Ischemic Stroke - Thrombolytic Therapy - Hemorrhagic Transformation

1/16/2008

Question:  What are the mechanisms of hemorrhagic transformation as an adverse consequence of thrombolytic therapy for ischemic stroke?

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<1>

Unique Identifier [PMID]: 17673718

Authors: Foerch C. Wunderlich MT. Dvorak F. Humpich M. Kahles T. Goertler M. Alvarez-Sabin J. Wallesch CW. Molina CA. Steinmetz H. Sitzer M. Montaner J.

Institution: Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. foerch@em.uni-frankfurt.de

Title: Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke.

Source: Stroke. 38(9):2491-5, 2007 Sep.

Abstract: BACKGROUND AND PURPOSE: Intracerebral hemorrhage constitutes an often fatal sequela of thrombolytic therapy in patients with ischemic stroke. Early blood-brain barrier disruption may play an important role, and the astroglial protein S100B is known to indicate blood-brain barrier dysfunction. We investigated whether elevated pretreatment serum S100B levels predict hemorrhagic transformation (HT) in thrombolyzed patients with stroke. METHODS: We retrospectively included 275 patients with ischemic stroke (mean age of 69+/-13 years; 46% female) who had received thrombolytic therapy within 6 hours of symptom onset. S100B levels were determined from pretreatment blood samples. Follow-up brain scans were obtained 24 hours after admission, and HT was classified as either hemorrhagic infarction (1, 2) or parenchymal hemorrhage (1, 2). RESULTS: HT occurred in 80 patients (29%; 45 hemorrhagic infarction, 35 parenchymal hemorrhage). Median S100B values were significantly higher in patients with HT (0.14 versus 0.11 mug/L; P=0.017). An S100B value in the highest quintile corresponded to an OR for any HT of 2.87 (95% CI: 1.55 to 5.32; P=0.001) in univariate analysis and of 2.80 (1.40 to 5.62; P=0.004) after adjustment for age, sex, symptom severity, timespan from symptom onset to hospital admission, vascular risk factors, and storage time of serum probes. A pretreatment S100B value above 0.23 mug/L had only a moderate sensitivity (0.46) and specificity (0.82) for predicting severe parenchymal bleeding (parenchymal hemorrhage 2). CONCLUSIONS: Elevated S100B serum levels before thrombolytic therapy constitute an independent risk factor for HT in patients with acute stroke. Unfortunately, the diagnostic accuracy of S100B is too low for it to function in this context as a reliable biomarker in clinical practice.

Publication Type: Journal Article.
 

<2>

Unique Identifier [PMID]: 17182976

Authors: Bang OY. Saver JL. Liebeskind DS. Starkman S. Villablanca P. Salamon N. Buck B. Ali L. Restrepo L. Vinuela F. Duckwiler G. Jahan R. Razinia T. Ovbiagele B.

Institution: Department of Neurology, School of Medicine, Sungkyunkwan University, Samsung Medical Center, Seoul, Korea.

Title: Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis.[see comment][erratum appears in Neurology. 2007 May 1;68(18):1547].

Source: Neurology. 68(10):737-42, 2007 Mar 6.

Abstract: BACKGROUND: Prestroke statin use may improve ischemic stroke outcomes, yet there is also evidence that statins and extremely low cholesterol levels may increase the risk of intracranial hemorrhage. We evaluated the independent effect of statin use and admission cholesterol level on risk of symptomatic hemorrhagic transformation (sHT) after recanalization therapy for acute ischemic stroke. METHODS: We analyzed ischemic stroke patients recorded in a prospectively maintained registry that received recanalization therapies (IV or intra-arterial fibrinolysis or endovascular embolectomy) at a university medical center from September 2002 to May 2006. The independent effect of premorbid statin use on sHT post intervention was evaluated by logistic regression, adjusting for prognostic and treatment variables known to predict increased HT risk after ischemic stroke. RESULTS: Among 104 patients, mean age was 70 years, and 49% were men. Male sex, hypertension, statin use, low total cholesterol and low-density lipoprotein (LDL) cholesterol, current smoking, elevated glucose levels, and higher admission NIH Stroke Scale (NIHSS) score were all associated with a greater risk of sHT in univariate analysis. After adjusting for covariates, low LDL cholesterol (odds ratio [OR], 0.968 per 1-mg/dL increase; 95% CI, 0.941 to 0.995), current smoking (OR, 14.568; 95% CI, 1.590 to 133.493), and higher NIHSS score (OR, 1.265 per 1-point increase; 95% CI, 1.047 to 1.529) were independently associated with sHT risk. CONCLUSIONS: Lower admission low-density lipoprotein cholesterol level with or without statin use, current smoking, and greater stroke severity are associated with greater risk for symptomatic hemorrhagic transformation after recanalization therapy for ischemic stroke.

Publication Type: Comparative Study. Evaluation Studies. Journal Article. Research Support, N.I.H., Extramural.
 

<3>

Unique Identifier [PMID]: 17220957

Authors: Montaner J.

Institution: Neurovascular Research Laboratory, Neurology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain. 31862jmv@comb.es

Title: Stroke biomarkers: Can they help us to guide stroke thrombolysis?[reprint in Timely Top Med Cardiovasc Dis. 2007;11:E11; PMID: 17473898]. [Review] [93 refs]

Source: Drug News & Perspectives. 19(9):523-32, 2006 Nov.

