Progression in acute stroke: value of the initial NIH stroke scale score on patient stratification in future trials.

BACKGROUND AND PURPOSE: The objective was to determine the occurrence of neurological changes during the first 48 hours after acute stroke as it relates to initial stroke severity. METHODS: The National Institutes of Health Stroke Scale (NIHSS) was performed serially for the first 48 hours on 127 consecutive ischemic stroke patients (129 strokes) admitted to the neuroscience intensive care unit. Incidence of stroke progression (a >/=3-point increase on the NIHSS) was recorded and analysis performed to determine its association with initial stroke severity and other demographic and physiological variables. Deficit resolution by 48 hours, defined as an NIHSS score of 0 or 1, measured the frequency of functional recovery predicted by the initial deficit. RESULTS: Overall progression was noted in 31% of events (40/129). Applying Bayes' solution to the observed frequency of worsening, the greatest likelihood of predicting future patient progression occurs with stratification at NIHSS scores of 7. Patients with an initial NIHSS of 7 with a 65.9% (27/41) worsening rate (P<0.000005). Forty-five percent (40/88) of those with an initial score of 7 returned to a normal examination within this period (chi2, P<0.000005). CONCLUSIONS: This study suggests that the early clinical course of the neurological deficit after acute stroke is dependent on the initial stroke severity and that a dichotomy in early outcome exists surrounding an initial NIHSS score of 7. These findings may have significant implications for the design and patient stratification in treatment protocols with respect to primary clinical outcome.     

Imaging the future of stroke: I. Ischemia

Envisioning the future of stroke appears daunting considering the milestones already achieved in stroke imaging. A historical perspective on the developments in stroke care provides a striking narrative of how imaging has transformed diagnosis, therapy, and prognosis of cerebrovascular disorders. Multimodal imaging techniques such as CT and MRI, incorporating parenchymal depictions, illustration of the vasculature, and perfusion data, can provide a wealth of information regarding ischemic pathophysiology. Key elements of ischemic pathophysiology depicted with imaging include vascular occlusion, compensatory collateral flow, resultant hemodynamic conditions that reflect these sources of blood flow, and the neurovascular injury that ensues. The mantra of “time is brain” has been perpetuated, but this does not provide an entirely accurate reflection of ischemic pathophysiology and imaging insight shows far more than time alone. Maximizing the potential of perfusion imaging will continue to expand the nascent concept that cerebral ischemia may be completely reversible in certain scenarios. Novel modalities provide a fertile ground for discovery of therapeutic targets and the potential to assess effects of promising strategies. Beyond clinical trials, imaging has become a requisite component of the neurological examination enabling tailored stroke therapy with the use of detailed neuroimaging modalities. In this first article on ischemia, the focus is on the most recent imaging advances and exploring aspects of cerebral ischemia where imaging may yield additional therapeutic strategies. A subsequent article will review recent and anticipated imaging advances in hemorrhage. These thematic overviews underscore that imaging will undoubtedly continue to dramatically shape the future of stroke. Ann Neurol 2009;66:574–590     

The experiences of an acute stroke unit--implications for multicentre acute stroke trials.

The suitability of 200 consecutive patients admitted to a newly established acute stroke unit was assessed for participation in two multicentre trials currently in their pilot phase: the International Stroke Trial of aspirin and heparin, and the Multicentre Acute Stroke Trial of streptokinase versus placebo. Of the 200 patients (74 men, 126 women, mean age 71 years), 96% had cerebral CT, and 94% had a final diagnosis of cerebrovascular disease. Overall, 50% of patients presented within 6 hours and 70% within 12 hours of the onset of ictus. A total of 113 patients (56.5%) were potentially eligible for trial treatment with aspirin/heparin. Only 9 patients (4.5%) were eligible for streptokinase treatment: 50% were excluded because they presented after 6 hours; 23% had a previous stroke with clinical sequelae and 23% had severe systemic illness. Forty eight per cent of patients had more than one exclusion criterion. The potentially high enrollment rates in trials of antithrombotic agents contrast with the restricted recruitment for trials of streptokinase, emphasising the need for multiple centres to achieve useful study enrollment.     

