Brain dysfunction is a frequent and severe complication of septic shock, as it occurs in up to 60% of patients 12 and is associated with increased mortality 3 and long-term cognitive impairment 45. It is clinically characterized by an acute alteration of consciousness, ranging from coma to delirium, and less frequently by seizures or focal neurologic signs 16. The neuroradiologic correlates of these symptoms are poorly known, as few imaging studies have been carried out in septic-shock patients. In a preliminary study of nine septic-shock patients who underwent a brain MRI because of an acute neurologic alteration, we found ischemic stroke and confluent or diffuse white matter lesions (which we called leukoencephalopathy) in two and five patients, respectively 7. These findings provided insight into the pathophysiology of sepsis-related brain dysfunction. The demonstration of ischemia suggests the importance of cerebral perfusion impairment and microcirculatory dysfunction, whereas leukoencephalopathy is indicative of a range of pathologic processes including impairment of the blood-brain barrier, axon loss, gliosis, dilated perivascular spaces, and lacunar infarcts 17. Recently, one group reported abnormalities on brain imaging in two-thirds of 64 critically ill patients who developed acute neurologic changes 8. However, only a small proportion of these patients were septic, and brain imaging was predominantly obtained by CT scan instead of MRI.

Our aim was to assess the prevalence of ischemic stroke and leukoencephalopathy and to identify their association with predisposing factors, clinical manifestations, and outcome in a cohort of septic-shock patients with acute clinical signs of brain dysfunction. It was not ethically conceivable to perform an MRI in septic-shock patients without neurological symptoms because of the risk of transport.

From November 2005 to June 2012, 170 patients were admitted for septic shock and developed acute brain dysfunction; of those, 71 (42%) patients were enrolled and underwent brain MRI, with a median time delay from acute brain dysfunction of three days. 57 (33%) patients were not enrolled because of patient's death before MRI (n = 40) or MRI contraindication (n = 17) whereas 42 (25%) were excluded from the study because of a prior central nervous system disorder, endocarditis, or age older than 80 years. CT scan was performed in 12 (17%) (Figure 1).

Our observational study shows that, in septic-shock patients with acute neurologic changes, brain MRI can reveal leukoencephalopathy or ischemic stroke, which is associated with increased ICU mortality and increased odds of having GOS > 3 at 6 months. We found that the prevalence of ischemic stroke (31%) is higher than previously reported by Suchyta et al. (31 versus10%, respectively) 8. This discrepancy may be explained by the fact that in the retrospective study from Suchytha et al. 8, brain imaging was obtained by means of CT scan, thus probably underestimating the rate of brain lesions.

The occurrence of ischemic stroke in sepsis patients raises questions on the role of cerebral perfusion in this population of patients. Although some studies did not show impaired perfusion 20, others indicated a decrease in cerebral perfusion pressure or in cerebral blood flow and alterations in the regulation of cerebral perfusion, including impaired CO₂-reactivity and cerebrovascular-pressure autoregulation 21. It is plausible that the risk of stroke would be increased in patients with hypotension and impaired cerebral blood-flow autoregulation. The prevalence of watershed infarction suggests that hypotension might contribute to the occurrence of stroke.

We did not find an association between duration or severity of hypotension and cerebral ischemia in the present study or in previous neuropathologic studies 22. However, cerebral autoregulation is altered in patients with sepsis-associated encephalopathy and would represent a better marker of cerebral hypoperfusion compared with hypotension alone 23. Cerebral blood flow and autoregulation were not measured in our study, which was arbitrarily defined as MAP < 60 mm Hg. One way to determine the importance of cerebral perfusion in septic shock would be to determine whether perfusion monitoring and optimization reduces the prevalence of stroke. In addition to impairment of cerebral blood flow and its determinants, cerebral microcirculatory dysfunction has also been shown to be associated with brain lesions in various experimental models of sepsis but not yet in humans 124, although it may probably be linked to diffuse ischemic damage and microhemorrhages observed in brains of patients who died of septic shock 22. Our findings of significantly reduced platelet counts, increased PTT, and increased prevalence of DIC in patients with ischemic stroke suggest that the presence of coagulation derangement may be involved in the occurrence of brain lesions. Thrombosis of cerebral arteries has been reported in septic-shock patients with fulminant DIC 7. Microcirculatory dysfunction and coagulopathy are both consequences of endothelial activation 124 but are not easily preventable or treatable.

We found that a cardioembolic (essentially atrial fibrillation) or thromboembolic factor was present in 70% of patients with ischemic stroke. Interestingly, it was very recently shown that new-onset atrial fibrillation is associated with increased prevalence of stroke and mortality in sepsis patients 25. Thus, our results suggest that ischemic stroke in sepsis patients can be favored by previous predisposing factors, result from sepsis-related particular conditions (DIC, microcirculatory alterations, and so on), or both..

