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Bluhmki, Werner Hacke and Rdiger von KummerChristian Berger, Marco Fiorelli, Thorsten Steiner, Wolf-Rdiger Schbitz, Luigi Bozzao, ErichHemorrhagic Transformation of Ischemic Brain Tissue : Asymptomatic or Symptomatic?

Print ISSN: 0039-2499. Online ISSN: 1524-4628Copyright 2001 American Heart Association, Inc. All rights reserved.

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Hemorrhagic Transformation of Ischemic Brain TissueAsymptomatic or Symptomatic?

Christian Berger, MD; Marco Fiorelli, MD; Thorsten Steiner, MD; Wolf-Rdiger Schbitz, MD;Luigi Bozzao, MD; Erich Bluhmki, MD; Werner Hacke, MD; Rdiger von Kummer, MD

Background and PurposeThe term symptomatic hemorrhage secondary to ischemic stroke implies a clear causal

relationship between clinical deterioration and hemorrhagic transformation (HT) regardless of the type of HT. The aim

of this study was to assess which type of HT independently affects clinical outcome.

MethodsWe used the data set of the European Cooperative Acute Stroke Study (ECASS) II for a post hoc analysis. All

patients had a control CT scan after 24 to 96 hours or earlier in case of rapid and severe clinical deterioration. HT was

categorized according to radiological criteria: hemorrhagic infarction type 1 and type 2 and parenchymal hematoma type

1 and type 2. The clinical course was prospectively documented with the National Institutes of Health Stroke Scale and

the modified Rankin Scale. The independent risk of each type of HT was calculated for clinical deterioration at 24 hours

and disability and death at 3 months after stroke onset and adjusted for possible confounding factors such as age, severity

of stroke syndrome at baseline, and extent of the ischemic lesion on the initial CT.

ResultsCompared with absence of HT, only parenchymal hematoma type 2 was associated with an increased risk for

deterioration at 24 hours after stroke onset (adjusted odds ratio, 18; 95% CI, 6 to 56) and for death at 3 months (adjusted

odds ratio, 11; 95% CI, 3.7 to 36). All other types of HT did not independently increase the risk of late deterioration.

ConclusionsOnly parenchymal hematoma type 2 independently causes clinical deterioration and impairs prognosis. It

has a distinct radiological feature: it is a dense homogeneous hematoma 30% of the ischemic lesion volume with

significant space-occupying effect. (Stroke. 2001;32:1330-1335.)

Key Words: hematoma hemorrhagic stroke stroke outcome thrombolysis

Several large, randomized, placebo-controlled trials ofthrombolytic therapy in acute ischemic stroke have beenconducted during the past years. Secondary hemorrhagic

transformations (HT) after different types of thrombolytic

therapy are frequently reported as important safety parame-

ters in these studies, but they also occur as natural events in

the evolution of a cerebral infarct.14 The increase of HT in

the actively treated arm is often used as evidence against the

treatment tested, as reported in the early streptokinase trials,

with a concurrent increase of mortality and HT in the actively

treated groups.57 Although the large European and American

tissue plasminogen activator (tPA) trials provided evidence of

a benefit in ischemic stroke patients, the fear of hemorrhagic

events frequently precludes the use of thrombolysis in clinical

practice. Unfortunately, previous trials addressing safety and

efficacy of thrombolytic therapy in acute stroke applieddifferent definitions for the termsymptomatic hemorrhageor

