In cervical traumatic spinal cord injury (TSCI), the therapeutic effect of timing of surgery on neurological recovery remains uncertain. Additionally, the relationship between extent of decompression, imaging biomarker evidence of injury severity, and outcome is incompletely understood. We investigated the effect of timing of decompression on long-term neurological outcome in patients with complete spinal cord decompression confirmed on postoperative magnetic resonance imaging (MRI). American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade conversion was determined in 72 AIS grades A, B, and C patients 6 months after confirmed decompression. Thirty-two patients underwent decompressive surgery ultra-early (< 12 h), 25 underwent decompressive surgery early (12-24 h), and 15 underwent decompressive surgery late (> 24-138.5 h) after injury. Age, gender, injury mechanism, intramedullary lesion length (IMLL) on MRI, admission ASIA motor score, and surgical technique were not statistically different among groups. Motor complete patients (p = 0.009) and those with fracture dislocations (p = 0.01) tended to be operated on earlier. Improvement of one grade or more was present in 55.6% of AIS grade A, 60.9% of AIS grade B, and 86.4% of AIS grade C patients. Admission AIS motor score (p = 0.0004) and pre-operative IMLL (p = 0.00001) were the strongest predictors of neurological outcome. AIS grade improvement occurred in 65.6%, 60%, and 80% of patients who underwent decompression ultra-early, early, and late, respectively (p = 0.424). Multiple regression analysis revealed that IMLL was the only significant variable predictive of AIS grade conversion to a better grade (odds ratio, 0.908; confidence interval [CI], 0.862-0.957; p < 0.001). We conclude that in patients with post-operative MRI confirmation of complete decompression following cervical TSCI, pre-operative IMLL, not the timing of surgery, determines long-term neurological outcome.

OBJECTIVE Optimal strategies for fixation in the osteoporotic lumbar spine remain a clinical issue. Classic transpedicular fixation in the osteoporotic spine is frequently plagued with construct instability, often due to inadequate cortical screw–bone purchase. A cortical bone trajectory maximizes bony purchase and has been reported to provide increased screw pullout strength. The aim of the current investigation was to evaluate the biomechanical efficacy of cortical spinal fixation as a surgical alternative to transpedicular fixation in the osteoporotic lumbar spine under physiological loading. METHODS Eight fresh-frozen human spinopelvic specimens with low mean bone mineral densities (T score less than or equal to –2.5) underwent initial destabilization, consisting of laminectomy and bilateral facetectomies (L2–3 and L4–5), followed by pedicle or cortical reconstructions randomized between levels. The surgical constructs then underwent fatigue testing followed by tensile load to failure pullout testing to quantify screw pullout force. RESULTS When stratifying the pullout data with fixation technique and operative vertebral level, cortical screw fixation exhibited a marked increase in mean load at failure in the lower vertebral segments (p = 0.188, 625.6 ± 233.4 N vs 450.7 ± 204.3 N at L-4 and p = 0.219, 640.9 ± 207.4 N vs 519.3 ± 132.1 N at L-5) while transpedicular screw fixation demonstrated higher failure loads in the superior vertebral elements (p = 0.024, 783.0 ± 516.1 N vs 338.4 ± 168.2 N at L-2 and p = 0.220, 723.0 ± 492.9 N vs 469.8 ± 252.0 N at L-3). Although smaller in diameter and length, cortical fixation resulted in failures that were not significantly different from larger pedicle screws (p > 0.05, 449.4 ± 265.3 N and 541.2 ± 135.1 N vs 616.0 ± 384.5 N and 484.0 ± 137.1 N, respectively). CONCLUSIONS Cortical screw fixation exhibits a marked increase in mean load at failure in the lower vertebral segments and may offer a viable alternative to traditional pedicle screw fixation, particularly for stabilization of lower lumbar vertebral elements with definitive osteoporosis.

Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.

First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

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