Studying missingness in spinal cord injury data: challenges and impact of data imputation.

BACKGROUND: In the last decades, medical research fields studying rare conditions such as spinal cord injury (SCI) have made extensive efforts to collect large-scale data. However, most analysis methods rely on complete data. This is particularly troublesome when studying clinical data as they are prone to missingness. Often, researchers mitigate this problem by removing patients with missing data from the analyses. Less commonly, imputation methods to infer likely values are applied. OBJECTIVE: Our objective was to study how handling missing data influences the results reported, taking the example of SCI registries. We aimed to raise awareness on the effects of missing data and provide guidelines to be applied for future research projects, in SCI research and beyond. METHODS: Using the Sygen clinical trial data (n = 797), we analyzed the impact of the type of variable in which data is missing, the pattern according to which data is missing, and the imputation strategy (e.g. mean imputation, last observation carried forward, multiple imputation). RESULTS: Our simulations show that mean imputation may lead to results strongly deviating from the underlying expected results. For repeated measures missing at late stages (> = 6 months after injury in this simulation study), carrying the last observation forward seems the preferable option for the imputation. This simulation study could show that a one-size-fit-all imputation strategy falls short in SCI data sets. CONCLUSIONS: Data-tailored imputation strategies are required (e.g., characterisation of the missingness pattern, last observation carried forward for repeated measures evolving to a plateau over time). Therefore, systematically reporting the extent, kind and decisions made regarding missing data will be essential to improve the interpretation, transparency, and reproducibility of the research presented.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Methylprednisolone in acute traumatic spinal cord injury: case-matched outcomes from the NASCIS2 and Sygen historical spinal cord injury studies with contemporary statistical analysis.

OBJECTIVE: Methylprednisolone (MP) to treat acute traumatic spinal cord injury (ATSCI) remains controversial since the release of the second National Acute Spinal Cord Injury Study (NASCIS2) in 1990. As two historical studies, NASCIS2 and Sygen in ATSCI, used identical MP dosages, it was possible to construct a new case-level pooled ATSCI data set satisfying contemporary criteria and able to clarify the effect of MP. METHODS: The new pooled data set was first modernized by excluding patients with injury levels caudal to T10, lower-extremity American Spinal Injury Association (ASIA) motor scores (LEMSs) ≥ 46, Glasgow Coma Scale scores ≤ 11, and age < 15 or > 75 years, and then standardized to the ASIA grading and scoring format. A new updated NASCIS2 data set from this pooled data set contained 31.6% fewer patients than the 1990 NASCIS2 data set. RESULTS: In the new pooled data set, recovery of LEMSs from baseline to 26 weeks, the primary outcome variable, was separated statistically into five different injury severity cohorts (p < 0.0001). The severity cohorts contained groups with severe floor (62.9%) and ceiling (10.7%) effects, which do not contribute to drug effects. The new NASCIS2 data set duplicated the p value for MP versus placebo in the sub-subgroup analysis of MP initiated ≤ 8 hours (the subgroup) and recovery of motor function on only the right side of the body (a further subgroup within the ≤ 8-hour subgroup), presented as the positive MP effect in the original NASCIS2 reporting. However, current statistical interpretation considers results seen only in post hoc sub-subgroups, without multi-test corrections, to be random effects without clinical significance. The combined case-level pooled data set from the NASCIS2 and Sygen studies increased the MP group from 106 to 431 patients, creating a new MP combined group. This new data set served as a surrogate for a contemporary MP study and found that administration of MP did not enhance ASIA motor score improvement in the lower extremities at 26 weeks. Secondary analysis of descending ASIA motor and sensory cervical neurological levels in cervical ATSCI patients at 26 weeks also found no MP drug effect. CONCLUSIONS: Analysis of both the new updated NASCIS2 data set and the new case-matched pooled data set from two historical ATSCI studies revealed that administration of MP after spinal cord injury did not demonstrate any enhancement in neurological recovery at 26 weeks. The results of this analysis warrant review by clinical guideline groups.

Early vs Late Surgical Decompression for Central Cord Syndrome.

