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Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions., Summary: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced., (© 2021 S. Karger AG, Basel.)

Background: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions., Methods: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the -upper PF threshold as defined by PET cerebral blood flow <20 mL/100 g/min., Results: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET., Conclusions: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke., (© 2018 S. Karger AG, Basel.)

Prediction measures of recovery and outcome after stroke perform with only modest levels of accuracy if based only on clinical data. Prediction scores can be improved by including morphologic imaging data, where size, location, and development of the ischemic lesion is best documented by magnetic resonance imaging. In addition to the primary lesion, the involvement of fiber tracts contributes to prognosis, and consequently the use of diffusion tensor imaging (DTI) to assess primary and secondary pathways improves the prediction of outcome and of therapeutic effects. The recovery of ischemic tissue and the progression of damage are dependent on the quality of blood supply. Therefore, the status of the supplying arteries and of the collateral flow is not only crucial for determining eligibility for acute interventions, but also has an impact on the potential to integrate areas surrounding the lesion that are not typically part of a functional network into the recovery process. The changes in these functional networks after a localized lesion are assessed by functional imaging methods, which additionally show altered pathways and activated secondary centers related to residual functions and demonstrate changes in activation patterns within these networks with improved performance. These strategies in some instances record activation in secondary centers of a network, for example, also in homolog contralateral areas, which might be inhibitory to the recovery of primary centers. Such findings might have therapeutic consequences, for example, image-guided inhibitory stimulation of these areas. In the future, a combination of morphological imaging including DTI of fiber tracts and activation studies during specific tasks might yield the best information on residual function, reserve capacity, and prospects for recovery after ischemic stroke., (© 2017 S. Karger AG, Basel.)

Background: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction., Methods: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex., Results: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct., Conclusion: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology., (© 2016 S. Karger AG, Basel.)

Background: With regard to acute stroke, patients with unknown time from stroke onset are not eligible for thrombolysis. Quantitative diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) MRI relative signal intensity (rSI) biomarkers have been introduced to predict eligibility for thrombolysis, but have shown heterogeneous results in the past. In the present work, we investigated whether the inclusion of easily obtainable clinical-radiological parameters would improve the prediction of the thrombolysis time window by rSIs and compared their performance to the visual DWI-FLAIR mismatch., Methods: In a retrospective study, patients from 2 centers with proven stroke with onset <12 h were included. The DWI lesion was segmented and overlaid on ADC and FLAIR images. rSI mean and SD, were calculated as follows: (mean ROI value/mean value of the unaffected hemisphere). Additionally, the visual DWI-FLAIR mismatch was evaluated. Prediction of the thrombolysis time window was evaluated by the area-under-the-curve (AUC) derived from receiver operating characteristic (ROC) curve analysis. Factors such as the association of age, National Institutes of Health Stroke Scale, MRI field strength, lesion size, vessel occlusion and Wahlund-Score with rSI were investigated and the models were adjusted and stratified accordingly., Results: In 82 patients, the unadjusted rSI measures DWI-mean and -SD showed the highest AUCs (AUC 0.86-0.87). Adjustment for clinical-radiological covariates significantly improved the performance of FLAIR-mean (0.91) and DWI-SD (0.91). The best prediction results based on the AUC were found for the final stratified and adjusted models of DWI-SD (0.94) and FLAIR-mean (0.96) and a multivariable DWI-FLAIR model (0.95). The adjusted visual DWI-FLAIR mismatch did not perform in a significantly worse manner (0.89). ADC-rSIs showed fair performance in all models., Conclusions: Quantitative DWI and FLAIR MRI biomarkers as well as the visual DWI-FLAIR mismatch provide excellent prediction of eligibility for thrombolysis in acute stroke, when easily obtainable clinical-radiological parameters are included in the prediction models., (© 2016 S. Karger AG, Basel.)

