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.

Symptomatic post-thrombolytic intracerebral hemorrhage is not related to the cause of stroke.

BACKGROUND AND PURPOSE: The development of intracerebral hemorrhage following intravenous thrombolysis (IVT) can be influenced by various confounders related to the underlying vessel and tissue conditions. There are some data on association of cause of the stroke and the hemorrhage transformation. We tested the hypothesis that the cause of stroke is associated with the development of symptomatic intracerebral hemorrhage (sICH) following IVT. METHODS: A consecutive cohort of 2485 IVT-treated patients at the Helsinki University Central Hospital was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. An sICH was classified according to the European Cooperative Acute Stroke Study II criteria. The associations of sICH with nominal, ordinal and continuous variables were analyzed in a univariate binary regression model and adjusted in multivariate binary regression models. RESULTS: In univariate analyses, cardioembolism [odds ratio (OR), 1.14; 95% confidence interval (CI), 0.79-1.64] and large-artery atherosclerosis (OR, 1.30; 95% CI, 0.85-2.00) were not associated with sICH, and small-vessel occlusion was associated with lower odds for sICH (OR, 0.18; 95% CI, 0.06-0.57). When adjusted for previously identified factors associated with sICH, none of the TOAST categories was associated with a higher or lower frequency of sICH. CONCLUSIONS: The development of sICH in IVT-treated patients is not related to the cause of stroke.

Post-thrombolytic blood pressure and symptomatic intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Most guidelines for intravenous thrombolysis (IVT) in acute ischaemic stroke patients advise keeping systolic blood pressure (BP) below 180/105 mmHg prior to the bolus injection. Less is known about optimal management of BP thereafter. We assessed temporal changes in post-thrombolytic systolic BP values and their impact on development of symptomatic intracerebral hemorrhage (sICH). METHODS: The study cohort included 1868 consecutive acute ischaemic stroke patients treated with IVT at the Helsinki University Central Hospital. sICH was defined according to the European Cooperative Acute Stroke Study II (ECASS-II) (primary outcome), National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke criteria. We evaluated BP at admission, prior to IVT and at 2, 4, 8, 12, 24 and 48 h after thrombolysis. We used univariate and multivariable models to test the effect of BP at various time-points on development of post-thrombolytic sICH. RESULTS: Prevalence of sICH in the cohort was 5.8% (ECASS-II). Patients with sICH had significantly higher systolic BP at several time-points after IVT compared with those without sICH (P < 0.01 at 2 and 4 h; P < 0.05 at 12 and 48 h). The odds ratios for development of sICH per 10 mmHg increase in BP were 1.14 [95% confidence interval (CI), 1.03-1.25], 1.14 (95% CI, 1.03-1.25), 1.12 (95% CI, 1.01-1.23) and 1.12 (95% CI, 1.01-1.23), respectively. At 8 h, we observed a trend (P = 0.07) for ECASS-II and a significant effect (P < 0.05) for National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke criteria. Thus, the only time-point with no difference observed was 24 h. CONCLUSIONS: Patients with post-thrombolytic sICH have significantly higher systolic BP at several time-points compared with patients without sICH.

Association of multiple sclerosis and sudden sensorineural hearing loss.

BACKGROUND: Multiple sclerosis (MS) may affect other cranial nerves besides the optic nerve. Sudden sensorineural hearing loss (SSHL), possibly caused by a deficit in the auditory tract, including the vestibulocochlear nerve, is sometimes associated with MS. OBJECTIVES: We aimed to assess the incidence of SSHL among MS patients, its frequency as an initial symptom of MS, and magnetic resonance imaging (MRI) findings associated with SSHL in MS. METHODS: We collected retrospectively all patients diagnosed with MS and SSHL at the Helsinki University Hospital between 2004 and 2014. Patients with both diagnoses were re-evaluated using hospital medical records, audiograms and head MRI scans. RESULTS: A total of 2736 patients were diagnosed with MS, 1581 patients with SSHL, and 18 patients (0.7% of all MS patients) with both; two patients presented with SSHL as an initial symptom of MS. The annual incidence of SSHL was 59.8/100 000 (95% confidence interval (CI) 37.7-94.9) in MS patients, and 12.4/100 000 (95% CI 11.8-13.0) in the normal population. CONCLUSION: SSHL is a rare symptom of MS and is even less frequent as an initial symptom. Its incidence in MS patients, however, markedly exceeds that in the normal population.

Recognition of posterior circulation stroke.

