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.

CT perfusion identifies increased salvage of tissue in patients receiving intravenous recombinant tissue plasminogen activator within 3 hours of stroke onset.

BACKGROUND AND PURPOSE: In spite of the advent of thrombolytic therapy, CT-perfusion imaging is currently not fully used for clinical decision-making and not included in published clinical guidelines for management of ischemic stroke. We investigated whether lesion volumes on cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) maps predict final infarct volume and whether all these parameters are needed for triage to intravenous recombinant tissue plasminogen activator (rtPA). We also investigated the effect of intravenous rtPA on affected brain by measuring salvaged tissue volume in patients receiving intravenous rtPA and in controls. MATERIALS AND METHODS: Forty-four patients receiving intravenous rtPA and 19 controls underwent CT perfusion (CTP) studies in the emergency department within 3 hours of stroke onset. Lesion volumes were measured on MTT, CBV, and CBF maps by region-of-interest analysis and were compared with follow-up CT volumes by correlation and regression analysis. The volume of salvaged tissue was determined as the difference between the initial MTT and follow-up CT lesion volumes and was compared between intravenous rtPA-treated patients and controls. RESULTS: No significant difference between the groups was observed in lesion volume assessed from the CTP maps (P > .08). Coefficients of determination for MTT, CBF, and CBV versus follow-up CT lesion volumes were 0.3, 0.3, 0.47, with intravenous rtPA; and 0.53, 0.55, and 0.81 without intravenous rtPA. Regression of MTT on CBF lesion volumes showed codependence (R(2) = 0.98, P < .0001). Mean salvaged tissue volumes with intravenous rtPA were 21.8 +/- 17.1 and 13.2 +/- 13.5 mL in controls; these were significantly different by using nonparametric (P < .03) and Fisher exact tests (P < .04). CONCLUSIONS: Within 3 hours of stroke onset, CBV lesion volume does not necessarily represent dead tissue. MTT lesion volume alone can be used to identify the upper limit of the size of abnormally perfused brain. More brain is salvaged in patients with intravenous rtPA than in controls.

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.

Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment.

The authors reorganized the emergency room (ER) by moving CT to the ER and streamlining triage by prenotification by emergency medical services (EMS), which reduced in-hospital delays and enhanced access to stroke thrombolysis. CT delay dropped from 1 hour 3 minutes +/- 14 minutes in 1999 to 7 +/- 2 minutes in 2004 (p < 0.0001). Door-to-needle time dropped from 1 hour 28 minutes +/- 7 minutes to 50 +/- 3 minutes (p < 0.001), while symptom-to-needle time dropped from 2 hours 44 minutes +/- 6 minutes to 2 hours 5 minutes +/- 4 minutes (p < 0.0001). From 23 patients in 1999, thrombolysis access was increased to 100 patients in 2004 and 183 patients in 2005.

Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype.

There is growing evidence that in Alzheimer's disease (AD) amyloid beta-protein (Abeta) triggers a chronic inflammatory reaction in cerebral amyloid plaques, including complement proteins. Abeta also accumulates cerebrovascularly in age- and AD-associated cerebral amyloid angiopathy (CAA). We investigated complement proteins in CAA in a population-based series using histological and immunohistochemical staining methods. The 74 subjects, aged 95 years or more, had undergone clinical neurological examination and apolipoprotein E (ApoE) genotyping. The brains had been studied for AD post-mortem, allowing us to relate the histopathological findings to clinical and genetic conditions. CAA with congophilic amyloid was found in 36/74 individuals (48.6%). The vascular amyloid deposits immunoreacted with antibodies to Abeta and complements 3d (C3d) and 9 (C9). The positivity in complement stains increased with growing severity of CAA (P = 0.001). The presence of CAA associated with ApoE epsilon4 (P = 0.0005) and overrepresentation of epsilon4 among those with moderate or severe vs. mild CAA (P = 0.03) was demonstrated. The presence of CAA associated with dementia (P = 0.01), which was contributed by both epsilon4+ (P = 0.02) and epsilon4- (P = 0.06) subjects. Our study shows that complement proteins are deposited in the affected vessels in Abeta-associated CAA. They may solely represent the cerebral Abeta- burden associated to inflammatory stimuli, or signal a contribution in the clearance of cerebral Abeta, thereby contributing to the events associated with evolution of clinical dementia. Our results demonstrate a strong association between CAA and ApoE epsilon4 as well as dementia and suggest that the contribution of CAA to dementia is largely independent of ApoE epsilon4.