Background: Malignant middle cerebral artery infarction is a devastating condition, with up to 80% mortality in conservatively treated patients. The pathophysiology of this stroke is characterized by a large core of severe ischemia and only a relatively small rim of penumbra. Due to the fast development of irreversible morphological damage, cytotoxic edema occurs immediately in a large portion of the ischemic territory. The subsequent damage of the tight junctions leads to the breakdown of the blood brain barrier and vasogenic brain edema, resulting in space-occupying brain swelling. The progressive vasogenic edema reaches its maximum after 1 to several days and exerts a mechanical force on surrounding tissue structures leading to midline shift and transtentorial herniation and finally brain stem compression and death., Summary: Early severe neurological symptoms--hemiparesis, gaze deviation, higher cortical signs--followed by headache, vomiting, papillo edema and reduced consciousness may predict the deleterious course. Imaging supports the suspected diagnosis with hypodense changes on CT extending beyond 50% of the MCA territory. The size of the probably infarcted tissue and a midline shift on CT as well as the size of the lesion on diffusion-weighted MRI are predictive of a malignant course. Reduction of cerebral blood flow below a critical value and volume of irreversible tissue damage detected by positron emission tomography in the early hours after the stroke are indicative of progression to malignant infarction with increased intracranial pressure (ICP) and decreased tissue oxygen tension observed by multimodal neuromonitoring in the later course. Treatment options of malignant infarction include general measures to limit the extent of space-occupying edema, but these therapies have not been efficacious. Only surgical intervention with decompressive hemicraniectomy (DHC) was successful in relieving the effects of increased ICP and of the deleterious shifts of brain tissue. Several controlled clinical trials have proven the efficacy of DHC with a significant decrease in mortality and improved functional outcome. However, DHC must be performed early and with a large diameter, regardless of the age of patients, but in patients beyond 60 years, the higher likelihood of resulting severe disability should be taken into consideration., Key Messages: Malignant MCA infarction can be predicted early with a high sensitivity by neuroimaging. The early diagnosis is mandatory for DHC, which was shown to reduce mortality and improve functional outcome in several controlled clinical trials., (© 2015 S. Karger AG, Basel.)

Background: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported., Methods: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers., Results: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres., Conclusion: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.

The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed 'penumbra', and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established - proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool, perfusion/diffusion-weighted (PW/DW) MRI is used, and the 'mismatch' between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusion thresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited., (Copyright © 2011 S. Karger AG, Basel.)

Background and Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke., Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium., Results: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures., Conclusions: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress., (Copyright (c) 2010 American Heart Association. Inc., S. Karger AG, Basel, and John Wiley & Sons, Inc.)

Background: We studied the effect of partial aortic occlusion on cerebral perfusion and cardiac performance using the intra-aortic NeuroFlo catheter., Methods: Adult pigs were instrumented to determine cardiac parameters; unique isotope-labeled microspheres were used to determine cerebral blood flow (CBF) before, during and after sequential partial aortic occlusion., Results: Six pigs were studied; there was no relevant change in cardiac output, and the desired pressure drop of 10-15 mm Hg across the balloons was achieved. CBF increased significantly with inflation of the suprarenal balloon and remained elevated 90 min after deflation., Conclusions: Partial aortic occlusion with the NeuroFlo catheter significantly increased cerebral perfusion without adversely affecting cardiac performance., (Copyright 2009 S. Karger AG, Basel.)

