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Stroke. 2004;35:360-362
doi: 10.1161/01.STR.0000115260.19243.64
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(Stroke. 2004;35:360.)
© 2004 American Heart Association, Inc.

Advances in Stroke 2003

Acute Neurovascular Syndromes: Hurry Up, Please, It’s Time1

J. Kennedy, MB, MSc, MRCP A.M. Buchan, MD, FRCP

From the Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.

Correspondence to Dr A.M. Buchan, Stroke Research Office, Room 1162, Foothills Medical Centre, 1403 29th St NW, Calgary, Alberta, Canada T2N 2T9. E-mail abuchan{at}ucalgary.ca


Key Words: Advances in Stroke • cerebral ischemia, transient • diagnosis • stroke

A Brief History of Time

"It isn’t that they can’t see the solution. It is that they can’t see the problem."2

Less than 20 years ago, the most common cited reason for the admission of a patient with stroke to hospital was for nursing or general nonmedical care.3 Admission to make or confirm the diagnosis or for medical treatment were mentioned less than half as often. In the same study, the most common reasons for patients remaining in the community were that they had suffered a minor stroke or services were available in the community for assessment and work-up. The evidence surrounding the benefit of aspirin in acute stroke, the reduction of death and dependence with admission of patients to dedicated stroke units, and perhaps most controversially, the demonstration of the efficacy of thrombolysis, by either intravenous or intra-arterial routes, in reducing disability following acute ischemic stroke had yet to appear.4,5

This article does not seek to re-examine the debate surrounding the use of thrombolysis in acute ischemic stroke. This has been explored at length elsewhere.6–8 The aim of this article is to explore the new perspective on the treatment of hyperacute cerebral ischemia that has arisen because of the increasing use of tissue plasminogen activator (tPA), in particular the influence of time.

The organization of acute stroke services is now required to be time sensitive to ensure that the maximum number of patients eligible for thrombolysis have the greatest chance of a good neurological outcome as possible.9 As a result, patients are presenting sooner, emergency services are prioritizing the transport of these patients to hospital, and physicians are assessing these patients more quickly.10 However, thrombolysis in acute cerebral ischemia is not a panacea, just as it has not been in acute coronary syndromes. Rather, it has provided a lever for change for all patients with acute cerebral ischemia.11 It has allowed us a broader view of the whole spectrum of the biology of acute cerebral ischemia, and perhaps where new solutions may be found.

Acute Neurovascular Syndromes

Cardiology made a paradigm shift in the study of spectrum of acute coronary syndromes with the publication of Braunwald’s classification.12 It has not only allowed the standardization of patients that are entered into randomized trials, but most importantly improved clinical care. Patients with acute coronary syndromes are stratified by the presence or absence of ST-segment elevation on baseline ECG to define the risk of early recurrent ischemia.13 ST-segment elevation on presentation predicts a higher mortality rate. However, the risks of early recurrent ischemic events and long-term morbidity and mortality are lower compared with patients without ST-segment elevation at presentation. Current AHA guidelines recognize that different presentations have different prognoses requiring different therapeutic approaches.14,15 Acute neurovascular syndromes now require an analogous paradigm shift. There is a growing appreciation of the high early risk of recurrent ischemia that those with minor or recovered events face (non–ST-elevation myocardial infarction/ unstable angina equivalent) when compared with completed events (ST-elevation myocardial infarction equivalent).

The 10% incidence of stroke within 3 months of an incident transient ischemic attack (TIA) has long been understood.16 Recent data from Northern California have shown that half of this stroke risk occurs within the first 2 days after a TIA.17 Five factors were shown to independently predict the early risk of stroke: age >60 years (odds ratio [OR], 1.8 [95% CI, 1.1 to 2.7]), diabetes mellitus (OR, 2.0 [95% CI, 1.4 to 2.9]), symptom duration >10 minutes (OR, 2.3 [95% CI, 1.3 to 4.2]), weakness (OR, 1.9 [95% CI, 1.4 to 2.6]), and speech impairment (OR, 1.5 [95% CI, 1.1 to 2.1]). The other important message from this article is that these patients are not just at risk of cerebrovascular events. In the 90-day follow period following TIA, a further 2.6% experienced cardiac events requiring hospitalization and 2.6% of patients died.

