The molecular basis of thrombolysis and its clinical application in stroke.

The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them.

Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. METHODS: In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and, when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533. FINDINGS: All patients were included in the analyses. The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to 2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI 2.40-7.27). INTERPRETATION: These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results. FUNDING: Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network.

WITHDRAWN: Surgery for cervical radiculomyelopathy.

BACKGROUND: Cervical spondylosis causes pain and disability by compressing the spinal cord or roots. Surgery to relieve the compression may reduce the pain and disability, but is associated with a small but definite risk. We sought to assess the balance of risk and benefit from surgery. OBJECTIVES: To determine whether: 1) surgical treatment of cervical radiculopathy or myelopathy is associated with improved outcome, compared with conservative management and 2) timing of surgery (immediate or delayed upon persistence/progression of relevant symptoms and signs) has an impact on outcome. SEARCH STRATEGY: We searched Medline (between 1966 and 1998), Embase (between 1980 and 1998) and the Cochrane Controlled Trials Register. Authors of the identified randomised controlled trials were contacted to detect any additional published or unpublished data. SELECTION CRITERIA: All unconfounded truly or quasi-randomised controlled trials allocating patients with cervical radiculopathy or myelopathy to 1) "best medical management" or "decompressive surgery (with or without some form of fusion) plus best medical management" 2) "early decompressive surgery" or "delayed decompressive surgery". DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Two trials involving a total of 130 patients were included. One trial with 81 patients compared surgical decompression with either physiotherapy or cervical collar immobilization in patients with cervical radiculopathy. The short-term effects of surgery, in terms of pain, weakness or sensory loss were superior, however, at one year no significant differences between groups were present. One trial with 49 patients compared the effects of surgery with those of conservative treatment in patients with mild functional deficit associated with cervical myelopathy. No significant differences were observed between groups, up to two years following treatment. AUTHORS' CONCLUSIONS: The available small randomised trials do not provide reliable evidence on the effects of surgery for cervical spondylotic radiculopathy or myelopathy. It is not clear whether the short-term risks of surgery are offset by any long-term benefits.

Geographical access to imaging facilities for stroke patients in Scotland.

This study examines the geographical access to imaging facilities for suspected stroke patients in Scotland. A survey of Scottish clinical directors of radiology was initially undertaken to determine the current and future provision of brain imaging for the diagnosis of stroke. We analysed geographical and digital population data with geographical information systems software to determine access to brain imaging services for stroke patients during 'normal' working hours and 'out-of-hours'. The findings suggest that, in general, most departments are able to deliver scanning for stroke as set within current guidelines, at least in normal working hours. However, radiological departments are generally operating at full capacity, and there is restricted availability of scanning services for stroke in certain regions during weekend periods. It is vital that policy makers consider these findings when reviewing the guidelines for recommending scanning for stroke.

Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).

BACKGROUND: The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data. METHODS: We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). FINDINGS: Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47, 0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44-1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001). INTERPRETATION: The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.

What is the best imaging strategy for acute stroke?

OBJECTIVES: To determine the cost-effectiveness of computed tomographic (CT) scanning after acute stroke. To assess the contribution of brain imaging to the diagnosis and management of stroke, and to estimate the costs, benefits and risks of different imaging strategies in order to provide data to inform national and local policy on the use of brain imaging in stroke. DESIGN: A decision-analysis model was developed to represent the pathway of care in acute stroke using 'scan all patients within 48 hours' as the comparator against which to cost 12 alternative scan strategies. SETTING: Hospitals in Scotland. PARTICIPANTS: Subjects were patients admitted to hospital with a first stroke and those managed as outpatients. INTERVENTIONS: The effect on functional outcome after ischaemic or haemorrhagic stroke, tumours or infections, of correctly administered antithrombotic or other treatment; of time to scan and stroke severity on diagnosis by CT or MRI; on management, including length of stay, functional outcome, and quality-adjusted life years (QALYs), of the diagnostic information provided by CT scanning; the cost-effectiveness (cost versus QALYs) of different strategies for use of CT after acute stroke. MAIN OUTCOME MEASURES: Death and functional outcome at long-term follow-up; accuracy of CT and MRI; cost of CT scanning by time of day and week; effect of CT diagnosis on change in health outcome, length of stay in hospital and QALYs; cost-effectiveness of various scanning strategies. RESULTS: CT is very sensitive and specific for haemorrhage within the first 8 days of stroke only. Suboptimal scanning used in epidemiology studies suggests that the frequency of primary intracerebral haemorrhage (PICH) has been underestimated. Aspirin increases the risk of PICH. There were no reliable data on functional outcome or on the effect of antithrombotic treatment given long term after PICH. In 60% of patients with recurrent stroke after PICH, the cause is another PICH and mortality is high among PICH patients. A specific MR sequence (gradient echo) is required to identify prior PICH reliably. CT scanners were distributed unevenly in Scotland, 65% provided CT scanning within 48 hours of stroke, and 100% within 7 days for hospital-admitted patients, but access out of hours was very variable, and for outpatients was poor. The average cost of a CT brain scan for stroke was pounds 30.23 to pounds 89.56 in normal working hours and pounds 55.05 to pounds 173.46 out of hours. Average length of stay was greatest for severe strokes and those who survived in a dependent state. For a cohort of 1000 patients aged 70-74 years, the policy 'scan all strokes within 48 hours', cost pounds 10,279,728 and achieved 1982.3 QALYS. The most cost-effective strategy was 'scan all immediately' (pounds 9,993,676 and 1982.4 QALYS). The least cost-effective was to 'scan patients on anticoagulants, in a life-threatening condition immediately and the rest within 14 days'. CONCLUSIONS: In general, strategies in which most patients were scanned immediately cost least and achieved the most QALYs, as the cost of providing CT (even out of hours) was less than the cost of inpatient care. Increasing independent survival by even a small proportion through early use of aspirin in the majority with ischaemic stroke, avoiding aspirin in those with haemorrhagic stroke, and appropriate early management of those who have not had a stroke, reduced costs and increased QALYs.

