Tiina Sairanen

Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke

Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use. Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables. Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage. Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke

Background and Purpose— Tumor necrosis factor-&agr; (TNF-&agr;) 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-&agr; during human stroke is not known. Methods— We examined TNF-&agr; 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-&agr; content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed. Results— Neuronal TNF-&agr; 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-&agr; immunoreactivity was detected during the acute phase, with the astrocytic TNF-&agr; expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-&agr; immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-&agr; levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-&agr; staining overlapped, although not completely, during the first days. Conclusions— The data support the hypothesis that TNF-&agr; 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.

Symptomatic intracranial hemorrhage after stroke thrombolysis: The SEDAN Score

A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis.

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

The mRNA expression of the proinflammatory cytokine interleukin-1β (IL-1β) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1β 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-1β and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1β mRNA. The number of IL-1β 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-1β 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-1β 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-1β production.

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.

SMASH-U: A Proposal for Etiologic Classification of Intracerebral Hemorrhage

Background and Purpose— The purpose of this study was to provide a simple and practical clinical classification for the etiology of intracerebral hemorrhage (ICH). Methods— We performed a retrospective chart review of consecutive patients with ICH treated at the Helsinki University Central Hospital, January 2005 to March 2010 (n=1013). We classified ICH etiology by predefined criteria as structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). Clinical and radiological features and mortality by SMASH-U (Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease, Hypertension, Undetermined) etiology were analyzed. Results— Structural lesions, namely cavernomas and arteriovenous malformations, caused 5% of the ICH, anticoagulation 14%, and systemic disease 5% (23 liver cirrhosis, 8 thrombocytopenia, and 17 various rare conditions). Amyloid angiopathy (20%) and hypertensive angiopathy (35%) were common, but etiology remained undetermined in 21%. Interrater agreement in classifying cases was high (&kgr;, 0.89; 95% CI, 0.82–0.96). Patients with structural lesions had the smallest hemorrhages (median volume, 2.8 mL) and best prognosis (3-month mortality 4%), whereas anticoagulation-related ICHs were largest (13.4 mL) and most often fatal (54%). Overall, median ICH survival was 5½ years, varying strongly by etiology (P<0.001). After adjustment for baseline characteristics, patients with structural lesions had the lowest 3-month mortality rates (OR, 0.06; 95% CI, 0.01–0.37) and those with anticoagulation (OR, 1.9; 1.0–3.6) or other systemic cause (OR, 4.0; 1.6–10.1) the highest. Conclusions— In our patients, performing the SMASH-U classification was feasible and interrater agreement excellent. A plausible etiology was determined in most patients but remained elusive in one in 5. In this series, SMASH-U based etiology was strongly associated with survival.

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.

Thrombolysis of basilar artery occlusion: Impact of baseline ischemia and time

To evaluate the impact of extensive baseline ischemic changes on functional outcome after thrombolysis of basilar artery occlusion (BAO), and to study the effect of time to treatment in the absence of such findings.

Intravenous Thrombolysis of Basilar Artery Occlusion Predictors of Recanalization and Outcome

Background and Purpose— Basilar artery occlusion has a high mortality rate (85% to 95%) if untreated. We describe a large single-center cohort treated mostly with intravenous alteplase and heparin. Methods— The cohort included 116 patients with angiography-verified basilar artery occlusion. We studied baseline characteristics, frequencies of recanalization and symptomatic intracranial hemorrhage, and 3-month outcome (modified Rankin Scale [mRS]). Results— Thirty patients (25.9%) had mRS 0 to 2, 42 patients (36.2%) had moderate outcome (mRS, 0–3), 26 patients (22.4%) required daily help (mRS, 4–5), and 48 patients (41.4%) died. Eighteen patients (15.7%) developed symptomatic intracranial hemorrhage. In patients with post-treatment angiogram available (n=91), 59 patients (64.8%) had a complete or partial recanalization. Radiological location of basilar artery occlusion was known in 55 of 91 instances, and recanalization was associated directly with clot location at the top-of-basilar (odds ratio, 4.8 [1.1–22]; P=0.048). Independent outcome (mRS 0-2) was associated with lower age and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Age, nil or minimal recanalization, and symptomatic intracranial hemorrhage were independently associated with fatal outcome. Sixteen of 71 patients (22.5%) who presented with coma eventually reached moderate outcome, and additional 8 patients (11.3%) progressed to mRS 4. Conclusions— Whereas recanalization after intravenous thrombolysis strongly predicts survival and moderate outcome, therapeutic techniques should concentrate on clot location. Although most adverse baseline variables, age, symptom severity, but also coma are beyond control, it should not preclude thrombolysis, which may permit independent survival.

Differential cellular expression of tumor necrosis factor-α 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.