Abstract: The use of blood biomarkers is getting increasingly popular in the field of cerebrovascular diseases, since biomarkers might aid physicians in several steps of stroke evaluation. We will discuss whether stroke diagnosis might be possible using some specific brain biomarkers and if this approach will permit rapid referral of stroke patients to hospitals with acute treatments such as tissue plasminogen activator (t-PA) available. Although thrombolytic therapy in acute stroke is effective since it accelerates clot lyses and earlier restoration of blood flow, up to 40-50% of treated patients do not recanalize or do it too late, and between 6 and 15% suffer hemorrhagic transformations with high death rates. In the context of the neurovascular unit, t-PA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood-brain barrier leakage, edema and hemorrhage. In humans, biomarkers such as matrix metalloproteinase-9 (MMP-9) or fibronectin, which might be used to select patients at higher risk of hemorrhagic transformation, and high plasminogen activator inhibitor-1 (PAI-1) interfering with tPA-induced recanalization, thus predicting clot-lyses resistance and poor outcome, have been recently identified. Moreover, high levels of MMP-9 and MMP-13 are involved in DWI lesion growth in spite of thrombolytic therapy suggesting its ultra-early role in brain injury. Other biomarkers such as C-reactive protein may accurately predict stroke mortality following reperfusion therapies. Finally, we will also show that genetic background of stroke patients may condition plasma levels of some of these biomarkers and influence therapeutic response in t-PA-treated patients. Copyright 2006 Prous Science. All rights reserved. [References: 93]

Publication Type: Journal Article. Research Support, Non-U.S. Gov't. Review.
 

<4>

Unique Identifier [PMID]: 16439694

Authors: IMS Study Investigators.

Title: Hemorrhage in the Interventional Management of Stroke study.

Source: Stroke. 37(3):847-51, 2006 Mar.

Abstract: BACKGROUND AND PURPOSE: The incidence of hemorrhage after combined intravenous (IV) and intra-arterial (IA) recombinant tissue plasminogen activator (rt-PA) was examined in patients entered into the Interventional Management of Stroke (IMS) trial. We also analyzed factors predicting symptomatic and asymptomatic intracerebral hemorrhage (ICH). METHODS: The IMS study treated patients within 3 hours of stroke onset with 0.6 mg/kg IV rt-PA followed by up to 22 mg IA rt-PA. Any hemorrhage within 36 hours associated with clinical deterioration was considered symptomatic. Logistic regression analysis was applied to possibly relevant variables selected from the baseline data to test for associations between these factors and symptomatic hemorrhage, asymptomatic hemorrhage, and all hemorrhage. RESULTS: Symptomatic hemorrhage occurred in 6% and asymptomatic hemorrhage in 43% of patients. The rate of symptomatic hemorrhage was similar to the National Institute of Neurological Disorders and Stroke (NINDS) trial with IV rt-PA alone. Asymptomatic hemorrhage was more frequent but consistent with the rate observed in more recent IV and IA thrombolytic trials. The small number of symptomatic hemorrhages precluded meaningful analysis of risk factors. Significant factors associated with ICH in univariate analysis were baseline National Institutes of Health Stroke Scale score (asymptomatic and all ICH), edema or mass effect on initial computed tomography (asymptomatic ICH), atrial fibrillation (all ICH), and location of arterial occlusion (internal carotid artery [ICA] compared with middle cerebral artery [MCA]; asymptomatic and all ICH). In multivariate analysis, ICA versus MCA occlusion remained an independent factor associated with asymptomatic and all hemorrhage, and atrial fibrillation was significantly associated with all hemorrhage. CONCLUSIONS: Symptomatic and asymptomatic hemorrhage with combined IV and IA rt-PA occurred at rates similar to previous thrombolytic trials. Site of vascular occlusion and atrial fibrillation may be risk factors for hemorrhagic transformation.

Publication Type: Journal Article. Research Support, N.I.H., Extramural.
 

<5>

Unique Identifier [PMID]: 16499561

Authors: Chen TY. Lee MY. Chen HY. Kuo YL. Lin SC. Wu TS. Lee EJ.

Institution: Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan.

Title: Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice.

Source: Journal of Pineal Research. 40(3):242-50, 2006 Apr.

Abstract: Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood-brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P < 0.001). Additionally, we found that at 6 hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction (P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation (P < 0.05), and the event was effectively reversed by co-treatment with melatonin (P < 0.05). Thus, melatonin improved postischemic preservation of the BBB permeability and a decreased risk of adverse hemorrhagic transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients.

Publication Type: Journal Article. Research Support, Non-U.S. Gov't.
 

<6>

Unique Identifier [PMID]: 16135384

Authors: Bentley P. Sharma P.

Institution: Hammersmith Hospitals Acute Stroke Unit (HHASU), Imperial College, Fulham Palace Road, London W6 8RF, United Kingdom.

Title: Pharmacological treatment of ischemic stroke.

Source: Pharmacology & Therapeutics. 108(3):334-52, 2005 Dec.