Very early risk of stroke after a first transient ischemic attack.

BACKGROUND AND PURPOSE: The commonly quoted early risks of stroke after a first transient ischemic attack (TIA)-1% to 2% at 7 days and 2% to 4% at 1 month-are likely to be underestimates because of the delay before inclusion into previous studies and the exclusion of patients who had a stroke during this time. Therefore, it is uncertain how urgently TIA patients should be assessed. We used data from the Oxford Community Stroke Project (OCSP) to estimate the very early stroke risk after a TIA and investigated the potential effects of the delays before specialist assessment. METHODS: All OCSP patients who had a first-ever definite TIA during the study period (n=209) were included. Three analyses were used to estimate the early stroke risk after a first TIA starting from 3 different dates: assessment by a neurologist, referral to the TIA service, and onset of first TIA. RESULTS: The stroke risk from assessment by a neurologist was 1.9% [95% confidence interval (CI), 0.1 to 3.8] at 7 days and 4.4% (95% CI, 1.6 to 7.2) at 30 days. The 7- and 30-day stroke risks from referral were 2.4% (95% CI, 0.3 to 4.5) and 4.9% (95% CI, 1.9 to 7.8), respectively, and from onset of first-ever TIA were 8.6% (95% CI, 4.8 to 12.4) and 12.0% (95% CI, 7.6 to 16.4), respectively. CONCLUSIONS: The early risk of stroke from date of first-ever TIA is likely to be higher than commonly quoted. Public education about the symptoms of TIA is needed so that medical attention is sought more urgently and stroke prevention strategies are implemented sooner.

Internet resources for neurologists.

This fourth and final review in the JNNP internet series summarises the essential internet resources for adult and paediatric clinical neurology, neuroradiology, and neurophysiology. This article is freely available on the JNNP website (www.jnnp.com), where-within seconds-the complete list of recommended websites can be easily downloaded and incorporated into your web browser as a Bookmark/Favorite file. The further progress of clinical neurology on the world wide web will be monitored in JNNP Neuronline fillers and JNNP Neurology in Practice supplements.

Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis.

BACKGROUND AND PURPOSE: Recombinant tissue plasminogen activator (rtPA; Actilyse) is not as widely used in clinical practice as it could be. Have new data since 1995 strengthened the evidence sufficiently to justify more widespread use of rtPA? METHODS: We performed a sequential year-to-year cumulative meta-analysis of randomized controlled trials of rtPA in acute ischemic stroke. RESULTS: Although the amount of data has doubled since 1995, effect estimates for key outcomes remain imprecise, and significant between-trial heterogeneity persists. In the most recent analysis, rtPA up to 6 hours after stroke yielded 55 fewer dead or dependent people per 1000 treated (95% CI, 18 to 92) despite some risk (nonsignificant excess of 19 deaths per 1000 patients treated; 95% CI, 6 fewer to 48 more). Severity of stroke, patient age, and aspirin use were possible sources of heterogeneity. CONCLUSIONS: Despite doubling of the data since 1995, the magnitude of risks and benefits with rtPA remains imprecise. This gap in knowledge may be hindering clinical use of rtPA and can be filled only by new trials designed to address these specific issues.

Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?

