Validation of the Calgary Postoperative Pain after Spine Surgery Score for Poor Postoperative Pain Control after Spine Surgery.

OBJECTIVE: The Calgary Postoperative Pain after Spine Surgery (CAPPS) score was developed to identify patients at risk of experiencing poorly controlled pain after spine surgery. The goal of this study was to independently validate the CAPPS score on a prospectively collected patient sample. METHODS: Poor postoperative pain control was defined as a mean numeric rating scale (NRS) for pain >4 at rest in the first 24 hours after surgery. Baseline characteristics in this study (validation cohort) were compared to those of the development cohort used to create the CAPPS score. Predictive performance of the CAPPS score was assessed by the area under the curve (AUC) and percentage misclassification for discrimination. A graphical comparison between predicted probability vs. observed incidence of poorly controlled pain was performed for calibration. RESULTS: Fifty-two percent of 201 patients experienced poorly controlled pain. The validation cohort exhibited lower depression scores and a higher proportion using daily opioid medications compared to the development cohort. The AUC was 0.74 [95%CI = 0.68-0.81] in the validation cohort compared to 0.73 [95%CI = 0.69-0.76] in the development cohort for the eight-tier CAPPS score. When stratified between the low- vs. extreme-risk and low- vs. high-risk groups, the percentage misclassification was 21.2% and 30.7% in the validation cohort, compared to 29.9% and 38.0% in the development cohort, respectively. The predicted probability closely mirrored the observed incidence of poor pain control across all scores. CONCLUSIONS: The CAPPS score, based on seven easily obtained and reliable prognostic variables, was validated using a prospectively collected, independent sample of patients.

Systematic review of health economic studies in cranial neurosurgery.

OBJECTIVE As the cost of health care continues to increase, there is a growing emphasis on evaluating the relative economic value of treatment options to guide resource allocation. The objective of this systematic review was to evaluate the current evidence regarding the cost-effectiveness of cranial neurosurgery procedures. METHODS The authors performed a systematic review of the literature using PubMed, EMBASE, and the Cochrane Library, focusing on themes of economic evaluation and cranial neurosurgery following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Included studies were publications of cost-effectiveness analysis or cost-utility analysis between 1995 and 2017 in which health utility outcomes in life years (LYs), quality-adjusted life years (QALYs), or disability-adjusted life years (DALYs) were used. Three independent reviewers conducted the study appraisal, data abstraction, and quality assessment, with differences resolved by consensus discussion. RESULTS In total, 3485 citations were reviewed, with 53 studies meeting the inclusion criteria. Of those, 34 studies were published in the last 5 years. The most common subspecialty focus was cerebrovascular (32%), followed by neurooncology (26%) and functional neurosurgery (24%). Twenty-eight (53%) studies, using a willingness to pay threshold of US$50,000 per QALY or LY, found a specific surgical treatment to be cost-effective. In addition, there were 11 (21%) studies that found a specific surgical option to be economically dominant (both cost saving and having superior outcome), including endovascular thrombectomy for acute ischemic stroke, epilepsy surgery for drug-refractory epilepsy, and endoscopic pituitary tumor resection. CONCLUSIONS There is an increasing number of cost-effectiveness studies in cranial neurosurgery, especially within the last 5 years. Although there are numerous procedures, such as endovascular thrombectomy for acute ischemic stroke, that have been conclusively proven to be cost-effective, there remain promising interventions in current practice that have yet to meet cost-effectiveness thresholds.

Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome.

BACKGROUND: Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI. METHODS: Longitudinal measurement of serum NfL was performed in patients with central cord syndrome (CCS, n=4), motor-incomplete SCI (iSCI, n=10), motor-complete SCI (cSCI, n=13) and healthy controls (HC, n=67), and correlated with clinical severity, neurological outcome, and neuroprotective effect of the drug minocycline. RESULTS: Baseline NfL levels were higher in iSCI (21 pg/mL) and cSCI (70 pg/mL) than in HC (5 pg/mL, p=0.006 and p<0.001) and CCS (6 pg/mL, p=0.025 and p=0.010). Levels increased over time (p<0.001) and remained higher in cSCI versus iSCI (p=0.011) and than in CCS (p<0.001). NfL levels correlated with American Spinal Injury Association (ASIA) motor score at baseline (r=-0.53, p=0.004) and after 24 h (r=-0.69, p<0.001) and 3-12-month motor outcome (baseline NfL: r=-0.43, p=0.026 and 24 h NfL: r=-0.72, p<0.001). Minocycline treatment showed decreased NfL levels in the subgroup of cSCI patients. CONCLUSIONS: Serum NfL concentrations in SCI patients show a close correlation with acute severity and neurological outcome. Our data provide evidence that serum NfL is of prognostic value in SCI patients for the first time. Further, blood NfL levels may qualify as drug response markers in SCI.