Importance: The optimal clinical management of central cord syndrome (CCS) remains unclear; yet this is becoming an increasingly relevant public health problem in the face of an aging population. Objective: To provide a head-to-head comparison of the neurologic and functional outcomes of early (<24 hours) vs late (≥24 hours) surgical decompression for CCS. Design, Setting, and Participants: Patients who underwent surgery for CCS (lower extremity motor score [LEMS] - upper extremity motor score [UEMS] ≥ 5) were included in this propensity score-matched cohort study. Data were collected from December 1991 to March 2017, and the analysis was performed from March 2020 to January 2021. This study identified patients with CCS from 3 international multicenter studies with data on the timing of surgical decompression in spinal cord injury. Participants were included if they had a documented baseline neurologic examination performed within 14 days of injury. Participants were eligible if they underwent surgical decompression for CCS. Exposures: Early surgery was compared with late surgery. Main Outcomes and Measures: Propensity scores were calculated as the probability of undergoing early compared with late surgery using the logit method and adjusting for relevant confounders. Propensity score matching was performed in a 1:1 ratio by an optimal-matching technique. The primary end point was motor recovery (UEMS, LEMS, American Spinal Injury Association [ASIA] motor score [AMS]) at 1 year. Secondary end points were Functional Independence Measure (FIM) motor score and complete independence in each FIM motor domain at 1 year. Results: The final study cohort consisted of 186 patients with CCS. The early-surgery group included 93 patients (mean [SD] age, 47.8 [16.8] years; 66 male [71.0%]), and the late-surgery group included 93 patients (mean [SD] age, 48.0 [15.5] years; 75 male [80.6%]). Early surgical decompression resulted in significantly improved recovery in upper limb (mean difference [MD], 2.3; 95% CI, 0-4.5; P = .047), but not lower limb (MD, 1.1; 95% CI, -0.8 to 3.0; P = .30), motor function. In an a priori-planned subgroup analysis, outcomes were comparable with early or late decompressive surgery in patients with ASIA Impairment Scale (AIS) grade D injury. However, in patients with AIS grade C injury, early surgery resulted in significantly greater recovery in overall motor score (MD, 9.5; 95% CI, 0.5-18.4; P = .04), owing to gains in both upper and lower limb motor function. Conclusions and Relevance: This cohort study found early surgical decompression to be associated with improved recovery in upper limb motor function at 1 year in patients with CCS. Treatment paradigms for CCS should be redefined to encompass early surgical decompression as a neuroprotective therapy.

A Novel Method to Classify Cervical Incomplete Spinal Cord Injury Based on Potential for Recovery: A Group-Based Trajectory Analysis.

The outcomes of cervical incomplete spinal cord injury (SCI) are heterogeneous. This study sought to dissociate subgroups of cervical incomplete SCI patients with distinct longitudinal temporal profiles of recovery in upper limb motor function. Patients with cervical incomplete SCI (American Spinal Injury Association Impairment Scale [AIS] B-D; C1-C8) were identified from four prospective, multi-center SCI datasets. A group-based trajectory model was fit to longitudinal upper extremity motor scores out to 1 year. Multi-variable multinomial logistic regression was performed to identify features that characterize each trajectory group. A classification system for predicting trajectory group at baseline was developed by recursive partitioning. In total, 801 patients were eligible. Four distinct trajectory groups were identified: 1) "Poor outcome": Severe injury, very minimal recovery; 2) "Moderate recovery": Moderate-to-severe injury, moderate recovery; most recovery occurs by 6 months, with mild, gradual recovery continuing thereafter; 3) "Good recovery": Moderate injury, good recovery; most recovery occurs by 3 months, with mild, gradual recovery continuing thereafter; and 4) "Excellent outcome": Mild injury, recovery to normal/near-normal by 3 months. On adjusted analyses, older age was associated with lower likelihood of "excellent outcome" (p = 0.020). AIS C and D injuries were associated with "moderate recovery," "good recovery," and "excellent outcome" (p < 0.001). Mid-cervical injuries occurred more frequently in "moderate recovery," "good recovery," and "excellent outcome" (p < 0.001) groups. Early surgical decompression (< 24 h) was associated with increased propensity for "good recovery" (p = 0.039) and "excellent outcome" (p = 0.048). A classification model based on recursive partitioning could predict trajectory group using age, AIS grade, and neurological level with an area under the curve of 0.81. Patients with cervical incomplete SCI demonstrate distinct temporal profiles of recovery in upper limb motor function. The trajectory a patient is likely to follow may be predicted at baseline with fair accuracy.