symptomatic hemorrhagic transformation. In the tPA trial

sponsored by the National Institutes of Neurological Disor-

ders and Stroke (NINDS),8,9 symptomatic intracranial hem-

orrhage was defined as any CT-documented hemorrhage

that was temporally related to deterioration in the patients

clinical condition in the judgment of the clinical investiga-

tor, no matter how trivial the hemorrhage on the CT scan

might have been. In addition, symptomatic intracranial hem-

orrhage attributable to study medication was defined as

symptomatic hemorrhage that occurred within 36 hours

from treatment onset. In the Multicenter Acute Stroke Trial

of Italy and Europe,6,7 symptomatic HT was defined as

clinical deterioration temporally related to HT documented

by CT-scan or autopsy. A CT scan was regularly obtained at

5 days after stroke onset or earlier in the event of clinical

deterioration. Further studies continued to apply the term

symptomatic hemorrhage according to the NINDS proto-

col911 or without a definition.12,13

The European Cooperative Acute Stroke Study (ECASS) Iand II14,15 went in the opposite direction and used a pure

radiological, prospective definition: HT were categorized into

4 different subtypes without taking into consideration

whether or not any hemorrhage was associated with clinical

Received October 26, 2000; final revision received February 21, 2001;accepted February 22, 2001.From the Department of Neurology, University of Heidelberg (Germany) (C.B., T.S., W-R.S., W.H.); Department of Neuroradiology, University of

Dresden (Germany) (R. von K.); Department of Neuroradiology, University of Rome (Italy) (M.F., L.B.); and Boehringer Ingelheim, Biberach, Germany(E.B.).

Correspondence to Christian Berger, MD, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, D-69221 Heidelberg,Germany. E-mail [email protected]

2001 American Heart Association, Inc.

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deterioration. In addition to the pure radiological definition,

the category of symptomatic hemorrhage was used for pa-

tients with clinical deterioration by 4 points on the National

Institutes of Health Stroke Scale (NIHSS) and with no CT

findings that might have been responsible for this deteriora-

tion other than a hemorrhage.

Fiorelli et al16 recently demonstrated on the basis of the

ECASS I data that, in both the placebo and the rtPA groups,

only parenchymal hematomas (PH) 30% of the infarcted

area with significant space-occupying effect increased the

risk of early neurological deterioration and of 3-month death.

Hemorrhagic infarctions (HI) or PH with only mild space-

occupying effect did not modify the risk of early neurological

deterioration, death, and disability. The different clinical

outcome after different subtypes of HT illustrates the diffi-

culty in defining symptomatic hemorrhage precisely and

clearly. In fact, the spectrum of HTs differs widely and may

include some trivial hemorrhagic petechiae as well as PH

with space-occupying effect. To determine whether any

neurological deterioration is due to HT itself or due tomassive infarct and ischemic edema with a coincidental HT

remains crucial in thrombolysis or other stroke trials. The aim

of this study on the ECASS II data set was to define specific

HT that are independently associated with an increased risk

of clinical deterioration or worse outcome according to the

hypothesis of Fiorelli et al.16 We sought to further assess the

impact of possible confounding factors on clinical deteriora-

tion in patients with HT.

Subjects and MethodsThe study design and primary results of ECASS II have beendescribed in detail elsewhere.15 ECASS II was a double-blind,placebo-controlled trial evaluating safety and efficacy of 0.9 mg/kgIV recombinant tPA (rtPA) in patients presenting within 6 hoursfrom the onset of an acute hemispheric ischemic stroke. Intravenousheparin or oral anticoagulants within the first 24 hours were notallowed.

All patients were examined with CT scan before randomizationand after 24 to 96 hours (median, 1 day; range, 0 to 4 days). Ninepatients had their follow-up scan within 24 hours of stroke onset, 643patients between 24 and 48 hours, 128 between 48 and 72 hours, and3 between 72 and 96 hours. An additional CT was performed after 1week. We used this CT for analysis in 6 patients in whom the firstfollow-up CT was not available. Following the prospective ECASSprotocol, all CT scans were evaluated twice, first by the localinvestigators and then independently by 3 members of the CTreading panel. The members of the CT reading panel were blinded totreatment allocation, any clinical events occurring after randomiza-