OBJECTIVES: Better identification and triage of acute posterior circulation (PC) stroke patients is needed as the PC ischemic stroke (IS) patients may be allowed longer thrombolysis window than anterior circulation (AC) IS patients and PC patients with hemorrhagic stroke (ICH) may require care in a neurosurgical unit possibly remote from stroke unit. MATERIALS AND METHODS: Consecutive stroke patients treated at a tertiary center with thrombolysis (100% for IS) and/or comprehensive stroke unit care. RESULTS: Altogether, 1641 patients had AC (75%) and 553 PC strokes. The PC-IS patients were younger (65 vs 70), had less often prior hypertension (51 vs 61%), and were twice more often on warfarin. They presented 3.5 times more often with seizure, vomited five times more often, had headache twice as often, and required intubation 2 to 3 times more often despite equal NIHSS (9 vs 8) or GCS (15 both) scores with AC-IS patients. Among PC patients, IS (n = 190) associated with younger age, prior atrial fibrillation (AF) in 25% and dyslipidemia in ~40%. One-third of PC-ICH patients (n = 363) had headache and vomited at the onset. PC-ICH patients had BP median of 177/92 mmHg and blood glucose 7.4 mmol/l on ER arrival. Warfarin use was twice as common in PC-ICH. CONCLUSIONS: Despite being of typical age for multiple cardiovascular conditions the PC-ICH patients less often have a previous history of AF or dyslipidemia than IS patients do. The vomiting PC-ICH patient with hypertensive BP values often has headache and a red flag for hemorrhage is warfarin treatment.

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.

Higher baseline international normalized ratio value correlates with higher mortality in intracerebral hemorrhage during warfarin use.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulation (OAC). Our aim was to investigate the impact of the international normalized ratio (INR) level on mortality in OAC-associated ICH compared with non-OAC-associated ICH. METHODS: A retrospective chart review of consecutive ICH patients treated at the Helsinki University Central Hospital from January 2005 to March 2010 (n = 1013) was performed. An ICH was considered to be OAC-associated if the patient was on warfarin at ICH onset. The association of INR with 3-month mortality was adjusted in a multivariable logistic regression model for factors influencing the crude odds ratios (ORs) in bivariable logistic regression by more than 5%. RESULTS: One in eight ICHs was OAC-associated (n = 132). Of these, 50% had therapeutic INR (2.0-3.0), 7% had INR <2.0 and 43% had high INR (>3.0) on admission. Patients on OAC were older (median 76 vs. 66 years; P < 0.001) with more severe symptoms (median National Institutes of Health Stroke Scale 14 vs. 10; P < 0.001) and larger hematomas (median 11.4 vs. 9.7 ml; P < 0.001) on admission than patients not on OAC. After adjustment for confounders, 3-month mortality in the whole cohort was associated with higher baseline INR (OR 1.06; CI 1.03-1.09 per 0.1 increment). Mortality was higher with both therapeutic (51% at 3 months; OR 3.59; CI 1.50-8.60) and high (61%; OR 5.26; CI 1.94-14.27) INR values compared with non-OAC-associated ICH (29%). CONCLUSIONS: Patients with OAC-associated ICH had more severe strokes and higher mortality compared with patients with ICH not related to OAC. Higher baseline INR was associated with increased 3-month mortality.

Lost potential of kidney and liver donors amongst deceased intracerebral hemorrhage patients.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) has high acute mortality. The number of potential kidney and liver donors amongst deceased ICH patients was estimated to improve our institutional guidelines on acute care of neurocritical patients to increase organ donation. METHODS: A chart review was carried out by a multi-professional team for consecutive ICH patients admitted to the emergency department at Helsinki University Central Hospital and dying within 14 days between 2005 and 2010. RESULTS: In all, 955 patients had follow-up data, of whom 254 (27%) died within 14 days and eight ended up as organ donors. An additional 51 potentially suitable donors not different from actual donors were identified: nine suitable for kidney donation, 11 for liver and 31 for both. In 49/51 (96%) cases prognosis seemed non-existent and do-not-resuscitate orders were issued early, which led to refrainment from intensive care in 76.5%. These potential donors differed from those ICH patients surviving a whole year (n = 529) by male preponderance, more severe symptoms (median National Institutes of Health Stroke Scale 25 vs. 6 and Glasgow Coma Scale 7 vs. 15), larger hematoma volumes of 24.8 cm(3) (vs. 6.7), and frequent finding of midline shift and intraventricular rupture of the hemorrhage in admission brain CT. Based on the results, our guidelines were revised towards more active treatment including mechanical ventilation for neurocritical patients at the emergency department for at least 48 h, resulting in an increase in organ donations in 2012. CONCLUSIONS: A considerable number of ICH patients are potential organ donors if the evaluation takes place on arrival and organ donation is considered as part of usual end-of-life care.

