Magnetic resonance perfusion diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date

Background

The mismatch between perfusion and diffusion lesions on magnetic resonance perfusion‐weighted imaging (PWI)/diffusion‐weighted imaging (DWI) may help identify patients for thrombolysis. Evidence underlying this hypothesis was assessed.

Methods

All papers describing magnetic resonance PWI/DWI findings in patients with acute ischaemic stroke, and their functional and/or radiological outcome at 1 month, with or without thrombolysis were systematically reviewed.

Results

11 papers fulfilled the inclusion criteria. Among these, there were 5 different mismatch definitions and at least 7 different PWI methods. Only 3 papers including 61 patients with and 18 without mismatch provided data on mismatch, outcome and influence of thrombolysis. Mismatch (v no mismatch) without thrombolysis was associated with a non‐significant twofold increase in the odds of infarct expansion (odds ratio (OR) 2.2, 95% confidence interval (CI) 0.34 to 14.1), which did not change with thrombolysis (OR 2.0, 95% CI 0.37 to 10.9). Half of the patients without mismatch also had infarct growth (with or without thrombolysis). No data were available on functional outcome.

Conclusions

Standardised definitions of mismatch and perfusion are needed. Infarct growth may occur even in the absence of mismatch. Currently, data available on mismatch are too limited to guide thrombolysis in routine practice. More data are needed from studies including patients with and without mismatch, and randomised treatment allocation, to determine the role of mismatch.Ischaemic stroke is a global problem, for which few acute treatments are available. Thrombolysis has to be given rapidly and, when guided by plain computed tomography scan of the brain, carries a risk of intracranial haemorrhage. Imaging the mismatch between diffusion‐weighted imaging (DWI) and perfusion‐weighted imaging (PWI) on magnetic resonance imaging (MRI) (or presumed reversible ischaemia on computed tomography perfusion¹) might help identify patients with tissue at risk of infarction (even beyond the current 3 h time window), thereby avoiding thrombolysis in those with little chance of benefit.^2,3 These techniques are used increasingly where technology is available, and in acute‐stroke trials (http://www.strokecenter.org/trials).⁴The increasing use of this approach in trials and routine practice suggests that there are clear definitions of what constitutes mismatch and substantial evidence to justify its use. However, it is now known that the DWI lesion is not irreversible (initial DWI lesions may disappear spontaneously or after thrombolysis⁵), and that the appearance of PWI lesion depends on which of the many methods were used to calculate it. Different perfusion parameters (eg, mean transit time (MTT), regional cerebral blood flow⁶ and arterial input function⁷) give different perfusion lesion volumes in the same patient. Thus, it is unclear whether the presence (v absence) of mismatch affects prognosis. If mismatch is to be used to select patients for treatment, then the key point is to determine whether thrombolysis has a greater effect in the presence than in the absence of mismatch. This requires a randomised controlled trial in which patients with and without mismatch are randomly selected to receive thrombolysis or control treatment, an expensive and difficult undertaking given the large sample size needed.⁸As there is already a considerable body of literature available on the magnetic resonance mismatch concept, we undertook this systematic review to assess all current evidence on the effect of magnetic resonance PWI/DWI mismatch in patients with acute ischaemic stroke on outcome (clinical and radiological) and whether this is modified by thrombolysis. We set rigorous prespecified inclusion and exclusion criteria based on scientific principles for observational studies and randomised trials to minimise bias.     

Alteplase and ischaemic stroke: have new reviews of old data helped?

