Predicting outcomes after acute reperfusion therapy for basilar artery occlusion.

BACKGROUND AND PURPOSE: Basilar artery occlusion (BAO) leads to high rates of morbidity and mortality, despite successful recanalization. The discordance between flow restoration and long-term functional status clouds clinical decision-making regarding further aggressive care. We sought to develop and validate a practical, prognostic tool for the prediction of 3-month favorable outcome after acute reperfusion therapy for BAO. METHODS: This retrospective, multicenter, observational study was conducted at four high-volume stroke centers in the USA and Europe. Multivariate regression analysis was performed to identify predictors of favorable outcome (90-day modified Rankin scale scores 0-2) and derive a clinically applicable prognostic model (the Pittsburgh Outcomes after Stroke Thrombectomy-Vertebrobasilar (POST-VB) score). The POST-VB score was evaluated and internally validated with regard to calibration and discriminatory ability. External validity was assessed in patient cohorts at three separate centers. RESULTS: In the derivation cohort of 59 patients, independent predictors of favorable outcome included smaller brainstem infarct volume on post-procedure magnetic resonance imaging (P < 0.01) and younger age (P = 0.01). POST-VB score was calculated as: age + (10 × brainstem infarct volume). POST-VB score demonstrated excellent discriminatory ability [area under the receiver-operating characteristic curve (AUC) = 0.91] and adequate calibration (P = 0.88) in the derivation cohort (Center A). It performed equally well across the three external validation cohorts (Center B, AUC = 0.89; Center C, AUC = 0.78; Center D, AUC = 0.80). Overall, a POST-VB score < 49 was associated with an 88% likelihood of favorable outcome, as compared to 4% with a score ≥ 125. CONCLUSIONS: The POST-VB score effectively predicts 3-month functional outcome following acute reperfusion therapy for BAO and may aid in guiding post-procedural care.

Thrombolysis and adjunct anticoagulation in patients with acute basilar artery occlusion.

BACKGROUND AND PURPOSE: Patients suffering from basilar artery occlusion (BAO) and treated with intravenous thrombolysis are, in some centers, started on adjunct anticoagulation in hyperacute settings. We aimed to assess the outcome of such patients and to compare low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) in this context. METHODS: We examined 211 patients with angiography-proven BAO treated with intravenous thrombolysis and either adjunct UFH or LMWH. Main outcome variables were rate of symptomatic intracranial hemorrhage (sICH) according to European Cooperative Acute Stroke Study II criteria and modified Rankin Scale (mRS) at 3 months. RESULTS: The overall rate of sICH was 11.4% and driven by the UFH group (13.3%). None of the LMWH group developed sICH. Recanalization rate did not significantly differ between the LMWH and UFH groups. An additional propensity analysis was made to balance anticoagulation groups regarding baseline characteristics. Propensity analysis showed a significant difference in sICH rate (0.0% vs. 14.8%, P = 0.044) in favor of LMWH. Independent outcome (mRS score 0-2) was achieved in a total of 31.0% and in 44.8% and 29.1% in the LMWH and UFH group, respectively (P = 0.09). Propensity analysis showed a significant difference in the risk of ending up bedridden or dead (mRS score 5-6; 34.5% vs. 63.0%, P = 0.033) in favor of LMWH. CONCLUSIONS: Our study showed a lower rate of sICH and a shift towards improved outcome in thrombolysed patients with BAO treated with LMWH as compared with UFH.

Ultra-acute diagnostics for stroke: Large-scale implementation of prehospital biomarker sampling.

