Thrombolytic therapy for acute ischemic stroke

The treatment of acute stroke changed dramatically since the publication of the NINDS trail for IV rt-PA for acute stroke. While this was not the first trial, it was the first positive trial. Subsequently there has been an explosion in acute treatment modalities since the NINDS trial showed that acute stroke treatment is feasible. The following chapter reviews the thrombolysis trials, the inclusion and exclusion criteria of intravenous and intra-arterial use of pharmacologic and mechanical thrombolysis in acute ischemic stroke. Also discussed are the new pharmacotherapies and mechanical devices that will hopefully expand the treatment window and make thrombolysis safer and more effective.     

Early blood-brain barrier disruption in human focal brain ischemia

Loss of integrity of the blood-brain barrier (BBB) resulting from ischemia/reperfusion is believed to be a precursor to hemorrhagic transformation (HT) and poor outcome. We used a novel magnetic resonance imaging marker to characterize early BBB disruption in human focal brain ischemia and tested for associations with reperfusion, HT, and poor outcome (modified Rankin score >2). BBB disruption was found in 47 of 144 (33%) patients, having a median time from stroke onset to observation of 10.1 hours. Reperfusion was found to be the most powerful independent predictor of early BBB disruption (p = 0.018; odds ratio, 4.09; 95% confidence interval, 1.28-13.1). HT was observed in 22 patients; 16 (72.7%) of those also had early BBB disruption (p < 0.001; odds ratio, 8.11; 95% confidence interval, 2.85-23.1). In addition to baseline severity (National Institutes of Health Stroke Scale score >6), early BBB disruption was found to be an independent predictor of HT. Because the timing of the disruption was early enough to make it relevant to acute thrombolytic therapy, early BBB disruption as defined by this imaging biomarker may be a promising target for adjunctive therapy to reduce the complications associated with thrombolytic therapy, broaden the therapeutic window, and improve clinical outcome.     

Thrombolytic therapy in an adolescent ischemic stroke

We report the case of a 16-year-old Caucasian girl who developed acute onset of left hemiplegia, left hemisensory deficit, and dysarthria. After a negative computed tomographic scan of the brain, the patient was given intravenous recombinant tissue plasminogen activator according to established adult guidelines. The patient experienced a marked improvement within 24 hours. Stroke etiology was determined to be a paradoxical embolus via a patent foramen ovale associated with pelvic vein thrombosis. This case illustrates the importance of early recognition of stroke and the utility of thrombolytics in treating ischemic infarcts in the adolescent population.     

Positive association between blood brain barrier disruption and osmotically-induced demyelination

Rapid correction of chronic hyponatremia can cause osmotic brain demyelination in animals and humans. Why demyelination develops is unknown, but blood brain-barrier disruption might expose oligodendrocytes to substances normally excluded from the brain. To test this hypothesis, chronic hyponatremia was induced and corrected using a new, reproducible rat model for producing osmotic brain demyelination. Blood brain barrier integrity was assessed by NMR imaging at either 3, 16 or 24 h during the first day of correction. Demyelination was determined histopathologically 5 - 6 days later. Of 96 rats studied, demyelination developed 5 - 6 days later in 37 rats, 89% of whom showed barrier disruption. In the 59 rats who did not develop demyelination, 45 (76%) had no barrier disruption. Thus, blood-brain barrier disruption during the first 24 h of correction was associated with a 70% risk of developing demyelination. By contrast, the risk of developing subsequent demyelination was only 8% when the barrier was intact. This strong association between barrier disruption and subsequent demyelination provides new insights into the role of blood brain barrier function in demyelinative disorders such as the osmotic demyelination syndrome and by extension to other demyelinative disorders such as multiple sclerosis.     

Thrombolytic therapy for acute ischemic stroke]

In this paper, results of the recent clinical trials were reviewed, and problems in treating patients with thrombolysis were discussed. Data generated from randomized controlled trials over the past few years have shown that acute intervention can improve neurological outcome in patients with ischemic stroke. Intravenous recombinant tissue plasminogen activator has become established as an acute treatment for stroke. Intra-arterial thrombolysis is a developing modality for the treatment of the acute stroke that shows promise in restoring cerebral arterial supply. However, thrombolysis have not approved yet in any forms in Japan. Under this circumstance, thrombolysis should be carried out in GCP-compatible clinical trials, so far. The overall results of a clinical trial cannot necessarily generalized to all patients in the trial and all similar future patients. A difference between settings of a clinical trial and of general practice should be also noted. Early recognition of stroke symptoms and immediate transfer to a suitable treatment facility should bring thrombolysis to a larger number of stroke victims. Finally, successful treatment is due in part to selecting patients who are not at increased risk for intracranial hemorrhage based on clinical and imaging features, and therefore rapid in-hospital triage protocols are mandatory.     

Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia

Summary The mechanism of exacerbation of ischemic brain edema after blood flow restoration was studied in 20 cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow was measured by the hydrogen clearance method, and the left middle cerebral artery (MCA) was occluded for 6 h in group A, and for 3 h with subsequent 3 h recirculation in group B. Severity of brain edema was assessed by specific gravity measurement of tissue samples taken from coronal brain sections at the MCA area, while severity of blood-brain barrier (BBB) disruption was determined by measuring the amount of extravasated serum albumin by using [¹²⁵I]albumin and tissue-uptake method in the same samples as those used for gravimetry. Structural and ultrastructural change was correlated with the severity of ischemic brain edema and BBB disruption. The results obtained showed that: (i) ischemic brain edema observed in group A was not associated with BBB opening to serum proteins; (ii) ischemic edema in group B was exacerbated significantly after recirculation in correlation with serum protein extravasation in most of the postischemic area; (iii) in the severely edematous area, serum protein extravasation reached a plateau and morphological examination at this type of area revealed cell membrane disruption especially of astrocytes, with leakage of intracellular substances. Our study indicated that the increase of extracellular osmotic pressure due to leakage of serum proteins via the disrupted BBB and of intracellular substances via the ischemically injured cell membrane into the extracellular space is the mechanism responsible for edema fluid accumulation in exacerbated ischemic brain edema.     

Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke

Background

Vagus nerve stimulation (VNS) significantly reduces infarct volume in rat models of cerebral ischemia, but the mechanism of this protective effect remains open.

Thrombolytic therapy of acute ischemic stroke during pregnancy

The authors report eight pregnant women with acute ischemic stroke treated with thrombolysis (rt-PA [recombinant human tissue plasminogen activator] or urokinase). Seven women recovered. Two extracranial and two asymptomatic intracranial hemorrhages complicated treatment; one woman died of arterial dissection complicating angiography. Three patients had therapeutic abortions, two fetuses were miscarried, and two babies were delivered healthy. Although pregnant women may be treated safely with thrombolytics, risks and benefits to mother and fetus must be carefully weighed.     

Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20

Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-κB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases.     

The proteome of human brain after ischemic stroke

Although stroke is among the most common causes of death and chronic disability worldwide, the proteome of the ischemic human brain remains unknown. Only a few studies have investigated the ischemic brain proteome in rodent stroke models. We performed a proteomic study of the human brain after ischemic stroke using a 2-dimensional differential gel electrophoresis-based proteomic approach. In brain samples from 6 deceased stroke patients and 3 control subjects, there was an average of 1,442 ± 231 protein spots in the gels. Changes of at least 1.5-fold in the relative expression of 132 protein spots between different cerebral areas (infarct core, peri-infarct, and contralateral tissue) were identified (p < 0.05); 39 of these were successfully identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Among the identified protein spots, we validated the results of 10 proteins by Western blot and determined the cellular localization in brain parenchyma for 3 of the identified proteins: dihydropyrimidinase-related protein 2, vesicle-fusing ATPase, and Rho dissociation inhibitor 1. These results contribute to understanding the processes that follow cerebral ischemia; moreover, some of the identified proteins may be therapeutic targets or biologic markers for determining the diagnosis and prognosis of stroke.     

Thrombolytic therapy for acute ischemic stroke: 3 h and beyond

The current status of thrombolytic therapy approved by the US Food and Drug Administration is intravenous recombinant plasminogen activator given within 3 h of the onset of ischemic stroke. Intra-arterial therapy is possible for up to 6 h but is not Food and Drug Administration-approved for this purpose. Based on current radiologic methods (i.e., magnetic resonance imaging and perfusion computed tomography scans), it is being increasingly realized that the time window for effective thrombolytic therapy is variable, and salvageable tissue in the form of the ischemic penumbra may exist for longer periods of time and could therefore offer a greater time window based on these imaging studies. Development of an effective neuroprotective drug would greatly enhance the stability of the penumbra and offer further opportunities for extending the time window for reperfusion.     

Prognostic significance of blood brain barrier permeability in acute hemorrhagic stroke

BACKGROUND: Blood brain barrier (BBB) disruption is accompanied by edema in the surrounding areas of the intracerebral hemorrhage (ICH). The aim of the study was to clarify the correlation between BBB breakdown and outcome in ICH. PATIENTS: Twenty-seven patients with primary ICH were included in the study. Each patient underwent CT and DTPA-SPECT, and the National Institutes of Health (NIH) and modified Rankin score were performed as well. RESULTS: DTPA-SPECT had a significant correlation with the modified Rankin score after 3 months (p = 0.008) and 6 months (p = 0.01). The CT scan was directly correlated with the NIH score on days 1, 7 and 30 (p = 0.01, p = 0.01 and p = 0.04, respectively). No correlation was found between DTPA-SPECT and CT scan data. CONCLUSIONS: The degree of BBB breakdown, as imaged by the DTPA-SPECT technique, was directly correlated with the late functional outcome. The CT scan has an inverse correlation with the NIH score. These findings may have broad clinical implications.     