tion, and the reading of the local investigators and did not seefollow-up scans before evaluating the baseline CT. After the exclu-sion of 10 patients (3 rtPA, 7 placebo) with CT scans of too poorquality to allow unequivocal assessment of HT, 790 of 800 random-ized patients remained for the analysis. HT occurring on the firstfollow-up CT scan after randomization were prospectively catego-rized according to definitions previously described17,18: HI and PH.HI type 1 (HI-1) was defined as small petechiae along the margins ofthe infarct, and HI type 2 (HI-2) was defined as more confluentpetechiae within the infarcted area but without space-occupyingeffect. PH type 1 (PH-1) was defined as hematoma in 30% of theinfarcted area with some slight space-occupying effect; PH type 2(PH-2) was defined as dense hematoma 30% of the infarcted areawith substantial space-occupying effect or as any hemorrhagic lesionoutside the infarcted area (examples are shown in Figure 1). In cases

of 1 hemorrhagic lesion on CT scan, the worst possible HTcategory was assumed.

Baseline and follow-up CT scans were obtained nonenhanced andon the same scanner if possible. Windows and center levels were setto optimally distinguish gray and white matter. The study protocolrecommended a window width of 80 to 100 Hounsfield units and acenter level of 30 to 40 Hounsfield units. The chairman of the CTreading panel gathered the categorized findings from the panelmembers, checked them for disagreements, disclosed disagreementsto the other panel members, and discussed each discrepant CT toachieve consensus. The final judgments were sent to the datamanagement center, which then was allowed to send the follow-upscans to the members of the CT reading panel. We definedhypoattenuation as a visible decrease in x-ray attenuation of braintissue compared with other portions of the same anatomic structureor its contralateral counterpart. We categorized the extent of hypoat-tenuation of the middle cerebral artery (MCA) territory as none,33% (small), and 33% (large).19,20 The total MCA territory was

considered the brain volume between 2 lines being drawn from theanterior horn of the ventricle and from the trigonum perpendicular tothe skull involving most parts of the frontal, temporal, and parietallobe with the exception of the parasagittal structures. On follow-upCT scans, we measured the volume of acute ischemic lesions bymultiplying the maximum diameter of hypoattenuation, maximumdiameter perpendicular to it in the same slice, number of slicesaffected, slice distance, and a conversion factor of 0.5 using theformula for irregular volumes. In patients with HT, the entireischemic and hemorrhagic lesion was measured.

From the ECASS II database, we retrieved the following vari-ables: age, sex, allocation to placebo/rtPA treatment, severity ofneurological deficit on admission as quantified with the NIHSS andthe Scandinavian Stroke Scale,21 NIHSS score 242 hours afterstroke onset, extent of initial ischemic lesion on baseline CT scan

(none,33% of MCA territory, and 33% of MCA territory), bodytemperature, blood glucose, and blood pressure at the inclusion time.

Figure 1. Examples of different subtypes of HT: HI-1 with scat-tered, heterogeneous petechiae along the margins of the infarct(A); HI-2 with more confluent but still heterogeneous petechiaewithin the infarcted area (B); PH-1 with a homogeneous hema-toma covering 30% of the infarcted area and only mild space-occupying effect (C); and PH-2 with a dense hematoma 30%of the lesion volume with significant space-occupying effect (D).

Berger et al Hemorrhagic Transformation of Ischemic Brain Tissue 1331

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We calculated the frequencies of the different subtypes of HT forplacebo and rtPA groups. Statistical difference was tested with the 2

