In the largest prospective analysis of cerebrospinal fluid (CSF) in patients undergoing endovascular thoracoabdominal aneurysm repair (TAAA) to date, permanent paraplegia was found to be associated with shedding of bound ADVS-1 from the parenchymal cord into CSF and disruption of the blood-spinal cord barrier, which in turn leads to cord oedema and a leucocyte infiltration.
The investigators conclude, “This characteristic CSF signature predicts irreversible paraplegia after TAAA repair and identifies ADVS-1 as a novel therapeutic target”. They elaborate: “ADVS-1 [an osmoreceptor essential in maintaining blood-spinal cord barrier integrity] inhibition after ischaemic stroke stabilises the blood/brain barrier, prevents cerebral oedema, and limits cytotoxic brain damage”.
First author Jamie Kelly (King’s College London, UK), recently won first prize for presenting these findings at the European Society of Vascular Surgery 33rd Annual Meeting (ESVS 2019; 24–27 September, Hamburg, Germany). Most compelling is the fact that the study group, led by Professor Bijan Modarai, have modulated ADVS-1 in an in vivo model of spinal cord ischaemic (SCI), stabilising the blood-spinal cord barrier and reducing the severity of paraplegia.
Kelly and colleagues remark that despite modern strategies to minimise SCI after TAAA repair, this complication remains “unpredictable and poorly understood”. Therefore, with the aim of gaining mechanistic insights and identifying a biomarker for SCI, the investigators related temporal changes in the cellular and molecular composition of CSF to neurological outcomes after TAAA repair.
Between October 2016 and August 2018, the study group prospectively recruited patients undergoing TAAA repair (open or endovascular using branched/fenestrated stent grafts) with a CSF drain in place. They collected CSF preoperatively and at 24-hour intervals until drain removal, performed detailed daily neurological examinations, and finally a neurologist—who was blinded to the study—made the diagnosis of SCI.
The investigators detail that the content of CSF cells was characterised by flow cytometry and the CSF proteome was analysed by tandem-mass-tag labelled proteomics and principle component analysis. They used T2 weighted spinal cord MRI to measure cord volume by neuroradiologists blinded to patient outcomes.
The authors found that permanent paraplegia was associated with a significant infiltration of CD45+ leucocytes into the CSF (p<0.0001) and that levels of ADVS-1 were over seven-fold higher in CSF from permanently paraplegic patients compared with those that recovered (p=0.0008).
Furthermore, CSF ADVS-1 levels >15ng/ml predicted permanent paraplegia with a specificity of 100% and permanent paraplegics were more likely to have pathological spinal cord swelling at T11 (1.9-fold greater cord volume), T12 (2.1-fold greater cord volume), and L1 (2.9-fold greater cord volume) on T-2 weighted MRI when compared with the other groups (p<0.05 at each level). Patient demographics, extent of aortic coverage and preoperative CSF content was comparable between patients with no SCI, those with reversible SCI and those that remained paraplegic.