Research Article: The prognostic value of neurofilament levels in patients with sepsis-associated encephalopathy – A prospective, pilot observational study

Date Published: January 24, 2019

Publisher: Public Library of Science

Author(s): Johannes Ehler, Axel Petzold, Matthias Wittstock, Stephan Kolbaske, Martin Gloger, Jörg Henschel, Amanda Heslegrave, Henrik Zetterberg, Michael P. Lunn, Paulus S. Rommer, Annette Grossmann, Tarek Sharshar, Georg Richter, Gabriele Nöldge-Schomburg, Martin Sauer, Chiara Lazzeri.


Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of sepsis patients. Neurofilament (Nf) light (NfL) and heavy (NfH) chain levels as biomarkers for neuroaxonal injury were not evaluated in cerebrospinal fluid (CSF) and plasma of patients with sepsis-associated encephalopathy (SAE) before. We conducted a prospective, pilot observational study including 20 patients with septic shock and five patients without sepsis serving as controls. The assessment of SAE comprised a neuropsychiatric examination, electroencephalography (EEG), magnetic resonance imaging (MRI) and delirium screening methods including the confusion assessment method for the ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC). CSF Nf measurements in sepsis patients and longitudinal plasma Nf measurements in all participants were performed on days 1, 3 and 7 after study inclusion. Plasma NfL levels increased in sepsis patients over time (p = 0.0063) and remained stable in patients without sepsis. Plasma NfL values were significantly higher in patients with SAE (p = 0.011), significantly correlated with the severity of SAE represented by ICDSC values (R = 0.534, p = 0.022) and correlated with a poorer functional outcome after 100 days (R = -0.535, p = 0.0003). High levels of CSF Nf were measured in SAE patients. CSF NfL levels were higher in non-survivors (p = 0.012) compared with survivors and correlated with days until death (R = -0.932, p<0.0001) and functional outcome after 100 days (R = -0.749, p<0.0001). The present study showed for the first time that Nf levels provide complementary prognostic information in SAE patients indicating a higher chance of death and poorer functional/cognitive outcome in survivors.

Partial Text

During the last decades the main focus of sepsis care has been directed towards short- and long-term survival of patients [1]. Consequently patient management has improved reducing the overall mortality [2]. An important contributor to mortality and long-term morbidity is sepsis-associated encephalopathy (SAE) [3–6]. SAE is defined as a diffuse brain dysfunction secondary to sepsis and without evidence of a primary CNS infection or encephalopathy due to other reasons [7]. The pathophysiology of SAE is still unexplained but risk factors are emerging [8–11]. Structural evidence for brain injury in sepsis comes from imaging and neuroanatomy studies [9–13]. Clinical assessment of SAE is hampered by the altered level of consciousness due to sedation and the need for mechanical ventilation [6,14]. Neuropsychiatric examination, electroencephalography (EEG), neuroimaging and laboratory tests permit to monitor SAE [15–17]. Diagnostic accuracy especially of clinical examination and EEG monitoring, however remain low in more severe cases potentially confounded by the use of sedation [17]. Furthermore, the need for prolonged registration of EEG to detect abnormalities over time is not practicable in the ICU setting and previous studies showed no association between EEG and brain dysfunction detected by CAM-ICU [18]. In this context body fluid biomarkers may be of diagnostic value [6,19,20]. A common limitation to previous studies on SAE was that biomarkers investigated are not specific for the neuro-axonal compartment and results have been contradictory [21–26]. A more specific biomarker for neuro-axonal injury, the neurofilament proteins (Nf) can be accurately measured from the cerebrospinal fluid (CSF) and blood and consistently correlated with brain injury, disease severity and survival in a range of neurological diseases [9,27–32]. Nf proteins are an important part of the axonal cytoskeleton and represent an architectonic stable tube system [30]. They are classified as intermediate filaments of type IV [30]. As a consequence of axonal injury Nf are released into the extracellular fluid and can be measured by ELISA technique [30]. This is the first study on the value of neurofilament heavy (NfH) and neurofilament light chains (NfL) in cerebrospinal fluid (CSF) and plasma of patients with SAE. The aim is to evaluate the potential suitability of Nf as biomarkers to detect SAE, septic brain injury and to predict outcome in patients with sepsis.

This prospective longitudinal exploratory study was conducted to evaluate the prognostic value of Nf levels in patients with SAE. Nf levels are known to be increased in several disorders with neuropsychiatric symptoms [27,31,46]. The potential value for SAE has not yet been investigated. Preexisting studies on SAE analyzed non-specific biomarkers like interleukin-6, neuron-specific enolase (NSE) or S100B protein [19, 21–23,47,48,49]. The results were found to be controversial [19,48,49]. Our group is first to analyze the prognostic value of CSF and plasma NfH and NfL levels in SAE patients which might have importance for the prediction of long-term neurological sequelae and survival in sepsis. Biomarker research on SAE is necessary as most septic shock patients are sedated and mechanically ventilated and are not easily assessed for clinical signs of SAE [6,16,43]. Diagnostic measures to evaluate the extent of septic brain injury, as cerebral MRI or diffusion tensor imaging (DTI), are not universally available and require resources [50,51]. Specific markers of neuroaxonal injury in SAE could help to monitor SAE and to predict neurological outcome.

This is the first study on the relevance of neurofilament heavy (NfH) and neurofilament light chains (NfL) in cerebrospinal fluid (CSF) and plasma to detect SAE and to predict outcome in patients with sepsis. This prospective, longitudinal, registered study showed that NfL and NfH levels were found to be highly elevated in plasma and CSF of patients with SAE. Nf levels in sepsis correlated with the clinical appearance of SAE, the extent of neuroaxonal injury seen on MRI and with survival. Power calculations indicate that future studies on prediction of sepsis survival will require larger sample sizes compared to studies focused on cognitive/functional outcome in survivors. Given the difficulty in obtaining CSF samples in septic shock patients, the modest gain for study size calculation and the methodological developments we suggest future studies to focus on longitudinal plasma NfL and NfH levels using fourth generation immunoassays.




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