The brain can be affected by many different types of infections with differing degrees of severity. The mildest situation is acute sickness behavior induced by a short inflammatory burst in the systemic circulation communicated to the brain via (a) leaky regions of the blood–brain barrier in the circumventricular organs, (b) afferent fibers of the vagus nerve, and (c) direct communication across the blood–brain barrier leading to a short-term reduction of cognitive function without long-term sequelae (Perry et al., 2003; Tauber et al., 2021; Too et al., 2021; Zumofen et al., 2023). Here, the brain does not come into direct contact with the pathogen causing the acute infection or compounds produced by this pathogen (Figure 1). In contrast, the most severe end of the spectrum of involvement of the brain in infection is when the pathogen has entered the cerebrospinal fluid (CSF) or/and the brain. This is the case in bacterial or fungal meningitis, viral encephalitis and different forms of intracranial abscesses. In addition to pro-inflammatory mediators, microbes and components released by them, in particular hemolysins and free radicals, can target neurons, and their products can directly stimulate immune cells in the brain or are toxic to different cell types present in nervous tissue (Nau and Brück, 2002; Too et al., 2021).

Septic encephalopathy is a disease entity between these two extremes: circulating immune cells and mediators of inflammation communicate with the brain via the circumventricular organs, afferent fibers of the vagus nerve and the endothelium of the vessels in brain parenchyma, meninges and choroid plexus. The entry of bacterial products through leaks of the blood–brain barrier plays a minor role, and the pathogen itself does not enter the brain parenchyma or the CSF (Perry et al., 2003; Figure 1). Whereas the incidence of community-acquired meningitis has decreased substantially in industrialized countries over the past 50 years, the incidence of septic encephalopathy has risen due to increased numbers of susceptible persons, particularly those over the age of 50 years. The susceptibility of the brain to septic encephalopathy (or sepsis-associated encephalopathy) is age-dependent. It is high in newborns, infants and toddlers, then decreases in older children and is very low in young adults. Beyond the age of 50 years, it gradually increases due to aging of the immune system, concomitantly administered medications and co-morbidities, and a physiological age-related decline in the functional capacity of most organs (Werner and Kuntsche, 2000; Lu et al., 2022). For these reasons the incidence of sepsis in persons beyond 70 years is approximately 100 times higher than in young adults (Angus et al., 2001). Septic encephalopathy that manifests as delirium, stupor or coma has become a common problem in geriatric medicine. Whether it develops in an older person depends on the severity of the infectious challenge and the cognitive reserve, or cognitive resilience, of the individual (Cizginer et al., 2017; Figure 2). In the pathophysiology of septic encephalopathy in advanced age, the stimulation of microglial cells that are pre-activated by amyloid-β, α-synuclein and other endogenous compounds deposited in the brain during neurodegenerative diseases, and to an extent also during healthy aging, also play a key role (Perry et al., 2003).

Septic encephalopathy is the prototype of an organic psychosis. In contrast to septic embolic or metastatic encephalitis, where focal neurological deficits are present and often determine the clinical picture (Tauber et al., 2017, 2021; Figure 3), the main clinical manifestation of moderate septic encephalopathy is delirium, and of severe encephalopathy stupor or coma. In a large retrospective study comprising 2,513 patients with sepsis at ICU admission, potentially modifiable factors contributing to septic encephalopathy were acute renal failure, hypo- and hyperglycemia, hypercapnia and hypernatremia (Sonneville et al., 2017). One of the most delightful outcomes for a clinical geriatrician is the rapid recovery of some patients after appropriate antimicrobial treatment and fluid and electrolyte management. Unfortunately, after septic encephalopathy many persons do not reach their pre-infection cognitive level. Animal studies suggest a time-dependent recovery from anxiety and depression (Dal-Pizzol et al., 2021), whereas cognitive impairment apparently persists (Savi et al., 2021). Patients surviving septic encephalopathy have a higher risk of developing a neurodegenerative disease than persons without sepsis or, when a neurodegenerative disease already is present, experience an acute exacerbation or acceleration of their disease (Perry et al., 2003). Similarly, recent studies indicate that adults who survive a variety of infections severe enough to require hospitalization have a significantly increased risk of developing dementia over the next 10–20 years (Sipilä et al., 2021; Bohn et al., 2023). Severe sepsis in the elderly approximately triples the risk of the development of moderate to strong new cognitive impairment in this population (Peters van Ton et al., 2022; Piva et al., 2023). These findings in humans are recapitulated in a mouse model of intraperitoneal infection with Listeria monocytogenes followed by amoxicillin treatment (Cassidy et al., 2023). Here, systemic infections by neuroinvasive wild-type bacteria, as well as by non-neuroinvasive ∆hly mutants induced cognitive impairment manifest 4 months after infection. Similar to findings in patients (Sipilä et al., 2021), cognitive deficits were more profound after infection with neuroinvasive L. monocytogenes, and correlated significantly with the retention of CD8+ T-lymphocytes in the brain. The presence of cognitive decline after non-neuroinvasive infection, which did not lead to retained white blood cells in the brain, suggests that neuroinvasive and non-neuroinvasive infections may trigger cognitive decline via different mechanisms (Cassidy et al., 2023). In addition to CD8+ T-cell instigated neuroinflammation, another possible source of injury is through alterations in endothelial function. For example, the moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions, known as neurovascular coupling, was impaired in a geriatric L. monocytogenes sepsis model prior to the development of cognitive impairment (Csipo et al., 2021).

