Serious neurological events complicating epidural injections of glucocorticoid suspensions: evidence for a direct effect of some particulate steroids on red blood cells

Correspondence to Professor Jean-Denis Laredo; [email protected] The Food and Drug Administration (FDA) has not approved any injectable glucocorticoid product for epidural administration, but epidural injection of glucocorticoids is commonly used to manage radicular neck and back pain. Severe and sometimes fatal neurological events have occurred immediately after epidural injection of glucocorticoids. Indeed, 90 events were reported to the FDA Adverse Event Reporting System (FAERS) between 1997 and 2014. In the December 10, 2015 issue of the New England Journal of Medicine, Racoosin et al, from the FDA, found that all the catastrophic neurological events (brain and spinal cord infarctions resulting in permanent disability or death) reported to the FAERS were associated with injection of a glucocorticoid suspension, with only a few cases, involving temporary symptoms, reported with glucocorticoid solutions. However, the authors found that suspension formulations still accounted for more than 80% of the commercially available corticosteroid products used for epidural injections in 2013, according to Medicare and IMS health data, despite the increasing use of solutions. Potential causes of neurological complications after spinal injections of a suspension of particulate steroids include intrathecal injection, epidural hematoma, direct spinal cord injury and cord infarction due to an arterial spasm or vascular obliteration after inadvertent intra-arterial injection. However, the almost immediate onset of neurological deficit, as well as the MR findings performed in patients who underwent this complication, are very suggestive of spinal cord ischaemia following interruption of arterial blood supply. Brain or spinal cord ischaemia resulting from particulate steroid injection into the vertebral artery has also been demonstrated in an animal study. Occlusion of distal intramedullary arteries by steroid particles via an unexpected intra-arterial injection has been incriminated as the mechanism leading to cord infarction in severe neurological deficit occurring after foraminal steroid injections at the cervical spine. It has been suggested that the tendency of steroid particles to coalesce and the size of their final aggregates, which differ among the different types of particulate steroids, may influence the risk of arterial embolisation. To explore the mechanisms by which steroids provoke the cord infarction, we used intravital microscopy of mouse cremaster muscles to investigate the in vivo effects of an intra-arterial injection of four different particulate steroids, namely methylprednisolone acetate, triamcinolone acetonide, prednisolone acetate and cortivazol and one corticosteroid solution, namely dexamethasone sodium phosphate, on microvascular perfusion. Intra-arterial administration of 20 μL of pure prednisolone acetate or triamcinolone acetonide suspension completely stopped blood flow in all arterioles and venules, which decreased the functional capillary density to zero (see online supplementary material). Methylprednisolone acetate sharply decreased perfusion as well, although some blood flow was maintained in a few areas of the arteriolar and venular network. In contrast, intra-arterial administration of the cortivazol suspension or dexamethasone sodium phosphate solution did not change microvascular blood flow. The formation of macroaggregates of particulate steroids, which has been suggested to lead to vascular obliteration, was not observed in our animal experiments. An