Abstract: Current pharmacological strategies for acute ischemic stroke largely mirror those employed in acute coronary syndromes. However, important differences in the effectiveness and versatility of the principal agents have emerged between these 2 clinical settings. In general, the level of success achieved with drugs in acute coronary syndromes has not carried over to the same extent when the same drug types are used in stroke. The principal reason is that reperfusion or anticoagulant therapies in the setting of brain infarction run a significant risk of hemorrhagic transformation that has no direct equivalent in myocardial infarction. Consequently, a significant challenge in acute stroke therapeutics is the ability to select patients for drugs where only a narrow therapeutic margin exists and to identify methods that can minimize hemorrhage risk. Other brain-specific vascular factors also pertain in explaining differences in outcome of drugs generally regarded as having a broad cardiovascular remit. The relatively limited efficacy of antiplatelets in stroke might relate to the composition and heterogeneity of the cerebrovascular lesion, while the poor outcome associated with acute anti-hypertensive use is partly due to loss of cerebrovascular autoregulation. Finally, downstream consequences of arterial occlusion within the brain such as excitotoxicity and plasticity are organ specific and, as such, deserve their own pharmacological approaches. In this review, we describe the general mechanism of each drug class used in ischemic stroke and then report on the clinical experience and application for each.

Publication Type: Journal Article.
 

<7>

Unique Identifier [PMID]: 16219824

Authors: Kassner A. Roberts T. Taylor K. Silver F. Mikulis D.

Institution: Department of Medical Imaging, University of Toronto & UHN (Princess Margaret Hospital), Toronto, Ontario, Canada.

Title: Prediction of hemorrhage in acute ischemic stroke using permeability MR imaging.

Source: Ajnr: American Journal of Neuroradiology. 26(9):2213-7, 2005 Oct.

Abstract: Increased risk of hemorrhagic transformation (HT) limits the general use of thrombolytic therapy in acute ischemic stroke (AIS). This study shows that early blood-brain barrier defects in AIS can be assessed by using permeability MR imaging. Significantly increased permeability was found in 3 patients who later hemorrhaged. This method indicates the potential for identifying patients at higher risk of HT and offers the use of physiologic imaging rather than time from onset of symptoms to guide treatment decisions.

Publication Type: Journal Article.
 

<8>

Unique Identifier [PMID]: 15459442

Authors: Wang X. Tsuji K. Lee SR. Ning M. Furie KL. Buchan AM. Lo EH.

Institution: Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass, USA.

Title: Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. [Review] [50 refs]

Source: Stroke. 35(11 Suppl 1):2726-30, 2004 Nov.

Abstract: Reperfusion therapy with tissue plasminogen activator (tPA) is a rational therapy for acute ischemic stroke. Properly titrated use of tPA improves clinical outcomes. However, there is also an associated risk of hemorrhagic transformation after tPA therapy. Emerging data now suggest that some of these potentially neurotoxic side effects of tPA may be due to its signaling actions in the neurovascular unit. Besides its intended role in clot lysis, tPA is also an extracellular protease and signaling molecule in brain. tPA mediates matrix remodeling during brain development and plasticity. By interacting with the NMDA-type glutamate receptor, tPA may amplify potentially excitotoxic calcium currents. At selected concentrations, tPA may be vasoactive. Finally, by augmenting matrix metalloproteinase (MMP) dysregulation after stroke, tPA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood-brain barrier leakage, edema, and hemorrhage. Understanding these pleiotropic actions of tPA may reveal new therapeutic opportunities for combination stroke therapy. [References: 50]

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S.. Review.
 

<9>

Unique Identifier [PMID]: 14709787

Authors: Wang X. Lo EH.

Institution: Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Boston, MA. Wangxi@helix.mgh.harvard.edu

Title: Triggers and mediators of hemorrhagic transformation in cerebral ischemia. [Review] [125 refs]

Source: Molecular Neurobiology. 28(3):229-44, 2003 Dec.

Abstract: Intracerebral hemorrhagic transformation is a multifactorial phenomenon in which ischemic brain tissue converts into a hemorrhagic lesion with blood-vessel leakage, extravasation, and further brain injury. It has been estimated that up to 30-40% of all ischemic strokes undergo spontaneous hemorrhagic transformation, and this phenomenon may become even more prevalent with the increasing use of thrombolytic stroke therapy. An emerging conceptual model suggests that the loss of microvascular integrity and disruption of neurovascular homeostasis connects the experimental findings of blood-cell extravasation to brain injury after hemorrhage. In this short article, we examine mechanisms related to reperfusion injury and oxidative stress, leukocyte infiltration, vascular activation, and dysregulated extracellular proteolysis as potential triggers of hemorrhagic transformation. Perturbations in cell-cell and cell-matrix signaling within the hypothesized neurovascular unit may ultimately lead to neuroinflammation and apoptotic-like cell death in the parenchyma. Further investigations into the molecular mediators of hemorrhagic transformation may reveal new therapeutic targets for this clinically complex problem. [References: 125]

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S.. Review.
 

<10>

Unique Identifier [PMID]: 14600444

Authors: Hermier M. Nighoghossian N. Derex L. Adeleine P. Wiart M. Berthezene Y. Cotton F. Pialat JB. Dardel P. Honnorat J. Trouillas P. Froment JC.

Institution: Department of Radiology and MRI, Hopital Neurologique, Hospices Civils de Lyon, Lyon, France. marc.hermier@club-internet.fr

Title: Hypointense transcerebral veins at T2*-weighted MRI: a marker of hemorrhagic transformation risk in patients treated with intravenous tissue plasminogen activator.