OBJECTIVES: Blood-based biomarkers could enable early and cost-effective diagnostics for acute stroke patients in the prehospital setting to support early initiation of treatments. To facilitate development of ultra-acute biomarkers, we set out to implement large-scale prehospital blood sampling and determine feasibility and diagnostic timesavings of this approach. MATERIALS AND METHODS: Emergency medical services (EMS) personnel of the Helsinki metropolitan area were trained to collect prehospital blood samples from thrombolysis candidates using a cannula adapter technique. Time delays, sample quality, and logistics were investigated between May 20, 2013 and May 19, 2014. RESULTS: Prehospital blood sampling and study recruiting were successfully performed for 430 thrombolysis candidates, of which 50% had ischemic stroke, 14.4% TIA, 13.5% hemorrhagic stroke, and 22.1% stroke mimics. A total of 66.3% of all samples were collected during non-office hours. The median (interquartile range) emergency call to prehospital sample time was 33 minutes (25-41), and the median time from reported symptom onset or wake-up to prehospital sample was 53 minutes (38-85; n=394). Prehospital sampling was performed 31 minutes (25-42) earlier than hospital admission blood sampling and 37 minutes (30-47) earlier than admission neuroimaging. Hemolysis rate in serum and plasma samples was 6.5% and 9.3% for EMS samples, and 0.7% and 1.6% for admission samples. CONCLUSIONS: Prehospital biomarker sampling can be implemented in all EMS units and provides a median timesaving of more than 30 minutes to first blood sample. Large prehospital sample sets will enable development of novel ambulance biomarkers to improve early differential diagnosis and treatment of thrombolysis candidates.

Symptomatic intracranial haemorrhage after thrombolysis with adjuvant anticoagulation in basilar artery occlusion.

BACKGROUND AND PURPOSE: Our aim was to determine factors associated with symptomatic intracranial haemorrhage (sICH) in basilar artery occlusion patients treated with intravenous thrombolysis (IVT) and adjuvant anticoagulant therapy. METHODS: A registry of 176 consecutive patients with angiography-proven basilar artery occlusion who received IVT with alteplase and heparin between 1995 to 2013 was assessed. Post-treatment sICH was evaluated with the European Cooperative Acute Stroke Study II criteria. Unfavourable outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. RESULTS: Twenty-four patients developed sICH (13.6%, sICH+), all of whom had unfavourable outcome and only two (8.3%) sICH+ patients survived. On admission, sICH+ patients more frequently had extensive ischaemic changes defined as posterior circulation Acute Stroke Prognosis Early CT Score (PC-ASPECTS) < 8 (50% vs. 27% in sICH-, P = 0.031) and lower platelet counts (183 vs. 218 E9/l; P = 0.011). They also had higher systolic blood pressure (SBP) (median 160 vs. 147 mmHg, P = 0.034) immediately after IVT. In multivariable regression analysis, lower platelet values [odds ratio (OR) 0.99, 95% confidence interval (CI) 0.97-0.996; P = 0.006], PC-ASPECTS < 8 on admission (OR 3.6, 95% CI 1.3-10.3; P = 0.017) and higher SBP after treatment (OR 1.03, 95% CI 1.01-1.05; P = 0.017) were independently associated with sICH. Ninety per cent of the sICHs occurred within 48 h from IVT/anticoagulation treatment. No differences in activated partial thrompoplastin times prior to or after the treatment were observed between sICH+ and sICH- patients. CONCLUSIONS: The risk of sICH was largely determined by extension of ischaemic changes on admission computed tomography. Clinically relevantly, also higher post-thrombolytic SBP as described earlier and lower perithrombolytic platelet counts do increase the risk, a finding requiring confirmation in other patient series.

Vascular adhesion protein-1 in human ischaemic stroke.

AIMS: Leukocyte extravasation exacerbates tissue injury after ischaemic stroke. Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule with the potential capacity to guide transmigration of inflammatory cells into ischaemic brain. Moreover, VAP-1 could worsen ischaemic brain injury due to its function as a semicarbazide-sensitive amine oxidase (SSAO) producing toxic metabolites from primary amines. The purpose of this study was to elucidate these aspects of VAP-1-function in the pathogenesis of human ischaemic stroke. METHODS: We studied VAP-1 expression in infarcted and control brains post mortem using immunohistochemistry. Levels of soluble VAP-1 (sVAP-1) in the serum of patients with acute stroke and in control sera were determined using enzyme-linked immunosorbent assay. RESULTS: In the acute phase of ischaemic stroke, the frequency of VAP-1-stained vessels was strongly diminished in the ipsilateral hemisphere but in the contralateral hemisphere it was comparable with the expression in the control brains. In the serum of acute stroke patients with a symptom duration <6 h the level of sVAP-1 was significantly increased (652 +/- 224 ng/ml; mean +/- SD) when compared with an age- and sex-matched control group (542 +/- 104 ng/ml; P < 0.05). CONCLUSIONS: As both cell surface and sVAP-1 possess vasculopathy-promoting SSAO enzymatic activity, our results imply that by inducing SSAO-derived toxic metabolites, VAP-1 might aggravate ischaemic vascular changes. The subsequent release of sVAP-1 into circulation could be further examined as a potential marker of early ischaemic vasculopathy.