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.

Brain diffusion changes in carotid occlusive disease treated with endarterectomy.

BACKGROUND: Patients with unilateral high-grade carotid stenosis or occlusion have been reported to have more leukoaraiosis and ischemic lesions in ipsilateral than in contralateral cerebral hemisphere. The lesions alter apparent diffusion coefficient (ADC) values in diffusion-weighted MRI (DWI). The overall effects of carotid endarterectomy on ADC values have not yet been explored. OBJECTIVE: S: To find out whether 1) average ADC (ADC(av)) values differed between hemispheres, 2) diffusion changes induced by carotid endarterectomy could be detected in brain tissue with serial DWI, and 3) patients with asymptomatic carotid stenosis differed from patients with a symptomatic stenosis. METHODS: Forty-five patients (22 with asymptomatic carotid stenosis and 23 with symptomatic carotid stenosis) with unilateral high-grade carotid stenosis underwent DWI before carotid endarterectomy and 3 and 100 days afterward, and 45 age- and sex-matched healthy control subjects were imaged once. We evaluated ADC(av) values in normal-appearing gray and white matter, watershed regions (WsR), and thalamus. RESULTS: ADC(av) values of ipsilateral white matter and WsR were higher than those of contralateral white matter and WsR, both being higher than in white matter and WsR of control subjects. After carotid endarterectomy, these differences were diminished, but the levels remained higher than in controls. ADC(av) values of gray matter and thalamus remained unaffected. Asymptomatic carotid stenosis and symptomatic carotid stenosis patient groups did not differ from each other. CONCLUSIONS: Carotid stenosis has an effect on diffusion in the white matter of the ipsilateral hemisphere, and it is partly reversible by carotid endarterectomy. The finding may be associated with leukoaraiotic development ("preleukoaraiosis").

Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis.

BACKGROUND: Prior studies have suggested a central role for cellular adhesion molecules (CAMs) in the pathophysiology and symptoms of atherosclerotic carotid plaques (CPs). OBJECTIVE: This study examined the role of CAMs in symptom generation in patients with advanced carotid artery disease. METHODS: Ninety-two consecutive patients underwent carotid endarterectomy, six for both sides (54 symptomatic and 41 asymptomatic CPs). Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin were immunostained in fresh-frozen CP specimens and examined semiquantitatively in the endothelium and intima-media. Plasma concentrations of soluble ICAM-1 and sVCAM-1 were analyzed by ELISA. RESULTS: Endothelial expression of ICAM-1, VCAM-1, P-selectin, and E-selectin did not differ between symptomatic and asymptomatic CPs, but endothelial ICAM-1 was associated with serum sensitized C-reactive protein levels (p = 0.026). However, there was less ICAM-1 expression in the intima-media of the symptomatic CPs (p = 0.022), and there was a similar, but nonsignificant tendency for VCAM-1. Soluble ICAM-1 and soluble VCAM-1 were not associated with the symptom status. CONCLUSIONS: In contrast to earlier studies, it was found that symptomatic carotid disease is not associated with increased expression of adhesion molecules in the endothelium of advanced carotid plaques or in circulation. Rather, there was less expression of adhesion molecules in the intima-media of symptomatic carotid plaques.

Differential expression of cytokines (IL-2, IFN-gamma, IL-10) and adhesion molecules (VCAM-1, LFA-1, CD44) between spleen and lymph nodes associates with remission in chronic relapsing experimental autoimmune encephalomyelitis.

