What has gone wrong in stroke research?

There have been two main approaches to the acute treatment of stroke, thrombolysis and neuroprotection. After a number of disappointing thrombolytic trials using either streptokinase1-3 or an inappropriately long time-window,4 tissue plasminogen activator (t-PA) was demonstrated to improve clinical outcome at three months.5Patients who received t-PA within 3 hours of onset were 30% more likely to have minimal or no disability at 3 months when compared with placebo. This was at the price of 6.4% of patients, who received t-PA and developed symptomatic intracerebral haemorrhage, producing a non-statistical benefit in terms of mortality (17% vs 21%). For many patients, disability is a more important issue than death and t-PA reduces disability, but will cause some deaths from haemorrhage. Normal cerebral blood flow is approximately 100 ml/100 g of brain tissue per minute. In cerebral infarction there is a core of tissue with blood flows in the 0–10 ml/100 g/min range where neuronal death will occur within an hour and the damage is irreversible. Around this is an area of brain called the penumbra,6 where blood flow is in the 10–20 ml/100 g/min range. In the penumbra there is electrical failure and large scale release of the excitatory amino acids, glutamate and aspartate. This release of amino acids is associated with calcium influx into the neurones and a cascade of deleterious biochemical events that leads to cell death. The theoretical basis for neuroprotection lies in interrupting this process within the penumbra and reducing the final size of …