Peter D. Schellinger

Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

CT and diffusion-weighted MR imaging in randomized order: diffusion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke.

Background and Purpose— Diffusion-weighted MRI (DWI) has become a commonly used imaging modality in stroke centers. The value of this method as a routine procedure is still being discussed. In previous studies, CT was always performed before DWI. Therefore, infarct progression could be a reason for the better result in DWI. Methods— All hyperacute (<6 hours) stroke patients admitted to our emergency department with a National Institutes of Health Stroke Scale (NIHSS) score >3 were prospectively randomized for the order in which CT and MRI were performed. Five stroke experts and 4 residents blinded to clinical data judged stroke signs and lesion size on the images. To determine the interrater variability, we calculated &kgr; values for both rating groups. Results— A total of 50 patients with ischemic stroke and 4 patients with transient symptoms of acute stroke (median NIHSS score, 11; range, 3 to 27) were analyzed. Of the 50 patients, 55% were examined with DWI first. The mean delay from symptom onset until CT was 180 minutes; that from symptom onset until DWI was 189 minutes. The mean delay between DWI and CT was 30 minutes. The sensitivity of infarct detection by the experts was significantly better when based on DWI (CT/DWI, 61/91%). Accuracy was 91% when based on DWI (CT, 61%). Interrater variability of lesion detection was also significantly better for DWI (CT/DWI, &kgr;=0.51/0.84). The assessment of lesion extent was less homogeneous on CT (CT/DWI, &kgr;=0.38/0.62). The differences between the 2 modalities were stronger in the residents’ ratings (CT/DWI: sensitivity, 46/81%; &kgr;=0.38/0.76). Conclusions— CT and DWI performed with the same delay after onset of ischemic stroke resulted in significant differences in diagnostic accuracy. DWI gives good interrater homogeneity and has a substantially better sensitivity and accuracy than CT even if the raters have limited experience.

Effect of Intravenous Thrombolysis on MRI Parameters and Functional Outcome in Acute Stroke <6 Hours

Background and Purpose— The goals of this study were to examine MRI baseline characteristics of patients with acute ischemic stroke (AIS) and to study the influence of intravenous tissue plasminogen activator (tPA) on MR parameters and functional outcome using a multicenter approach. Methods— In this open-label, nonrandomized study of AIS patients with suspected anterior circulation stroke, subjects received a multiparametric stroke MRI protocol (diffusion- and perfusion-weighted imaging and MR angiography) within 6 hours after symptom onset and on follow-up. Patients were treated either with tPA (thrombolysis group) or conservatively (no thrombolysis group). Functional outcome was assessed on day 90 (modified Rankin Score; mRS). Results— We enrolled 139 AIS patients (no thrombolysis group, n=63; thrombolysis group, n=76). Patients treated with tPA were more severely affected (National Institutes of Health Stroke Scale score, 10 versus 13;P =0.002). Recanalization rates were higher in the thrombolysis group (Thrombolysis in Myocardial Infarction criteria 1 through 3 on day 1; 66.2% versus 32.7%;P <0.001). Proximal vessel occlusions resulted in larger infarct volumes and worse outcome (P =0.02). Thrombolysis was associated with a better outcome regardless of the time point of tPA treatment (≤3 hours or 3 to 6 hours) (univariate analysis: mRS ≤2, P =0.017; mRS ≤1, P =0.023). Age (P =0.003), thrombolytic therapy at 0 to 6 hours (P =0.01), recanalization (P =0.016), lesion volume on day 7 (P =0.001), and initial National Institutes of Health Stroke Scale score (P =0.001) affected functional outcome (mRS on day 90) positively (multivariate analysis). The time point of tPA therapy affected the recanalization rate (P =0.024) but not final infarct volume. Conclusions— In this pilot study, tPA therapy had a beneficial effect on vessel recanalization and functional outcome. Multiparametric MRI delineates tissue at risk of infarction in AIS patients, which may be helpful for the selection of patients for tPA therapy. tPA therapy appeared safe and effective beyond a 3-hour time window. This study delivers the rationale for a randomized, MR-based tPA trial.

