Deciding when to use thrombolytic therapy for suspected stroke can be such a tough call in emergency medicine that it's been summed up this way: Damned if you do, damned if you don't.
That catch phrase is just one of several colorful characterizations that crop up frequently in cyberspace discussions about tissue plasminogen activator (tPA) in the emergency department for potential stroke (http://academiclifeinem.blogspot.com.)
As most emergency physicians know all too well, utilizing tPA intravenously can mean patient recovery from ischemic stroke that was once considered irreversible, but it can heighten the risk of intracranial hemorrhage, too, causing understandable hesitation for reliance on this game-changing agent. Some fairly compelling evidence shows that allegedly inappropriate use of tPA leads to litigation, just as failure to use it can when negative outcomes result. (Ann Emerg Med 2009;53:404.) But the tide may be turning. Last year, a study of emergency physicians from two dozen hospitals documented that attitudes about intravenous tPA for stroke are a lot more favorable than previously reported. (Stroke 2010;41:2026.)
So you might think that new approaches in neurological imaging to determine brain-tissue loss and serologic markers that correlate to it would help clear up the confusion, and you'd be right, except that even the investigators behind those novel studies say they need quite a bit more refinement. As often happens in the transformation from research to practice, such developments seem to be raising more questions than answers.
Consider the team of Scottish researchers who last fall demonstrated how choline concentration — measured by proton magnetic-resonance (MR) spectroscopy — may be a possible predictor of brain tissue that is likely to become infarcted. In their small study, elevations in choline were consistent with the occurrence of infarction a few days later. (Neurology 2010;75:850.)
The findings could mean that brain choline concentration measured with MR spectroscopy immediately outside the ischemic lesion in stroke patients might offer a new method to define at-risk tissue, said Bartosz Karaszewski, MD, the lead author and a doctor of clinical neuroscience at the University of Edinburgh, UK. How soon? Dr. Karaszewski cautioned that “further, larger studies are needed to confirm these findings.”
The feasibility of choline-referenced penumbral imaging as a future point-of-care approach for differentiating stroke in the ED still has “no validation that the methods being used are precise enough,” said James Grotta, MD, the chairman of neurology at the University of Texas Medical School at Houston and the director of the stroke program at Memorial Hermann-Texas Medical Center.
Dr. Grotta and a UT colleague, Tzu-Ching Wu, MD, reported on the leading areas of stroke research in a paper last year, including a look at the extension of thrombolysis beyond the three-hour time window and an examination of penumbral imaging. (Neurology 2010;75[18 Suppl 1]:S16.)
Currently, “I think we are reasonably good at determining a subset of patients who we should definitely not treat because they are too far gone, but not good at determining among the others who will respond,” Dr. Grotta said.
Serologic markers, an increasingly active focus, constitute an advance, but not one that is not likely to be coming into clinical use anytime soon, said Dr. Wu, who co-wrote the forward-looking research publication with Dr. Grotta. Such markers do offer a way to tailor treatment, although their use for that kind of fine-tuning appears nowhere in the near future. “At the end of the day, we all want to be able to individualize therapy,” he said.
In fact, even imaging so far is relatively insensitive to outcome prediction, pointed out Philip Barber, MD, an assistant professor of clinical neurosciences at the University of Calgary in Alberta, Canada. He added that he “very much doubts” whether a single tool will provide the answer. So what conclusion can be drawn by the choline rise in structurally normal tissue that seems prone to infarct? That remains to be seen, according to an editorial he and coauthor Lawrence Wechsler, MD, wrote in Neurology. (2010;75:844.)
And then there is the “frontier” of magnetic resonance-based molecular imaging of the brain, a modality that holds new promise, according to a group of scientists from the Netherlands, who published a review on it. Because the endothelial cells and cerebral vasculature differ from others in physiologically significant ways, they theorized that such specialized imaging could “not only aid diagnosis, but potentially differentiate stages of disorders and treatments.” (AJNR Am J Neuroradiol 2010;31:1577.)
More precise results seem distant. Even so, such findings, appearing as they usually do in clinical journals, which once seemed unappealing reading material for those outside of EDs, stroke centers, or neurology practices, appear to be prompting press coverage. Over the past year, the Wisconsin State Journal looked at stroke treatment in a multipart series examining how technology can assist diagnosis for people who suffer attacks outside of large regional centers.
One feature story highlighted the difference between two possible stroke patients — a woman who didn't receive a fibrinolytic drug because doctors were not sure from her presentation that she was “treatable,” and a man who did receive the therapy after a video-teleconferencing evaluation with specialists. The latter suffered no serious impairment; the former still struggles to resume her previous life. (Wisconsin State Journal, Dec. 26, 2010; http://bit.ly/WIstroke.)
The question now being posed is whether serologic markers, used in conjunction with imaging methods, might substantially help. Could they provide more distinction between patients most likely to benefit from clot-lysing therapy and others who, conversely, could be harmed by it? Last year, internists and emergency physicians from University Hospital in Basel, Switzerland, weighed in, showing that copeptin levels provided a “useful complementary tool” to forecast functional outcome and death 12 months following stroke. (Stroke 2010;41:1564.)
Serologic tests already are used with brain imaging for diagnosing acute ischemic stroke, including helping to spot hemorrhagic stroke. But now confirmed brain biomarkers seem to be joining the list of rapid assays, at least experimentally, for diagnosing transient ischemic attack and ischemic stroke.
They do have a future in clinical settings to affirm stroke and gauge treatment, according to Svetlana Dambinova, PhD, Dsci, a visiting professor of chemistry at Emory University in Atlanta. Dr. Dambinova's research has honed in on auto-antibodies to N-methyl-D-aspartate neuroreceptors, known NR2 peptides, and their use in the assessment of acute stroke in ED and surgery settings. By comparison, “the NR2 antibodies assay is better to be used for assessment of prior isolated or multiple ischemic strokes,” Dr. Dambinova noted. He plans to present his results at a medical conference this year.
All of these results arrive at a time when there has been sharp criticism of recently unveiled treatment guidelines, particularly with regard to managing and preventing intracranial hemorrhage (EMN 2011;33:24; http://bit.ly/InFocusICH), during a period in which roiling arguments persist over whether there is more risk from using tPA than from not (Stroke 2010;41:2381; Arch Neurol 2010:67:559) and at a point when “a lack of collaboration between emergency physicians and vascular neurologists” has been identified as a key barrier to acute stroke therapy. (Stroke 2010;41:1051.)
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CT Scans Key in Acute Stroke Care
Computed tomography that aims to assess tissue viability by perfusion techniques has the most potential for future refinements in acute stroke care, according to Tzu-Ching Wu, MD, the principal investigator of a University of Texas study into blood-brain barrier permeability changes as a predictor of complications in tPA treated patients. The advantages over magnetic resonance imaging are the wide availability of CT scanners, ease of use, fewer contraindications and lower equipment costs, he added.
Such point-of-care scanning may one day tailor patient therapy, such as thrombolytics outside the traditional three-hour window for acute ischemic stroke treatment, or escalatation beyond standard care, such as intra-arterial therapy. Meanwhile, the imaging modality also can provide pertinent information such as determining which patients may need decompressive surgery for malignant swelling or help identify those who are at high risk for developing hemorrhagic transformation.
One challenge currently facing emergency use of CT for such diagnostic purposes is a lack of standardization of imaging techniques, parameters for tissue viability, and imaging post-processing algorithms and software, which make the results obtained by such studies open to relative interpretation, Dr. Wu said. “We need to know what the brain is telling us on that imaging,” he said, and having a system of evidence-based parameters would help reach that point, he stressed.