Poor postoperative pain control is associated with poor long-term patient-reported outcomes after elective spine surgery: an observational cohort study.

BACKGROUND CONTEXT: A significant proportion of patients experience poorly controlled surgical pain and fail to achieve satisfactory clinical improvement after spine surgery. However, a direct association between these variables has not been previously demonstrated. PURPOSE: To investigate the association between poor postoperative pain control and patient-reported outcomes after spine surgery. STUDY DESIGN: Ambispective cohort study. PATIENT SAMPLE: Consecutive adult patients (≥18-years old) undergoing inpatient elective cervical or thoracolumbar spine surgery. OUTCOME MEASURE: Poor surgical outcome was defined as failure to achieve a minimal clinically important difference (MCID) of 30% improvement on the Oswestry Disability Index or Neck Disability Index at follow-up (3-months, 1-year, and 2-years). METHODS: Poor pain control was defined as a mean numeric rating scale score of >4 during the first 24-hours after surgery. Multivariable mixed-effects regression was used to investigate the relationship between poor pain control and changes in surgical outcomes while adjusting for known confounders. Secondarily, the Calgary Postoperative Pain After Spine Surgery (CAPPS) Score was investigated for its ability to predict poor surgical outcome. RESULTS: Of 1294 patients, 47.8%, 37.3%, and 39.8% failed to achieve the MCID at 3-months, 1-year, and 2-years, respectively. The incidence of poor pain control was 56.9%. Multivariable analyses showed poor pain control after spine surgery was independently associated with failure to achieve the MCID (OR 2.35 [95% CI=1.59-3.46], p<.001) after adjusting for age (p=.18), female sex (p=.57), any nicotine products (p=.041), ASA physical status >2 (p<.001), ≥3 motion segment surgery (p=.008), revision surgery (p=.001), follow-up time (p<.001), and thoracolumbar surgery compared to cervical surgery (p=.004). The CAPPS score was also found to be independently predictive of poor surgical outcome. CONCLUSION: Poor pain control in the first 24-hours after elective spine surgery was an independent risk factor for poor surgical outcome. Perioperative treatment strategies to improve postoperative pain control may lead to improved patient-reported surgical outcomes.

Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury.

Preclinical studies have attributed neuroprotective properties to the antibiotic minocycline. Animal studies and early clinical trials support its use in several neurological diseases. In animal spinal cord injury models, minocycline improved neurological and histological outcomes, reduced neuronal and oligodendroglial apoptosis, decreased microglial activation and reduced inflammation. A single-centre, human, double-blind, randomized, placebo-controlled study of minocycline administration after spinal cord injury was undertaken for the purposes of dose optimization, safety assessment and to estimate outcome changes and variance. Neurological, functional, pharmacological and adverse event outcomes were compared between subjects administered 7 days of intravenous minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord injury. The secondary outcome used to assess neurological differences between groups that may warrant further investigation was motor recovery over 1 year using the American Spinal Cord Injury Association examination. Recruitment and analyses were stratified by injury severity and injury location a priori given the expected influence of these on the sensitivity of the motor exam. Minocycline administered at higher than previously reported human doses produced steady-state concentrations of 12.7 µg/ml (95% confidence interval 11.6-13.8) in serum and 2.3 µg/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking efficacious serum levels measured in animal studies. Transient elevation of serum liver enzymes in one patient was the only adverse event likely related to the study drug. Overall, patients treated with minocycline experienced six points greater motor recovery than those receiving placebo (95% confidence interval -3 to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic spinal cord injury (n = 16). A difference of 14 motor points that approached significance was observed in patients with cervical injury (95% confidence interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury may have experienced a larger difference (results not statistically significant, n = 9). Functional outcomes exhibited differences that lacked statistical significance but that may be suggestive of improvement in patients receiving the study drug. The minocycline regimen established in this study proved feasible, safe and was associated with a tendency towards improvement across several outcome measures. Although this study does not establish the efficacy of minocycline in spinal cord injury the findings are encouraging and warrant further investigation in a multi-centre phase III trial. ClinicalTrials.gov number NCT00559494.