Delirium is defined as “a disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) accompanied by reduced awareness of the environment” (American Society for Psychiatry, 2022). It has a range of severities and typically presents with fluctuating symptoms. Therefore, repeated clinical assessments are necessary to quantify its severity. Two widely applied rapid methods are the general ward confusion assessment method (CAM) and the confusion assessment method in the intensive care unit (CAM-ICU). Usually measurements are performed 3 times daily in order to assess the mental status of patients at risk for, or already suffering from delirium. CAM (applied on general wards) and CAM-ICU (applied on intensive care wards) in several studies showed a high sensitivity and specificity (CAM: 94–100%, 89–95%; CAM-ICU: 97–100%, 89–100%) (data summarized by Yuechen et al., 2023). The severity of delirium also can be estimated by scales, e.g. the CAM-S (Khan et al., 2017).

Unlike septic-embolic or -metastatic encephalitis, which can be visualized by cranial computer tomography (CCT) or – more sensitive and specific, but less suitable in agitated geriatric patients - cranial magnetic resonance imaging (cMRI) without and with contrast enhancement (Tauber et al., 2017, 2021), septic encephalopathy often cannot be detected or visualized by routine imaging with CCT or cMRI. Therefore, the clinician is confronted with the problem to substantiate the diagnosis “septic encephalopathy” in order not to overlook other diagnoses requiring more specific treatment.

The pathophysiology of septic encephalopathy is complex involving cross-talk across the blood–brain barrier, microglial activation, endothelial swelling, a disruption of the blood–brain barrier, vasogenic edema, leukocyte migration, impairment of cerebral autoregulation and perfusion, excitotoxicity, mitochondrial dysfunction and neuronal and axonal injury. The most extreme manifestation of septic encephalopathy occurs in deep septic shock with bilateral hippocampal necrosis as a consequence of watershed infarctions (Tauber et al., 2017). Pathophysiological mechanisms have been discussed in detail in several recent publications (Perry et al., 2003; Tauber et al., 2017, 2021; Robba et al., 2018; Too et al., 2021; Sekino et al., 2022; Dumbuya et al., 2023; Barichello et al., 2023; Piva et al., 2023). This review will focus on biomarkers of septic encephalopathy which have already been successfully applied in clinical practice and which show promise as prognostic markers in older patients.

Sepsis affects multiple organ systems, and many biomarkers are produced/released by cells not belonging to the central nervous system (CNS). Therefore, general biomarkers of sepsis alone or in combination generally do not display sufficiently high levels of specificity to discriminate between sepsis without and with septic encephalopathy. For this reason, it is crucial to differentiate between biomarkers of sepsis from those of septic encephalopathy. Specific markers of septic encephalopathy are compounds produced/released exclusively by the brain. For sepsis, a large variety of biomarkers has been identified, including soluble pattern recognition molecules (PRMs), elements of the complement system, several cyto- and chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, microRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors (Barichello et al., 2022).

The unambiguous diagnosis of septic encephalopathy can be complicated, because electrolyte and metabolite disturbances (in particular hyponatremia, hypernatremia and hypercalcemia, hypo- and hyperglycemia, lactate acidosis) and renal or hepatic failure, which may or may not be related to sepsis in an individual patient, can cause similar clinical symptoms. For this reason, there is a strong need to clearly differentiate between neural injury caused by septic encephalopathy and damage caused by other mechanisms.

Considering the high variability in human samples, investigations with low patient numbers must be interpreted cautiously. Although the incidence of septic encephalopathy is highest in old age, there is a lack of studies specifically addressing the utility of the available biomarkers in older persons.

Basically, the pathology of septic encephalopathy can be characterized by three steps, and biomarkers of each step should be defined (Ehler et al., 2020; Figure 6):

1. Systemic inflammation causes dysfunction of the cerebral endothelium. Since C-type natriuretic peptide is predominantly expressed in by endothelial cells and released during sepsis (Koch et al., 2011) and septic encephalopathy from endothelial cells, its N-terminal propeptide (NT-proCNP) may serve as an indicator of injury to the cerebrovascular endothelium (Ehler et al., 2020). Whether it is really more specific for cerebrovascular dysfunction than procalcitonin or C-reactive protein remains to be determined.

2. The key event causing neuronal injury in septic encephalopathy is the activation of microglial cells (Yan et al., 2022). In the absence of plasma/serum biomarkers of microglial activation, S100B as a marker of glial cell damage has been proposed for the monitoring of microglial activity (Ehler et al., 2020). A specific marker truly quantifying microglial activity would represent a major advance for the monitoring of sepic encephalopathy.

3. Death of neurons and damage to axons and synapses is the morphological correlate of long-term neurocognitive deficits after septic encephalopathy. Although primarily an indicator of axonal injury, neurofilament light chains (NfL) have been proposed as an indicator of neuronal damage (Ehler et al., 2020). We suggest that it may be advantageous to also determine neuron-specific enolase (NSE) in plasma/serum. When hemolytic samples are excluded, NSE already established as a prognostic marker in hypoxic brain injury (Sharma et al., 2022; Kim et al., 2023) probably is a valuable tool for the quantification of neuronal injury in septic encephalopathy of older persons.

Among new biomarkers for septic encephalopathy not yet established in clinical practice, brain-specific microRNAs appear most promising (Suster and Feng, 2021; Antonakos et al., 2022; Li et al., 2023; Yuechen et al., 2023).

RN conceived the study. SS, DD, ST, and RN searched the literature and analyzed previously published data, and designed the figures. SS wrote the first draft of the manuscript. All authors contributed to the Discussion, reviewed and approved the final version of this manuscript.

This work was funded by the Open Access Publication Fund of the Georg-August University of Göttingen and the German Society of Geriatrics.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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