Source: Journal of Cerebral Blood Flow & Metabolism. 23(11):1362-70, 2003 Nov.

Abstract: Prediction of hemorrhagic transformation (HT) in patients treated by intravenous recombinant tissue-type plasminogen activator (rt-PA) is a challenging issue in acute stroke management. HT may be correlated with severe hypoperfusion. Signal changes may be observed at susceptibility-weighted magnetic resonance imaging (MRI) within large perfusion defects. A signal drop within cerebral veins at T2*-weighted gradient-echo MRI may be expected in severe ischemia, and may indicate subsequent risk of HT. The authors prospectively searched for an abnormal visibility of transcerebral veins (AVV) within the ischemic area in patients with hemispheric ischemic stroke, before they were treated with intravenous rt-PA therapy. Any correlation between AVV and baseline clinical or MRI findings, or further HT, was noted. An AVV was present in 23 of 49 patients (obvious, n = 8; moderate, n = 15), and was supported by severe hemodynamic changes at baseline MRI. The AVV was correlated with the occurrence of parenchymal hematoma type 2 at computed tomography during the first week (r = 0.44, P = 0.002). Five of six type 2 parenchymal hematomas occurred in association with obvious AVV. At multiple regression analysis, two baseline MRI factors had an independent predictive value for HT risk during the first week: the AVV and the cerebral blood volume ratio (Nagelkerke R2 = 0.48).

Publication Type: Journal Article. Research Support, Non-U.S. Gov't.
 

<11>

Unique Identifier [PMID]: 12510185

Authors: Bayramoglu M. Karatas M. Leblebici B. Cetin N. Sozay S. Turhan N.

Institution: Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Baskent University, Ankara, Turkey.

Title: Hemorrhagic transformation in stroke patients.

Source: American Journal of Physical Medicine & Rehabilitation. 82(1):48-52, 2003 Jan.

Abstract: OBJECTIVE: To identify the predictors of hemorrhagic transformation in stroke patients and to evaluate the impact of hemorrhagic transformation on rehabilitation outcome. DESIGN: The records of 203 hemiplegic patients hospitalized for rehabilitation after the acute phase of stroke were retrospectively analyzed. In 121 cases, the first computed tomographic scan and a repeat scan were compared to determine whether hemorrhagic transformation occurred. Correlations between the occurrence of hemorrhagic transformation and use of anticoagulants, antiaggregants, and antiedema drugs were evaluated. Admission and discharge FIM trade mark and Adapted Patient Evaluation Conference System scores were noted, and functional gain was calculated from these. These data were also analyzed for associations with hemorrhagic transformation. RESULTS: Hemorrhagic transformation was detected in 39 of the 121 cases. There was no significant difference in functional outcome between patients who did and did not show hemorrhagic transformation. Although not statistically significant, the use of antiedema drugs was found to increase the risk of hemorrhagic transformation, whereas the use of anticoagulants and antiaggregants had no influence. CONCLUSIONS: Hemorrhagic transformation of an ischemic lesion does not affect rehabilitation outcome in stroke survivors. The study results favor the use of anticoagulants and antiaggregants in the acute phase unless these drugs are contraindicated by the patient's condition. Still, prospective trials are needed to make definite conclusions.

Publication Type: Journal Article.
 

<12>

Unique Identifier [PMID]: 12450244

Authors: Tambasco N. Corea F. Luccioli R. Ciorba E. Parnetti L. Gallai V.

Institution: Dipartimento di Neuroscienze, Universita di Perugia, Perugia, Italy. n.tambasco@libero.it

Title: Brain CT scan in acute ischemic stroke: early signs and functional outcome. [Review] [40 refs]

Source: Clinical & Experimental Hypertension (New York). 24(7-8):687-96, 2002 Oct-Nov.

Abstract: There is evidence that an improvement of the diagnostic abilities could have a value for prognosis and therapy of the ischemic stroke. New neuroradiological strategies could be used with an amelioration of the evaluation and standardization of the ischemic damage. The value of early vascular sign remains controversial as a predictor of patient outcome. Early parenchymal changes are related to a poor outcome. The risk of hemorrhagic transformation increases with trombolytic therapy and especially with the onset of therapy. Between hemorrhagic transformation, only the large hematomas seems to be related to early deterioration and death. Brain Computed Tomography (CT) examination can give information about prognosis and therapeutic choice. [References: 40]

Publication Type: Journal Article. Review.
 

<13>

Unique Identifier [PMID]: 12215587

Authors: Arenillas JF. Rovira A. Molina CA. Grive E. Montaner J. Alvarez-Sabin J.

Institution: Cerebrovascular Unit, Vall d'Hebron Hospital, Barcelona, Spain. juanfarenillas@terra.es

Title: Prediction of early neurological deterioration using diffusion- and perfusion-weighted imaging in hyperacute middle cerebral artery ischemic stroke.[see comment].

Source: Stroke. 33(9):2197-203, 2002 Sep.