International surveillance study in acute spinal cord injury confirms viability of multinational clinical trials.

BACKGROUND: The epidemiological international landscape of traumatic spinal cord injury (SCI) has evolved over the last decades along with given inherent differences in acute care and rehabilitation across countries and jurisdictions. However, to what extent these differences may influence neurological and functional recovery as well as the integrity of international trials is unclear. The latter also relates to historical clinical data that are exploited to inform clinical trial design and as potential comparative data. METHODS: Epidemiological and clinical data of individuals with traumatic and ischemic SCI enrolled in the European Multi-Center Study about Spinal Cord Injury (EMSCI) were analyzed. Mixed-effect models were employed to account for the longitudinal nature of the data, efficiently handle missing data, and adjust for covariates. The primary outcomes comprised demographics/injury characteristics and standard scores to quantify neurological (i.e., motor and sensory scores examined according to the International Standards for the Neurological Classification of Spinal Cord Injury) and functional recovery (walking function). We externally validated our findings leveraging data from a completed North American landmark clinical trial. RESULTS: A total of 4601 patients with acute SCI were included. Over the course of 20 years, the ratio of male to female patients remained stable at 3:1, while the distribution of age at injury significantly shifted from unimodal (2001/02) to bimodal distribution (2019). The proportional distribution of injury severities and levels remained stable with the largest percentages of motor complete injuries. Both, the rate and pattern of neurological and functional recovery, remained unchanged throughout the surveillance period despite the increasing age at injury. The findings related to recovery profiles were confirmed by an external validation cohort (n=791). Lastly, we built an open-access and online surveillance platform ("Neurosurveillance") to interactively exploit the study results and beyond. CONCLUSIONS: Despite some epidemiological changes and considerable advances in clinical management and rehabilitation, the neurological and functional recovery following SCI has remained stable over the last two decades. Our study, including a newly created open-access and online surveillance tool, constitutes an unparalleled resource to inform clinical practice and implementation of forthcoming clinical trials targeting neural repair and plasticity in acute spinal cord injury.

A New Score Based on the International Standards for Neurological Classification of Spinal Cord Injury for Integrative Evaluation of Changes in Sensorimotor Functions.

Sensorimotor function of patients with spinal cord injury (SCI) is commonly assessed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). From the ISNCSCI segmental motor and sensory assessments, upper and lower extremity motor scores (UEMS and LEMS), sum scores of pinprick (PP) and light touch (LT) sensation, the neurological level of injury (NLI) and the classification of lesion severity according to the American Spinal Injury Association Impairment Scale (AIS) grade are derived. Changes of these parameters over time are used widely to evaluate neurological recovery. Evaluating recovery based on a single ISNCSCI scoring or classification variable, however, may misestimate overall recovery. Here, we propose an Integrated Neurological Change Score (INCS) based on the combination of normalized changes between two time points of UEMS, LEMS, and total PP and LT scores. To assess the agreement of INCS with clinical judgment of meaningfulness of neurological changes, changes of ISNCSCI variables between two time points of 88 patients from an independent cohort were rated by 20 clinical experts according to a five-categories Likert Scale. As for individual ISNCSCI variables, neurological change measured by INCS is associated with severity (AIS grade), age, and time since injury, but INCS better reflects clinical judgment about meaningfulness of neurological changes than individual ISNCSCI variables. In addition, INCS is related to changes in functional independence measured by the Spinal Cord Independence Measure (SCIM) in patients with tetraplegia. The INCS may be a useful measure of overall neurological change in clinical studies.

Natural Progression of Routine Laboratory Markers after Spinal Trauma: A Longitudinal, Multi-Cohort Study.