Stroke Magnetic Resonance Imaging Is Accurate in Hyperacute Intracerebral Hemorrhage: A Multicenter Study on the Validity of Stroke Imaging

Background and Purpose— Although modern multisequence stroke MRI protocols are an emerging imaging routine for the diagnostic assessment of acute ischemic stroke, their sensitivity for intracerebral hemorrhage (ICH), the most important differential diagnosis, is still a matter of debate. We hypothesized that stroke MRI is accurate in the detection of ICH. To evaluate our hypotheses, we conducted a prospective multicenter trial. Methods— Stroke MRI protocols of 6 university hospitals were standardized. Images from 62 ICH patients and 62 nonhemorrhagic stroke patients, all imaged within the first 6 hours after symptom onset (mean, 3 hours 18 minutes), were analyzed. For diagnosis of hemorrhage, CT served as the “gold standard.” Three readers experienced in stroke imaging and 3 final-year medical students, unaware of clinical details, separately evaluated sets of diffusion-, T2-, and T2*-weighted images. The extent and phenomenology of the hemorrhage on MRI were assessed separately. Results— Mean patient age was 65.5 years; median National Institutes of Health Stroke Scale score was 10. The experienced readers identified ICH with 100% sensitivity (confidence interval, 97.1 to 100) and 100% overall accuracy. Mean ICH size was 17.3 mL (range, 1 to 101.5 mL). The students reached a mean sensitivity of 95.16% (confidence interval, 90.32 to 98.39). Conclusions— Hyperacute ICH causes a characteristic imaging pattern on stroke MRI and is detectable with excellent accuracy. Even raters with limited film-reading experience reached good accuracy. Stroke MRI alone can rule out ICH and demonstrate the underlying pathology in hyperacute stroke.

Imaging-Based Decision Making in Thrombolytic Therapy for Ischemic Stroke Present Status

Background— Thrombolysis is the treatment of choice for acute stroke within 3 hours after symptom onset. Treatment beyond the 3-hour time window has not been shown to be effective in any single trial; however, meta-analyses suggest a somewhat lesser but still significant effect within 3 to 6 hours after stroke. It seems reasonable to apply improved selection criteria that allow differentiation between patients with and without a relevant indication for thrombolytic therapy. Summary of Review— The present literature on imaging in stroke has been thoroughly reviewed, covering Doppler ultrasound (DU), arteriography, CT, and MRI and including modern techniques such as perfusion CT, diffusion- and perfusion-weighted MRI (DWI, PWI), CT angiography and MR angiography (CTA, MRA), and CTA source image analysis (CTA-SI). The authors present their view of a comprehensive diagnostic approach to acute stroke, which challenges the concept of a rigid therapeutic time window. Conclusions— Information about the presence or absence of a vessel occlusion, whether by means of DU, CTA, or MRA, is essential before recombinant tissue plasminogen activator is given in the 3- to 6-hour time window. Clear demarcation of the irreversibly damaged infarct core and the ischemic but still viable and thus salvageable tissue at risk of infarction as seen on DWI/PWI/MRA or alternatively CT/CTA/CTA-SI should be obtained before thrombolysis is initiated within 3 to 6 hours. Once these advanced techniques are used, the therapeutic time window can be extended with acceptable safety. However, comprehensive informed consent is mandatory, especially when thrombolytic therapy is considered beyond established time windows.

A standardized MRI Stroke protocol : Comparison with CT in hyperacute intracerebral hemorrhage

Background and Purpose—Diagnostic imaging in hyperacute ischemic stroke has been revolutionized by the introduction of diffusion- and perfusion-weighted MRI (DWI and PWI). CT, however, is still needed to exclude intracerebral hemorrhage (ICH). The purpose of our study was to determine the diagnostic accuracy of a standardized, multimodal MRI (mMRI) stroke protocol in the qualitative and quantitative assessment of hyperacute ICH (<6 hours). Methods—We investigated 9 patients with hyperacute ICH with CT followed immediately by a standardized mMRI stroke protocol (DWI, PWI [T2*-WI], FLAIR, T2-WI, and MRA). The time interval between MRI and symptom onset ranged from 3 hours to 5 hours 45 minutes. We analyzed and compared the size of the hematoma on CT and all mMRI images by semiautomatic volumetry. Results—ICH was unambiguously identified on the basis of all mMRI sequences. With increasing susceptibility effect (T2*-WI), the ICH, appearing as an area of hyperintensity with central signal loss, became qualitat...

Comparison of Perfusion Computed Tomography and Computed Tomography Angiography Source Images With Perfusion-Weighted Imaging and Diffusion-Weighted Imaging in Patients With Acute Stroke of Less Than 6 Hours’ Duration

Background and Purpose— We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke <6 hours. Methods— Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting <6 hours. We analyzed ischemic lesion volumes on patients’ arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI (Wilcoxon, Spearman, Bland–Altman) and compared them to the infarct extent as shown on day 5 NECT. Results— Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP (P =0.686 for patients who did not undergo thrombolysis/ P =0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV (P =0.893/ P =0.169). CTA-SI volumes did not differ from DWI volumes (P =0.465/ P =0.086). Lesion volumes measured in PCT maps significantly correlated with lesion volumes on PWI (P =0.0047, r =1.0/ P =0.0019, r =0.897 for TTP; P =0.0054, r =0.983/ P =0.0026, r =0.871 for CBV). Also, PCT-CBV lesion volumes significantly correlated with follow-up CT lesion volumes (P =0.0047, r =1.0/ P =0.0046, r =0.819). Conclusions— In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT (NECT), perfusion CT (PCT), and CT angiography (CTA) can render additional information within <15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients.

Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy Comparison of Acute Treatment Strategies Using Vitamin K, Fresh Frozen Plasma, and Prothrombin Complex Concentrates

Background and Purpose— Intracerebral hemorrhage (ICH) is the most serious and potentially fatal complication of oral anticoagulant therapy (OAT). Still, there are no universally accepted treatment regimens for patients with OAT-ICH, and randomized controlled trials do not exist. The aim of the present study was to compare the acute treatment strategies of OAT-associated ICH using vitamin K (VAK), fresh frozen plasma (FFP), and prothrombin complex concentrates (PCCs) with regard to hematoma growth and outcome. Methods— In this retrospective study, a total of 55 treated patients were analyzed. Three groups were compared by reviewing the clinical, laboratory, and neuroradiological parameters: (1) patients who received PCCs alone or in combination with FFP or VAK (n=31), (2) patients treated with FFP alone or in combination with VAK (n=18), and (3) patients who received VAK as a monotherapy (n=6). The end points of early hematoma growth and outcome after 12 months were analyzed including multivariate analysis. Results— Hematoma growth within 24 hours occurred in 27% of patients. Incidence and extent of hematoma growth were significantly lower in patients receiving PCCs (19%/44%) compared with FFP (33%/54%) and VAK (50%/59%). However, this effect was no longer seen between PCC- and FFP-treated patients if international normalized ratio (INR) was completely reversed within 2 hours after admission. The overall outcome was poor (modified Rankin scale 4 to 6 in 77%). Predictors for hematoma growth were an increased INR after 2 hours, whereas administration of PCCs was significantly protective in multivariate analyses. Predictors for a poor outcome were age, baseline hematoma volume, and occurrence of hematoma growth. Conclusions— Overall, PCC was associated with a reduced incidence and extent of hematoma growth compared with FFP and VAK. This effect seems to be related to a more rapid INR reversal. Randomized controlled trials are needed to identify the most effective acute treatment regimen for lasting INR reversal because increased levels of INR were predisposing for hematoma enlargement.

Early recanalisation in acute ischaemic stroke saves tissue at risk defined by MRI.

these patients MRA at day 1 showed occlusion of a main cerebral artery (intracranial internal carotid artery or middle cerebral artery). 14/35 patients did not have a PWI/DWI mismatch, in these patients MRA did not show a major vessel occlusion. 11/21 patients of the mismatch group received alteplase, five of them received the drug after 3 h from symptom onset. MRA at day 2 showed recanalisation in 8/21 patients with a mismatch, 6 of whom had received alteplase intravenously within 5 h after symptom onset and two had had spontaneous recanalisation; in the other 13 patients the vessel remained occluded. Of the 6 patients who received altepase and had early recanalisation, three were treated within the first 3 h of stroke onset and three were treated between 3 h and 5 h. Clinical follow-up examination showed for the recanalisation group a significantly better outcome on day 30 (NIHSS, p=0·0016; SSS, p=0·003; BI, p=0·0013; RS, p=0·0011), and on day 90 (NIHSS, p=0·017; SSS, p=0·011; BI, p=0·005; RS, p=0·006); there was also significantly greater improvement from day 1 to day 30 (NIHSS, p=0·0074). The significance regarding improvement disappeared, though, at day 90 (NIHSS, p=0·49), because there was one late death in this group due to cardiopulmonary embolism. Follow-up MRI showed significantly smaller infarcts in the recanalisation group than in the non-recanalisation group at day 2 as evident on DWI (p=0·0016) and at day 5 as evident on T2WI (p=0·0005). Furthermore, the increase of infarct size from day 1 to day 2 on DWI (p=0·0055) and from day 1 to day 5 on T2WI (p=0·0011) was significantly smaller in the recanalisation group than in the non-recanalisation group (table). for at least some patients with hemiparesis following stroke, giving impetus to do larger trials of mirror therapy.

MRI-Based and CT-Based Thrombolytic Therapy in Acute Stroke Within and Beyond Established Time Windows An Analysis of 1210 Patients

Background and Purpose— The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods— Five European stroke centers pooled the core data of their CT- and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT <3 hours, MRI <3 hours and >3 hours), and onset to treatment time as variables. Results— A total of 1210 patients were included (CT <3 hours: N=714; MRI <3 hours: N=316; MRI >3 hours: N=180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (P=0.66); 12, 13, and 14 points (P=0.019); and 130, 135, and 240 minutes (P<0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (P=0.213); mortality was 13.7%, 11.7%, and 13.3% (P=0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (P=0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, P=0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, P=0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard <3-hour CT-based treatment. Conclusion— Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis.