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.

Although decompressive surgery following traumatic spinal cord injury (TSCI) is recommended, adequate surgical decompression is rarely verified via imaging. We utilized magnetic resonance imaging (MRI) to analyze the rate of spinal cord decompression after surgery. Pre-operative (within 8 h of injury) and post-operative (within 48 h of injury) MRI images of 184 motor complete patients (American Spinal Injury Association Impairment Scale [AIS] grade A = 119, AIS grade B = 65) were reviewed to verify spinal cord decompression. Decompression was defined as the presence of a patent subarachnoid space around a swollen spinal cord. Of the 184 patients, 100 (54.3%) underwent anterior cervical discectomy and fusion (ACDF), and 53 of them also underwent laminectomy. Of the 184 patients, 55 (29.9%) underwent anterior cervical corpectomy and fusion (ACCF), with (26 patients) or without (29 patients) laminectomy. Twenty-nine patients (16%) underwent stand-alone laminectomy. Decompression was verified in 121 patients (66%). The rates of decompression in patients who underwent ACDF and ACCF without laminectomy were 46.8% and 58.6%, respectively. Among these patients, performing a laminectomy increased the rate of decompression (72% and 73.1% of patients, respectively). Twenty-five of 29 (86.2%) patients who underwent a stand-alone laminectomy were found to be successfully decompressed. The rates of decompression among patients who underwent laminectomy at one, two, three, four, or five levels were 58.3%, 68%, 78%, 80%, and 100%, respectively (p < 0.001). In multi-variate logistic regression analysis, only laminectomy was significantly associated with successful decompression (odds ratio 4.85; 95% confidence interval 2.2-10.6; p < 0.001). In motor complete TSCI patients, performing a laminectomy significantly increased the rate of successful spinal cord decompression, independent of whether anterior surgery was performed.

Although many laboratories currently use small molecule inhibitors of the BMP (Dorsomorphin/DM) and TGF-β (SB431542/SB) signaling pathways in protocols to generate midbrain dopamine (mDA) neurons from hES and hiPS cells, until now, these substances have not been thought to play a role in the mDA differentiation process. We report here that the transient inhibition of constitutive BMP (pSMADs 1, 5, 8) signaling, either alone or in combination with TGF-β inhibition (pSMADs 2, 3), is critically important in the upstream regulation of Wnt1-Lmx1a signaling in mDA progenitors. We postulate that the mechanism via which DM or DM/SB mediates these effects involves the up-regulation in SMAD-interacting protein 1 (SIP1), which results in greater repression of the Wnt antagonist, secreted frizzled related protein 1 (Sfrp1) in stem cells. Accordingly, knockdown of SIP1 reverses the inductive effects of DM/SB on mDA differentiation while Sfrp1 knockdown/inhibition mimics DM/SB. The rise in Wnt1-Lmx1a levels in SMAD-inhibited cultures is, however, accompanied by a reciprocal down-regulation in SHH-Foxa2 levels leading to the generation of few TH+ neurons that co-express Foxa2. If however, exogenous SHH/FGF8 is added along with SMAD inhibitors, equilibrium in these two important pathways is achieved such that authentic (Lmx1a+Foxa2+TH+) mDA neuron differentiation is promoted while alternate cell fates are suppressed in stem cell cultures. These data indicate that activators/inhibitors of BMP and TGF-β signaling play a critical upstream regulatory role in the mDA differentiation process in human pluripotent stem cells.