Our objective was to track and quantify the natural course of serological markers over the 1st year following spinal cord injury. For that purpose, data on serological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau study). The primary outcomes were concentration/levels/amount of commonly collected serological markers at multiple time points. Two-way analysis of variance (ANOVA) and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of serological markers contained in both data sources were compared using the slope of progression. Our results show that, at baseline (≤ 2 weeks post-injury), most serological markers were at pathological levels, but returned to normal values over the course of 6-12 months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g., hematocrit, ANOVA test; χ2 = 68.93, df = 3, adjusted p value <0.001, and χ2 = 73.80, df = 3, adjusted p value <0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the serological markers, which are likely attributable to differences in study design, sample size, and standard of care. We conclude that because of trauma-induced physiological perturbations, serological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important, as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance web site (https://jutzelec.shinyapps.io/Haemosurveillance/) and GitHub repository (https://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury).

Trajectory-Based Classification of Recovery in Sensorimotor Complete Traumatic Cervical Spinal Cord Injury.

OBJECTIVE: To test the hypothesis that sensorimotor complete traumatic cervical spinal cord injury is a heterogenous clinical entity comprising several subpopulations that follow fundamentally different trajectories of neurologic recovery. METHODS: We analyzed demographic and injury data from 655 patients who were pooled from 4 prospective longitudinal multicenter studies. Group based trajectory modeling was applied to model neurologic recovery trajectories over the initial 12-months postinjury and to identify predictors of recovery trajectories. Neurologic outcomes included: Upper Extremity Motor Score, Total Motor Scores and AIS grade improvement. RESULTS: The analysis identified 3 distinct trajectories of neurologic recovery. These clinical courses included: (1) Marginal recovery trajectory: characterized by minimal or no improvement in motor strength or change in AIS grade status (remained grade A); (2) Moderate recovery trajectory: characterized by low baseline motor scores that improved approximately 13 points; or AIS conversion of one grade point; (3) Good recovery trajectory: characterized by baseline motor scores in the upper quartile that improved to near maximum values within 3 months of injury. Patients following the moderate or good recovery trajectories were of younger age, had more caudally located injuries, a higher degree of preserved motor and sensory function at baseline examination and exhibited a greater extent of motor and sensory function in the zone of partial preservation. CONCLUSION: Cervical complete SCI can be classified into one of 3 distinct subpopulations with fundamentally different trajectories of neurologic recovery. This study defines unique clinical phenotypes based on potential for recovery, rather than baseline severity of injury alone. This approach may prove beneficial in clinical prognostication and in the design and interpretation of clinical trials in SCI.

Routine Blood Chemistry Predicts Functional Recovery After Traumatic Spinal Cord Injury: A Post Hoc Analysis.

BACKGROUND: Spinal cord injury (SCI) leads to various degrees of lifelong functional deficits. Most individuals with incomplete SCI experience a certain degree of functional recovery, especially within the first-year postinjury. However, this is difficult to predict, and surrogate biomarkers are urgently needed. OBJECTIVE: We aimed to (1) determine if routine blood chemistry parameters are related to neurological recovery after SCI, (2) evaluate if such parameters could predict functional recovery, and (3) establish cutoff values that could inform clinical decision-making. METHODS: We performed a post hoc analysis of routine blood chemistry parameters in patients with traumatic SCI (n = 676). Blood samples were collected between 24 and 72 hours as well as at 1, 2, 4, 8, and 52 weeks postinjury. Linear mixed models, regression analysis, and unbiased recursive partitioning (URP) of blood chemistry data were used to relate to and predict walking recovery 1 year postinjury. RESULTS: The temporal profile of platelet counts and serum levels of albumin, alkaline phosphatase, and creatinine differentiated patients who recovered walking from those who remained wheelchair bound. The 4 blood chemistry parameters from the sample collection 8 weeks postinjury predicted functional recovery observed 1 year after incomplete SCI. Finally, URP defined a cutoff for serum albumin at 3.7 g/dL, which in combination with baseline injury severity differentiates individuals who regain ambulation from those not able to walk. Specifically, about 80% of those with albumin >3.7 g/dL recovered walking. CONCLUSIONS: Routine blood chemistry data from the postacute phase, together with baseline injury severity, predict functional outcome after incomplete SCI.

Serum albumin as a predictor of neurological recovery after spinal cord injury: a replication study.