BACKGROUND: The pathogenesis of and relationship between small deep (lacunar) infarcts, cerebral white matter disease (leukoaraiosis or white matter hyperintensities), and progressive cognitive impairment or dementia are much debated. SUMMARY OF COMMENT: We hypothesize that cerebral small-vessel endothelial (ie, blood-brain barrier) dysfunction, with leakage of plasma components into the vessel wall and surrounding brain tissue leading to neuronal damage, may contribute to the development of 3 overlapping and disabling cerebrovascular conditions: lacunar stroke, leukoaraiosis, and dementia. This hypothesis could explain the link between ischemic cerebral small-vessel disease and several apparently clinically distinct dementia syndromes. This hypothesis is supported by pathological, epidemiological, and experimental studies in lacunar stroke and leukoaraiosis and observations on the blood-brain barrier with MRI. We suspect that the potential significance of blood-brain barrier failure as a pathogenetic step linking vascular disease with common, disabling brain diseases of insidious onset has been overlooked. For example, lipohyalinosis, which has a pathological appearance of uncertain origin and is possibly responsible for some discrete lacunar infarcts, may be one end of a clinical spectrum of illness manifested by blood-brain barrier failure. CONCLUSIONS: Proof that blood-brain barrier failure is key to these conditions could provide a target for new treatments to reduce the effects of vascular disease on the brain and prevent cognitive decline and dementia.

Visible infarction on computed tomography is an independent predictor of poor functional outcome after stroke, and not of haemorrhagic transformation.

OBJECTIVES: To examine a very large dataset to provide a robust answer to the question of whether visible infarction on computed tomography was (a) an independent predictor of functional outcome at all times up to 48 hours after stroke, and (b) independently associated with haemorrhagic transformation, with or without antithrombotic treatment. METHODS: The study assessed associations between visible infarction, time to randomisation, baseline neurological deficit, stroke syndrome, allocated aspirin or heparin treatment, recurrent haemorrhagic stroke, early death and six month functional outcome in the International Stroke Trial. RESULTS: Of 12 550 patients, 6267 (50%) had visible infarction up to 48 hours after stroke. The prevalence of visible infarction increased with increasing time from onset and extent of the stroke syndrome. Visible infarction was independently associated with increased death within 14 days (odds ratio (OR) 1.17, 95% CI 1.02 to 1.35), and of death or dependency at six months (OR 1.42, 95% CI 1.31 to 1.55), an absolute increase of 13%, or 130 per 1000 more dead or dependent patients with visible infarction than without it. There was no significant independent relation between visible infarction and fatal or non-fatal haemorrhagic transformation, or interaction between visible infarction and aspirin or heparin treatment allocation with six month functional outcome. CONCLUSIONS: Visible infarction on computed tomography up to 48 hours after stroke is an independent adverse prognostic sign.

Surgery for cervical radiculomyelopathy.

BACKGROUND: Cervical spondylosis causes pain and disability by compressing the spinal cord or roots. Surgery to relieve the compression may reduce the pain and disability, but is associated with a small but definite risk. We sought to assess the balance of risk and benefit from surgery. OBJECTIVES: To determine whether: 1) surgical treatment of cervical radiculopathy or myelopathy is associated with improved outcome, compared with conservative management and 2) timing of surgery (immediate or delayed upon persistence/progression of relevant symptoms and signs) has an impact on outcome. SEARCH STRATEGY: We searched Medline (between 1966 and 1998), Embase (between 1980 and 1998) and the Cochrane Controlled Trials Register. Authors of the identified randomised controlled trials were contacted to detect any additional published or unpublished data. SELECTION CRITERIA: All unconfounded truly or quasi-randomised controlled trials allocating patients with cervical radiculopathy or myelopathy to 1) "best medical management" or "decompressive surgery (with or without some form of fusion) plus best medical management" 2) "early decompressive surgery" or "delayed decompressive surgery". DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Two trials involving a total of 130 patients were included. One trial with 81 patients compared surgical decompression with either physiotherapy or cervical collar immobilization in patients with cervical radiculopathy. The short-term effects of surgery, in terms of pain, weakness or sensory loss were superior, however, at one year no significant differences between groups were present. One trial with 49 patients compared the effects of surgery with those of conservative treatment in patients with mild functional deficit associated with cervical myelopathy. No significant differences were observed between groups, up to two years following treatment.

Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial.

