No abstract

Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.

Traumatic spinal cord injury (SCI) is a devastating condition of motor, sensory, and autonomic dysfunction. The significant cost associated with the management and lifetime care of patients with SCI also presents a major economic burden. For these reasons, there is a need to develop and translate strategies that can improve outcomes following SCI. Given the challenges in achieving regeneration of the injured spinal cord, neuroprotection has been at the forefront of clinical translation. Yet, despite many preclinical advances, there has been limited translation into the clinic apart from methylprednisolone (which remains controversial), hypertensive therapy to maintain spinal cord perfusion, and early decompressive surgery. While there are several factors related to the limited translational success, including the clinical and mechanistic heterogeneity of human SCI, the misalignment between animal models of SCI and clinical reality continues to be an important factor. Whereas most clinical cases are at the cervical level, only a small fraction of preclinical research is conducted in cervical models of SCI. Therefore, this review highlights the most promising neuroprotective and neural reparative therapeutic strategies undergoing clinical assessment, including riluzole, hypothermia, granulocyte colony-stimulating factor, glibenclamide, minocycline, Cethrin (VX-210), and anti-Nogo-A antibody, and emphasizes their efficacy in relation to the anatomical level of injury. Our hope is that more basic research will be conducted in clinically relevant cervical SCI models in order to expedite the transition of important laboratory discoveries into meaningful treatment options for patients with SCI.