STUDY DESIGN: This was a secondary analysis on an observational cohort study. OBJECTIVE: To determine if serum albumin significantly associates with long-term neurological outcome (i.e., 1-year post-injury) in a contemporary cohort of individuals with spinal cord injury. SETTING: Six rehabilitation centers across the United States. METHODS: A secondary analysis of neurological outcomes and serum albumin concentrations was performed on data from the Spinal Cord Injury Rehabilitation study. Data was accessed from the Archive of Data on Disability to Enable Policy and research (ADDEP). The primary analysis applied unbiased recursive partitioning to examine the relationship between serum albumin, injury severity, and long-term outcomes. The analysis is accessible via https://rpubs.com/AnhKhoaVo/586028 . RESULTS: Serum albumin concentration was significantly associated with lower extremity motor scores (LEMS) and American Spinal Injury Association Impairment Scale (AIS) grade at admission to rehabilitation. Serum albumin concentrations alone were also significantly associated with change of LEMS and marked recovery (improvement of at least 2 AIS grades and/or recovery to walking) at 1-year post injury. However, after adjusting for admission to rehabilitation LEMS and AIS grade, serum albumin was not significant. CONCLUSION: The current study partially confirms our previous observations that serum albumin concentrations are associated with neurological outcome after spinal cord injury. As a crude prognostic biomarker, serum albumin concentration could be useful in cases where injury severity cannot be accurately assessed.

The influence of timing of surgical decompression for acute spinal cord injury: a pooled analysis of individual patient data.

BACKGROUND: Although there is a strong biological rationale for early decompression of the injured spinal cord, the influence of the timing of surgical decompression for acute spinal cord injury (SCI) remains debated, with substantial variability in clinical practice. We aimed to objectively evaluate the effect of timing of decompressive surgery for acute SCI on long-term neurological outcomes. METHODS: We did a pooled analysis of individual patient data derived from four independent, prospective, multicentre data sources, including data from December, 1991, to March, 2017. Three of these studies had been published; of these, only one study previously specifically analysed the effect of the timing of surgical decompression. These four datasets were selected because they were among the highest quality acute SCI datasets available and contained highly granular data. Individual patient data were obtained by request from study authors. All patients who underwent decompressive surgery for acute SCI within these datasets were included. Patients were stratified into early (<24 h after spinal injury) and late (≥24 h after spinal injury) decompression groups. Neurological outcomes were assessed by American Spinal Injury Association (ASIA), or International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), examination. The primary endpoint was change in total motor score from baseline to 1 year after spinal injury. Secondary endpoints were ASIA Impairment Scale (AIS) grade and change in upper-extremity motor, lower-extremity motor, light touch, and pin prick scores after 1 year. One-stage meta-analyses were done by hierarchical mixed-effects regression adjusting for baseline score, age, mechanism of injury, AIS grade, level of injury, and administration of methylprednisolone. Effect sizes were summarised by mean difference (MD) for sensorimotor scores and common odds ratio (cOR) for AIS grade, with corresponding 95% CIs. As a secondary analysis, change in total motor score was regressed against time to surgical decompression (h) as a continuous variable, using a restricted cubic spline with adjustment for the same covariates as in the primary analysis. FINDINGS: We identified 1548 eligible patients from the four datasets. Outcome data at 1 year after spinal injury were available for 1031 patients (66·6%). Patients who underwent early surgical decompression (n=528) experienced greater recovery than patients who had late decompression surgery (n=1020) at 1 year after spinal injury; total motor scores improved by 23·7 points (95% CI 19·2-28·2) in the early surgery group versus 19·7 points (15·3-24·0) in the late surgery group (MD 4·0 points [1·7-6·3]; p=0·0006), light touch scores improved by 19·0 points (15·1-23·0) vs 14·8 points (11·2-18·4; MD 4·3 [1·6-7·0]; p=0·0021), and pin prick scores improved by 18·3 points (13·7-22·9) versus 14·2 points (9·8-18·6; MD 4·0 [1·5-6·6]; p=0·0020). Patients who had early decompression also had better AIS grades at 1 year after surgery, indicating less severe impairment, compared with patients who had late surgery (cOR 1·48 [95% CI 1·16-1·89]; p=0·0019). When time to surgical decompression was modelled as a continuous variable, there was a steep decline in change in total motor score with increasing time during the first 24-36 h after injury (p<0·0001); and after 36 h, change in total motor score plateaued. INTERPRETATION: Surgical decompression within 24 h of acute SCI is associated with improved sensorimotor recovery. The first 24-36 h after injury appears to represent a crucial time window to achieve optimal neurological recovery with decompressive surgery following acute SCI. FUNDING: None.