test.To examine which of the collected variables accounted for clinical

deterioration 24 hours after stroke onset (increase in NIHSS score by4 between baseline and after 242 hours22 according to theprospective definition used in ECASS II), for disability and death at3 months (modified Rankin Scale score 2), and for death up to 3months after stroke onset, we performed a logistic regressionanalysis on each of these variables. Variables with a P0.05 in theWald test and the logistic likelihood ratio test were assumed to beirrelevant for the outcome tested and were excluded from furtheranalysis. We calculated the odds ratios (ORs) and 95% CIs for eachHT subtype, comparing the ORs of each level of HT with no HT.Subsequently, we performed a multiple regression analysis includingall variables considered relevant factors from the univariate analysisand calculated ORs for clinical deterioration at 24 hours, disabilityand death after 3 months, and death at 3 months after stroke onset.In a backward stepwise regression, we excluded all variables fromour model that did not contribute significantly in at least 1 outcometest. The adjusted ORs are given for all variables finally kept in themodel. Variables leading to a clear change of the ORs for HT were

considered confounding factors.Finally, we evaluated the relationship between the frequency of

PH-2 and the extent of hypoattenuation on baseline CT scan andcalculated ORs for the development of PH-2. The Newman-Keuls

test was applied to assess the relationship between incidence ofdifferent types of HT and the lesion volume at 24 hours. In all tests,a statistical significance was assumed for P0.05. Analyses were

performed with StatView statistical software (edition 5.0.1).

ResultsOf a total of 790 intent-to-treat patients in ECASS II, 406

patients received rtPA (0.9 mg/kg), and 384 patients weretreated with placebo. In the first follow-up CT scan, signifi-

cantly more HT occurred in the rtPA group: 29.5% versus

18.5% in the placebo group (Table 1). This was mainly due to

a higher incidence of PH-2 in the rtPA group (7.6% versus

0.5%; P0.0001). The incidences of HI-1, HI-2, and PH-1

were statistically not different between the placebo and the

actively treated group, although there was a clear trend for

HI-2 and PH-1 to more likely occur after thrombolysis.

Table 2 presents the unadjusted and adjusted risk ratios for

the 4 different types of HT and for other factors found to

contribute significantly to outcome. Sex, body temperature,

and blood pressure at the inclusion time were irrelevant for

outcome and thus were excluded from analysis. PH-2 signif-icantly increased the risk of early deterioration, of disability

and death at 3 months, and of death at 3 months alone. PH-1

accounted for an increased risk of early deterioration but not

of disability or death at 3 months. Thus, outcome at 3 months

was modified only by presence of PH-2 on the first follow-up

CT scan. In our search for factors contributing significantly to

outcome, we found a confounding effect of severity of stroke

syndrome at onset and of presence of hypodensity 33% on

baseline CT scan. Both were associated with an increased risk

rate for disability and death. Presence of a large hypodensity

was associated with early deterioration. Other contributing

factors for outcome were age and glucose level. Increase of

age or glucose was associated with an increased risk of

disability and death at 3 months. Treatment with rtPA led to

a significantly decreased risk of disability or death after 3

TABLE 1. Frequencies of Different Types of Hemorrhage in the

Placebo and rtPA Groups

Placebo (n384) rtPA (n406)

No. % No. %

HI-1 53 13.8 50 12.3

HI-2 11 2.9 28 6.9

PH-1 5 1.3 11 2.7

PH-2* 2 0.5 31 7.6

Total* 71 18.5 120 29.5

*Significant difference in frequency between placebo and rtPA group

according to 2 test (P0.05).