BACKGROUND: Thrombolysis for stroke is still not widely used as current recommendations restrict treatment to selected patients. In general, these are patients who can be assessed quickly by specialised stroke teams, have intracranial haemorrhage excluded by appropriate brain imaging, and are treated with alteplase (recombinant tissue plasminogen activator; rt-PA) within 3 h of symptom onset. There is, however, still much debate regarding the scope of treatment and the reorganisation of services required to support an effective service. RECENT DEVELOPMENTS: Two recent publications have helped clarify some issues. The first was an individual-patient data meta-analysis of the alteplase trials. These analyses suggest treatment effects beyond the usual 3 h time window, but other than time to treatment no other factors influenced the effects of treatment. The second publication was a reanalysis of the original National Institute of Neurological Disorders and Stroke (NINDS) alteplase trial, done after criticism of the original study. The reanalysis confirmed that there was significant baseline imbalance of stroke severity between treatment and control groups in the NINDS trial, but established that this did not materially affect the positive results of the trial. However, the recording of blood pressure in the study was found to be inconsistent and therefore unsuitable for reanalysis. The previously published data on recommendations for blood-pressure control, arising from the NINDS trial, needs to be reconsidered in this light. Both studies included too few patients to provide reliable data on which clinical and radiological features influence the response to alteplase. WHERE NEXT?: The individual-patient data meta-analysis and reanalysis of the NINDS trial have probably exhausted the potential of previous trials to answer questions on the effects of thrombolysis. Further randomised trials comparing thrombolysis with control will be required to determine whether elderly people benefit from treatment or whether there are worthwhile benefits from alteplase beyond 3 h (and in such patients, whether advanced magnetic resonance imaging is an effective way to select those most likely to benefit). Various new approaches to reperfusion also require assessment in large-scale trials: new thrombolytic drugs, the combination of intravenous and intra-arterial thrombolytic drugs, combinations of thrombolytics with new antiplatelet agents, and augmentation of thrombolysis either with mechanical devices or with transcranial ultrasound.     

Randomized controlled trial of supervised exercise to evaluate changes in cardiac function in patients with peripheral atherosclerotic disease

INTRODUCTION: Peripheral atherosclerotic disease (PAD) is a condition characterized by low functional capacity which is associated with impaired free living, ambulation and low exercise tolerance. The purpose of this randomized controlled study was to evaluate whether changes in maximal walking time are associated with adaptations in cardiovascular function following supervised exercise. METHODS: After ethics approval, 28 patients (63 +/- 11 years) completed a graded treadmill test (2 min stages, 3.2 km h(-1), with gradient increasing 2% every 2 min) until they reached level three or four on the claudication pain scale. Peak oxygen consumption was assessed on a breath-by-breath basis, by online expiratory gas analysis. Following a 40-min recovery period, peak cardiac output was measured using the non-invasive carbon dioxide rebreathing method described by Defares (J Appl Physiol, 13, 1958, 159). Peak cardiac power output was then computed using the equation described by Cooke et al. (Heart, 1998, 79, 289). Patients were randomly assigned to one of two groups: supervised, who exercised at the hospital twice weekly for 12 weeks or control, who received normal treatment which included encouragement to walk regularly. RESULTS: After 12 weeks, there were no significant changes in body mass, peak oxygen consumption, peak cardiac output, peak heart rate, peak cardiac power output, respiratory exchange ratio or rating of perceived exertion in both the supervised and control group. There was a significant improvement (91%) in maximal walking distance following the supervised exercise programme. Although patients' peak cardiovascular measurements were unchanged, the patients in the supervised exercise group were able to complete a higher workload at the end of the 12 weeks of exercise, for the equivalent demands on the circulation system. CONCLUSIONS: The findings from this study suggest that a short-term period of supervised exercise training results in an improved walking time in patients with limiting claudication because of PAD. It also demonstrated that the cardiovascular system becomes more efficient in meeting the demands of exercise. It is recommended that individuals with PAD should undertake exercise as a form of treatment.     

The Impact of Short Term Supervised and Home-Based Walking Programmes on Heart Rate Variability in Patients with Peripheral Arterial Disease

The aims of the study were to determine whether heart rate variability (HRV) measured at rest and during exercise could be altered by an exercise training programme designed to increase walking performance in patients with peripheral arterial disease. Forty-four volunteers were randomised into 12 weeks of either: supervised walking training twice weekly for 30 min at 75% VO_2peak (SU), home-based walking training sessions: twice weekly, 30 min per week (HB) or no exercise (CT). HRV measures were calculated from a 5-min resting ECG. Each patient then underwent maximal, graded exercise treadmill testing. All measures were repeated after 12 weeks. The SU group showed significantly (p < 0.001) increased maximal walking time (MWT) but no change in VO_2peak. There were no statistically significant changes in any of the measures of HRV in any group. Effect sizes for change in HRV measures were all very small and in some cases negative. Improved walking performance was not accompanied by central cardiorespiratory or neuroregulatory adaptations in the present study. The lack of any change in HRV was possibly due to either the low intensity or discontinuous nature of exercise undertaken.

