predictor of HT, SPECT is the best single and probably the most practical adjunct to the triage of clinical and CT tests. Patients with brain hyperperfusion on HMPAO-SPECT after symptomatic HT have better chances for recovery.

	Selected Abbreviations and Acronyms

 

ACA = anterior cerebral artery CI = confidence interval CNS = Canadian Neurological Scale ECASS = European Cooperative Acute Stroke Study HMPAO = 99mTc–hexamethylpropyleneamine oxime HT = hemorrhagic transformation ICA = internal carotid artery MCA = middle cerebral artery OR = odds ratio PCA = posterior cerebral artery SPECT = single-photon emission computed tomography TCD = transcranial Doppler ultrasound TES = Toronto Embolic Scale

Received December 9, 1996; revision received February 12, 1997; accepted February 19, 1997.

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