Intra-arterial thrombolysis in acute ischaemic stroke

Several thrombolytic agents for the treatment of acute ischaemic stroke have been examined; however, to date, only the i.v. administration of recombinant tissue plasminogen activator is licensed in Australia. Although no trials directly comparing intra-arterial and i.v. delivery of thrombolytics exist, intra-arterial thrombolysis has several potential advantages, including angiographic assessment of the thrombus and the site of occlusion and collateral circulation, improved recanalization, and delivery of higher local concentrations of thrombolytic agents and extending the therapeutic time window for treatment. We conducted a retrospective audit of our experience with the use of intra-arterial urokinase to treat acute ischaemic stroke at an Australian tertiary-care hospital between June 1993 and June 2003. We examined time from stroke onset to assessment, computerized tomography scan, cerebral angiography and thrombolysis, anatomical classification of intra-arterial thrombus, rates of symptomatic intracerebral haemorrhage, and clinical outcome at 3 months. We believe that in carefully selected individuals in appropriate centres of expertise, intra-arterial thrombolytic therapy holds great promise.     

Electrocardiographic and troponin T changes in acute ischaemic stroke

BACKGROUND: The mechanisms explaining morphological electrocardiogram (ECG) changes and increased troponin T (TnT) in acute stroke are unclear. The aims of the present study were to assess the prevalence of ECG and TnT changes in acute ischaemic stroke, to investigate whether ischaemic-like ECG changes correlate to a rise in TnT and to examine whether ECG changes and elevated TnT predict a poor short-time outcome. METHODS: From 2000 to 2002 a total of 279 patients suffering from acute ischaemic stroke were included prospectively in the present study. ECG was carried out at admission and on day 1 in all patients. TnT was analysed at admission and on day 1. RESULTS: The most frequent ECG changes were: prolonged QTc 36.0%, ST depression 24.5%, atrial fibrillation 19.9% and T wave inversion 17.8%. In logistic regression analyses, ST depression and Q waves were significantly associated with a rise in TnT. TnT was elevated (>0.04 microg L(-1)) in 26 patients (9.6%). In logistic regression analyses, a rise in TnT was significantly associated with a poor short-term outcome (modified Rankin scale >3). CONCLUSION: ECG changes are prevalent in acute ischaemic stroke. ST depression and Q waves are related to an increase in TnT, suggesting that these ECG changes may indicate coexisting ischaemic heart disease. A rise in TnT predicts a poor outcome. Patients with acute ischaemic stroke should be offered adequate treatment with secondary prevention and preferably a follow-up with focus on cardiologic as well as neurological aspects.     

Management of acute ischaemic stroke in patients with dementia

An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56–10% vs. 1–16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case–control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre‐existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.     

Anterior pituitary axis hormones and outcome in acute ischaemic stroke

Abstract. Neidert S, Katan M, Schuetz P, Fluri F, Ernst A, Bingisser R, Kappos L, Engelter ST, Steck A, Müller B, Christ‐Crain M (University Hospital Basel, Basel, Switzerland; SphingoTec GmbH, Borgsorf, Germany; Kantonsspital Aarau, Aarau, Switzerland) Anterior pituitary axis hormones and outcome in acute ischaemic stroke. J Intern Med 2011; 269 : 420–432. Background. Early and accurate prediction of outcome in acute stroke is important and influences risk‐optimized therapeutic strategies. Endocrine alterations of the hypothalamic–pituitary axis are amongst the first measurable alterations after cerebral ischaemia. We therefore evaluated the prognostic value of cortisol, triiodothyronine (T3), free thyroxine (fT4), thyroid‐stimulating hormone (TSH) and growth hormone (GH) in patients with an acute ischaemic stroke. Methods. In an observational study including 281 patients with ischaemic stroke, anterior pituitary axis hormones (i.e. cortisol, T3, fT4, TSH and GH) were simultaneously assessed to determine their value to predict functional outcome and mortality within 90 days and 1 year. Results. In receiver operating characteristic curve analysis, the prognostic accuracy of cortisol was higher compared to all measured hormones and was in the range of the National Institutes of Health Stroke Scale (NIHSS). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio (OR) 1.0 (1.0–1.01) and 1.62 (1.37–1.92), respectively, P < 0.0002 for both, adjusted for age and the NIHSS] in patients with ischaemic stroke, but added no significant additional predictive value to the clinical NIHSS score. Conclusion. Cortisol is an independent prognostic marker for death and functional outcome within 90 days and 1 year in patients with ischaemic stroke. By contrast, other anterior pituitary axis hormones such as peripheral thyroid hormones and GH are only of minor value to predict outcome in stroke.     