Initial skepticism around these findings (due to the self-selection of the population studied) has fallen away with the reappraisal of older databases. Review of the Oxfordshire Community Stroke Project database highlighted how this problem has remained hidden from physicians’ view.18 This population-based study showed very eloquently how the model of outpatient assessment of patients with TIA ill serves those at the highest risk of stroke. The stroke risk from time of assessment by a neurologist was 1.9% at 7 days (95% CI, 0.1 to 3.8) and 4.4% (95% CI, 1.6 to 7.2) at 30 days. However, when the perspective was re-adjusted starting from the onset of the first-ever TIA, these risks rose to 8.6% (95% CI, 4.8 to 12.4) and 12.0% (95% CI, 7.6 to 16.4), respectively.

Review of patient data from the medical arm from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) trial suggested that within this population, there are patients at an even higher risk, with the risk of ipsilateral stroke after incident TIA of 8.5% at 7 days and 20.1% at 90 days.19 Contrary to the long-term risk reported in the primary analyses of the NASCET,20,21 and the pooled analysis of all the carotid endarterectomy trials for symptomatic carotid stenosis,22 this early risk was not stratified by the degree of stenosis as measured by angiography. This observation is congruent with observations from coronary artery disease, indicating that plaque activity rather than degree of stenosis may play a crucial role in determining the early risk of recurrent events.

Understanding this period of high early risk has become very important in the clinical care of patients because of the changes to the organization of acute stroke care brought about by thrombolysis. Of those presenting within 3 hours of symptom onset, the most common reasons for ineligibility for thrombolysis is that the deficit has resolved, is improving or is too mild to warrant treatment.23 However, one third of this group will be either dead or dependent at the time of discharge from hospital. New diagnostic and therapeutic strategies need assessment in this setting to identify those at risk more accurately and provide safe and effective hyperacute treatment to ameliorate this risk.

Diagnostic and Therapeutic Challenges

There is not yet enough evidence in the literature to characterize acute neurovascular syndromes in the same way that acute coronary syndromes have now been clarified with the additional information that electrocardiographic and soluble biomarkers, such as the troponins, play in determining a management plan for patients. The roles of imaging and soluble biomarkers in refining a patients’ neurovascular prognosis have yet to be defined.

The early imaging of this group of patients has been very revealing. A new ischemic lesion seen on head computed tomography scanning predicts risk of stroke in those with TIA (OR, 4.06 [95% CI, 1.16 to 14.14]).24 The use of diffusion-weighted MRI (DWI) has shown that these patients are not just at symptomatic risk. In patients who underwent DWI within 6 hours of a clinically symptomatic stroke and again within the first week afterward, 34% of patients were found to have had recurrence on imaging compared with just 2% with a clinical recurrence. Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (P=0.026). These silent changes found on DWI highlight the early period of increased ischemic risk. It also raises the possibility of using DWI as a possible surrogate measure for recurrent stroke in future studies.25

Soluble biomarkers have been explored as a means of refining risk prediction. Unfortunately, biomarkers such as S100B, neuron specific enolase (NSE), glial fibrillary associated protein (GFAP), and myelin basic protein (MBP) when tested in stroke patients at the time of clinical presentation suffer from low sensitivity for early diagnosis (S100B and GFAP), while NSE and MBP are nonspecific.26 This may reflect the challenge that larger proteins and peptides face in crossing the blood-brain barrier, which makes it difficult to measure brain-derived proteins or peptides in the circulation. C-reactive protein, however, is showing promise as an independent predictor of risk of subsequent stroke.27

In reviewing the randomized evidence of hyperacute therapeutic interventions in these patients, there is minimal literature available. All previous stroke prevention trials have either not focused on this early period of risk, or actively precluded enrollment during this period. The only clinical trials looking at hyperacute intervention are the International Stroke Trial (IST)28 and the Chinese Acute Stroke Trial (CAST),29 which enrolled patients with acute stroke of all severities within 48 hours of symptom onset. In the combined analysis of the 2 trials (40 000 patients), there was a highly significant reduction in recurrent ischemic stroke of 7 per 1000 patients, which outweighed the increased risk of hemorrhagic stroke or hemorrhagic conversion of the original infarct (2 per 1000 patients).30 The principle of early treatment with combination antiplatelet therapies and statins has been explored in the cardiology literature31,32 and merits investigation in those with acute neurovascular syndromes to ensure that these therapies are effective and like IST/CAST, these benefits prevail over any risk of early treatment.33

Conclusion

Thrombolysis has transformed the way we look at all those with acute neurovascular syndromes. The next step is to accurately define those at high-risk using imaging and soluble biomarkers, allowing the randomization of standardized patients into clinical trials. Only then will we have the chance to realize the solutions to these newly understood problems.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.

Received December 2, 2003; accepted December 3, 2003.

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