TABLE 2. Comparison of Adjusted and Unadjusted ORs

Deterioration After 24 h Disability/Death up to 3 mo Death up to 3 mo

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Nonadjusted HT

HI-1 0.6 (0.21.3) 0.2 1.4 (0.92.2) 0.09 0.9 (0.42.1) 0.9

HI-2 0.8 (0.22.6) 0.7 1.3 (0.72.6) 0.4 0.9 (0.33.2) 0.9

PH-1 4.2 (1.412.4) 0.01 1.2 (0.43.1) 0.8 2.6 (0.79.6) 0.1PH-2 41 (16104) 0.0001 6.5 (2.517.0) 0.0002 20 (943) 0.0001

Adjusted HT

HI-1 0.2 (0.10.6) 0.003 0.7 (0.41.2) 0.2 0.2 (0.070.6) 0.004

HI-2 0.5 (0.21.9) 0.3 0.9 (0.41.9) 0.8 0.6 (0.22.5) 0.5

PH-1 3.5 (1.111.6) 0.04 0.6 (0.21.9) 0.4 1.0 (0.24.8) 0.9

PH-2 18 (656) 0.0001 1.9 (0.75.7) 0.2 11.4 (3.736) 0.0001

Treatment with rtPA 0.8 (0.51.3) 0.4 0.7 (0.40.9) 0.02 0.6 (0.31.2) 0.2

Hypodensity 33% on initial CT 2.6 (1.06.5) 0.047 2.8 (1.26.4) 0.01 8 (3.319.5) 0.0001

Severe stroke syndrome at

onset

1.1 (0.62.1) 0.7 4.1 (2.56.5) 0.0001 4.3 (2.47.7) 0.0001

Age 1.0 (0.91.0) 0.8 1.04 (1.021.05) 0.0001 1.09 (1.051.13) 0.0001

Glucose 1.0 (0.91.1) 0.6 1.1 (1.041.13) 0.0006 1.1 (1.021.2) 0.02

1332 Stroke June 2001



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months; however, its influence for early deterioration or death

alone at 3 months was insignificant.

Figure 2 demonstrates the positive correlation between

large lesion volumes and large PH in both the actively treated

and the placebo-treated groups. In both treatment groups, the

total lesion volumes in patients with PH-2 were significantly

larger than those of all other groups, including the group

without HT. Thus, the space-occupying effect of PH-2

becomes evident. Table 3 presents the relationship between

incidence of PH-2 and extent of hypoattenuation on baseline

CT scan. Clearly, the incidence of PH-2 is more frequent with

presence of large hypodensity on CT scan. The risk ratio of

developing PH-2 with an initially large extent of the ischemiclesion was 4.4.

DiscussionHT of a brain infarct is a major concern when thrombolysis is

used in acute stroke. Frequently, HT of any type and extent

found on routine follow-up CT scans is considered a serious

adverse event and is often termed symptomatic hemorrhage

regardless of whether a certain type of HT was really causing

symptoms. In the larger thrombolysis studies, various defini-

tions for symptomatic hemorrhage consisting of radiological

and clinical criteria were applied. The NINDS tPA trial

defined symptomatic hemorrhage as any CT-documented

hemorrhage that was temporally related to deterioration in thepatients clinical condition in the judgment of the clinical

investigator.8 Symptomatic hemorrhage was considered to

be due to study medication if it occurred within 36 hours of

treatment. It appears inconceivable that a clinical deteriora-

tion under this definition could not be merely coincidental

with any HT appearing on CT scan. In fact, the deterioration

could well have been the natural course of a stroke indepen-

dent of the coinciding HT, especially if the HT was only a

minor part of a large infarct. In a post hoc analysis by the

NINDS Stroke Study Group,9 it was nevertheless stated that

presence of a severe neurological deficit and clear signs of

brain edema or mass effect on pretreatment CT increased the

risk of symptomatic hemorrhage. Again, pure radiological

criteria of different types of HT were not considered, and

other factors causing clinical deterioration were ignored.

Similar definitions for symptomatic hemorrhage were applied

in the Multicenter Acute Stroke Trial of Italy and Europe6,7

and in recent thrombolysis surveys.10,11

In ECASS I and II, prospective radiological definitions of

the 4 different subtypes of HT were applied regardless of

clinical events, and CT scans with or without HT were

analyzed regardless of clinical data. CT was performed at 24hours and 7 days after symptom onset and treatment and in