Impact of preoperative insomnia on poor postoperative pain control after elective spine surgery and the modified Calgary postoperative pain after spine surgery (MCAPPS) score.

Background: Approximately 30% to 64% of patients experience inadequate pain control following spine surgery. The Calgary postoperative pain after spine surgery (CAPPS) score was developed to identify this subset of patients. The impact of preoperative insomnia on postoperative pain control is unknown. This study aimed to investigate the relationship between preoperative insomnia and poor pain control after spine surgery, as well as improve the predictive accuracy of the CAPPS score. Methods: A prospective cohort study was conducted in patients undergoing elective spine surgery. Poor pain control was defined as a mean numeric rating scale pain score >4 at rest within the first 24-hours after surgery. Patients were evaluated using the CAPPS score, which included 7 prognostic factors. A multivariable logistic regression model was used to examine the association between preoperative insomnia severity index (ISI) and poor pain control, adjusting for the CAPPS score. The Modified CAPPS score was derived from this model. Results: Of 219 patients, 49.7% experienced poorly controlled pain. Prevalence of clinical insomnia (ISI≥15) was 26.9%. Preoperative ISI was independently associated with poor pain control (odds ratio [OR] 1.09, [95%CI=1.03-1.16], p=.004), after adjusting for the CAPPS score (OR 1.61, [95%CI=1.38-1.89], p<.001). The model exhibited good discrimination (c-statistics 0.80, [95%CI=0.74-0.86]) and calibration (Hosmer-Lemeshow chi-square=8.95, p=.35). The Modified CAPPS score also demonstrated good discrimination (c-statistic 0.78, [95%CI=0.72-0.84]) and calibration (Hosmer-Lemeshow chi-square=2.92, p=.57). Low-, high-, and extreme-risk groups stratified by the Modified CAPPS score had 17.3%, 49.1%, and 80.7% predicted probability of experiencing inadequate pain control compared to 32.0%, 64.0%, and 85.1% in the CAPPS score. Conclusions: Preoperative insomnia is prevalent and is a modifiable risk factor for poor pain control following spine surgery. Early identification and management of preoperative insomnia may lead to improved postoperative pain outcomes. Future external validation is needed to confirm the accuracy of the Modified CAPPS score.

Development and validation of a clinical prediction score for poor postoperative pain control following elective spine surgery.

OBJECTIVE: Thirty percent to sixty-four percent of patients experience poorly controlled pain following spine surgery, leading to patient dissatisfaction and poor outcomes. Identification of at-risk patients before surgery could facilitate patient education and personalized clinical care pathways to improve postoperative pain management. Accordingly, the aim of this study was to develop and internally validate a prediction score for poorly controlled postoperative pain in patients undergoing elective spine surgery. METHODS: A retrospective cohort study was performed in adult patients (≥ 18 years old) consecutively enrolled in the Canadian Spine Outcomes and Research Network registry. All patients underwent elective cervical or thoracolumbar spine surgery and were admitted to the hospital. Poorly controlled postoperative pain was defined as a mean numeric rating scale score for pain at rest of > 4 during the first 24 hours after surgery. Univariable analysis followed by multivariable logistic regression on 25 candidate variables, selected through a systematic review and expert consensus, was used to develop a prediction model using a random 70% sample of the data. The model was transformed into an eight-tier risk-based score that was further simplified into the three-tier Calgary Postoperative Pain After Spine Surgery (CAPPS) score to maximize clinical utility. The CAPPS score was validated using the remaining 30% of the data. RESULTS: Overall, 57% of 1300 spine surgery patients experienced poorly controlled pain during the first 24 hours after surgery. Seven significant variables associated with poor pain control were incorporated into a prediction model: younger age, female sex, preoperative daily use of opioid medication, higher preoperative neck or back pain intensity, higher Patient Health Questionnaire-9 depression score, surgery involving ≥ 3 motion segments, and fusion surgery. Notably, minimally invasive surgery, body mass index, and revision surgery were not associated with poorly controlled pain. The model was discriminative (C-statistic 0.74, 95% CI 0.71-0.77) and calibrated (Hosmer-Lemeshow goodness-of-fit, p = 0.99) at predicting the outcome. Low-, high-, and extreme-risk groups stratified using the CAPPS score had 32%, 63%, and 85% predicted probability of experiencing poorly controlled pain, respectively, which was mirrored closely by the observed incidence of 37%, 62%, and 81% in the validation cohort. CONCLUSIONS: Inadequate pain control is common after spine surgery. The internally validated CAPPS score based on 7 easily acquired variables accurately predicted the probability of experiencing poorly controlled pain after spine surgery.

