Septic encephalopathy in the elderly - biomarkers of potential clinical utility

Abstract

Next to acute sickness behavior, septic encephalopathy is the most frequent involvement of the brain during infection. It is characterized by a cross-talk of pro-inflammatory cells across the blood-brain barrier, by microglial activation and leukocyte migration, but not by the entry of infecting organisms into the brain tissue. Septic encephalopathy is very frequent in older persons because of their limited cognitive reserve. The predominant clinical manifestation is delirium, whereas focal neurological signs and symptoms are absent. Electroencephalography is a very sensitive method to detect functional abnormalities, but these abnormalities are not specific for septic encephalopathy and of limited prognostic value. Routine cerebral imaging by computer tomography usually fails to visualize the subtle abnormalities produced by septic involvement of the brain. Magnetic resonance imaging is by far more sensitive to detect vasogenic edema, diffuse axonal injury or small ischemic lesions. Routine laboratory parameters most suitable to monitor sepsis, but not specific for septic encephalopathy, are C-reactive protein and procalcitonin. The additional measurement of interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-α increases the accuracy to predict delirium and an unfavorable outcome. The most promising laboratory parameters to quantify neuronal and axonal injury caused by septic encephalopathy are neurofilament light chains (NfL) and S100B protein. Neuron-specific enolase (NSE) plasma concentrations are strongly influenced by hemolysis. We propose to determine NSE only in non-hemolytic plasma or serum samples for the estimation of outcome in septic encephalopathy.

Keywords: S100B protein; cerebrospinal fluid; electroencephalography; magnetic resonance tomography; neurofilament light chains; plasma; positron emission tomography; sepsis.

Figure 1

Conceptual relation between infection and cognition. During an acute, mild viral infection such as influenza, acute sickness behavior manifests as malaise, mild hypoxia, headache, and lost productivity (Zumofen et al., 2023) as a consequence of acute sickness behavior caused by a short systemic inflammatory reaction. Antiviral therapy usually is not indicated. On the other end of the spectrum when there is microbial invasion of the brain, e.g. in bacterial meningitis, pathogens and bacterial products are present in the cerebrospinal fluid and brain tissue causing direct and immune-mediated neuronal damage (Nau and Brück, 2002; Too et al., 2021). In septic encephalopathy, bacteria do not enter the brain, and neuronal injury predominantly is not caused directly by bacterial products, but by cross-talk of immune cells across the blood–brain barrier leading to microglial activation and entry of immune cells into the brain. In septic encephalitis, pathogens in low quantities enter the brain, either causing microabscesses (septic-metastatic form) or vasculitis and cerebral ischemia by infected emboli (septic-embolic form).

Figure 2

The vulnerability to septic encephalopathy depends on the cognitive reserve of the patient, which is determined by age and concomitant diseases. In the first years of life and beyond the age of 60, mild or moderate septicemia can cause septic encephalopathy. Conversely, in previously healthy adolescents and young adults, only very severe systemic infections can cause septic encephalopathy, i.e., the risk to develop septic encephalopathy is low.

Figure 3

Venn diagram illustrating the continuum between septic encephalopathy (microglial activation and tissue hypoxia as a consequence of septic shock predominate), septic-embolic (ischemic lesions caused by septic emboli predominate) and septic-metastatic encephalitis (microabscesses predominate).

Figure 4

Cranial magnetic resonance imaging (cMRI), fluid attenuated inversion recovery (FLAIR) sequence, of an 87 years old woman presenting with severe delirium upon Escherichia coli urosepsis. (A) Distinct vasogenic edema in the frontal and temporal lobe compatible with a posterior reversible encephalopathy syndrome (PRES) 2 days after onset of clinical symptoms. (B) Follow-up imaging 5 weeks later demonstrating complete resolution of the vasogenic edema.

Figure 5

Microglial activation and diffuse axonal injury typical for septic encephalopathy. (A) Strong microglial activation in a fatal case of Neisseria meningitidis sepsis (young woman), immunohistochemistry by polyclonal rabbit anti-Iba-1 (ionized calcium-binding adaptor molecule 1) antibodies (1:400, Wako, Neuss, Germany) counterstained with hemalum. Please note the strongly activated ameboid microglia without processes (red arrows) and the moderately activated microglia with shortened processes of increased thickness (closed arrowheads) and the mildly activated microglial cell with preserved processes (open arrowhead) (objective: x40). (B) Diffuse axonal injury (red, marked by black arrows) in a 75 years old man with liver cirrhosis, sepsis and endocarditis, immunohistochemistry by a mono.clonal mouse antibody against amyloid-β precursor protein (APP) (1:2000, Chemicon, Temecula, CA, USA) counterstained with hemalum (objective: x20).

Figure 6

Diagnostic biomarkers of activation and injury in septic encephalopathy. The biomarkers are arranged according to the site of origin. The markers of endothelial activation are not specific for the brain, whereas the markers of glial activation (and injury) and of neuronal or axonal injury are relatively specific for the central nervous system.