Postischemic regulation of central histamine receptors.

This study characterizes changes occurring in the central histaminergic system associated with ischemia-reperfusion pathology in the rat. Specifically, after a postocclusion time period of 48 h, we have analyzed histamine H(1) receptor mRNA expression, histamine H(2) receptor protein amount and binding densities, and histamine H(3) receptor mRNA expression and binding densities in brain regions that have been suggested to be selectively vulnerable to transient global ischemia, i.e. hippocampus, thalamus, caudate-putamen, and cerebral cortex. We found an increase in H(1) receptor mRNA expression in the caudate-putamen: given that ischemia reduces glucose uptake and H(1) receptor activation has been shown to decrease this effect, an increase of expression levels may result in mitigating tissue damage due to energy failure observed in ischemia. A decrease in H(2) receptor binding densities in the caudate-putamen was also observed; the ischemia-induced decrease in H(2) receptor protein was also detectable by Western blot analysis. This phenomenon may underlie the previously reported ischemia induced striatal dopamine release. H(3) receptor mRNA expression was increased in the caudate putamen of the postischemic brain but was decreased in the globus pallidus and the thalamus; in association with this, H(3) receptor binding densities were increased in the cortex, caudate-putamen, globus pallidus, and hippocampus. The upregulation of H(3) receptor ligand binding may be involved in the previously reported continuous neuronal histamine release. Our data suggest that central histamine receptor expression and ligand binding are altered in brain ischemia in distinct areas, and may participate in neuroprotection and/or ischemia-associated neuronal damage.

Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is detected in ischemic brain cells in experimental animal models and is believed to play an important role in apoptosis. However, the natural expression of TNF-alpha during human stroke is not known. METHODS: We examined TNF-alpha immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in brain samples of stroke victims (n=16) after variable survival (15 hours to 18 days). Systemic TNF-alpha content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed. RESULTS: Neuronal TNF-alpha was demonstrated from 0.6 to 5.4 days after the onset of stroke symptoms, peaking bilaterally during days 2 and 3. Bilateral glial TNF-alpha immunoreactivity was detected during the acute phase, with the astrocytic TNF-alpha expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-alpha immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-alpha levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-alpha staining overlapped, although not completely, during the first days. CONCLUSIONS: The data support the hypothesis that TNF-alpha may be involved both in the acute propagation of inflammatory processes and cell death and possibly in the more delayed reconstitutive processes of human ischemic stroke.

Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level.

The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.

Heat-shock protein and C-fos expression in focal microvascular brain damage.

Cortical brain damage was produced in rats by a focal pulse from a Nd-YAG laser, and evolution of the lesion was evaluated at 30 min, and 2, 8, and 24 h with respect to microvascular perfusion, blood-brain barrier (BBB) permeability, and expression of both the heat-shock/stress protein, hsp72, and the c-fos proto-oncogene transcription factor. A double-labeling fluorescence technique employing intravenously injected Evans blue albumin (EBA) and fluorescein-labeled dextran was used to map and measure BBB damage and microvascular perfusion in fresh frozen brain sections. Hsp72 and c-fos mRNAs were localized by in situ hybridization, and the respective proteins were identified by immunocytochemistry. Parallel sections were stained for glial fibrillary acidic protein and for routine histologic examination. Striking hsp72 mRNA expression was evident by 2 h in an approximately 300 microns wide rim surrounding an area of expanding BBB damage. Increased hsp72 mRNA was observed only in regions of preserved microcirculation, where the hsp72 protein was subsequently localized exclusively in the vasculature at 24 h after the insult. Hsp72-positive endothelial cells spanned the narrow margin between the lesion and histologically normal, glial fibrillary acidic protein (GFAP)-positive cortical tissue. There was no hsp72 expression in the area of subcortically migrating edema fluid. Inductions of c-fos mRNA and Fos protein were not strikingly evident around the focal brain lesion, but were observed transiently throughout the injured hemisphere at 30 min and 2.5 h, respectively, indicating that spreading depression was triggered by the focal injury. These results are in striking contrast to those previously obtained from studies of models of focal ischemic or traumatic brain injury, which are characterized by a complex pattern of glial and neuronal hsp72 expression in the periphery of an infarct, and which suggest that the tightly demarcated lesion produced by the Nd-YAG laser lacks these components of graded injury that are evident following other types of focal brain damage.