case of clinical deterioration. Almost all major hemorrhages

were detected by the first follow-up CT. However, local

investigators collecting data on neurological status might

have created some unavoidable bias in that they knew the

result of the CT scan and might have implemented a precon-

ceived notion of any relationship between HT and neurolog-

ical deterioration. We believe that a prospective protocol for

CT scanning at predetermined dates is necessary to study the

question of whether certain types of hemorrhage are associ-

ated with clinical deterioration. In our view, an early

follow-up CT within 48 hours of treatment is necessary to

detect hemorrhages caused by rtPA.In this post hoc analysis of the ECASS II data set, we

confirm previous results by Fiorelli et al16 that only PH

30% of the infarcted area with considerable space-

occupying effect (PH-2) significantly increased the risk of

early clinical deterioration and of a worse long-term outcome,

including death. Other types of HT, particularly HI-1 and

HI-2, were not associated with clinical deterioration. This

was also true for PH-1, which at least did not increase the risk

of disability or death up to 3 months after stroke onset. Thus,

while these latter types of HT would have been termed

symptomatic hemorrhages according to the definition of

many ongoing trials, their presence might not have been

responsible for deterioration. Instead, other factors such asage, initial glucose level, extent of initial hypodensity on

baseline CT scan, and severity of stroke syndrome at baseline

Figure 2. Comparison between lesion volume and presence ofhemorrhage, showing mean lesion volume (error bars indicateSD) and corresponding group of patients with a certain type ofHT or without any HT. In both treatment groups, significant dif-ference in lesion volume was reached between PH-2 and allother groups, including the group without any HT. In the rtPAgroup, lesion volume in patients without HT was also signifi-cantly lower than in patients with HI-1 and HI-2 (Newman-Keulstest). See Table 1 for frequencies of different HT subtypes.

TABLE 3. Observed Frequencies of PH-2 With Different Extents of

Hypoattenuation on Baseline CT Scan and Their ORs for the Development of PH-2

Hypoattenuation

at Baseline

Frequency OR

PH-2 % Total OR (95% CI) P

No 12 3.3 356 0.04 (0.020.07) 0.0001

33% 18 4.5 398 1.8 (0.83.7) 0.1

33% 3 8.3 36 4.4 (1.116.8) 0.03

Total 33 4.2 790




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additionally contributed to clinical outcome, as described in a

previous study.23 Treatment with rtPA, although associated

with a higher incidence of PH-2, decreased the overall risk of

disability and death at 3 months.

In particular, stroke severity and the presence of large

hypodensity on the initial CT scan were associated with a

significantly increased risk for disability and death up to 3

months after stroke onset. Thus, they appear as confounding

factors for the influence of HT on outcome. After adjustment

for these confounding factors, the risk for disability or death

at 3 months was increased insignificantly after PH-2, but with

respect to a long-term outcome, PH-2 independently and

significantly increased only the risk of death at 3 months.

HI-1 was even associated with some clinical improvement

and may, at least in this early stage, indicate the effect of

successful early reperfusion. Since PH-2 is of major clinical

relevance or may in fact be considered hemorrhage that is

most likely to be symptomatic, emphasis must be placed on

the recognition of stroke patients who are more likely to

develop large PH and subsequently should be excluded fromthrombolysis. PH-2 occurred more frequently in patients with

hypodensity 33% on early CT. These early ischemic

changes identified on the pretreatment CT represent early

cytotoxic edema and possibly the development of irreversible

injury.24 In a study by Hamann et al,25 the presence of

microscopic hemorrhages in the ischemic area has been

related to a loss of cerebrovascular basal lamina integrity.

Since these microscopic hemorrhages always occur within

the infarcted area, particularly in the subcortical core, a large

infarct volume a priori offers a larger area of lost basal lamina

integrity, thus possibly leading more frequently to parenchy-

mal hemorrhages. We were able to confirm this relationship

by demonstrating a positive correlation between large lesionvolume and presence of PH-2. Thus, to detect signs of early

infarction on CT remains crucial, although it is questioned

whether these signs can be detected reliably.26 In a previous

study the interobserver agreement in assessing subtle CT

signs of cerebral infarction was moderate to substantial.20

Similar results for assessment of the hypoattenuation in thirds

of the MCA territory were obtained by the Alberta Stroke

Programme Early CT Score (ASPECTS) study group.27

Whether general reading of CT scans can be improved by

quantification and division of the MCA territory into many

regions of interest remains to be confirmed in clinical

practice. To date, presence of hypoattenuation larger than one

third of the MCA territory on baseline CT seems to be the

most simple and readily available predictor of the develop-

ment of large PH.

