Pathophysiology of ischaemic stroke

Ischaemic stroke usually occurs due to occlusion of a cerebral artery or, less often, a reduction in perfusion distal to a severe stenosis. As cerebral blood flow falls, neuronal function is affected in two stages. Initially, as blood flow falls below a critical threshold of about 20 ml of blood per 100 g of brain per minute (normal being over 50 ml/100 g/min), loss of neuronal electrical function occurs. Crucially, this is a potentially reversible stage. Irreversible damage occurs within minutes as blood flow falls below a second critical threshold of 10 ml/100 g/min; below this level, aerobic mitochondrial metabolism fails and the inefficient anaerobic metabolism of glucose takes over, rapidly leading to lactic acidosis. Consequently, the normal energy dependent cellular ion homoeostasis fails, resulting in potassium leaking out of the cell and sodium and water entering the cell, leading to cytotoxic oedema. Calcium also enters the cell, exacerbating mitochondrial failure. This loss of cellular ion homoeostasis leads to neuronal death.

The identification of these two stages of neuronal failure has led to the concept of the ischaemic penumbra; that is, an area of brain which has reached the reversible stage of electrical failure but has not yet passed onto the second irreversible stage of cellular homoeostatic failure. In theory, therefore, this tissue could be "rescued", either by early reperfusion (using agents to dissolve the acute thrombotic lesion and restore normal blood flow) or by administering agents which could protect these potentially viable neurons from further damage

(neuroprotection); the combination of reperfusion and neuroprotection would seem a logical conclusion.86 Although there is evidence that the concept of the ischaemic penumbra is valid,87,88 it remains unclear how long ischaemic human brain might survive; in other words, the time window for intervention is unknown. It seems likely that the duration of any time window will vary between individuals and it will be increasingly important to identify the factors which influence it.

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