Advances in endovascular treatment of acute ischaemic stroke

Over the past decade, there have been rapid advancements in ischaemic stroke reperfusion treatments. However, clear clinical benefit is yet to be shown in large clinical trials. In this review, the major studies in different types of endovascular treatments including intra‐arterial thrombolysis, aspiration devices, mechanical clot retrievers and the new stent retrievers are discussed. First‐generation mechanical thrombectomy devices such as the MERCI Retriever (Stryker, Kalamazoo, MI, USA) and Penumbra aspiration device (Penumbra Inc., Alameda, CA, USA) demonstrated safety and higher rates of recanalisation in the MERCI and Penumbra Pivotal Stroke Trial; however, there was no significant improvement in clinical outcome. Second‐generation endovascular stent retrieval devices Solitaire (ev3 Neurovascular, Irvine, CA, USA) and Trevo (Stryker) have shown promising results. In preliminary trials, SOLITAIRE with the Intention for Thrombectomy (SWIFT) and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), both showed rates of recanalisation close to 90% and significantly improved clinical outcomes compared with the MERCI study, but the recent landmark studies for endovascular treatment (Interventional Management of Stroke (IMS III), Mechanical Retrieval and Recanalisation of Stroke Clots Using Embolectomy (MR‐RESCUE) and SYNTHESIS) did not show any clinical benefit from endovascular treatment compared with standard intravenous therapy. However, moving forward, the recent Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR‐CLEAN) study results have shown marked improvements in recanalisation, reperfusion and functional outcome in patients receiving endovascular treatment (97% using stent retrievers) within 6 h in addition to standard medical care. Overall, although evidence regarding the efficacy of endovascular treatment in acute stroke has been equivocal, recent publications of large multicentre randomised controlled trials indicate benefit of intra‐arterial stent retriever reperfusion in patients selected by appropriate imaging and treated early by experienced operators, and it will likely remain an important adjunct to established medical treatment with intravenous tPA.     

Secondary prevention of ischaemic stroke

Recent trials within the past few years have influenced not only how we treat patients immediately after acute ischaemic stroke, but also how we investigate for aetiology. With the advent of improved medications, procedures and monitoring devices, modern stroke prevention strategies are more individualised, but the decision‐making process is more complex. We provide an approach to navigating these management options.     

Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology

Wardlaw JM (Western General Hospital, Edinburgh, UK). Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology (Review). J Intern Med 2010; 267: 172–190. Abstract. The treatment of acute ischaemic stroke is based on the principle that there is ischaemic but still potentially salvageable tissue that could be rescued if blood flow could be restored quickly. It is assumed that salvage might only be possible in the first few hours, and that infarct expansion is a direct result of failed recanalization of the main artery. This concept arose from experimental work in the 1970s, supported more recently by studies using imaging to identify penumbral tissue. However, although magnetic resonance diffusion and perfusion imaging is a way of imaging penumbral tissue and has been around for over a decade, it is not an easy technique to apply in practice and its use has produced conflicting results. Computed tomography perfusion, and any other tissue perfusion imaging technique, is likely to encounter the same difficulties. Indeed many factors, other than the presence of a diffusion‐perfusion mismatch acutely, may determine or influence ultimate tissue fate even days after the stroke, and in turn, clinical outcome. Many of these potential influences are beginning to emerge from studies using different forms of imaging at later times after stroke. This review will explore the information now emerging from imaging studies in large artery ischaemic stroke to summarize knowledge to date and indicate unresolved issues for the future.     

Prospective multicentre cohort study of heparin-induced thrombocytopenia in acute ischaemic stroke patients

Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti-platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score ≥4 points, positive-ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64·4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12·8%) in the heparin group. Seven patients had 4Ts ≥ 4 points. Among them, three patients (1·7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16-23) and in-hospital mortality was very high (66·7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1·7% (95% confidence interval: 0·4-5·0). The clinical severity and outcome of definite HIT were unfavourable.     

