Brain inflammation following surgery for fractured neck of femur

Abstract

This thesis explored how neuroinflammation, known to cause confusion and sometimes dementia, might be detected following surgery for hip fracture. There were two main studies. 1. Cytokine study Introduction Cytokines are key components of the inflammatory response which develops after surgery. Many studies have shown associations between inflammation and various peripheral pro-inflammatory cytokines in plasma. Some studies have measured central cytokines in the Cerebrospinal Fluid (CSF) as markers of neuroinflammation although most only measured these cytokines before surgery. Knowledge of the changes in both peripheral and central cytokines following surgery is essential in further understanding neuroinflammation as a prelude to the development of treatments for Post-operative Neurocognitive Disorder. Method Following regulatory approval, patients admitted to a single hospital with a fractured neck of femur (broken hip) were invited to participate in this study. Participants had a spinal catheter inserted just prior to induction of anaesthesia. Samples of blood and CSF were taken before surgery, immediately following surgery, and on the first postoperative morning. Subsequently, samples were analysed for the presence of 10 pro-inflammatory cytokines using a highly sensitive electrochemiluminescence plate (MSD, USA). Results Over 18 months 21 participants were recruited, although a spinal catheter was only successfully inserted in 12. Plasma levels of IL-4, IL-6, IL-10, IL-12 and IL-13 rose significantly following surgery, whereas there were significant rises of all 10 cytokines measured in the CSF (IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IFN-γ and TNF-α). Central cytokine levels were consistently higher than their peripheral counterparts. There were no significant correlations between cytokines prior to surgery. Several of the peripheral cytokines showed strong correlations immediately after surgery but not the following day. There was significant correlation centrally between all cytokines except for IL-8. Peripheral IL-2, IL-4, IL-6 and IL-13 immediately following surgery had strong correlations with most central cytokines although this did not persist to the first post-operative day. Discussion This is the first study to analyse paired samples of plasma and CSF for changes in levels of pro-inflammatory cytokines before and after emergency orthopaedic surgery. Levels of central cytokines were lower than the periphery following fracture but before surgery. Following surgery central cytokine levels were much higher than the periphery, giving evidence to the concept that despite the peripheral insult of orthopaedic surgery, a central release of cytokines occurs. That there was almost complete correlation between levels of central cytokines following surgery provides some evidence that the neuroinflammatory cascade is large in some, but less in others. Correlations between plasma IL-2, IL-6, IL-8, IL-12 and IL-13 and CSF cytokines may indicate that measurement of some plasma cytokines immediately following surgery could provide a useful indicator of which patients might be having a large CSF cytokine response. The study lacked sufficient participants and cognitive evaluation to provide any association between cytokine levels and symptoms of PND. Future work in this area should include an analysis of the collected fluid for other biomarkers using Mass Spectroscopy, and the collection of further CSF samples of other surgical groups possibly without using spinal catheters.

2. Neurophysiology study Introduction Neurophysiological testing of brain function through electroencephalography (EEG) has been used in the detection of PND since the 1940s. Quantitative EEG (qEEG) techniques have been found to be useful in patients who cannot participate in paper-based tests of cognitive function. In this study, peri-operative EEG recordings were used to examine their usefulness in identifying brain inflammation. Method In a linked study, participants undergoing peri-operative collection of cytokines, also had EEG recordings, using the Enobio 20 Soft-Cap EEG device (Neuroelectrics, Spain). Five-minute recordings alternating eyes-open (EO) and eyes-closed (EC) states every 10 seconds were carried out at same time as the first and last cytokine samples were collected. The recordings were analysed to produce power data for 19 standard electrodes in four separate frequency bands. Three participants with the highest central cytokine response after surgery were identified and their EEG data analysed as a separate “highly inflamed group”. Results Of the 12 patients that had samples of CSF taken, ten also had good quality paired EEG recordings. Significant reduction in power in the delta region during EC was seen in 7 bands located in the parietal and occipital areas. Significant increase in power in the beta region was seen in 6 bands located in the frontal part of the brain. Three participants in the “highly inflamed” group showed increase in beta power in the posterior part of the brain when compared with the rest. Discussion Decrease in power in the alpha band when moving from EC to EO confirmed reliability of the recordings. The relative loss of this difference in the alpha band following surgery also indicated a change in cognitive function consistent with PND. This is the first study to analyse EEG recordings before and after surgery with simultaneous measurement of cytokines in the plasma and CSF. Neuroinflammation which occurs after surgery may be associated with certain EEG changes, some of which can be detected before surgery. Peri-operative EEG is an easy to use tool that provides rich data, and future studies should include its use but with dedicated neurocognitive assessment to identify PND by more widely accepted tests.