Abstract: BACKGROUND AND PURPOSE: Early neurological deterioration (END) occurs in approximately one third of all ischemic stroke patients and is associated with a poor outcome. Our study sought to assess the value of ultra-early MRI in the prediction of END in stroke patients. METHODS: Between August 1999 and November 2001, 38 stroke patients with a proven middle cerebral artery (MCA) or intracranial internal carotid artery (ICA) occlusion on MR angiography underwent perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) within 6 hours after onset, and 30 fulfilled all inclusion criteria. Control DWI and MR angiography were performed between days 3 and 5. Cranial CT was performed to rule out hemorrhagic transformation. Vascular risk factors, temperature, blood pressure, glycemia, and blood count were assessed on admission. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and at 6, 12, 24, and 48 hours. At the same time points, transcranial Doppler (TCD) examinations were conducted to assess arterial recanalization. END was defined as an increase in the NIHSS score >4. A logistic regression model was applied to detect independent predictors of END. The Kruskal-Wallis test was used to evaluate the relationship between infarct growth and duration of vessel occlusion. RESULTS: Initial MR angiography showed an occlusion of intracranial ICA in 7 patients (23.3%), of proximal MCA in 14 (46.6%), and of distal MCA in the remaining 9 (30%). A PWI-DWI mismatch >20% was observed in 28 patients (93.3%). END occurred in 7 patients (23.3%). Baseline NIHSS score (P=0.05), proximal site of occlusion (P=0.002), initial DWI (P=0.002) and PWI (P=0.003) volumes, and reduced PWI-DWI mismatch (P=0.038) were associated with END in the univariate analysis. Only hyperacute DWI volume remained as a predictor of END when a logistic regression model was applied (odds ratio, 11.5; 95% CI, 2.31 to 57.10; P=0.0028). A receiver operator characteristic curve identified a cutoff point of DWI >89 cm(3) (sensitivity, 85.7%; specificity, 95.7%) to predict END. A graded response was seen in DWI lesion expansion in relation to duration of arterial occlusion (P=0.017). CONCLUSIONS: Ultra-early DWI is a powerful predictor of END after MCA or intracranial ICA occlusion.

Publication Type: Journal Article.
 

<14>

Unique Identifier [PMID]: 11984472

Authors: Oppenheim C. Samson Y. Dormont D. Crozier S. Manai R. Rancurel G. Fredy D. Marsault C.

Institution: Federation de Neuroradiologie, Universite Paris VI, Groupe Hospitalier Pitie-Salpetriere, 47 boulevard de l'Hopital, 75013, Paris.

Title: DWI prediction of symptomatic hemorrhagic transformation in acute MCA infarct.

Source: Journal of Neuroradiology. Journal de Neuroradiologie. 29(1):6-13, 2002 Mar.

Abstract: PURPOSE: Symptomatic hemorrhagic transformation is a severe complication of acute ischemic stroke which occurs at a higher frequency after thrombolysis. The present study was designed to analyze whether early DWI can be used for predicting the risk of hemorrhagic transformation with clinical worsening in MCA stroke patients. MATERIALS AND METHODS: Of 28 patients with a middle cerebral artery (MCA) infarct and proven MCA or carotid T occlusion on DWI and MR angiography performed within 14 hours after onset (mean 6.5 +/- 3.5 hours, median 5.2 hours), 4 developed hemorrhagic transformation with clinical worsening, while 24 did not. For the 2 groups, we compared admission NIHSS score, site of arterial occlusion, volume of DWI abnormalities, and several apparent diffusion coefficient (ADC) measurements: ADC(infarct) (mean ADC value of the whole infarct), ADC(core) (peak ADC decrease as calculated in a 57 mm(2) circular ROI, manually centered on the ischemic area with the lowest ADC value on the ADC maps), ADC(superficial) and ADC(deep). Discriminant function analysis was used to determine the most accurate predictors of symptomatic hemorrhagic transformation. RESULTS: The best predictor was the ADC(core) (F=5.34, p=2.9%, cut-off value=300 x 10(-6) mm(2)/s). This monovariate model allowed to correctly classify all 4 patients (ADC(core) 300 x 10(-6) mm(2)/s) with subsequent symptomatic hemorrhage, and 17 of the 24 patients without symptomatic hemmorrhage (ADC(core)>300 x 10(-6) mm(2)/s) (100% sensitivity, 71% specificity). CONCLUSION: Although preliminary, these results suggest that a simple measurement of minimum ADC values within an acute MCA stroke could be useful in targeting those patients with a high risk of severe hemorrhagic transformation.

Publication Type: Journal Article.
 

<15>

Unique Identifier [PMID]: 11898581

Authors: Lapchak PA.

Institution: Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MTF316, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu

Title: Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. [Review] [75 refs]

Source: Current Neurology & Neuroscience Reports. 2(1):38-43, 2002 Jan.

Abstract: Hemorrhagic transformation (HT) is a frequent consequence of ischemic stroke that becomes more prevalent after thrombolytic therapy. Despite concerns about safety parameters, thrombolytic drugs remain the first course of action available to clinicians for stroke management. However, recent efforts in preclinical studies have attempted to discover other drugs that can lessen the risk of hemorrhage associated with thrombolytic administration. This review focuses on three classes of pharmacologic agents that have shown some promise in animal models of stroke, and can thus be considered as possible candidates for coadministration with thrombolytics in the treatment of stroke. These include the following: 1) spin trap agents, such as alpha-phenyl-N-t-butylnitrone (PBN) that scavenge free radicals; 2) matrix metalloproteinase (MMP) inhibitors, such as BB-94, that prevent membrane and vessel remodeling following ischemia; and 3) the novel glycoprotein (GP) IIb/IIIa platelet receptor antagonist SM-20302. Although these drugs affect different mechanisms, the common denominator seemed to be their effectiveness in reducing the incidence of hemorrhage in response to thrombolytic infusion following an embolic stroke. [References: 75]

Publication Type: Journal Article. Review.
 

