SAN DIEGO—The relationship between acute ischemic stroke and infection is complex, with evidence suggesting that infection can act as a trigger for stroke or occur poststroke, in both cases adversely affecting functional outcome, reported Hedley Emsley, MBChB, MRCP, PhD, at the 2009 International Stroke Conference.
“Overall, infection in the week preceding stroke is in the order of 10% to 35% of patients,” said Dr. Emsley, Consultant Neurologist at the Royal Preston Hospital and Honorary Lecturer at the University of Liverpool in the United Kingdom. Similarly, poststroke infection can occur in as many as a third of patients. These data highlight the importance of delineating the mechanisms involved in the interaction between stroke and infection, as well as the need for developing appropriate interventions.
Infection as a Trigger for Stroke?
“Systemic infection seems to induce a transient state of increased stroke susceptibility in the week, and particularly the three days, following infection,” said Dr. Emsley. “This short window of elevated risk seems to point to infection as a potential stroke trigger, with the highest risk period after infection coinciding with a high-level proinflammatory phase of the immune response.
“The majority of patients who ultimately succumb to stroke have risk factors associated with chronic systemic inflammation,” he explained. “But superimposed on this there can be acute episodes of high-grade inflammation.”
According to Dr. Emsley, the transient nature of increased stroke risk after bacterial infection was well documented by Smeeth et al. Their study, based on information from the UK General Practice Research Database, assessed first ever or recurrent stroke in relation to previous infection or vaccination. Findings indicated that the risk of stroke was highest in the three days after respiratory tract or urinary tract infections, with incidence ratios of 3.2 and 2.7, respectively. Although risk declined gradually over subsequent weeks, it was still elevated from baseline at three months. Similar findings, based on data from a different UK database, were reported by Clayton and colleagues, who found an increased risk of stroke in the three days after a respiratory tract infection (odds ratio, 4.1).
Preceding Infection Adversely Affects Stroke Outcome
A wide range of clinical studies supports the idea that acute infection prior to stroke is associated with worse functional outcome, reported Dr. Emsley. In experimental models, a systemic challenge with the bacterial endotoxin lipopolysaccharide appears to exacerbate ischemic brain damage. “It seems that interleukin-1 (IL-1) is a pivotal cytokine in that observation, because blocking the actions of IL-1 with IL-1 receptor antagonist blocks that effect,” he said, “and there’s a similar sort of exacerbation of injury to that with lipopolysaccharide caused by IL-1β.” In addition, toll-like receptor 4 (TLR4) signaling appears to be a key pathway for lipopolysaccharide, as evidenced by lipopolysaccharide resistance in dysfunctional TLR4 signaling. “In short, the mechanisms responsible for worsening of ischemic damage are complex.”
Dr. Emsley referred to a model proposed by McColl et al, which outlines potential mechanisms for how systemic inflammation worsens stroke outcome. These could include peripheral inflammation potentiating peripheral inflammatory pathways and activation of inflammation in peripheral organs (eg, bone marrow), increasing trafficking and entry of blood-brain barrier–destabilizing neurotoxic immune cells into the CNS. “Another effect could be to switch normally regulated T-cell responses to autoreactive and harmful T-cell responses to brain antigens,” he said. “And thirdly, systemic inflammation appears to be capable of preactivating resident brain microglia to activation states that would alter subsequent responses.”
Ischemic Preconditioning and Cross Tolerance
The idea that infection may be a trigger for stroke and can worsen outcome seems to be inconsistent with the concepts of “ischemic preconditioning” and “cross tolerance,” suggested Dr. Emsley. “Ischemic preconditioning is a concept that refers to protection of tissue afforded by brief ischemia before the final ischemic insult,” he told Neurology Reviews. “Thus, the severity of injury caused by the definitive ischemic insult appears to be reduced by a preceding, subinjurious, ischemic insult.” Cross tolerance refers to other subinjurious preceding events conferring protection against subsequent ischemia, he said. For instance, evidence from experimental settings has shown that preceding, subinjurious exposure to lipopolysaccharide (used as a model for infection) appears to confer protection against subsequent ischemia.
“This raises the theoretical concept that preceding infection might, in some circumstances, be protective against subsequent ischemia, perhaps if occurring at a particular interval before or at a certain level of exposure,” said Dr. Emsley. “But what we see [in the clinical setting] is exacerbation of damage with ischemia during the early proinflammatory phase after infection, which is slightly at odds with that.” Further investigation into the impact of the timing or severity of a preceding infection is needed, he recommended.