Another consequence of endothelial activation is the failure of the blood-brain barrier (BBB), leading to the passage of inflammatory mediators and neurotoxic factors into the brain 1. We hypothesized that leukoencephalopathy reflects BBB alteration, originating within the Virchow-Robin spaces and potentially propagating to other brain structures 7. An alteration of BBB was identified neuropathologically in a patient with a diffuse leukoencephalopathy 7. The present study confirmed that severe leukoencephalopathy is the second most frequent brain lesions (21%). We did not find a significant association between leukoencephalopathy and any specific acute neurological sign. The fact that comparable white matter lesions have not been reported in nonsepsis critically ill patients 8 is consistent with an inflammatory process. However, this pathophysiological hypothesis is not supported by our findings, as the severity of septic shock and other biologic markers of inflammation or endothelial activation did not correlate with leukoencephalopathy. That we could not find any significant association between the presence of leukoencephalopathy and severity of illness and markers of inflammation may be due to the small number of this subgroup of patients rather than a true lack of association. Moreover, we limited our analyses to conventional clinical biomarkers of inflammation and endothelial activation. More-sophisticated analysis, including plasma cytokines and adhesion molecules levels, will be warranted for future studies.

Finally, we found that the MRI was normal in 52% of our cohort of patients. Our results are consistent with those obtained by Suchyta et al. 8 in critically ill patients. The risk stratification of MRI lesions in sepsis patients might be based on the electroencephalographic pattern. Indeed, we found that malignant EEG pattern, as defined in Synek's classification, is correlated with the presence of ischemic stroke or leukoencephalopathy on MRI in comatose or delirious patients. This result suggests that EEG should be done and before MRI.

The current study has several limitations. This observational study investigated the prevalence of neuroradiologic lesions in a very selected patient population with septic shock with acute neurological symptoms, without contraindication to MRI and preexisting cerebral disease. Forty patients died before MRI could be performed. It is possible that those patients would have shown more-severe brain lesions, as suggested by postmortem neuropathologic studies 22. The prevalence and type of brain lesion in asymptomatic patients or in those with more-subtle brain dysfunction was not analyzed. However, neuroradiologic assessment of these patients would raise some ethical issues related mainly to the risks of transporting potentially unstable patients with no neurologic signs to MRI, unless neuroimaging were performed at the time of recovery from septic shock. It has been shown that patients with sepsis are at high risk of developing long-term cognitive disability 5 and that cognitive impairment is more frequent in critically ill patients with abnormal brain imaging 82627. We are not able to determine either the time-to-recovery of a normal neurologic examination or the relations between neuroimaging and long-term cognitive function. Prevalence of coma, delirium, and convulsive seizures in our cohort is consistent with the prevalence previously reported in the literature 6. Furthermore, the use of MRI with higher field strength, use of spectroscopy, and use of diffusion tensor imaging might have allowed detection of smaller ischemic lesions or other anatomic or neurochemical abnormalities.

A larger cohort of patients would allow a more accurate estimation of the prevalence of each type of brain lesion and the respective risk factors. Yet available MRI studies in septic-shock patients are scant, often retrospective, single center, and have included fewer than 10 cases 78, indicating the difficulties of performing such an exploration in sepsis patients. The occurrence of focal neurologic signs, delirium, or coma, as well as prevalence of ischemic stroke and leukoencephalopathy, remained steady over the study period. No significant change in monitoring and treatment of patients with septic shock was found in our ICU during the study period. Larger multicenter studies with the standardization of both clinical and imaging protocols across centers are needed.

Finally, it is conceivable that the use of continuous or daily standard EEG would have enabled to us to detect more accurately sepsis-associated encephalopathy or nonconvulsive seizures 6.

The present study showed that the MRI is abnormal in half of septic-shock patients who developed acute brain dysfunction. Our data also showed that ischemic stroke and leukoencephalopathy are the two most frequent lesions in sepsis patients and that ischemia is associated with increased mortality and mid-term neurologic disability, defined as GOS >3. Larger multicenter cohort studies are warranted to elucidate the potential benefit of strategies aimed at manipulating both cerebral perfusion and coagulation in patients with septic shock.

1. MRI can reveal leukoencephalopathy or ischemic stroke in septic-shock patients with acute brain dysfunction.

2. Ischemic stroke is associated with increased mortality, mid-term neurologic disability, and biological DIC.

3. Severity and type of neuroradiologic lesions correlate with EEG alterations.

ADC: apparent diffusion coefficient; ATICE: adaptation to the intensive care environment; BBB: blood-brain barrier; CAM-ICU: confusion assessment method for the ICU; DIC: disseminated intravascular coagulation; DWI: diffusion-weighted imaging; ECG: electrocardiogram; EEG: electroencephalography; EPI: echo-planar imaging; FLAIR: fluid-attenuated inversion recovery; GCS: Glasgow Coma Scale; GOS: Glasgow Outcome Scale; ICU: intensive care unit; MBP: mean blood pressure; MRI: magnetic resonance imaging; MTC: magnetization transfer contrast; PT: prothrombin time; PTT: partial thromboplastin time; RASS: Richmond Agitation Sedation Scale; SaO₂: oxygen saturation; SAPS II: New Simplified Acute Physiology Score; SOFA: Sequential Organ Failure Assessment.

The authors declare that they have no competing interests.

AndP conceived of the study, helped acquire data, and wrote the manuscript. FE, aided in acquisition of data. ALM, acquired data. AngP performed the statistical analysis and helped to draft the manuscript. EA, acquired data. DA, helped in interpretation of data. FC helped in interpretation of data. RS conceived of the study and helped to revise the manuscript. RC participated in coordination of the study and the acquisition and interpretation of data. TS conceived of the study and wrote the manuscript.

All authors read and approved the final manuscript.