Nerve Root Sedimentation Sign: Can It Predict the Success for Surgical Intervention in Patients With Symptomatic Lumbar Spinal Stenosis?

INTRODUCTION:  The use of interspinous process devices are less invasive surgical methods designed to manage mild to moderate lumbar spinal stenosis symptoms. Symptomatic relief may not be seen in all patients undergoing this procedure. Magnetic resonance imaging (MRI) parameters have been used to predict the success of clinical outcomes in patients with symptomatic lumbar spinal stenosis for decompressive surgeries. The purpose of this study was to determine the feasibility of using nerve root sedimentation sign to predict mid- to long-term clinical outcomes of patients treated with interspinous spacers for lumbar spinal stenosis. METHODS: This was a retrospective study using prospective multicenter Food and Drug Administration Investigational Device Exemption (FDA IDE) trial (Superion™ and X-STOP®) data. Inclusion criteria were patients treated with interspinous spacers, aged 45 or older with lumbar spinal stenosis at one or more contiguous levels from L1 to L5 and symptoms of neurogenic claudication. Preoperative axial T2 weighted MRI images were used to determine nerve root sedimentation sign. Preoperative, six-week, one- and two-year postoperative clinical outcomes were measured using Oswestry Disability Index (ODI) scores. Clinical outcomes were compared between positive and negative nerve root sedimentation sign groups; p ≤0.05 was considered significant. RESULTS: This study included n=374 patients; 40 excluded; 334 included (113=positive nerve root sedimentation sign (NRSS) (34%) and 221=negative NRSS (66%)). At six weeks, significant postoperative ODI correction was noted in both groups (p<0.001). No significant differences in ODI scores were identified between groups. A subgroup analysis with MRI image quality grade 3 and certainty determination grade 5, six-week postoperative ODI correction was significant in both groups. Six-week, one- and two-year postoperative ODI scores were greater by 6 points in the positive nerve root sedimentation sign group compared to the negative nerve root sedimentation sign group. CONCLUSIONS:  Although satisfactory postoperative improvement occurred in both groups, there were statistically significant differences noted in certain sub-categories. The subgroup analysis indicated MRI image quality and nerve root sedimentation sign certainty of determination may be factors that may aid with planning the surgical management of lumbar spinal stenosis.

Gangliosides: Treatment Avenues in Neurodegenerative Disease.

Gangliosides are cell membrane components, most abundantly in the central nervous system (CNS) where they exert among others neuro-protective and -restorative functions. Clinical development of ganglioside replacement therapy for several neurodegenerative diseases was impeded by the BSE crisis in Europe during the 1990s. Nowadays, gangliosides are produced bovine-free and new pre-clinical and clinical data justify a reevaluation of their therapeutic potential in neurodegenerative diseases. Clinical experience is greatest with monosialo-tetrahexosyl-ganglioside (GM1) in the treatment of stroke. Fourteen randomized controlled trials (RCTs) in overall >2,000 patients revealed no difference in survival, but consistently superior neurological outcomes vs. placebo. GM1 was shown to attenuate ischemic neuronal injuries in diabetes patients by suppression of ERK1/2 phosphorylation and reduction of stress to the endoplasmic reticulum. There is level-I evidence from 5 RCTs of a significantly faster recovery with GM1 vs. placebo in patients with acute and chronic spinal cord injury (SCI), disturbance of consciousness after subarachnoid hemorrhage, or craniocerebral injuries due to closed head trauma. In Parkinson's disease (PD), two RCTs provided evidence of GM1 to be superior to placebo in improving motor symptoms and long-term to result in a slower than expected symptom progression, suggesting disease-modifying potential. In Alzheimer's disease (AD), the role of gangliosides has been controversial, with some studies suggesting a "seeding" role for GM1 in amyloid ß polymerization into toxic forms, and others more recently suggesting a rather protective role in vivo. In Huntington's disease (HD), no clinical trials have been conducted yet. However, low GM1 levels observed in HD cells were shown to increase cell susceptibility to apoptosis. Accordingly, treatment with GM1 increased survival of HD cells in vitro and consistently ameliorated pathological phenotypes in several murine HD models, with effects seen at molecular, cellular, and behavioral level. Given that in none of the clinical trials using GM1 any clinically relevant safety issues have occurred to date, current data supports expanding GM1 clinical research, particularly to conditions with high, unmet medical need.