Thrombolytic therapy in acute ischemic stroke in Asia: The first prospective evaluation

OBJECTIVE: Intravenous thrombolytic therapy has been widely recommended as a standard treatment for acute ischemic stroke in most clinical practice guidelines. However, the experience in Asia is still limited. We report the first prospective case series of thrombolytic therapy in a developing Asian country. PATIENTS AND METHODS: Consecutive patients with acute ischemic stroke who presented within 3 h of onset were screened under stroke fast track program. Those who were eligible were treated with intravenous recombinant tissue plasminogen activator (rt-PA). General and neurological examinations together with the National Institute of Health stroke scale (NHISS) and modified Rankin scale (MRS) were recorded prior to and after the treatment at 1 h, 24 h, on discharge and at 3 months. Hemorrhagic brain lesion and death within 3 months were also recorded. RESULTS: Thirty-four patients or 2.1% of patients with acute stroke received intravenous thrombolysis. The mean pretreatment NIHSS was 18.8 and the majority of patients had stroke in the middle cerebral artery territory. The mean door-to-needle time was 72.6 min (ranged 20-150 min). Major neurological improvement, defined as improving of the NIHSS >8 points or NIHSS of 0 points at 24 h, was observed in 17 patients (50%). Intracerebral hemorrhage was detected in four cases (11.8%), two of them were symptomatic (5.9%) and one was fatal. CONCLUSION: Intravenous thrombolysis can be given in patients with acute stroke in our population. Our cases were more severe than other studies. However, half of them experienced major neurological improvement. The risk of hemorrhagic brain lesion is not much higher than previously reported.     

Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats

We monitored alterations in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability following middle cerebral artery occlusion (MCAo) and intrastriatal transplantation of mouse bone marrow stromal cells (BMSCs) or saline infusion in adult Sprague-Dawley rats. Laser Doppler and Evans Blue assay revealed that BMSC grafts dose-dependently restored CBF and BBB to near normal levels at a much earlier period (Days 4-5 post-MCAo) in transplanted stroke animals compared to stroke animals that received saline infusion (Days 11-14 post-MCAo). Xenografted BMSCs survived in the absence of immunosuppression, and elevated levels of transforming growth factor-beta superfamily of neurotrophic factors were detected in transplanted stroke animals. These data suggest that early restoration of CBF and BBB following transplantation of BMSCs could mediate the reported functional outcomes in stroke animals.     

The effect on the tumor vessel permeability by hyperosmotic blood brain barrier disruption

The limited effect of chemotherapy on malignant brain tumors has been related to tumor cell insensitivity to the drugs and to their ineffectual delivery to the tumor. The studies by Groothuis and Neuwelt et al have shown that the studies of tumor vessel permeability show considerable variability in different areas of tumors and between different tumor models. The present studies used the 9L gliosarcoma model in Fischer 344 rats to evaluate the increase of tumor vessel permeability by osmotic BBB opening on drug delivery to the tumor, brain adjacent to tumor (BAT), and brain distant to tumor using cis-diamminedichloroplatinum (CDDP) as a chemotherapeutic agent which was water soluble and rarely permeable to BBB. In addition the difference of delivery to normal brain and tumor tissue were studied on intravenous or intracarotid administration of cisplatin with or without intracarotid infusion of graded (20%, 25%) hyperosmolar mannitol. Evans blue, which binds to plasma albumin, was used to provide a visual marker of BBB opening. 20% or 25% hyperosmolar mannitol infusion to right internal carotid artery for BBB disruption was done at 0.12 ml/sec for 30 sec with controlled respiration after temporally clipping of right common carotid artery. Then cis-diamminedichloroplatinum (CDDP) was infused at 0.5 mg/ml/100 gr (body weight). In control studies isotonic saline instead of mannitol was infused to intracarotid artery at identical rate and volume. In 14 9L gliosarcoma bearing rats and 3 normal rats cis-diamminedichloroplatinum (CDDP) delivery to tumor and normal brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombolytic therapy in acute ischemic stroke patients with cardiac thrombus.

The authors describe the outcome of five patients with a cardiac thrombus selected among 183 patients with stroke (2.7 %) who were given IV tissue plasminogen activator (tPA). No early systemic or cerebral embolism occurred. Two patients made a complete recovery at 3 months. Two patients had a moderate outcome. One patient had late recurrent cerebral embolism and died. These data suggest that the presence of a cardiac thrombus is not associated with a high risk of recurrent embolism in patients with stroke who are given IV tPA.     

Thrombolytic and newer mechanical device treatment for acute ischemic stroke

For 8 years, only intravenous tissue plasminogen activator was approved by the US FDA for acute stroke treatment. The US FDA has now cleared the Merci Retriever (Concentric Medical, Inc.), a corkscrew-like device attached to a catheter, for the removal of clots causing ischemic strokes. Since the clearance was based on nonrandomized treatment trials, practitioners must scrutinize available data describing effects of the device on recanalization of the vessel, outcomes and important adverse events, such as symptomatic intracranial hemorrhage. This article reviews the study findings that are likely to contribute to current treatment decisions.