Cortical microcirculation in a new model of focal laser-induced secondary brain damage.

To study the causes of spatial and temporal evolution of progressive neuro-injury in focal brain ischemia, models with consistent lesion topography are required. In such models, continuous monitoring of the microcirculation in a penumbral area undergoing progressive damage could be possible. We used a fixed-pulse (1.0 s, 40 W) Nd-YAG laser (NYL) to produced discrete brain lesions in rats and monitored the cerebral blood flow (CBF) with laser-Doppler flowmetry (LDF) in nonirradiated areas directly adjacent to the maturing lesion. We also examined the time evolution of the lesion topography over a 4 day period. The lesion volume determined by histopathological methods increased from 3.1 +/- 0.5 to 4.5 +/- 0.5 mm3 (p less than 0.05) during the first 2 h. Simultaneously, LDF indicated severe hypoperfusion (-60 +/- 21%, p less than 0.01) at a zone (1 mm distance from the laser lesion) where progressive neuronal degeneration and increased tissue water content (80.0 +/- 3.3% versus 76.8 +/- 2.1% in normal tissue, n = 7, p less than 0.05) were also observed. At a 4 mm distance from the lesion, hyperemic CBF responses were observed, but no histopathological signs or edema. Secondary brain damage progressed up to 4 days (lesion volume of 6.0 +/- 0.7 mm3). The NYL-induced brain lesion produced a highly reproducible focal injury and progressive neuronal death in a spatial relationship with microcirculatory failure and edema formation. The model allows prospective study of tissue state at a discrete zone, which is separate from the initial injury, but susceptible to secondary brain damage.

Long-term sampling of cerebral venous blood in conscious rats.

The mechanisms of secondary brain damage following cerebral ischemia or CNS trauma are still unknown. A variety of mediators, released by the injured brain, are held to be responsible for delayed neuronal cell damage. No technique is available yet for repeated sampling of cerebral venous blood (CVB) on a long-term basis, which allows to assess the neurobiochemical responses to brain injury chronically in conscious laboratory animals. This is a report on the establishment of a method to sample CVB from the superior sagittal sinus (SSS) for at least 7 days in conscious freely moving rats. The torcular was exposed for implantation of a catheter into the caudal SSS. Patency was preserved by perfusion with a nonsystemic dose of heparin by an Alzet osmotic pump and verified daily by aspirating of 0.5 ml CVB for blood analysis. No neuropathology was seen in histological examination. The rats appeared comfortable and without distress, and the transient weight loss was rapidly regained. The present model provides the opportunity to evaluate acute or chronic neurobiochemical responses to stroke, CNS trauma, or any other typ of brain injury in the conscious rat.

Tolerization against loss of neuronal function after ischemia-reperfusion injury.

To investigate whether sublethal ischemia preserves neuronal function otherwise lost after stroke, anesthesized rabbits were subjected to clamping of abdominal aorta to cause lumbar spinal cord ischemia. An occlusion period of 12.5 min was followed 12 or 48 h later by a second occlusion for 30 min. When scored 24 h later for hindlimb function on a 0-6 scale, the rabbits that underwent tolerizing ischemia 12 h before infarction had better motor function (n = 7; 4.29+/-0.21,p < 0.0001) than sham-operated controls (n = 7; 1.00+/-0.27), but those infarcted at 48 h had mixed outcomes (n = 5; 2.20+/-0.21, ns). In correlation, the proportion of neurons with histological evidence of damage was lower in the tolerized rabbits (0.15+/-0.04) than in sham-operated controls (0.74+/-0.09, p < 0.001). We conclude that ischemic tolerance also improves neurological function of infarcted spinal cord and could be studied for clinical application.