<16>

Unique Identifier [PMID]: 11872915

Authors: Adams HP Jr.

Institution: Department of Neurology, University of Iowa College of Medicine, Iowa City 52242, USA. harold-adams@uiuowa.edu

Title: Emergent use of anticoagulation for treatment of patients with ischemic stroke.[see comment]. [Review] [36 refs]

Source: Stroke. 33(3):856-61, 2002 Mar.

Abstract: BACKGROUND: Several clinical trials have tested the potential utility of emergent anticoagulation for acute ischemic stroke. SUMMARY OF REVIEW: Rather than performing a meta-analysis that combines the data from several trials, this review focuses on individual studies. Although these trials do have inherent limitations, they demonstrate that emergent use of an anticoagulant is associated with a modest but significantly increased risk of hemorrhagic transformation of the ischemic stroke or serious nonneurological bleeding. The trials do not demonstrate a benefit from emergent anticoagulation in improving outcome, reducing mortality, and preventing early recurrent stroke. CONCLUSIONS: These results suggest that most patients with acute stroke should not be treated with unfractionated heparin or other rapidly acting anticoagulants after stroke. Prevention of deep vein thrombosis and pulmonary embolism among bedridden patients is the only established indication for early anticoagulation after acute ischemic stroke. [References: 36]

Publication Type: Journal Article. Review.
 

<17>

Unique Identifier [PMID]: 11340213

Authors: Molina CA. Montaner J. Abilleira S. Ibarra B. Romero F. Arenillas JF. Alvarez-Sabin J.

Institution: Cerebrovascular Unit, Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain. carmolcate@demasiado.com

Title: Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke.

Source: Stroke. 32(5):1079-84, 2001 May.

Abstract: BACKGROUND AND PURPOSE: The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain. Therefore, we aimed to clarify the relationship between the time course of recanalization and the risk of HT in patients with cardioembolic stroke studied within 6 hours of symptom onset. METHODS: Fifty-three patients with atrial fibrillation and nonlacunar stroke in the middle cerebral artery (MCA) territory admitted within the first 6 hours after symptom onset were prospectively studied. Serial TCD examinations were performed on admission and at 6, 12, 24, and 48 hours. CT was performed within 6 hours after stroke onset and again at 36 to 48 hours. RESULTS: Proximal and distal MCA occlusions were detected in 32 patients (60.4%) and 18 patients (34%), respectively. Early spontaneous recanalization occurring within 6 hours was identified in 10 patients (18.8%). Delayed recanalization (>6 hours) occurred in 28 patients (52.8%). HT on CT scan was detected in 17 patients (32%) within the first 48 hours. Only large parenchymal hemorrhage (PH2) was significantly associated with an increase (P=0.038, Kruskal-Wallis test) in the National Institutes of Health Stroke Scale (NIHSS) score compared with the other subtypes of HT. Univariate analysis revealed that an NIHSS score of >14 on baseline (P=0.001), proximal MCA occlusion (P=0.004), hypodensity >33% of the MCA territory (P=0.012), and delayed recanalization occurring >6 hours of stroke onset (P=0.003) were significantly associated with HT. With a multiple logistic regression model, delayed recanalization (OR 8.9; 95% CI 2.1 to 33.3) emerged as independent predictor of HT. CONCLUSIONS: Delayed recanalization occurring >6 hours after acute cardioembolic stroke is an independent predictor of HT.

Publication Type: Clinical Trial. Journal Article.
 

<18>

Unique Identifier [PMID]: 11295989

Authors: Tong DC. Adami A. Moseley ME. Marks MP.

Institution: Stanford Stroke Center, Palo Alto, CA 94304, USA. dct@stanford.edu

Title: Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusion-weighted magnetic resonance imaging.[see comment].

Source: Archives of Neurology. 58(4):587-93, 2001 Apr.

Abstract: BACKGROUND: Acute diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) findings may correlate with secondary hemorrhagic transformation (HT) risk in patients with stroke. This information could be of value, particularly in individuals being considered for thrombolytic therapy. OBJECTIVE: To determine the relationship between DWI and PWI findings and the risk of secondary HT in patients with acute stroke. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Twenty-seven patients with acute stroke capable of being evaluated with DWI/PWI 8 hours or less after symptom onset. MAIN OUTCOME MEASURES: Apparent diffusion coefficient values, perfusion delay measurements, and subsequent MRI or computed tomographic scans detected HT. RESULTS: The mean +/- SD apparent diffusion coefficient of ischemic regions that experienced HT was significantly lower than the overall mean +/- SD apparent diffusion coefficient of all ischemic areas analyzed (0.510 +/- 0.140 x 10(-3) mm(2)/s vs 623 +/- 0.113 x 10(-3) mm(2)/s; P =.004). This difference remained significant when comparing the HT-destined ischemic areas with the non-HT-destined areas within the same ischemic lesion (P =.02). Patients receiving recombinant tissue-type plasminogen activator (rt-PA) experienced HT significantly earlier than patients not receiving rt-PA (P =.002). Moreover, a persistent perfusion deficit in the area of subsequent hemorrhage at 3 to 6 hours after the initial MRI scan was identified in significantly more patients who experienced HT than in those who did not (83% vs 30%; P =.03). CONCLUSION: Both DWI and PWI scans detect abnormalities that are associated with HT. These findings support a role for MRI in identifying patients who are at increased risk for secondary HT following acute ischemic stroke.