Background: Predictors of outcome and safety in intravenous thrombolysis within 3 h in clinical routine is a matter of ongoing debate. Available reports contain small patient numbers or summarize heterogeneous multicenter data., Methods: Four hundred and fifty patients received intravenous thrombolysis within 3 h after stroke. Pretreatment NIHSS score and detailed medical history were analyzed. Noncontrast CT was performed before thrombolysis, 24-36 h later and in case of clinical deterioration. Symptomatic intracranial hemorrhage (SICH; any bleeding with an NIHSS increase of > or =4 points) and clinical outcome (modified Rankin Scale, mRS) after 3 months were recorded. Logistic regression identified parameters predictive of independence (mRS 0-2) and SICH., Results: Median onset to admission, door to needle and onset to treatment time was 75, 50 and 135 min, respectively. Direct presentation by emergency service (64%) was the fastest way of referral. Median pretreatment NIHSS was 11 points. Independence (mRS 0-2) was reached by 53%. Mortality was 11% (7% intracerebral, 4% extracerebral complications). Logistic regression identified low NIHSS, low age and absent diabetes as predictors of independence. Overall hemorrhagic complications and SICH were found in 18 and 4% of the patients, respectively. Extracerebral bleeding complications and allergic reactions were found in 3 and 1%, respectively., Conclusion: This largest single center report presents a sample in the range of the 3 h rt-PA cohort of all randomized controlled trials. Outcome was comparable to randomized studies with a higher rate of independence and a lower rate of mortality and SICH.

Background: Although it is recognized that carotid endarterectomy (CEA) is the treatment of choice in symptomatic internal carotid artery (ICA) stenosis, in the past, very early CEA has been shown to carry substantial risks. We assessed an interdisciplinary concept of very early CEA in patients with high-grade (>70%) symptomatic ICA stenosis at a single center., Patients and Methods: The course of treatment and outcomes of patients who underwent CEA as early as possible after being referred to the stroke unit for symptoms of transient ischemic attack and stroke were prospectively evaluated, including the following parameters: age, severity of ischemia-related symptoms according to the modified Rankin scale, duration of symptoms until admission, multimodal imaging findings (color-coded duplex, cranial computed tomography, magnetic resonance imaging, positron emission tomography), duration until CEA, perioperative course and complications, as well as duration of in-hospital care., Results: Fifty consecutive patients (median age 68 years, range 44-90) with clinical and imaging signs of transient ischemic attack (n = 19) or stroke (n = 31) were included from January 2000 until December 2004. All except 1 patient showed a preoperative Rankin < 4. There was a median time period of 6 h between the onset of symptoms and admission (range 1 h to 15 days) and a median duration of 4 days after admission until operation (range 1-21 days). Seven patients underwent CEA of the contralateral, severely stenosed ICA after symptomatic ipsilateral ICA occlusion. Four out of 5 patients who primarily underwent systemic thrombolysis recovered almost completely. Three patients (6%) experienced a clinical deterioration before surgery. In the majority of patients (43/50), CEA was performed under local anesthesia with selective shunt use which became necessary in 26%. Three patients (6%) had postoperative worsening due to new infarcts. In 2 cases, an intracerebral hemorrhage occurred, of which 1 remained asymptomatic. In 1 case, surgical revision was necessary because of an ICA thrombosis without permanent neurological decline. Patients were discharged after a median time of 14.5 days (range 4-44)., Conclusions: After careful selection and preparation in a stroke unit, patients with acute stroke due to carotid stenosis can undergo very early CEA under local anesthesia with a perioperative risk comparable with the risk of later endarterectomy, therefore preventing very early stroke recurrences., (Copyright 2006 S. Karger AG, Basel.)

Background: Brain tissue hypoattenuation on early computed tomography is frequently included in decision making in acute stroke management. However, its pathophysiological counterpart needs further evaluation., Methods: By comparative imaging with diffusion-weighted imaging and 15O-water positron emission tomography we aimed to interpret early (<6 h) hypoattenuation., Results: In 11 patients, the hypoattenuation corresponded to a decreased proton diffusion (median 115.9% relative DWI value) measured by magnetic resonance imaging and to a severe hypoperfusion (below 12 ml/100 g/ min) assessed by positron emission tomography. The volume of parenchymal hypoattenuation correlated to the tissue with disturbed diffusion (Spearman's rho=0.73), but largely underestimated the hypoperfusion below 20 ml/100 g/min., Conclusions: Early hypoattenuation reflects the coupling of the severity of ischemia and resulting diffusion changes. It allows an estimate of the infarct core but underestimates the penumbral hypoperfusion., (Copyright (c) 2006 S. Karger AG, Basel.)

Background: The risk of intracerebral hemorrhage in systemic thrombolysis for acute ischemic stroke after acetylsalicylic acid (ASA) pretreatment or with subsequent heparin is controversially discussed., Methods: 300 consecutive stroke patients were treated with recombinant tissue-type plasminogen activator (rt-PA) in a prospective open study (92 pretreated with ASA, 202 ASA nonusers) with 3 months of follow-up. After thrombolysis, 122 patients received low-dose, 153 patients high-dose heparin., Results: Logistic regression analysis showed no relationship of hemorrhagic complications within the first 48 h to ASA pretreatment (p = 0.15), or heparin application (p = 0.38), but dependency on stroke severity (NIHSS) at baseline (p = 0.01)., Conclusion: ASA pretreatment does not increase the risk of symptomatic bleeding after systemic thrombolysis with rt-PA, even if thrombolysis is followed by anticoagulation., (Copyright 2003 S. Karger AG, Basel)

Background and Purpose: Computed tomographic angiography (CTA) is suggested to be a promising tool for patient selection for thrombolytic therapy of acute stroke. It does not only provide information on intracranial vasculature, but also on the capacity of the collateral circulation and the pattern of poorly perfused brain tissue. The objective of our study was to evaluate whether the presence and size of critically hypoperfused tissue assessed with flow positron emission tomography (PET) as a gold standard can reliably be identified on CTA source images., Methods: Fifteen potential candidates for early thrombolysis underwent CTA 65-170 min (mean 107 min) after the onset of acute anterior circulation stroke. Regional cerebral perfusion was measured between 27 and 86 min (mean 59 min) later with [(15)O]-H(2)O and PET, and the volume of critically hypoperfused cortical tissue was assessed. CTA source images were evaluated by a neuroradiologist and an experienced stroke neurologist. The patients were classified into three groups according to the presumed size of the perfusion deficit on CTA (large, small, no perfusion deficit)., Results: PET revealed the presence of critical cortical hypoperfusion in 10 patients, 5 had no critical cortical hypoperfusion. The neuroradiologist correctly identified the presence of a perfusion deficit in all patients, the neurologist had two false negative and one false positive ratings. Concerning the size of the perfusion deficit, there was considerable inaccuracy in both raters., Conclusions: The usefulness of CTA source images in yielding information about the perfusion state of stroke patients in clinical routine should not be overestimated., (Copyright 2002 S. Karger AG, Basel)

Repeat studies in animal models of acute focal ischemia can be compared to incidental studies in the course of ischemic stroke in order to shed light on the development of changes causing ischemic infarcts or recovery of critically perfused tissue. Positron emission tomography (PET) studies of regional cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction (OEF), cerebral metabolic rate of glucose and flumazenil (FMZ) binding in the cat middle cerebral artery occlusion (MCAO) model and in patients with acute ischemic hemispheric stroke were reviewed. After permanent MCAO, the development of "misery-perfused" penumbral tissue and its centrifugal conversion into necrosis could be demonstrated, resembling focal pathophysiological changes in patients with ischemic attacks. In the experimental model and in vascular insults in humans, a chance of recovery existed if collateral perfusion developed spontaneously within the first hours. In transient MCAO, reperfusion was only effective in preventing infarction when it was initiated as long as misery perfusion persisted; in these cases tissue was salvaged and large infarcts did not develop. In the other instances when oxygen metabolism broke down, and an increased OEF was no longer seen, reperfusion even at levels above preocclusion had no effect, and large space-occupying infarcts developed. These experimental findings are comparable to the variable outcome after thrombolytic therapy; if reperfusion is achieved within the therapeutic window of tissue viability, large infarcts are prevented and complete or partial recovery can be achieved. In the experimental model of focal ischemia and in human stroke, FMZ can be utilized as a marker of neuronal integrity. If FMZ binding in the cortex is decreased below 4 times the mean value of white matter in the acute stage, permanent infarcts were observed on late CT/MRI; this irreversible damage could not be prevented by thrombolytic therapy. These results demonstrated that PET studies in suitable ischemia models in cats can help to explain various courses and diverging outcomes of acute ischemic stroke. Comparable findings from experimental ischemia and human stroke may affect the selection of appropriate therapeutic strategies., (Copyright 2001 S. Karger AG, Basel)