Decreasing the delay to carotid endarterectomy in symptomatic patients with carotid stenosis--outcome of an intervention.

OBJECTIVES: Surgical treatment of carotid stenosis after the onset of ischaemic symptoms should be performed within 2 weeks. This aim was accomplished only in 11% during the years 2007-2008 in the Helsinki University Central Hospital (HUCH) region. Since then, special efforts have been made in order to shorten the delay. The aim of this study was to find out how these changes affected the symptom-to-knife time (SKT). MATERIALS AND METHODS: All symptomatic patients (n = 144) who had carotid endarterectomy (CEA, n = 145) in HUCH in 2010 were retrospectively analysed and the SKT was determined. RESULTS: Of the operations, 37% (n = 53) were performed within the recommended 2 weeks. The median SKT was 19 days (1-183). Of the patients who came to HUCH on an emergency basis (n = 80), 55% (n = 45) were operated within 2 weeks and their median SKT was 13 days (1-148). CONCLUSIONS: The changes that were made in 2008-2009 have significantly shortened the delay in the treatment of carotid stenosis, but the desired time frame of 2 weeks was reached far too seldom. The greatest benefit from preventive CEA is achieved when patients are referred emergently to a clinic where neurologist, imaging resources and vascular surgeon are available.

Intravenous thrombolysis in ischemic stroke patients with isolated homonymous hemianopia.

BACKGROUND: Patients with posterior ischemic stroke were usually excluded from thrombolytic treatment in clinical trials and clinical practice, and little is known about effectiveness of thrombolysis treatment in such patients who may end up with severe disability. AIMS OF THE STUDY: We aimed to describe the outcome of acute ischemic stroke patients presenting with isolated homonymous hemianopia and treated with intravenous thrombolysis. METHODS: A case report of three patients presenting with homonymous hemianopia owing to posterior circulation stroke treated with intravenous thrombolysis at the Helsinki University Central Hospital. Main outcome measures were modified Rankin Scale and neuropsychological examination at 3 months after thrombolysis. We further evaluated Goldmann visual field examination at 6 months. RESULTS: No acute findings appeared on admission non-contrast head-computed tomography scan. All patients had a perfusion deficit on admission-computed tomography perfusion imaging. All patients scored 0 on 3-month modified Rankin Scale, and their neuropsychological evaluation was normal. Goldmann examination revealed no visual field deficit in both female patients, and a modest visual field defect was detected in the male patient. CONCLUSIONS: Our experience encourages application of intravenous thrombolytic treatment (especially when supported with multimodality neuroimaging) in patients with homonymous hemianopia, for which rehabilitation options are limited.

Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis.

OBJECTIVES: To assess the impact of symptomatic intracerebral hemorrhage (sICH) on outcome of thrombolysis-treated ischemic stroke patients, as additional to recognized prognosticators. METHODS: The study cohort included 985 ischemic stroke patients treated with IV thrombolysis at the Helsinki University Central Hospital (1995-2008). In a multivariable model adjusted for baseline stroke severity, age, onset-to-treatment time, baseline glucose, hyperdense cerebral artery sign, and early infarct signs on baseline imaging, and prior modified Rankin Scale (mRS), we calculated risk ratios (RRs) of patients with sICH (separately per Safe Implementation of Thrombolysis in Stroke[SITS]-Monitoring Study, European Cooperative Acute Stroke Study II [ECASS-II], and National Institute of Neurological Disorders and Stroke [NINDS] definitions) for poor 3-month outcome (mRS 3-6) and mortality. Receiver operating characteristic (ROC) curve and integrated discrimination improvement (IDI) evaluated impact of sICH on outcome. Internal cross-validation of the model was done with bootstrap statistics. RESULTS: The frequency of sICH was 2.1% (SITS), 7.0% (ECASS-II), and 9.4% (NINDS). RRs for poor and fatal outcome, respectively, were 1.7 and 4.8 (SITS), 1.6 and 3.8 (ECASS-II), and 1.6 and 3.4 (NINDS). In IDI analyses, sICH improved prediction model for 3-month mRS of 3-6 and 4-6, respectively, by 1.4% and 3.0% (SITS), 4.0% and 5.9% (ECASS-II), and 4.7% and 6.1% (NINDS). In case of 3-month mRS 5-6 and mortality, it was 6.1% and 5.3% (SITS), 11.3% and 9.3% (ECASS-II), and 10.3% and 8.0% (NINDS). ROC analysis revealed similar results. CONCLUSIONS: Patients with sICH have increased risk of poor and fatal outcome. Compared with recognized stroke prognosticators, contribution of sICH is smaller. Definition-wise, ECASS-II- and NINDS-based sICH contribute relatively more; ECASS-II has the largest contribution to worst outcomes.