Does glutamate mediate brain damage in acute encephalitis?

Cerebrospinal fluid (CSF) amino acid neurotransmitter concentrations in 23 patients with acute encephalitis were compared with those in patients with acute brain infarction, multiple sclerosis and controls. The concentration of glutamate was significantly higher in encephalitis (5.2+/-6.7 micromol/l) and stroke patients (9.6+/-14.2 micromol/l) than in MS patients (1.6+/-0.9 micromol/l) and controls (1.7+/-0.8 micromol/l; p < 0.001). The concentration of glycine was significantly higher in encephalitis (11.0+/-4.7 micromol/l) than in stroke (7.6+/-3.2 micromol/l) and MS patients (6.3+/-2.1 micromol/l) or controls (5.6+/-1.8 micromol/l; p < 0.002). Taurine levels were significantly lower in encephalitis patients than in the other groups (p = 0.04). The correlation of high glutamate levels with poor outcome was almost significant (Kendall tau 0.63, p = 0.06). Our observations suggest that exicitotoxic neurotransmission may play an important role in the series of events that lead to neuronal damage in encephalitis.

Differential cellular expression of tumor necrosis factor-alpha and Type I tumor necrosis factor receptor after transient global forebrain ischemia.

We examined the expression of tumor necrosis factor-alpha (TNF-alpha) and the Type I tumor necrosis factor receptor, (TNFR1), in relation to c-fos, a known regulator gene of immediate cellular responses, after an extended period of global ischemia. The number of TNF-alpha mRNA expressing cells peaked in most brain areas after 8 h of reperfusion. Significant increases in TNFR1 mRNA expression were evident in the cortex at 2 and 8 h of reperfusion and after 8 h of reperfusion in the CA3/CA4 region of the hippocampus. Transient neuronal c-fos mRNA expression preceded these responses. TNF-alpha immunoreactivity was seen in neurons>>>oligodendrocytes=perivascular cells=ependymal cells=vessel wall structures. After ischemia/reperfusion, increased TNF-alpha immunoreactivity was evident only in oligodendrocytes. TNFR1 immunoreactivity in sham brains manifested in bundles of cellular fibers of variable length and thickness. In post-ischemic brains, immunoreactivity in these cellular processes representing mainly astroglial extensions was suppressed at 2 h but recovered partially by 8 and 24 h of reperfusion. In contradiction, transient ischemia-induced TNFR1 immunoreactivity was observed in somas of large cortical neurons, in activated microglia/macrophages, perivascular and endothelial cells.Taken together, the increase in neuronal TNF-alpha mRNA appeared not to be followed by substantial translation to protein in the cerebral tissue after an extended period of global ischemia. However, there was increased neuronal TNFR1 immunostaining in conjunction with increased immunostaining for TNF-alpha in oligoglial elements, which suggests signaling to neurons by enhanced oligoglial TNF-alpha.

Antagonism of neutrophil adherence in the deteriorating stroke model in rabbits.