Key points

• It is known that exercise can positively influence heart rate variability in some cardiac patients.
• It is known that exercise can increase walking performance in peripheral vascular disease patients.
• Exercise training improved walking performance in peripheral vascular disease patients but HRV was unaltered.
• This may be due to low overall physiological demands on the cardiovascular system or the intermittent nature of the exercise.

Key words: Exercise, ischemia, autonomic nervous system     

Are hypertension or cardiac embolism likely causes of lacunar infarction?

We tested the hypothesis that hypertension is more common and cardiac embolism less common in patients with lacunar infarction than in patients with other types of cerebral infarction. We studied risk factor profiles in a series of 102 consecutive patients with a lacunar infarct and 202 consecutive patients with a carotid artery-distribution infarct involving the cortex registered in the Oxfordshire Community Stroke Project, a community-based study of first-ever stroke. The two groups did not differ in the prevalence of prestroke hypertension (defined in a number of ways) or in the prevalence of markers of sustained hypertension. The presence of atrial fibrillation and a history of myocardial infarction, particularly during the 6 weeks before the stroke, were significantly more common in the group with carotid-distribution infarcts involving the cortex. There was no significant difference in the prevalence of other accepted risk factors for ischemic stroke, including previous transient ischemic attack, cervical bruit, diabetes mellitus, peripheral vascular disease, or cigarette smoking. Our results suggest that hypertension is no more important in the development of lacunar infarction than it is in the development of other types of ischemic stroke that are presumed to be due to atherosclerotic thromboembolism in a major cerebral artery. Our data support the autopsy evidence that cardioembolic occlusion is an unusual cause of lacunar infarction.     

Predictors of shuttle walking test performance in patients with cardiovascular disease

Objective

The incremental shuttle walking test (ISWT) is used to estimate cardiorespiratory fitness, but data from healthy individuals suggest that demographic and anthropometric measures account for much of the variance in test performance. The aim of this study was to determine whether anthropometric, demographic and selected gait measures also predict ISWT performance (i.e. distance walked) in patients with cardiovascular disease.

Design

Observational study.

Setting

A community-based cardiac rehabilitation centre (Cohort 1) and a hospital outpatient cardiac rehabilitation programme (Cohort 2).

Participants

Sixteen patients with clinically stable cardiovascular disease (Cohort 1) and 113 patients undergoing cardiac rehabilitation (Cohort 2).

Interventions

Patients in Cohort 1 performed the ISWT on two occasions. Anthropometric data and walking and turning variables were collected. Linear regression analyses were used to identify the predictors of test performance. The authors subsequently attempted to validate the equation created by comparing predicted and actual ISWT values in a larger (n = 113) validation sample (Cohort 2).

Main outcome measures

Distance walked during ISWT, step length and height.

Results

No gait or turning measures were significantly associated with ISWT performance. Distance walked correlated most strongly with step length (r = 0.83, P < 0.05) and height (r = 0.74, P < 0.05). Given the similarity of these correlations and the rarity of step length assessment in clinical practice, ISWT performance was predicted using patient's height; this explained 55% of the variance in ISWT performance. Height was also the best predictor in Cohort 2, explaining 17% of test variance (P < 0.01). Body mass index explained an additional 3% of variance (P < 0.05) in ISWT performance.

Conclusions

Routine clinical measures, particularly patient's height, are predictive of ISWT performance. The findings of the present study are in partial agreement with similar studies performed in healthy individuals, and it remains unclear whether the ISWT performance of patients with cardiovascular disease is influenced by the same factors as the ISWT performance of healthy individuals.