Subgroup analyses of data from an open-label study of intravenous recombinant tissue plasminogen activator (rt-PA) administered to stroke patients were performed. Clinical outcome and incidence of intracranial hemorrhage were evaluated in 20 patients diagnosed by transcranial Doppler ultrasound as having proximal middle cerebral artery (MCA) occlusion. Additionally early infarct signs and size of final infarction were assessed. A favorable outcome (mRS 0-2) was seen in 30% of all patients. The incidence of symptomatic intracranial hematoma (10%) in patients with proximal MCA occlusion was higher than the overall hemorrhage rate of intravenous rt-PA treatment, but comparable to the data on intra-arterial thrombolysis in this stroke subgroup. All patients except 1 developed ischemic infarction in the MCA territory. Intravenous rt-PA treatment within 3 h may also be effective in patients with proximal MCA occlusion. The risk of intracerebral hematoma does not seem to be greater than in intra-arterial thrombolysis., (Copyright 2001 S. Karger AG, Basel)

Whether 'malignant' brain edema following ischemic stroke is due to or aggravated by reperfusion and therefore more frequent after thrombolytic therapy of stroke is still under debate. From 3/96 to 1/97, we treated 51 patients with acute supratentorial stroke within 3 h after symptom onset with rt-PA following a protocol similar to the NINDS study. The results of thrombolytic therapy were evaluated by repeated clinical examination and computed tomography (CT) during the first week after ictus. The incidence of space-occupying brain edema following intravenous thrombolytic therapy of acute ischemic stroke was lower than the edema frequency after conventional treatment, but mortality from 'malignant' edema was higher in the patients with thrombolysis. Thus, space-occupying edema after acute ischemic stroke may be aggravated by thrombolytic treatment. Forced reperfusion of already irreversibly damaged tissue increases edema formation and enlarges developing infarcts with a deleterious increase of intracranial pressure.

A prerequisite for the successful treatment of acute ischaemic stroke is the existence of viable tissue that is morphologically intact but functionally impaired due to a flow decrease below a certain threshold. At this stage, tissue at risk of infarction can be identified only by functional imaging. This penumbral tissue can be classified as having a critical flow decrease with preservation of oxygen consumption and therefore increased oxygen extraction. Such 'misery-perfused' tissue has been observed consistently in the first few hours following ischaemic stroke but usually develops into necrosed tissue at follow-up observations. Several studies have indicated that penumbral tissue can be identified up to 17 h or even 48 h after stroke in the border zones of ischaemic tissue and that this condition is occasionally reversible without resulting in permanent infarction. Positron emission tomography studies of cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) can be used to demonstrate the effect of treatment on functional variables within tissue showing perfusional disturbances. Such studies have shown the value of these markers of ischaemia, which also correlate with clinical efficacy. However, when therapeutic strategies, such as thrombolysis, do not permit arterial blood sampling, quantitative determinations of CBF and CMRO2 are not feasible. In such cases relative indices, such as those for CBF, must be applied. Such qualitative assessments of perfusion, which were calibrated in an independent cohort of patients with acute stroke, were used to demonstrate the effect of early systemic treatment of acute ischaemia with recombinant tissue plasminogen activator. By applying operationally defined thresholds for tissue viability and the penumbra, and co-registering these tissue compartments to infarcted and non-infarcted tissue on late magnetic resonance imaging, the proportions of at-risk tissue salvaged from infarction could be revealed in individual patients. In the future, functional imaging modalities that could eventually include tracers for neuronal integrity could be used to select patients for thrombolytic therapy. In some instances such techniques may permit the extension of the critical time period for inclusion of patients to aggressive stroke management strategies.