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S..
 

<19>

Unique Identifier [PMID]: 11157179

Authors: Larrue V. von Kummer R R. Muller A. Bluhmki E.

Institution: Department of Neurology, University of Toulouse, Toulouse, France. larrue.v@chu-toulouse.fr

Title: Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II).

Source: Stroke. 32(2):438-41, 2001 Feb.

Abstract: BACKGROUND AND PURPOSE: Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) improves the outcome for ischemic stroke patients who can be treated within 3 hours of symptom onset. The efficacy of thrombolysis has been demonstrated despite an increased risk of severe hemorrhagic transformation (HT) in patients treated with rtPA. We performed an analysis of risk factors for severe HT in the second European-Australasian Acute Stroke Study (ECASS II). METHODS: HTs were classified by using clinical and radiological criteria as follows: hemorrhagic infarction (HI), parenchymal hemorrhage (PH), and symptomatic intracranial hemorrhage (SICH). Potential risk factors for HT were tested by stepwise logistic regression analysis, including rtPA-by-variable interactions. In addition, the distribution of bad outcome (modified Rankin score 5 to 6) at day 90 was stratified according to each category of HT. RESULTS: PH and SICH but not HI were associated with rtPA. Also, PH and SICH but not HI were more severe in rtPA-treated patients than in those receiving placebo. Risk factors for PH were rtPA, extent of parenchymal hypoattenuation on baseline CT, congestive heart failure, increasing age, and baseline systolic blood pressure. The risk of PH on rtPA was increased in older patients and in those who were treated with aspirin before thrombolysis. Risk factors for SICH were rtPA, congestive heart failure, extent of parenchymal hypoattenuation, and increasing age. The risk of SICH on rtPA was increased in patients who were treated with aspirin before thrombolysis. CONCLUSIONS: This secondary analysis of ECASS II has confirmed the importance of the extent of hypoattenuation as a risk factor for severe HT. The findings also suggest that older patients and those who have used aspirin before stroke are at higher risk of a severe HT on rtPA.

Publication Type: Journal Article. Research Support, Non-U.S. Gov't.
 

<20>

Unique Identifier [PMID]: 11083233

Authors: Ogasawara K. Ogawa A. Doi M. Konno H. Suzuki M. Yoshimoto T.

Institution: Department of Neurosurgery, Iwate Medical University, Morioka, Japan.

Title: Prediction of acute embolic stroke outcome after local intraarterial thrombolysis: value of pretreatment and posttreatment 99mTc-ethyl cysteinate dimer single photon emission computed tomography.

Source: Journal of Cerebral Blood Flow & Metabolism. 20(11):1579-86, 2000 Nov.

Abstract: The aim of this study was to investigate the efficacy of pre- and posttreatment 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) for predicting the ischemic outcome of embolic middle cerebral artery occlusion after treatment with local intraarterial thrombolysis. The authors examined 28 patients with a moderately ischemic area (ratio of affected regional activity to cerebellar activity (A/C ratio) of 0.4 to 0.7) determined using pretreatment SPECT, and with complete recanalization within 6 hours. Posttreatment dynamic and static SPECT studies were performed immediately after thrombolysis. The extent of the affected area outlined on pretreatment SPECT was used for the posttreatment SPECT images, and A/C ratios were calculated. The relative retention ratio of 99mTc-ECD in the affected area was also analyzed using posttreatment dynamic SPECT. Fourteen patients either without infarction or with small subcortical and basal ganglial infarction, 11 patients with medium or large cortical infarction, and 3 patients with hemorrhage were identified by follow-up computed tomography. Ischemic outcome correlated with the relative retention ratio of 99mTc-ECD more closely than either the pre- or posttreatment A/C ratios. In particular, a threshold value for the development of hemorrhage was distinct only in the relative retention ratio of 99mTc-ECD. Pretreatment 99mTc-ECD SPECT did not always predict the occurrence of hemorrhagic transformation, whereas dynamic 99mTc-ECD SPECT performed immediately after thrombolysis allowed clear identification of patients at risk for hemorrhagic transformation.

Publication Type: Clinical Trial. Journal Article.
 

<21>

Unique Identifier [PMID]: 10695495

Authors: Hamann GF. del Zoppo GJ. von Kummer R.

Institution: Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Munich, Germany. hamann@brain.nefo.med.uni-muenchen.de

Title: Hemorrhagic transformation of cerebral infarction--possible mechanisms. [Review] [29 refs]

Source: Thrombosis & Haemostasis. 82 Suppl 1:92-4, 1999 Sep.

Abstract: To analyse the risk/benefit of cerebral thrombolysis the role of hemorrhagic transformation, either as clinically silent hemorrhagic infarction or disastrous parenchymal hemorrhage, is crucial. Thrombolysis in acute ischemic stroke increases the risk of severe, life-threatening hemorrhagic complications by up to 10 times compared to controls. In this paper, previous proposed concepts for the development of intracerebral hemorrhage and hemorrhagic transformation are presented. The role of the cerebral microvasculature will be emphasized. In experimental focal cerebral ischemia a significant loss of basal lamina components of the cerebral microvessels has been demonstrated. This loss in vessel wall integrity is associated with the development of petechial hemorrhage. The mechanisms for this microvascular damage may include plasmin-generated laminin degradation, matrix metalloproteinases activation, transmigration of leukocytes through the vessel wall, and other processes. We propose that attenuation of the microvascular integrity loss with subsequent reduction in hemorrhage is theoretically possible 1) by an improvement in the definition of an individual time window of therapy (by means of imaging techniques), 2) by a biochemical quantification of the basal lamina damage to avoid dangerous interventions, and 3) by pharmacological strategies to protect the basal lamina during thrombolysis. [References: 29]

Publication Type: Journal Article. Review.
 

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Unique Identifier [PMID]: 9040679

Authors: Motto C. Aritzu E. Boccardi E. De Grandi C. Piana A. Candelise L.

Institution: Istituto di Clinica Neurologica, Universita degli Studi di Milano, Italia.

Title: Reliability of hemorrhagic transformation diagnosis in acute ischemic stroke.[see comment]. [Review] [22 refs]

Source: Stroke. 28(2):302-6, 1997 Feb.

Abstract: BACKGROUND AND PURPOSE: Diagnosis of hemorrhagic transformation (HT) could influence the prognosis and the management of acute ischemic stroke. The interobserver reliability of CT-scan HT classification is evaluated in the present study. METHODS: Fifty 5-day CT scans of patients enrolled in the Multicenter Acute Stroke Trial-Italy (MAST-I) were reviewed independently by two neuroradiologists and one neurologist with CT training. They evaluated the presence and type of intraparenchymal HT (hemorrhagic infarction types I, II, and III and intracerebral hemorrhage) (five-item scale), as well as the presence of intraventricular and/or subarachnoid bleeding according to standardized definitions. RESULTS: Agreement for exclusion of HT and intraventricular/ subarachnoid bleeding was good between the neuroradiologists (kappa = 0.70 and kappa = 0.72) and excellent between the neurologist and each neuroradiologist (kappa = 0.87 and kappa = 0.77, kappa = 0.83, and kappa = 0.81, respectively). The overall agreement for the five-item HT scale between the two neuroradiologists was good (kappa n = 0.65) because of discordance over the last three items. Better overall agreement was obtained with a three-item scale: no hemorrhage, petechial type I hemorrhagic infarction, and other HT (type II and type III hemorrhagic infarction and intracerebral hemorrhage) together (kappa w = 0.82 CONCLUSIONS: Exclusion of HT is a reliable CT diagnosis when made by neuroradiologists and also by a neurologist with CT training. Five- and three-item scales of HT types showed good to excellent reliability. The validity of the scale for predicting short- and long-term outcome should be evaluated in future studies. [References: 22]

Publication Type: Journal Article. Multicenter Study. Review.
 

<23>

Unique Identifier [PMID]: 8452759

Authors: Lyden PD. Zivin JA.

Institution: Department of Neurosciences, UCSD School of Medicine 92161.

Title: Hemorrhagic transformation after cerebral ischemia: mechanisms and incidence. [Review] [66 refs]

Source: Cerebrovascular & Brain Metabolism Reviews. 5(1):1-16, 1993.

Abstract: Hemorrhagic infarction and cerebral hematoma are feared events that may follow cerebral ischemia. Newly developed thrombolytic agents may be effective stroke therapy, but may also promote hemorrhagic complications after ischemic stroke. It is therefore critically important to understand the true incidence of hemorrhagic transformation after ischemic stroke, and to identify if possible the mechanisms underlying the phenomenon. In recent years, studies using serial computed tomography to identify hemorrhage have shown that transformation occurs in 15 to 43% of patients presenting with ischemia. Experimental and clinical evidence support the notion that hemorrhage results from augmented collateral circulation into the ischemic zone, perhaps in concert with hypertension. Recanalization and distal migration of the thrombus are not factors that are associated with transformation. Pharmacologic recanalization using thrombolytic drugs are not likely to be associated with hemorrhage if reperfusion is accomplished very soon after the onset of neurologic symptoms. [References: 66]

Publication Type: Journal Article. Review.
 

<24>

Unique Identifier [PMID]: 1633483

Authors: Teal PA. Pessin MS.

Institution: Department of Neurology (Stroke Service), Tufts University School of Medicine, Boston, Massachusetts.

Title: Hemorrhagic transformation. The spectrum of ischemia-related brain hemorrhage. [Review] [71 refs]

Source: Neurosurgery Clinics of North America. 3(3):601-10, 1992 Jul.

Abstract: Hemorrhagic transformation of ischemic cerebral injury occurs commonly in embolic strokes. The incidence, timing, and clinical consequences of hemorrhagic transformation are reviewed. Hemorrhagic complications resulting from heparin therapy and results from recent preliminary thrombolytic treatment trials are discussed. [References: 71]

Publication Type: Journal Article. Review.