The stroke trials directory: An online registry of clinical trials in cerebrovascular disease

The Stroke Trials Directory is a freely accessible Web-based database of ongoing and completed stroke clinical trials, provided as a service of the Internet Stroke Center at Washington University //www.strokecenter.org. The Web site presently includes some 505 trials testing over 200 therapeutic interventions for cerebrovascular disease prevention, treatment, or recovery. Trial information is extensively cross-linked with other online resources, including the National Library of Medicine's PubMed and ClinicalTrials.gov sites, the Cochrane Collaboration, conference abstracts, and individual trial Web sites. We describe goals and design of the Stroke Trials Directory, and outline selected listings for current trials of antithrombotic agents in stroke prevention.     

Oxidative stress in the context of acute cerebrovascular stroke

BACKGROUND AND PURPOSE: Free radical generation and consequent oxidative stress in thrombotic cerebrovascular stroke have a distinctive role in the pathogenesis of ischemic brain injury. One of the potential injurious effects of homocyst(e)ine in occlusive vascular diseases is free radical generation. In the current study, we investigated the status of oxidant stress in the acute phase of thrombotic cerebrovascular stroke and the possible role of homocyst(e)ine. METHODS: We determined levels of plasma homocyst(e)ine, lipid peroxide, ascorbic acid, superoxide dismutase, and nitric oxide in 30 patients with thrombotic cerebrovascular stroke within 2 days of the onset of the attack as well as in 22 healthy volunteers of comparable age and gender. RESULTS: Statistically significant elevation of homocyst(e)ine (P<0. 001), lipid peroxide (P<0.001), and nitric oxide (P<0.001) plasma levels were observed in stroke patients compared with healthy controls. On the other hand, the antioxidant ascorbic acid plasma levels were significantly lower in the patient group compared with healthy control subjects (P<0.001). Meanwhile, superoxide dismutase plasma levels were not statistically different in either groups. The study also revealed a significant and strong positive correlation between homocyst(e)ine and lipid peroxide (r=0.85, P<0.001). Ascorbic acid plasma levels were significantly negatively correlated with both homocyst(e)ine (r=-0.875, P<0.001) and lipid peroxide (r=-0.576, P<0.001). The nitric oxide level was positively correlated with superoxide dismutase (r=0.396, P<0.05). CONCLUSIONS: We conclude that hyperhomocyst(e)inemia is a possible causal factor in free radical generation during the acute phase of thrombotic cerebrovascular stroke. Pharmacological intervention could potentially be beneficial in this setting and warrants further evaluation.     

Pharmacological therapies in post stroke recovery: recommendations for future clinical trials

Stroke is a leading cause of serious long-term disability in adults and is the second leading cause of death worldwide. Early reperfusion and neuroprotection techniques have been the focus of much effort with the aim of very acute treatment of the stroke. Targeting different mechanisms, pharmacological therapies have the potential to reduce disability in a large fraction of patients who survive the acute stroke. The brain’s capacity to reorganize after stroke through plasticity mechanisms can be modulated by pharmacological agents. A number of therapeutic interventions are under study, including small molecules, growth factors, and monoclonal antibodies. Recently it has been shown that the SSRI fluoxetine improved motor deficit in patients with ischaemic stroke and hemiplegia which appeared to be independent of the presence of depression. In this context, it is of major importance to support innovative research in order to promote the emergence of new pharmacological treatments targeting neurological recovery after stroke, as opposed to acute de-occlusion and neuroprotection. This paper is the work of a group of 14 scientists with aim of (1) addressing key areas of the basic and clinical aspects of human brain plasticity after stroke and potential pharmacological targets for recovery, (2) asking questions about the most appropriate characteristics of clinical trials testing drugs in post stroke recovery and (3) proposing recommendations for future clinical trials.     

Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials

The concept of neuroprotective therapy for acute ischemic stroke to salvage tissue at risk and improve functional outcome is based on sound scientific principles and extensive preclinical animal studies demonstrating efficacy. The failure of most neuroprotective drugs in clinical trials has been due to inadequate preclinical testing and flawed clinical development programs. The Stroke Therapy Academic Industry Roundtable (STAIR) group has outlined rational approaches to preclinical and clinical studies. The positive results from the first Stroke-Acute-Ischaemic-NXY-Treatment (SAINT-I) trial of the free-radical spin-trap drug, NXY-059, which followed many of the STAIR guidelines, reinvigorated enthusiasm in neuroprotection, but the SAINT-II trial did not replicate the positive effect on the same primary prespecified outcome measure. This has led to concerns about the future of neuroprotection as a therapeutic strategy for acute ischemic stroke. We discuss new suggestions to bridge the chasm between preclinical animal modeling and acute human stroke trials to potentially enhance the future assessment of novel neuroprotective drugs.     

NINDS clinical trials in stroke: lessons learned and future directions

Since 1977 the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) has sponsored 28 phase 3 trials to evaluate treatments of stroke, which when all completed will have randomized a total of 44 862 patients in the United States and other countries. NINDS stroke clinical trials have been successful in finding beneficial and cost-effective treatments for cerebrovascular disease. Future trials are likely to be larger and have simpler designs which allow for the inclusion of more patients and which collect less data for each patient. In addition, measures of cognitive outcomes, particularly timed tests of executive function, disability scales, and quality-of-life outcomes will become more common. The stroke research community can take pride in the solid base of evidence that has been built over the past 2 decades. If we continue to follow the discoveries of science, continue to create new trial methodology, and increase participation in clinical trials, significant advances in the treatment of cerebrovascular disease will continue.     

Extending the time window for thrombolysis: evidence from acute stroke trials

Data from intravenous tissue plasminogen activator studies have shown rapidly diminishing clinical benefit beyond 3 hours when noncontrast CT is used for treatment triage. Newer trials, such as the Desmoteplase in Acute Ischemic Stroke trial, have now successfully pushed the time window out to 9 hours using the concept of penumbral imaging and treatment of the perfusion-diffusion mismatch. Advanced imaging with CT or MR imaging protocols is providing a means for rational physiologic selection and outcomes assessment in stroke treatment.     

PET imaging in ischemic cerebrovascular disease: current status and future directions

Cerebrovascular diseases are caused by interruption or significant impairment of the blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphological damage. These pathophysiological changes can be assessed by positron emission tomography (PET), which permits the regional measurement of physiological parameters and imaging of the distribution of molecular markers. PET has broadened our understanding of the flow and metabolic thresholds critical for the maintenance of brain function and morphology: in this application, PET has been essential in the transfer of the concept of the penumbra (tissue with perfusion below the functional threshold but above the threshold for the preservation of morphology) to clinical stroke and thereby has had great impact on developing treatment strategies. Radioligands for receptors can be used as early markers of irreversible neuronal damage and thereby can predict the size of the final infarcts; this is also important for decisions concerning invasive therapy in large (“malignant”) infarctions. With PET investigations, the reserve capacity of blood supply to the brain can be tested in obstructive arteriosclerosis of the supplying arteries, and this again is essential for planning interventions. The effect of a stroke on the surrounding and contralateral primarily unaffected tissue can be investigated, and these results help to understand the symptoms caused by disturbances in functional networks. Chronic cerebrovascular disease causes vascular cognitive disorders, including vascular dementia. PET permits the detection of the metabolic disturbances responsible for cognitive impairment and dementia, and can differentiate vascular dementia from degenerative diseases. It may also help to understand the importance of neuroinflammation after stroke and its interaction with amyloid deposition in the development of dementia. Although the clinical application of PET investigations is limited, this technology had and still has a great impact on research into cerebrovascular diseases.     

Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials.

A formal statistical overview of all truly randomised trials was undertaken to determine whether antithrombotic therapy is effective and safe in the early treatment of patients with acute stroke. There were 15 completed randomised controlled trials of the value of early antithrombotic treatment in patients with acute stroke. The regimes tested in acute presumed or confirmed ischaemic stroke were: heparin, 10 trials with 1047 patients: oral anticoagulants, one trial with 51 patients: antiplatelet therapy, three trials with 103 patients. Heparin was tested in one trial with 46 patients with acute haemorrhagic stroke. Outcome measures were deep venous thrombosis (confirmed by I125 scanning or venography), pulmonary embolism, death from all causes, haemorrhagic transformation of cerebral infarction, level of disability in survivors. In patients with acute ischaemic stroke, allocation to heparin was associated with a highly significant 81% (SD 8, 2p < 0.00001) reduction in deep venous thrombosis detected by I125 fibrinogen scanning or venogram. Only three trials systematically identified pulmonary emboli, which occurred in 6/106 (5.7%) allocated control vs 3/132 (2.3%) allocated heparin, a non-significant 58% reduction (SD 45.7, 2p > 0.1). There were relatively few deaths in the trials in patients with presumed ischaemic stroke: 94/485 (19.4%) among patients allocated to the control group vs 79/497 (15.9%) among patients who were allocated heparin. The observed 18% (SD 16) reduction in the odds of death was not statistically significant. The least biased estimated of the effect of treatment on haemorrhagic transformation of the cerebral infarct (HTI) comes from trials where all patients were scanned at the end of treatment, irrespective of clinical deterioration; using this analysis, haemorrhagic transformation occurred in 7/102 (6.9%) control vs 8/106 (7.5%) treated, a non-significant 12% increase (SD 56, 2p > 0.1). These data cannot exclude the possibility that heparin substantially increases the risks of HTI. No data on disability in survivors could be obtained. Early heparin treatment might be associated with substantial reductions in deep venous thrombosis (and probably also pulmonary embolism) and possibly a one fifth reduction in mortality (equivalent to the avoidance of 20-40 early deaths per thousand patients treated.) However, the data were wholly inadequate on safety, particularly on the risk of haemorrhagic transformation of the infarct and on the hazards of heparin therapy in patients with known intracerebral haemorrhage. The trials of oral anticoagulants (15 deaths among 57 patients) and antiplatelet therapy (two deaths among 103 patients) were too small to be informative. Much larger randomized trials-comparing aspirin, heparin and the combination of both drugs against control-in patients with acute ischaemic stroke are justified (and several are now planned or underway).     

Rasch analysis of the upper-limb subscale of the stroke rehabilitation assessment of movement (STREAM) tool in an acute stroke cohort Rasch analysis of the upper-limb subscale of the STREAM tool in an acute stroke population

Background: Stroke is a leading cause of disability worldwide. The most common impairment resulting from stroke is upper-limb weakness.

Objectives: To determine the usefulness and psychometric validity of the upper-limb subscale of the STREAM in an acute stroke population.

Methods: Rasch Analysis, including unidimensionality assumption testing, determining model fit, and analysis of: reliability, residual correlations, and differential item functioning.

Results: 125 individuals were assessed using the upper-limb subscale of the Stroke Rehabilitation Assessment of Movement (STREAM) tool. Rasch analysis suggests the STREAM is a unidimensional measure. However, when scored using the originally proposed method (0–2), or using the response pattern (0–5) neither variant fit the Rasch model (p < 0.05). Although, the reliability was good (Person-Separation Index – 0.847 and 0.903, respectively). Correcting for the disordered thresholds, and thereby producing the new scoring pattern, led to substantial improvement in the overall fit (chi-square probability of fit – 22%), however, the reliability was slightly reduced (PSI – 0.806).

Conclusions: The study proposes a new scoring method for the upper-limb subscale of the STREAM outcome measure in the acute stroke population.