In this study of acute stroke patients, we found that higher levels of circulating markers of the acute inflammatory response were associated with higher temperatures in normal brain. Later after stroke, higher body temperature was associated with higher temperature in DWI-abnormal brain. We also confirmed our previous finding that tissue temperature of DWI-abnormal (ischemic) brain was higher than in areas of normal brain ipsi- or contralateral to the stroke.1
We used a validated noninvasive imaging technique to measure brain temperature in patients with ischemic stroke. Previous studies of brain diseases15,16
have measured local brain temperature invasively in patients on intensive care units, who have other reasons—usually neurosurgical—for invasive monitoring devices. Such monitoring is impractical in a less intensive ward-based setting and only measures temperature in tissue close to the probe whereas MRS measures temperature across a slice of brain allowing direct comparison between DWI-abnormal and normal-appearing brain. While the recruitment of patients for our study is not immune from a number of selection biases, these patients are more likely to be more representative of most populations of stroke patients than invasively monitored patients, and therefore of the potential target population for hypothermic treatments.
Our study has several limitations. First, we recruited relatively few patients, a reflection of the difficulties inherent in performing complex MRI in acute stroke patients. This has limited the strength of our conclusions, and the power of our analyses. While we have not found a significant difference between the association of blood markers of inflammation and brain temperature in different regions of the brain, it is possible that one exists. Only a larger number of patients would strengthen this conclusion. Second, because we took blood and measured brain temperature serially in a group of patients where clinical priorities led to early discharge from hospital, or some patients were too ill, we had missing data for a number of patients. It is likely therefore that those patients in whom data were missing differed systematically from those patients in whom we had complete data even though we were not able to demonstrate a statistical difference. This may have biased our results and either overestimated or underestimated the strength of any associations. Third, as an observational study, we were not able to draw strong conclusions about the causative role of inflammatory markers on body or brain temperature, or body on brain temperature or vice versa, nor can we comment on potential effects of therapeutic hypothermia. Fourth, we measured only 3 inflammatory markers at daily intervals; measurement more frequently, or of different markers, might provide more information.
The data from this study support the following conclusions: first, that the rise in brain temperature early after stroke in ischemic brain is not associated strongly and consistently with body temperature (though we cannot exclude such an association). Second, later after stroke, body temperature is associated with brain temperature, most strongly in abnormal brain tissue. Third, brain temperature is associated with markers of inflammation. However, although our results do not show whether this effect is significantly stronger in DWI-normal or DWI-abnormal brain, significant relationships were more frequent with DWI-normal than abnormal brain. Fourth, mean body temperature is associated with mean markers of inflammation.
The relationship between body and temperature in DWI-normal and DWI-abnormal brain is therefore complex, and could imply that early temperature elevation in DWI-abnormal brain is due to different mechanisms than temperature elevation in DWI-normal brain and the rest of the body. Early and rapid cooling of body temperature may not result in an equally rapid brain cooling, particularly of the ischemic tissue.
Studies of therapeutic hypothermia in acute stroke are of great interest, and we look forward to the successful completion of randomized controlled trials; they are the only way to reliably explore the causal relationship between body temperature and poor outcome after stroke, and embedded studies of biomarkers could explore the influence of body temperature on circulating markers of inflammation.
This study should inform the design of those trials: although body temperature may be measured as a surrogate endpoint of the efficacy of body cooling, a more relevant biomarker is brain cooling, as body temperature and brain temperature have a complex relationship that is not always easy to predict. Early temperature elevation in ischemic tissue may result from a different mechanism from that which elevates body temperature, as body temperature may not peak until several days after stroke17
and temperature in DWI-normal brain was higher at the second scan. The mechanisms by which brain or body cooling lead to improved outcomes in animal models after stroke—or potentially in patients—are uncertain, and there may be other important intermediate biomarkers of treatment efficacy. The association between higher levels of inflammation and higher brain temperature hints at a causal relationship between the two and is an important question for further research.