Medication compliance in ischaemic stroke patients

Aim: This study aimed to assess the degree of patient compliance with medications prescribed at hospital discharge following ischaemic stroke, and concordance between self‐reported medication use and general practitioner (GP) records. Methods: The Auckland City Hospital Stroke database was used to identify consecutive patients with ischaemic stroke over a three‐month period. Participants were contacted and invited to participate in a telephone questionnaire that asked about current medications. GPs were also asked to list the medications their patients were taking. Results: Fifty‐one patients were approached to participate of whom 48 consented to be interviewed at 6 weeks and 47 at 6 months. At 6 weeks, 36 of 38 (95%) were compliant with aspirin, 12 of 13 (92%) dipyridamole, 8 of 9 (88%) warfarin, 36 of 41 (88%) statins, 33 of 38 (87%) antihypertensive medications, and 7 of 7 (100%) diabetes medications. At 6 months, 97% were compliant with aspirin, 100% dipyridamole, 100% warfarin, 94% statins, 91% antihypertensive medications, and 100% diabetes medications. Natural or herbal remedy use was reported by 10 of 48 (21%) at 6 weeks and 11 of 47 (23%) at 6 months. Blister packs were used by 8 of 48 (17%) at 6 weeks and 5 of 47 (11%) at 6 months. Conclusion: Adherence to secondary stroke prevention medication was between 87% and 100% at 6 weeks with similar findings at 6 months after discharge. We speculate that these high compliance rates may be due to one‐on‐one stroke nurse counselling and the use of stroke information packs, which include information about the importance of adherence to secondary prevention medication.     

Management of ischaemic stroke in the acute setting: review of the current status

Abstract

Acute ischaemic stroke can be treated by clot busting and clot removal. Thrombolysis using intravenous recombinant-tissue plasminogen activator (IV r-TPA) is the current gold standard for the treatment of acute ischaemic stroke (AIS). The main failure of this type of treatment is the short time interval from stroke onset within which it has to be used for any benefit. The evidence is that IV r-TPA has to be used within 4.5 hours.Other modalities of treatment are not as effective and need more scrutiny and examination. The available modalities are intra-arterial thrombolysis and clot-retrieval devices. Not unexpectedly, recanalisation treatments have flourished at a rapid rate. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques.Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable intravenous r-tPA treatment within the 4.5-hour period following onset of stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of ‘stroke attack’ should be revisited, especially in the resource-limited context. This approach at present will halt to some extent the stroke pandemic that we are facing.     

Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke

BACKGROUND AND SCOPE: Recent literature has demonstrated that inflammation contributes to all phases of atherosclerosis and brain damage caused by stroke. In acute phase of cerebrovascular diseases biochemical markers of inflammation, such as C-reactive protein (CRP), could represent an indicator of severity of stroke, but few studies have verified this hypothesis, especially in very old patients. The aim of this study was to evaluate the role of CRP on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. MATERIALS AND METHODS: We retrospectively evaluated CRP values (nephelometric method), performed within 12 h from hospital admission, in 196 elderly patients (124 females and 72 males with mean age+/-SD 83.32+/-10.46 years), discharged with diagnosis of acute ischaemic stroke, 68 of them with atherothrombotic large vessel stroke, 38 with lacunar stroke and 90 with cardioembolic stroke. We studied the relationship between CRP values and short-term prognosis [30-day mortality, length of hospitalization (LOS) and physical disability measured by modified Rankin scale and long-term prognosis (12-month mortality and re-hospitalization)]. RESULTS: Mean values of CRP were significantly higher in patients with cardioembolic stroke compared with atherothrombotic large vessel and lacunar stroke, in patients who died in the first 30 days from the acute event compared with survivors. LOS and physical disability score rose with increasing values of CRP for all subtypes of stroke. Higher CRP values were associated with the 12-month re-hospitalization for cerebrovascular events, whereas it did not influence the 12-month cumulative re-hospitalization and 12-month mortality. CONCLUSIONS: Elevation of CRP values at hospital admission could represent a negative prognostic index in elderly patients with ischaemic stroke, in particular, for short-term prognosis.     

Protein Z in ischaemic stroke

Many risk factors associated with ischaemic stroke are known, including high levels of fibrinogen or factor VII. Protein Z is a vitamin K-dependent coagulation factor, which was found to promote the assembly of thrombin with phospholipid vesicles that might promote coagulation. Indeed, a low protein Z level may be associated with a varying bleeding tendency. Therefore, we hypothesized that high protein Z levels could induce a hypercoagulable state and performed a case-control study to investigate a potential association between high protein Z plasma levels and ischaemic stroke. We measured protein Z in plasma samples from 157 patients with stroke of unknown aetiology and 192 control subjects. All patients had survived an ischaemic stroke or transient ischaemic attack (TIA) for at least 2 months. We found an increased relative risk of ischaemic stroke with increasing protein Z levels, with an odds ratio of 4.3 [95% confidence interval (CI): 1.7--11] for protein Z plasma levels > or = 160%. Excluding patients with a history of venous thromboembolism from the analysis, the same result was obtained (odds ratio 4.2; 95% CI: 1.6--11.2). Using a logistic regression model, this association also remained significant (P = 0.04) after adjustment for established risk factors. Our data indicated that a high plasma level of protein Z is an independent risk factor for ischaemic stroke.     