Adhesion of leukocytes to the endothelium can occur in a few hours after the onset of ischemia, and the actions of leukocytes have been suggested to aggravate reperfusion injury. Adhesion is a prerequisite for the harmful leukocyte actions. Rapid mediation of leukocyte adhesion and aggravation of reperfusion injury can occur through production of platelet-activating factor (PAF). The authors hypothesized that prevention of leukocyte adhesion during ischemia reperfusion would have beneficial effects and that these effects might be enhanced by a PAF antagonist. To test this hypothesis, rabbits were anesthetized with pentobarbital and subjected to severe spinal cord ischemia (25 minutes) followed by 30 minutes of reperfusion, at which time either vehicle, antibody against the CD11/CD18 (anti-CD) leukocyte adhesion molecule (1 mg/kg), or the anti-CD and PAF antagonist, WEB 2086 (3 mg/kg), was administered intravenously and the animals were monitored for 6.5 hours. Using a score from 0 to 5, recovery of motor function was improved at 5.5 hours by the CD antibody (2.0 +/- 0.5 versus 0.4 +/- 0.2 in the six animals in the vehicle group, p < 0.05). No further improvement was induced by WEB 2086 in the six anti-CD treated animals (1.6 +/- 0.7). Spinal cord blood flow (laser Doppler flowmetry) at 6 hours was at the preischemic level in the control animals (-7% +/- 20%), but clearly increased in the anti-CD group (+73% +/- 29%, p < 0.5). The severity of blood-brain barrier damage in the spinal cord gray matter was decreased by the treatments. Extravasation of intravenously injected Evans blue albumin (EBA), measured by detection of EBA fluorescence, was reduced by approximately 50% in both treated groups (p < 0.05). The number of morphologically normal motor neurons in the lumbar anterior horns of the infarcted spinal cord showed protection in the seven animals in the anti-CD treated group at 6.5 hours: 12.7 +/- 1.7 versus 5.3 +/- 1.6 (vehicle), p < 0.05 without an additional effect by PAF antagonist 12.2 +/- 2.6 (anti-CD + WEB 2086). Our results suggest that ultraacute treatment of reperfusion injury based on special inhibition of leukocyte effects may be beneficial. Platelet-activating factor antagonism failed to enhance this therapeutic effect, which may suggest dependency on a common mechanism.

Platelet-activating factor and progressive brain damage following focal brain injury.

The effects of a platelet-activating factor (PAF) antagonist on brain edema, cortical microcirculation, blood-brain barrier (BBB) disruption, and neuronal death following focal brain injury are reported. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used to induce highly reproducible focal cortical lesions in anesthetized rats. Secondary brain damage in this model was characterized by progressive cortical hypoperfusion, edema, and BBB disruption in the vicinity of the hemispheroid lesion occurring acutely after injury. The histopathological evolution was followed for up to 4 days. Neuronal damage in the cortex and the hippocampus (CA-1) was assessed quantitatively, revealing secondary and progressive loss of neuronal tissue within the first 24 hours following injury. Pretreatment with the PAF antagonist BN 50739 ameliorated the severe hypoperfusion in 12 rats (increasing local cerebral blood flow from a mean +/- standard error of the mean of 40.5% +/- 8.3% to 80.2% +/- 7.8%, p less than 0.01) and reduced edema by 70% in 10 rats (p less than 0.05) acutely after injury. The PAF antagonist also reduced the progression of neuronal damage in the cortex and the CA-1 hippocampal neurons (decrease of neuronal death from 88.0% +/- 3.9% to 49.8% +/- 4.2% at 24 hours in the cortex and from 40.2 +/- 5.0% to 13.2% +/- 2.1% in the hippocampus in 30 rats; p less than 0.05). This study provides evidence to support progressive brain damage following focal brain injury, associated with secondary loss of neuronal cells. In this latter process, PAF antagonists may provide significant therapeutic protection in arresting secondary brain damage following cerebral ischemia and neurological trauma.

The future of stroke treatment.

The concept of the therapeutic window of opportunity in ischemic neuronal injury and understanding the necessity of well organized stroke services revolutionized the management of acute ischemic stroke during the last years of the second millennium. Thrombolysis with IV rt-PA within 3 hours from the onset of symptoms is an established therapy for selected patients. The challenge of stroke therapy at the outset of this millennium is how to translate basic pathophysiologic evidence of ischemic neuronal injury into novel neuroprotective therapies either independently or combined with thrombolysis. Great hopes are placed in identification of pivotal molecular events in ischemic brain tissue and design of effective pharmacological interventions to target them. Aggressive, invasive procedures are also being developed and therapies such as intra-arterial clot lysis, hemicraniectomy and mild hypothermia may improve the bleakest outcomes associated with the most severe forms of ischemic stroke, but their role must be rigorously evaluated. There is, however, no need to wait for future breakthroughs. The existing evidence strongly implies that good care of patients with stroke starts with organization of the entire stroke chain; from the prehospital scene, through the emergency room, to the stroke unit. Without structured stroke services no pharmacological or intervening therapy is likely to improve the outcome of the patient with a stroke.