We have recently established chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE) in SJL mice with a modified protocol. In this model, splenectomy aborts the relapsing-remitting course of the disease, and adoptive transfer of lymphocytes of the local draining lymph nodes (LNs) to naive recipients exacerbates the disease. Adoptive transfer of splenic cells converted acute EAE into CR-EAE in the naive recipients. In light of the different roles of the spleen and LNs in the evolution of CR-EAE, we examined by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) whether a differential mRNA expression profile of cytokines and cellular adhesion molecules (CAMs) in spleen versus LN was associated with relapse or remission in CR-EAE. All the cytokines tested (interleukin-1beta (IL-1beta), IL-2, IL-4, IL-7, IL-10, interferon-gamma (IFN-gamma)) as well as CAMs (ICAM-1, ICAM-2, VCAM-1, LFA-1 and CD44) were expressed at substantial levels in both spleen and LNs. Interestingly, disease remission was found to be associated with an increased mRNA expression of IL-2 and IFN-gamma in LNs and a decreased IL-10 mRNA level in the spleen. On the other hand, an increased mRNA expression of VCAM-1, LFA-1 and CD44 was observed in the spleens in comparison with that in LNs of mice, with remission. During relapses, mRNA expression of the tested molecules did not significantly differ between spleens and LNs. Our results suggest that a differential and polarized expression profile of certain cytokines and CAMs in spleen versus LN could provide molecular correlates of the cyclic pathogenesis of CR-EAE.

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.

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.

Splenectomy and adoptive cell transfer reveal a prominent role for splenic memory lymphocytes in the development of chronic relapsing experimental autoimmune encephalomyelitis.

We previously reported that acute experimental autoimmune encephalomyelitis (EAE), induced by active immunization of SJL mice, could be converted into chronic relapsing EAE (CR-EAE) by a pretreatment with neuroantigen and killed mycobacteria 2 months earlier. This finding indicates that immune memory, established by the pretreatment, influences the subsequent EAE induction. The present study shows that splenectomy and lymphadenectomy, applied 1 week before the subsequent active immunization of the pretreated mice, efficiently abort the chronic nature of CR-EAE. Furthermore, we have found that adoptive transfer of lymphocytes from the spleen (but not of those from the local draining lymph nodes) of the pretreated mice to naive syngeneic recipients 1 week before the acute EAE-induction immunization results in the development of CR-EAE. On the other hand, the transfer of lymphocytes from the local draining lymph nodes aggravates the acute disease. These data support a critical role for immune memory of the previous suboptimal challenge in the development of chronic relapsing demyelinating disease.

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.

Stanniocalcin: A molecular guard of neurons during cerebral ischemia.

Stanniocalcin (STC) is a glycoprotein hormone originally found in bony fish, in which it regulates calcium/phosphate homeostasis and protects against hypercalcemia. The recently characterized human STC shows about 70% homology with fish STC. We previously reported a constitutive expression of STC in terminally differentiated neurons. Here, we show that exposure of human neural-crest-derived cell line Paju to hypercalcemic culture medium induced expression of STC. Treatment of Paju cells with recombinant human STC increased their uptake of inorganic phosphate. Paju cells expressing STC by cDNA transfection displayed increased resistance to ischemic challenge and to elevated intracellular free calcium induced by treatment with thapsigargin. An up-regulated and redistributed expression of STC was observed in neurons surrounding the core of acute infarcts in human and rat brains. Given that mobilization and influx of calcium is considered a main neurotoxic mechanism following ischemia, our results suggest that the altered expression of STC contributes to the protection of cerebral neurons against hypoxic/ischemic damage. Manipulation of the STC expression may therefore offer a therapeutic approach to limit the injury after ischemic brain insults.

Bilateral sphenoid wing metastases of prostate cancer presenting with extensive brain edema.

A 76-year-old man insidiously developed diffuse neurological symptoms: cognitive decline, dysphagia, dysphasia and mental disturbance. Computed tomography of the cranium revealed widespread bilateral brain edema and symmetrical bilateral sphenoid wing hyperostosis. Adjacent to the hyperostosis that resembled skull base meningiomas, two separate parenchymatous temporal lobe lesions enhancing with contrast medium were observed. The patient had earlier been diagnosed to have prostatic carcinoma. Dexamethasone therapy resulted in discontinuation of the neurological symptoms. The diagnosis of metastasized adenocarcinoma of the prostate was confirmed histologically on autopsy after a sudden death from pneumonia. Intracranial metastases of prostate cancer may have a predilection site at the sphenoid wing, and can mimic a skull base meningioma. Intracranial spread of prostatic adenocarcinoma should be considered in elderly men as a treatable cause of gradual neurological deterioration, especially if cranial malignancy or hyperostosis is found.