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Alexander Grunsfeld, MD
Martha Jefferson Stroke Center
Alexander Grunsfeld graduated from Rutgers University with Highest Honors. He attended Robert Wood Johnson Medical School (UMDNJ) and completed his residency in Neurology and a fellowship in NeuroCritical Care at the University of Virginia. He is board certified in Neurology, NeuroCritical Care and Vascular Neurology. He is currently the director of the Martha Jefferson Stroke Center. His academic interests include disorders of consciousness, traumatic brain injury, status epilepticus and stroke. He lives in Charlottesville with his wife, Karen, and children Kylie and Jakey. His passions are hiking, backcountry camping and diving.
Regardless of the etiology of a stroke, the final common pathway that leads to permanent neurological dysfunction is cellular ischemia—either due to blood vessel occlusion or mechanical disruption. Neuronal ischemia is a dynamic process that is influenced by multiple factors, such as duration of ischemia, cerebral blood flow (CBF), temperature and glucose metabolism. The brain is entirely dependent on aerobic metabolism and cannot store its own glucose. Therefore, short periods of ischemia deplete ATP stores and trigger a cascade of events leading to the release of excitotoxic neurotransmitters and calcium, cytokines, proteases and other inflammatory mediators. If this process is sustained, neuronal infarction through coagulation necrosis and apoptosis occurs. Within an hour of vessel occlusion, an irreversible core of infarction forms, characterized by minimal CBF, surrounded by an ischemic penumbra—a zone of moderately ischemic tissue that may be receiving limited blood flow from collateral vessels (Figure 1). The ischemic penumbra is salvageable brain if normal blood flow can be restored, and is the target of thrombolytic therapy.
There have been two general approaches to the problem of treating acute ischemic strokes. One targeting neuroprotective mechanisms, such as hypothermia and pharmacological agents, has yet to demonstrate any success. The second has been to target mechanisms that recanalize the occluded blood vessel, either pharmacologically or mechanically. This strategy has met with greater success. In fact, studies have shown convincingly that intravenous tissue plasminogen activator (tPA), a molecule that activates the clot lysing enzyme plasmin, has the ability to deliver remarkable results, but with one significant limitation—its efficacy diminishes with time (Figure 2).
The groundbreaking NINDS studies with tPA were completed in 1995 and for the first time established the benefit of this drug if given intravenously within 3 hours of stroke symptom onset. Patients receiving the therapy were approximately 30% more likely to have minimal or no disability at 3 months. Although an increased risk of intracerebral hemorrhage was established for patients receiving tPA, those patients did not have a higher mortality rate and were 10 times more likely to benefit from than be harmed by the drug. Importantly, the study also found that even within the 3-hour window, the likelihood of a patient benefitting from the tPA was time sensitive. Not surprisingly, ever since IV tPA was established as a beneficial therapy, the hunt for ways to extend the therapeutic window has been under way.
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