The Effect of Non-Gabapentinoid Anticonvulsants on Sensorimotor Recovery After Human Spinal Cord Injury.

BACKGROUND: Recent observational studies have shown an association between gabapentinoid anticonvulsants and greater motor recovery after spinal cord injury. There is preclinical evidence to suggest that other anticonvulsants, such as sodium channel blockers, may also confer beneficial effects. PURPOSE: The aim of the current study was to determine if non-gabapentinoid anticonvulsants were associated with neurological recovery after acute, traumatic spinal cord injury. METHODS: This was an observational cohort study using data from the Sygen clinical trial. The primary outcome was total motor score recovery in the first year after injury. Anticonvulsant use was extracted from concomitant medication records; individuals were classified based on early administration (within 30 days of injury), or late/no administration. Motor recovery was compared using linear mixed effects regression models with a drug-by-time interaction, and adjustment for confounders. A secondary analysis incorporated a propensity score matched cohort. RESULTS: Of the cohort (n = 570), 6% received anticonvulsants (carbamazepine, phenytoin, clonazepam, phenobarbital, and valproic acid) early after injury. After adjustments for initial injury level and severity, early exposure to non-gabapentinoid anticonvulsants was not associated with motor neurological outcomes (p = 0.38 for all anticonvulsants, p = 0.83 for sodium channel blockers, p = 0.82 in propensity-matched cohort). CONCLUSION: Non-gabapentinoid anticonvulsant exposure was not associated with greater or lesser neurological recovery. This suggests that these medications, as administered for the acute management of spinal cord injury, do not impact long-term neurological outcomes.

A Longitudinal Study of the Neurologic Safety of Acute Baclofen Use After Spinal Cord Injury.

The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with "marked recovery" defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5-3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.

Interspinous Process Decompression Improves Quality of Life in Patients with Lumbar Spinal Stenosis.

Lumbar spinal stenosis has been shown to negatively impact health-related quality of life. Interspinous process decompression (IPD) is a minimally invasive procedure that utilizes a stand-alone spacer to serve as a joint extension blocker to relieve neural compression in patients with spinal stenosis. Using the 5-year results from an FDA randomized controlled trial of IPD, the quality of life in 189 patients treated with the Superion® spacer was evaluated with the SF-12. Physical and mental component summary (PCS, MCS) scores were computed preoperatively and at annual intervals. For the PCS, mean scores improved from 29.4 ± 8.1 preoperatively to 41.2 ± 12.4 at 2 years (40%) and to 43.8 ± 11.6 at 5 years (49%) (p<0.001 for both comparisons). At 2 years, 81% (103 of 128) of subjects demonstrated maintenance or improvement in PCS scores. The mean MCS score improved from 50.0 ± 12.7 preoperatively to 54.4 ± 10.6 and 54.7 ± 8.6 at 2 and 5 years, respectively (p>0.10 for both comparisons). These results demonstrate that the significant impairment in physical well-being found in patients with lumbar spinal stenosis can be ameliorated, in large part, by IPD treatment.

Serum Albumin Predicts Long-Term Neurological Outcomes After Acute Spinal Cord Injury.

BACKGROUND: There is a need to identify reliable biomarkers of spinal cord injury recovery for clinical practice and clinical trials. OBJECTIVE: Our objective was to correlate serum albumin levels with spinal cord injury neurological outcomes. METHODS: We performed a secondary analysis of patients with traumatic spinal cord injury (n = 591) participating in the Sygen clinical trial. Serum albumin concentrations were obtained as part of routine blood chemistry analysis, at trial entry (24-72 hours), 1, 2, and 4 weeks after injury. The primary outcomes were "marked recovery" and lower extremity motor scores, derived from the International Standards for the Neurological Classification of Spinal Cord Injury. Data were analyzed with multivariable logistic and linear regression to adjust for potential confounders. RESULTS: Serum albumin was significantly associated with spinal cord injury neurological outcomes. Higher serum albumin concentrations at 1, 2, and 4 weeks were associated with higher 52-week lower extremity motor score. Similarly, the odds of achieving "marked neurological recovery" was greater for individuals with higher serum albumin concentrations. The association between serum albumin concentrations and neurological outcomes was independent of initial injury severity, treatment with GM-1, and polytrauma. CONCLUSIONS: In spinal cord injury, serum albumin is an independent marker of long-term neurological outcomes. Serum albumin could serve as a feasible biomarker for prognosis at the time of injury and stratification in clinical trials.

