Stroke
Course of disease
Origin of ischemic stroke1
Most ischemic strokes are thromboembolic in origin, with common sources of embolism being large artery atherosclerosis and cardiac diseases, particularly atrial fibrillation. Other causes of ischemic stroke include small vessel disease, which is associated with elevated blood pressure and diabetes mellitus and is particularly common in Asia. Less common overall, but proportionally more prevalent in younger patients, are arterial dissection, vasculitis, patent foramen ovale (PFO) with paradoxical embolism (that is, whereby venous thrombi enter the systemic and cerebral circulation) and hematological disorders (Figure 1)1.
Figure 1. Ischemic stroke mechanisms1: The heart and cerebrovascular tree illustrating cardioembolic stroke from the left atrial appendage in atrial fibrillation, carotid artery atherosclerosis and small vessel disease due to lipohyalinosis and parent vessel atherosclerosis. When a thrombus occludes the middle cerebral artery distal to the circle of Willis (that is, the circulatory anastomosis that supplies blood to the brain and surrounding structures), leptomeningeal anastomoses with anterior cerebral artery (ACA) and posterior cerebral artery (PCA) branches will supply retrograde blood flow to a variable proportion of the middle cerebral artery territory. This collateral flow might be sufficient to sustain metabolic viability but not electrical activity in the ischemic penumbra. The penumbra will contribute to the clinical deficit, but this is reversible with rapid reperfusion. Regions without adequate collateral blood flow will become irreversibly injured, termed the ischemic core, and the extent of irreversible injury expands with time.
The Concept of the Ischemic Penumbra2
The concept of the ischemic penumbra was first introduced by Astrup in 1981. In the ischemic brain, two tissue areas can be distinguished – the core of the infarction and the surrounding zone which is called the (ischemic) penumbra2.
Almost immediately after vessel occlusion, the ischemic core is defined where cells are destined to die irrespective of therapeutic interventions unless rapid restoration of blood flow can be achieved. The massive reduction of blood flow in the ischemic core leads to a breakdown of cellular metabolism and energy supply, ion homeostasis, and a consecutive loss of cellular integrity. The result is cell death within minutes: necrosis of cells and tissue evolves2.
Collaterals provide residual circulation in the surrounding penumbra. This tissue is functionally silent albeit metabolically still active and therefore salvageable. However, the disruption of cellular homeostasis in the penumbra leads to slow cell death and a step-by-step growth of the lesion, and previously viable brain becomes infarcted tissue. In the penumbra, apoptotic and inflammatory signaling cascades play an important role. Early after the onset of a stroke, the penumbra can account for up to 50 % of the volume that later becomes infarcted (Figure 2)2.
Figure 2. The ischemic penumbra2
Mechanisms of recovery1
The extent of recovery of behavioral function in animal models of stroke can be remarkable, and similar improvements can indeed be seen in young patients following stroke or traumatic brain injury. Much of this recovery is due to neuroplasticity. This plasticity might involve local sprouting, synaptogenesis or simply the strengthening of transmission at existing synapses. Importantly, this plasticity seems to come at some cost; it is very common for younger patients to experience very good physical recovery but be left with problems attending to simultaneous events and of fatigue1.
Human post-mortem studies have shown the presence of endogenous stem cells in peri-infarct regions, suggesting a role for these cells in human stroke. Most, if not all, of the beneficial effects of experimentally introduced exogenous stem cells observed in animal models is probably mediated through the production of various trophic and supportive factors at the site of injury, and a subsequent alteration of the local environment to one more supportive of regeneration and repair, rather than to their direct integration into signaling pathways1.
Footnotes:
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ACA, anterior cerebral artery; PCA, posterior cerebral artery; PFO, patent foramen ovale.
References:
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Campbell BCV, De Silva DA, Macleod MR, et al. Ischaemic stroke. Nat Rev Dis Primers. 2019;5(1):70.
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Mergenthaler P., Dirnagl U., Kunz A. (2016) Ischemic Stroke: Basic Pathophysiology and Clinical Implication. In: Pfaff D., Volkow N. (eds) Neuroscience in the 21st Century.
Springer, New York, NY.