In summary, only large PH 30% of the infarcted area

with space-occupying effect (PH-2) independently modify

the risk of a worse clinical outcome both early and late after

stroke onset. Smaller but still homogeneous PH (PH-1)

increase the risk of early deterioration but not of a worse

long-term outcome. Heterogeneous, petechial HI are not

associated with worse early or late outcome. Thus, the term

symptomatic hemorrhage should be applied with caution

because it implies a causal relationship between signs of HT

found on CT and clinical deterioration. Additional factors,such as extent of the lesion, edema formation, and severity of

the stroke syndrome, however, offer an explanation for a

patients deterioration or bad outcome. In future reports

dealing with safety aspects of thrombolysis, a clearer distinc-

tion between nonrelevant forms of HT and PH with risk of

clinical deterioration should be made.

AcknowledgmentECASS II was supported exclusively by Boehringer Ingelheim,Biberach, Germany.

References1. Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction: a

prospective study. Stroke. 1986;17:179185.

2. Bozzao L, Angeloni U, Bastianello S, Fantozzi LM, Pierallini A, Fieschi

C. Early angiographic and CT findings in patients with hemorrhagic

infarction in the distribution of the middle cerebral artery. AJNR Am J

Neuroradiol. 1991;12:11151121.

3. Moulin T, Crepin-Leblond T, Chopard JL, Bogousslavsky J. Hemor-

rhagic infarcts. Eur Neurol. 1994;34:6477.

4. Toni D, Fiorelli M, Bastianello S, Sacchetti ML, Sette G, Argentino C,

Montinaro E, Bozzao L. Hemorrhagic transformation of brain infarct:

predictability in the first 5 hours from stroke onset and influence on

clinical outcome. Neurology. 1996;46:341345.5. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ,

Rosen D, Stewart-Wynne EG, Tuck RR, for the Australian Streptokinase

(ASK) Trial Study Group. Streptokinase for acute ischemic stroke with

relationship to time of administration. JAMA. 1996;276:961966.

6. . The Multicentre Acute Stroke TrialItaly Group (MAST-I). Randomised

controlled trial of streptokinase, aspirin, and combination of both in

treatment of acute ischaemic strokeLancet. 1995;346:15091514.

7. The Multicenter Acute Stroke TrialEurope (MAST-E). Thrombolytic

therapy with streptokinase in acute ischemic stroke. N Engl J Med.

1996;335:145150.

8. The National Institute of Neurological Disorders and Stroke rt-PA Stroke

Study Group. Tissue plasminogen activator for acute ischemic stroke.

N Engl J Med. 1995;333:15811587.

9. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after

intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28:

21092118.

10. Tanne D, Bates VE, Verro P, Kasner SE, Binder JR, Patel SC, Mansbach

HH, Daley S, Schultz LR, Karanjia PN, Scott P, Dayno JM, Vereczkey-

Porter K, Benesch C, Book D, Coplin WM, Dulli D, Levine SR, for the

t-PA Stroke Survey Group. Initial clinical experience with IV tissue

plasminogen activator for acute ischemic stroke: a multicenter survey.

Neurology. 1999;53:424427.

11. Buchan AM, Barber PA, Newcommon N, Karbalai HG, Demchuk AM,

Hoyte KM, Klein GM, Feasby TE. Effectiveness of t-PA in acute ische-

mic stroke: outcome relates to appropriateness. Neurology. 2000;54:

679684.

12. Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern LB,

Bratina PL, Yatsu FM, Grotta JC. Intravenous tissue plasminogen acti-

vator for acute ischemic stroke: feasibility, safety, and efficacy in the first

year of clinical practice.Stroke. 1998;29:1822.

13. Gonner F, Remonda L, Mattle H, Sturzenegger M, Ozdoba C, Lovblad

KO, Baumgartner R, Bassetti C, Schroth G. Local intra-arterial

thrombolysis in acute ischemic stroke. Stroke. 1998;29:18941900.14. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R,

Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al, for the European

Cooperative Acute Stroke Study (ECASS). Intravenous thrombolysis

with recombinant tissue plasminogen activator for acute hemispheric

stroke. JAMA. 1995;274:10171025.

15. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,

Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E,

Trouillas P, for the Second European-Australasian Acute Stroke Study

Investigators. Randomised double-blind placebo-controlled trial of

thrombolytic therapy with intravenous alteplase in acute ischaemic stroke

(ECASS II). Lancet. 1998;352:12451251.

16. Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V,

Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L. Hemor-

rhagic transformation within 36 hours of a cerebral infarct: relationships

with early clinical deterioration and 3-month outcome in the European

Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke. 1999;30:22802284.

1334 Stroke June 2001



7/7

17. Pessin MS, del Zoppo GJ, Estol CJ. Thrombolytic agents in the treatment

of stroke. Clin Neuropharmacol. 1990;13:271289.

18. Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del

Zoppo GJ, for the rt-PA Acute Stroke Study Group. Neuroradiologic

evaluation of patients with acute stroke treated with recombinant tissue

plasminogen activator. AJNR Am J Neuroradiol. 1993;14:313.

19. von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C,

Bluhmki E, Ringleb P, Meier DH, Hacke W. Acute stroke: usefulness of

early CT findings before thrombolytic therapy. Radiology. 1997;205:

327333.

20. von Kummer R, Holle R, Gizyska U, Hofmann E, Jansen O, Petersen D,

Schumacher M, Sartor K. Interobserver agreement in assessing early CT

signs of middle cerebral artery infarction. AJNR Am J Neuroradiol.

1996;17:17431748.

21. The Scandinavian Stroke Study Group. Multicenter trial of hemodilution

in ischemic stroke: background and study protocol. Stroke. 1985;16:

885890.

22. Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL,

Spilker J, Kongable GL, Massey S, Reed R, Marler JR. Urgent therapy for

stroke, part I: pilot study of tissue plasminogen activator administered

within 90 minutes. Stroke. 1992;23:632 640.

23. Larrue V, von Kummer R, del Zoppo G, Bluhmki E. Hemorrhagic

transformation in acute ischemic stroke: potential contributing factors in

the European Cooperative Acute Stroke Study. Stroke. 1997;28:957960.

24. del Zoppo GJ, von Kummer R, Hamann GF. Ischaemic damage of brain

microvessels: inherent risks for thrombolytic treatment in stroke.J Neurol

Neurosurg Psychiatry. 1998;65:19.

25. Hamann GF, Okada Y, del Zoppo GJ. Hemorrhagic transformation and

microvascular integrity during focal cerebral ischemia/reperfusion.

J Cereb Blood Flow Metab. 1996;16:13731378.

26. Wardlaw JM, Dorman PJ, Lewis SC, Sandercock PA. Can stroke phy-

sicians and neuroradiologists identify signs of early cerebral infarction on

CT? J Neurol Neurosurg Psychiatry. 1999;67:651653.

27. Barber PA, Demchuk AM, Zhang J, Buchan AM, for the ASPECTS

Study Group (Alberta Stroke Programme Early CT Score). Validity and

reliability of a quantitative computed tomography score in predicting

outcome of hyperacute stroke before thrombolytic therapy. Lancet. 2000;

355:16701674.



hemorrhagic conversion classification

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