Five-year durability of stand-alone interspinous process decompression for lumbar spinal stenosis.

BACKGROUND: Lumbar spinal stenosis is the most common indication for spine surgery in older adults. Interspinous process decompression (IPD) using a stand-alone spacer that functions as an extension blocker offers a minimally invasive treatment option for intermittent neurogenic claudication associated with spinal stenosis. METHODS: This study evaluated the 5-year clinical outcomes for IPD (Superion®) from a randomized controlled US Food and Drug Administration (FDA) noninferiority trial. Outcomes included Zurich Claudication Questionnaire (ZCQ) symptom severity (ss), physical function (pf), and patient satisfaction (ps) subdomains, leg and back pain visual analog scale (VAS), and Oswestry Disability Index (ODI). RESULTS: At 5 years, 84% of patients (74 of 88) demonstrated clinical success on at least two of three ZCQ domains. Individual ZCQ domain success rates were 75% (66 of 88), 81% (71 of 88), and 90% (79 of 88) for ZCQss, ZCQpf, and ZCQps, respectively. Leg and back pain success rates were 80% (68 of 85) and 65% (55 of 85), respectively, and the success rate for ODI was 65% (57 of 88). Percentage improvements over baseline were 42%, 39%, 75%, 66%, and 58% for ZCQss, ZCQpf, leg and back pain VAS, and ODI, respectively (all P<0.001). Within-group effect sizes were classified as very large for four of five clinical outcomes (ie, >1.0; all P<0.0001). Seventy-five percent of IPD patients were free from reoperation, revision, or supplemental fixation at their index level at 5 years. CONCLUSION: After 5 years of follow-up, IPD with a stand-alone spacer provides sustained clinical benefit.

Superion Interspinous Spacer Treatment of Moderate Spinal Stenosis: 4-Year Results.

OBJECTIVE: To determine 4-year clinical outcomes in patients with moderate lumbar spinal stenosis treated with minimally invasive stand-alone interspinous process decompression using the Superion device. METHODS: The 4-year Superion data were extracted from a randomized, controlled Food and Drug Administration investigational device exemption trial. Patients with intermittent neurogenic claudication relieved with back flexion who failed at least 6 months of nonsurgical management were enrolled. Outcomes included Zurich Claudication Questionnaire (ZCQ) symptom severity (ss), physical function (pf) and patient satisfaction (ps) subdomains, leg and back pain visual analog scale (VAS), and Oswestry Disability Index (ODI). At 4-year follow-up, 89 of the 122 patients (73%) provided complete clinical outcome evaluations. RESULTS: At 4 years after index procedure, 75 of 89 patients with Superion (84.3%) demonstrated clinical success on at least 2 of 3 ZCQ domains. Individual component responder rates were 83% (74/89), 79% (70/89), and 87% (77/89) for ZCQss, ZCQpf, and ZCQps; 78% (67/86) and 66% (57/86) for leg and back pain VAS; and 62% (55/89) for ODI. Patients with Superion also demonstrated percentage improvements over baseline of 41%, 40%, 73%, 69%, and 61% for ZCQss, ZCQpf, leg pain VAS, back pain VAS, and ODI. Within-group effect sizes all were classified as very large (>1.0): 1.49, 1.65, 1.42, 1.12, and 1.46 for ZCQss, ZCQpf, leg pain VAS, back pain VAS, and ODI. CONCLUSIONS: Minimally invasive implantation of the Superion device provides long-term, durable relief of symptoms of intermittent neurogenic claudication for patients with moderate lumbar spinal stenosis.