The therapeutic significance of timing of decompression in acute traumatic central cord syndrome (ATCCS) caused by spinal stenosis remains unsettled. We retrospectively examined a homogenous cohort of patients with ATCCS and magnetic resonance imaging (MRI) evidence of post-treatment spinal cord decompression to determine whether timing of decompression played a significant role in American Spinal Injury Association (ASIA) motor score (AMS) 6 months following trauma. We used the t test, analysis of variance, Pearson correlation coefficient, and multiple regression for statistical analysis. During a 19-year period, 101 patients with ATCCS, admission ASIA Impairment Scale (AIS) grades C and D, and an admission AMS of ≤95 were surgically decompressed. Twenty-four of 101 patients had an AIS grade C injury. Eighty-two patients were males, the mean age of patients was 57.9 years, and 69 patients had had a fall. AMS at admission was 68.3 (standard deviation [SD] 23.4); upper extremities (UE) 28.6 (SD 14.7), and lower extremities (LE) 41.0 (SD 12.7). AMS at the latest follow-up was 93.1 (SD 12.8), UE 45.4 (SD 7.6), and LE 47.9 (SD 6.6). Mean number of stenotic segments was 2.8, mean canal compromise was 38.6% (SD 8.7%), and mean intramedullary lesion length (IMLL) was 23 mm (SD 11). Thirty-six of 101 patients had decompression within 24 h, 38 patients had decompression between 25 and 72 h, and 27 patients had decompression >72 h after injury. Demographics, etiology, AMS, AIS grade, morphometry, lesion length, surgical technique, steroid protocol, and follow-up AMS were not statistically different between groups treated at different times. We analyzed the effect size of timing of decompression categorically and in a continuous fashion. There was no significant effect of the timing of decompression on follow-up AMS. Only AMS at admission determined AMS at follow-up (coefficient = 0.31; 95% confidence interval [CI]:0.21; p = 0.001). We conclude that timing of decompression in ATCCS caused by spinal stenosis has little bearing on ultimate AMS at follow-up.

BACKGROUND Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily). OBJECTIVE To assess the safety and efficacy of LDIVH in aSAH patients. METHODS We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). RESULTS The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. CONCLUSION This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

OBJECTIVE The authors sought to evaluate whether a sustained systemic inflammatory response was associated with shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage. METHODS A retrospective analysis of 193 consecutive patients with aneurysmal subarachnoid hemorrhage was performed. Management of hydrocephalus followed a stepwise algorithm to determine the need for external CSF drainage and subsequent shunt placement. Systemic inflammatory response syndrome (SIRS) data were collected for all patients during the first 7 days of hospitalization. Patients who met the SIRS criteria every day for the first 7 days of hospitalization were considered as having a sustained SIRS. Univariate and multivariate regression analyses were used to determine predictors of shunt dependence. RESULTS Sixteen percent of patients required shunt placement. Sustained SIRS was observed in 35% of shunt-dependent patients compared to 14% in non-shunt-dependent patients (p = 0.004). On multivariate logistic regression, female sex (OR 0.35, 95% CI 0.142-0.885), moderate to severe vasospasm (OR 3.78, 95% CI 1.333-10.745), acute hydrocephalus (OR 21.39, 95% CI 2.260-202.417), and sustained SIRS (OR 2.94, 95% CI 1.125-7.689) were significantly associated with shunt dependence after aneurysmal subarachnoid hemorrhage. Receiver operating characteristic analysis revealed an area under the curve of 0.83 for the final regression model. CONCLUSIONS Sustained SIRS was a predictor of shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage even after adjustment for potential confounding variables in a multivariate logistic regression model.

Over the past four decades, there have been progressive changes in the epidemiology of traumatic spinal cord injury (tSCI). We assessed trends in demographic and injury-related variables in traumatic cervical spinal cord injury (tCSCI) patients over an 18-year period at a single Level I trauma center. We included all magnetic resonance imaging-confirmed tCSCI patients ‡15 years of age for years 2001-2018. Among 1420 patients, 78.3% were male with a mean age 51.5 years. Etiology included falls (46.9%), motor vehicle collisions (MVCs; 34.2%), and sports injuries (10.9%). Median American Spinal Injury Association (ASIA) Motor Score (AMS) was 44, complete tCSCI was noted in 29.6% of patients, fracture dislocations were noted in 44.7%, and median intramedullary lesion length (IMLL) was 30.8 mm (complete injuries 56.3 mm and incomplete injuries 27.4 mm). Over the study period, mean age and proportion of falls increased ( p < 0.001) whereas proportion attributable to MVCs and sports injuries decreased ( p < 0.001). Incomplete injuries, AMS, and the proportion of patients with no fracture dislocations increased whereas complete injuries decreased significantly. IMLL declined ( p = 0.17) and proportion with hematomyelia did not change significantly. In adjusted regression models, increase in age and decreases in prevalence of MVC mechanism and complete injuries over time remained statistically significant. Changes in demographic and injury-related characteristics of tCSCI patients over time may help explain the observed improvement in outcomes. Further, improved clinical outcomes and drop in IMLL may reflect improvements in initial risk assessment and pre-hospital management, advances in healthcare delivery, and preventive measures including public education.

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