Pathophysiological aspects of transient ischemic attacks

Abstract

Current views of the pathophysiology of transient ischemic attacks (TIA) are based on the concept of focal cerebral ischemic brain lesions [1‐6]. Many aspects of transient focal cerebral ischemia have been studied both in carefully controlled experimental conditions and in clinical studies. At the same time, detailed pathophysiological characterization of reversible focal ischemic brain lesions represents a very complex problem. In clinical studies on patients, this is restricted by a multitude of factors which are difficult to control: the difficulty of identifying accurately the time of onset of ischemia, the heterogeneity of patients in terms of age, gender, and genetic differences, etc. Serious difficulties occur on comparison of clinical and experimental data because of anatomical, pathophysiological, genetic, and other differences between people and laboratory animals [3, 5, 7‐10]. One major point in the concept of focal cerebral ischemic brain lesions is the “ischemic cascade,” which is a chain of complex molecular genetic and biochemical derangements in brain cells occurring in response to decreases in local cerebral blood flow (CBF) which, in certain conditions, ends with irreversible structural brain damage [1, 3, 5, 11]. The sequence of steps in the “ischemic cascade” has been established: 1) a decrease in brain blood flow; 2) glutamate excitotoxicity; 3) intracellular accumulation of calcium; 4) activation of intracellular enzymes; 5) increases in nitric oxide synthesis and development of oxidant stress; 6) expression of early response genes; 7) the long-term effects of ischemia (local inflammatory reactions, microvascular lesions, damage to the blood-brain barrier); 8) apoptosis [1, 11]. The time framework of the occurrence of the steps in the “ischemic cycle” have been identified: energy deficiency in ischemic tissue occurs in the first three hours, glutamate excitotoxity occurs at 3‐6 h, and impairments to calcium homeostasis and lactate acidosis occur at one day. The long-term effects of ischemia start 2‐3 h from the onset of ischemia and reach a maximum at 12‐36 h (oxidative stress, local inflammation) and 2‐3 days (apoptosis), but persist for long periods (several months) [1, 11].