Structure of delay in carotid surgery--an observational study.

OBJECTIVES AND DESIGN: Undelayed investigation and surgical treatment of symptomatic carotid artery stenosis are recommended as per guidelines on stroke prevention. We evaluated patient referral pathways and delays from symptom to surgery in Helsinki University Central Hospital (HUCH) region. MATERIALS AND METHODS: One hundred consecutive symptomatic patients scheduled for carotid endarterectomy (CEA) between August 2007 and September 2008 were identified and the delay between ischaemic index symptom and CEA was analysed. RESULTS: The median time from the index symptom to surgery was 47 days (range: 3-688 days). The longest delay was surgery related with a median of 25 days (range: 2-202 days) from the consultation of the vascular surgeon to the operation. Only 11% of the patients were operated within the recommended 2 weeks' time. It was more likely that CEA was performed within 2 weeks if an emergent consultation to Meilahti Hospital neurologist on call did take place (odds ratio (OR) 12.6, 95% confidence interval (CI) 1.5-104, p = 0.019). CONCLUSION: Delays from symptom to surgery were generally too long and the in-hospital door-to-knife time (DKT) was long mostly due to waiting for the operation theatre. The investigation of all stroke, amaurosis fugax and transient ischaemic attack patients should be performed on an emergency basis and most optimally centralised to hospitals were carotid surgery is performed.

Two years of Finnish Telestroke: thrombolysis at spokes equal to that at the hub.

BACKGROUND: Official guidelines on stroke promote the use of telemedicine via bidirectional videoconferencing equipment, which provides a valid and reliable means of facilitating thrombolysis delivery to patients in distant or rural hospitals. METHODS: The present prospective cohort study describes the characteristics and 3-month outcome of the thrombolysis patients treated in 5 community hospitals served by the Helsinki University Central Hospital (HUCH) in a telestroke network during 2007 to 2009. The characteristics and outcome of telestroke thrombolysis patients are compared with consecutive thrombolysis patients (n = 985) treated at HUCH. RESULTS: A total of 106 consecutive telestroke consultations in 2 years led to IV thrombolysis in 61 patients (57.5%). The median NIH Stroke Scale score was 10 (range 3-26), onset to treatment time 120 minutes (interquartile range [IQR] 49), length of consultation 25 minutes (IQR 18) if the consultation led to thrombolysis and 15 minutes (IQR 10) if not (p = 0.032). The rate of symptomatic intracranial bleedings was 6.7% (4/60) according to the National Institute of Neurological Disorders and Stroke definition. Half (28/57) of the thrombolysis patients with complete follow-up data had a favorable outcome (modified Rankin Scale [mRS] 0-2) and a third (17/57) had an excellent recovery (mRS 0-1). Thus the patients treated with thrombolysis based on teleconsultation had similar outcome with those treated at HUCH (mRS 0-2: 49.1% vs 58.1%, p = 0.214 and mRS 0-1: 17/57 [29.4%] vs 352/957 [36.8%], p = 0.289). CONCLUSIONS: A special feature of the Finnish pilot is the high percentage of consultations leading to thrombolytic treatment with features and results very similar to on-site thrombolysis at the neurologic emergency room of HUCH.

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.

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.

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.

Cyclooxygenase-2 is induced globally in infarcted human brain.

Cyclooxygenase (COX) catalyzes synthesis of prostanoids after liberation of arachidonic acid, an important biochemical sequela of cerebral ischemia that aggravates brain injury. We investigated expression of inducible COX-2 in infarcted human brains (symptom duration, 15 hours to 18 days) and found that COX-2 protein was present in both neuronal and glial cells throughout the brain in accord with infarct topography and duration. These results emphasize the global yet temporally regulated nature of COX-2 induction during focal ischemia in humans, clearly different from the circumscribed acute expression reported in experimental animal models. We speculate that early induction of COX-2 may fuel tissue damage through prostanoids and free radicals, and delayed induction in remote brain areas may promote reconstitutive processes in the face of tissue scarring and remodeling of the surviving neural networks.

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.