BACKGROUND AND PURPOSE: We sought to investigate the apparently high risk of early death after an ischemic stroke among patients with atrial fibrillation (AF), identify the main factors associated with early death, and assess the effect of treatment with different doses of subcutaneous unfractionated heparin (UFH) given within 48 hours. METHODS: We studied the occurrence of major clinical events within 14 days among 18 451 patients from the International Stroke Trial, first for all treatment groups combined. Then, among patients with AF, we examined the effects of treatment with subcutaneous UFH started within 48 hours and continued until 14 days after stroke onset. RESULTS: A total of 3169 patients (17%) had AF. Seven hundred eighty-four patients were allocated to UFH 12 500 IU SC BID, 773 to UFH 5000 IU SC BID, and 1612 to no heparin. Within each of these groups, half of the patients were randomly assigned to aspirin 300 mg once daily. Compared with patients without AF, patients with AF were more likely to be female (56% versus 45%), to be old (mean age, 78 versus 71 years), to have an infarct on prerandomization CT (57% versus 47%), and to have impaired consciousness (37% versus 20%). The initial ischemic stroke type was more often a large-artery infarct (36% versus 21%). A lacunar stroke syndrome was less common (13% versus 26%). Death within 14 days was more common in patients with AF (17% versus 8%) and more often attributed to neurological damage from the initial stroke (10% versus 4%). The frequency of recurrent ischemic or undefined stroke was not significantly different (3.9% versus 3.3%). The proportion of AF patients with further events within 14 days allocated to UFH 12 500 IU (n=784), UFH 5000 IU (n=773), and to no-heparin (n=1612) groups were as follows: ischemic stroke, 2.3%, 3.4%, 4.9% (P=0.001); hemorrhagic stroke, 2.8%, 1.3%, 0.4% (P<0.0001); and any stroke or death, 18.8%, 19.4% and 20.7% (P=0.3), respectively. No effect of heparin on the proportion of patients dead or dependent at 6 months was apparent. CONCLUSIONS: Acute ischemic stroke patients with AF have a higher risk of early death, which can be explained by older age and larger infarcts but not by a higher risk of early recurrent ischemic stroke, although slightly more patients with AF died from a fatal recurrent stroke of ischemic or unknown type (1.3% versus 0.9%). In patients with AF the absolute risk of early recurrent stroke is low, and there is no net advantage to treatment with heparin. These data do not support the widespread use of intensive heparin regimens in the acute phase of ischemic stroke associated with AF.

Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: occlusion or other vascular pathology?

Lacunar infarction is associated with distinct clinical features. It is thought to result from occlusion of a deep perforating artery in the basal ganglia, centrum semiovale, or brain stem. However, occluded perforating arteries have only rarely been observed at postmortem in patients with lacunar stroke and have not been noted previously on imaging despite the increasing sophistication of the techniques. We observed nine patients with lacunar stroke imaged with computed tomography and magnetic resonance imaging in whom we observed a linear structure with density or signal features consistent with an occluded (or at least abnormal) perforating artery associated with the relevant lacunar infarct. The appearance might also have been caused by a leak of blood and fluid into the perivascular space around the artery, as in several patients the width of the tubular vessel-like structure (>1 mm in diameter) was greater than the expected width of a perforating artery (<0.8 mm in diameter). This interpretation is supported by the fact that the area of infarction was usually around the abnormal vessel, not at the end of it. We describe the patients' clinical and imaging features, and discuss alternative explanations for the imaging appearance and the implications for gaining insights into the cause of lacunar infarction.

Variations between countries in outcome after stroke in the International Stroke Trial (IST).

BACKGROUND AND PURPOSE: This study describes the large variations in outcome after stroke between countries that participated in the International Stroke Trial and seeks to define whether they could be explained by variations in case mix or by other factors. METHODS: We analyzed data from the 15 116 patients recruited in Argentina, Australia, Italy, the Netherlands, Norway, Poland, Sweden, Switzerland, and the United Kingdom: We compared crude case fatality and the proportion of patients dead or dependent at 6 months; we used logistic regression to adjust for age, sex, atrial fibrillation, systolic blood pressure, level of consciousness, and number of neurological deficits. We used the frequency of prerandomization head CT scan and prescription of aspirin at discharge to indicate quality of care. RESULTS: The differences in outcome (all treatment groups combined) between the "best" and "worst" countries were very large for death (171 cases per 1000 patients) and for death or dependency (375 cases per 1000 patients). The differences were somewhat smaller after adjustment for case mix (160 and 311 cases per 1000 patients, respectively). Process of care may have accounted for some but not all of the residual variation in outcome. CONCLUSIONS: Adjustment for case mix explained only some of the variation in outcome between countries. The residual differences in outcome were too large to be explained by variations in care and most likely reflect differences in unmeasured baseline factors. These findings demonstrate the need to achieve balance of treatment and control within each country in multinational randomized controlled stroke trials and the need for caution in the interpretation of nonrandomized comparisons of outcome after stroke between countries.