By Natalie R. Weathered, MD
Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital
Dr. Weathered reports no financial relationships relevant to this field of study.
SYNOPSIS: Measurement of postoperative plasma neurofilament light protein (NfL) in plasma appears to have a dose-dependent correlation with delirium severity, independent of inflammation. This observation provides evidence of neuronal injury from delirium.
SOURCE: Casey CP, Lindroth H, Mohanty R, et al. Postoperative delirium is associated with increased plasma neurofilament light. Brain 2020;143:47-54.
Delirium is a confusional state of acute onset characterized by inattention and decreased cognitive abilities due to an underlying medical condition, medication side effect, or intoxication. Surgical procedures and anesthesia both are risk factors for the development of delirium, with the onset of postoperative delirium typically occurring between one to three days after the operation.1 As with other categories of delirium, postoperative delirium is associated with increased morbidity and mortality, including having an association with the development of dementia. However, what remains unknown is whether delirium is simply an unmasking of an unrecognized neurodegenerative state, or whether delirium plays a causative role in the development of neurodegeneration and cognitive decline.
Neurofilament light (NfL) is a protein found in the cytoskeleton of central and peripheral neurons. Elevated levels of NfL, thought to be a reflection of neuronal injury, have been reported in both cerebrospinal fluid and plasma in multiple neurological and psychiatric conditions, including a few recent studies showing elevated levels in patients with delirium.2,3,4
Casey et al tested the hypothesis that postoperative delirium is associated with a greater rise in NfL from baseline on postoperative day 1 as compared to those participants who did not develop delirium. To strengthen an argument for possible causality, they also investigated whether there was a dose-dependent relationship correlating NfL levels with delirium severity. Given that inflammation is thought to play a role in the development of postoperative delirium, additionally they sent a panel of cytokines. They enrolled 114 patients undergoing non-intracranial, non-cardiac surgery, collecting plasma samples preoperatively as well as up to four days postoperatively. Six patients were later excluded for either canceled/aborted surgeries or alternative causes of delirium (e.g., alcohol withdrawal). Delirium was assessed using the Confusion Assessment Method (CAM)/3D-CAM, or, if the patient was intubated, the CAM-ICU score was used. Delirium severity was measured using the Delirium Rating Scale-98 (DRS).
In addition to plasma measures of NfL and inflammatory markers, they also obtained preoperative magnetic resonance imaging (MRI) of the brain on 52 patients to quantify white matter injury and grey matter atrophy, since these previously have been shown to correlate with plasma NfL. White matter injury was quantified using diffusion tensor imaging. Grey matter atrophy, defined by cortical thickness of the hippocampi, was measured using high-resolution T1-weighted images and T2-fluid attenuated inversion recovery (FLAIR).
Delirium occurred in 36% of subjects, with a mean peak DRS of 21.2 compared to a peak DRS of 6.8 for nondelirious subjects. Delirious patients were more likely to have had vascular surgery, or a higher risk surgery in general, but there was no statistical difference in age or sex. Although there was no statistically significant difference in preoperative levels of NfL between delirious and nondelirious subjects, the rise in NfL (comparing preoperative levels to postoperative day 1 levels) was more pronounced in those who developed delirium (P < 0.001). Additionally, there was a positive correlation between the peak DRS and NfL (P < 0.001). In assessing the relationship between inflammatory cytokines, NfL, and delirium development, using a Bonferroni correction for multiple comparisons, only IL-8 was found to be significantly correlated with NfL and delirium severity. Using a regression model controlling for confounders, NfL was shown to be associated with delirium severity independent of changes in inflammatory burden (P = 0.038).
Among patients who had both preoperative NfL measured as well as MRI (n = 46), both altered white matter integrity and reduced hippocampal volume were found to correlate with increased levels of NfL. Notably, there was no correlation between preoperative IL-8 and MRI changes.
Postoperative delirium is a common phenomenon and associated with subsequent development of dementia. Casey et al have provided evidence that postoperative delirium may in fact contribute to neuronal injury, which theoretically may contribute to neurodegeneration, and, ultimately, in some patients could set the stage for later development of dementia. It also appears that at least a portion of the neuronal injury that occurs in delirium is separate from an inflammatory cascade. Certainly, research investigating how delirium relates to dementia is in the early stages, but these results are intriguing. If the results are confirmed with future studies, the question ultimately is going to be what interventions can be done in the perioperative period to decrease the risk of neuronal injury. Are delirium precautions, such as avoiding benzodiazepines, minimizing sedative medications, avoiding urinary catheters, and treating dehydration and electrolyte abnormalities, of physiological benefit, or are the patients in whom we can accomplish all of these destined to have a milder course from the beginning? As our population continues to age, and with it an ever-increasing prevalence of dementia resulting in significant societal burden, any effort we can make to prevent incident cases of dementia will be of the utmost importance.
- Whitlock EL, Vannucci A, Avidan MS. Postoperative delirium. Minerva Anestesiol 2011;77:448-456.
- Halaas NB, Blennow K, Idland AV, et al. Neurofilament light in serum and cerebrospinal fluid of hip fracture patients with delirium. Dement Geriatr Cogn Disord 2018;46:346-357.
- Saller T, Petzold A, Zetterberg H, et al. A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2019;163:241-246.
- Ehler J, Petzold A, Wittstock M, et al. The prognostic value of neurofilament levels in patients with sepsis-associated encephalopathy — A prospective pilot observational study. PLoS One 2019;14:e0211184.