Hyperthermia is a surrogate marker of inflammation-mediated cause of brain damage in acute ischaemic stroke

The influence of temperature on the outcome observed in experimental models of ischaemic stroke has not been definitively proved in patients with stroke. Interleukin-6 (IL-6) acts as important endogenous pyrogen, and it is an important regulator of spontaneous body temperature during cerebral ischaemia. The objective of this study was to determine, during the acute phase of cerebral ischaemia, the potential relationship between proinflammatory cytokines and hyperthermia as a cause of larger cerebral infarcts. PATIENTS AND METHODS: We studied 229 patients with a first-ever acute hemispheric infarction admitted within the first 24 h from onset of symptoms. On admission, axillary temperature was recorded and blood chemistry studies and cranial computed tomography were performed. We classified body temperature into two groups: hyperthermia (>or=37.5 degrees C) and normothermia (<37.5 degrees C). We determined proinflammatory markers [IL-6, tumour necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule (ICAM-1) and vascular cellular adhesion molecule] on admission. Two outcome variables were evaluated: (i) infarct volume; (ii) Canadian Stroke Scale (CSS) at 3 months (CSS 7 good outcome). RESULTS: Patients with hyperthermia had higher infarct volume [46.5 (9.8-78.5) cm(3) vs. 19.1 (5.0-23.5) cm(3); P < 0.0001], as well as poor outcome at 3 months. Plasma levels of IL-6, TNF-alpha and ICAM-1 were significantly higher in the group of patients with hyperthermia than in the normothermic group. There was a significant correlation between body temperature on admission and infarct volume (r = 0.302; P < 0.0001), and between proinflammatory markers (IL-6 and TNF-alpha) and infarct volume. A significant association was also found between proinflammatory markers (IL-6, TNF-alpha, and ICAM-1) and poor outcome. However, after adjustment for potential confounders, hyperthermia was not independently associated with either larger infarct volume or with poor outcome at 3 months. CONCLUSIONS: Inflammatory mediators play a role in acute ischaemic brain damage independently of hyperthermia.     

The genetics of ischaemic stroke

Abstract. Matarin M, Singleton A, Hardy J, Meschia J (Laboratory of Neurogenetics, Bethesda, MD, USA; UCL Institute of Neurology, London, UK; Mayo Clinic, Jacksonville, FL, USA). The genetics of ischaemic stroke (Review). J Intern Med 2010; 267: 139–155. In this review, we discuss the genetic factors in both the aetiology and treatment of ischaemic stroke. We discuss candidate gene association studies, family linkage studies and the more recent whole genome association studies and whole genome expression studies. We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications.     

Nocturnal urine melatonin and 6-sulphatoxymelatonin excretion at the acute stage of ischaemic stroke

Abstract:  Melatonin's neuroprotective action has been demonstrated in experimental models of brain ischaemia. The relationship between stroke and melatonin levels has been based on scarce and small sample size studies. In addition, the changes have not been correlated with the age of patients. We compared levels of nocturnal urinary melatonin and its metabolite, 6-sulfatoxymelatonin (aMT6S) in a large series of acute ischaemic stroke patients and healthy volunteers. Consecutive ischaemic stroke patients with a first episode of anterior circulation stroke were recruited. Urine samples were collected in 127 patients on day 1 poststroke and in a control population including 216 healthy volunteers, from 20:00 to 08:00 hr. Melatonin and aMT6S were measured by radioimmunoassay. Differences in melatonin and aMT6S levels between ischaemic stroke patients and healthy volunteers were assessed by gender and age categories, using the Student's t -test. Melatonin excretion was decreased in stroke patients compared with healthy volunteers (74.1 ± 13.9 versus 211.9 ± 31.0 ng/hr; P  = 0.0004), whereas aMT6S level was not significantly reduced (6371 ± 1028 versus 4469 ± 508 ng/hr; P  = 0.10). Conversely, the stratification by age showed a significant reduction of both melatonin and aMT6S levels among ischaemic stroke patients over 70 yr ( P  = 0.001 and P  = 0.03 respectively). The impact of melatonin at the acute stage of stroke on clinical severity and lesion size needs further assessment, as melatonin may have potential neuroprotective effects.