Heterotopic ossification and radiographic adjacent-segment disease after cervical disc arthroplasty.

OBJECTIVE: Cervical disc arthroplasty (CDA) is an accepted motion-sparing technique associated with favorable patient outcomes. However, heterotopic ossification (HO) and adjacent-segment degeneration are poorly understood adverse events that can be observed after CDA. The purpose of this study was to retrospectively examine 1) the effect of the residual exposed endplate (REE) on HO, and 2) identify risk factors predicting radiographic adjacent-segment disease (rASD) in a consecutive cohort of CDA patients. METHODS: A retrospective cohort study was performed on consecutive adult patients (≥ 18 years) who underwent 1- or 2-level CDA at the University of Calgary between 2002 and 2015 with > 1-year follow-up. REE was calculated by subtracting the anteroposterior (AP) diameter of the arthroplasty device from the native AP endplate diameter measured on lateral radiographs. HO was graded using the McAfee classification (low grade, 0-2; high grade, 3 and 4). Change in AP endplate diameter over time was measured at the index and adjacent levels to indicate progressive rASD. RESULTS: Forty-five patients (58 levels) underwent CDA during the study period. The mean age was 46 years (SD 10 years). Twenty-six patients (58%) were male. The median follow-up was 29 months (IQR 42 months). Thirty-three patients (73%) underwent 1-level CDA. High-grade HO developed at 19 levels (33%). The mean REE was 2.4 mm in the high-grade HO group and 1.6 mm in the low-grade HO group (p = 0.02). On multivariable analysis, patients with REE > 2 mm had a 4.5-times-higher odds of developing high-grade HO (p = 0.02) than patients with REE ≤ 2 mm. No significant relationship was observed between the type of artificial disc and the development of high-grade HO (p = 0.1). RASD was more likely to develop in the lower cervical spine (p = 0.001) and increased with time (p < 0.001). The presence of an artificial disc was highly protective against degenerative changes at the index level of operation (p < 0.001) but did not influence degeneration in the adjacent segments. CONCLUSIONS: In patients undergoing CDA, high-grade HO was predicted by REE. Therefore, maximizing the implant-endplate interface may help to reduce high-grade HO and preserve motion. RASD increases in an obligatory manner following CDA and is highly linked to specific levels (e.g., C6-7) rather than the presence or absence of an adjacent arthroplasty device. The presence of an artificial disc is, however, protective against further degenerative change at the index level of operation.

Preoperative predictors of poor acute postoperative pain control: a systematic review and meta-analysis.

OBJECTIVES: Inadequate postoperative pain control is common and is associated with poor clinical outcomes. This study aimed to identify preoperative predictors of poor postoperative pain control in adults undergoing inpatient surgery. DESIGN: Systematic review and meta-analysis DATA SOURCES: MEDLINE, Embase, CINAHL and PsycINFO were searched through October 2017. ELIGIBILITY CRITERIA: Studies in any language were included if they evaluated postoperative pain using a validated instrument in adults (≥18 years) and reported a measure of association between poor postoperative pain control (defined by study authors) and at least one preoperative predictor during the hospital stay. DATA EXTRACTION AND SYNTHESIS: Two reviewers screened articles, extracted data and assessed study quality. Measures of association for each preoperative predictor were pooled using random effects models. RESULTS: Thirty-three studies representing 53 362 patients were included in this review. Significant preoperative predictors of poor postoperative pain control included younger age (OR 1.18 [95% CI 1.05 to 1.32], number of studies, n=14), female sex (OR 1.29 [95% CI 1.17 to 1.43], n=20), smoking (OR 1.33 [95% CI 1.09 to 1.61], n=9), history of depressive symptoms (OR 1.71 [95% CI 1.32 to 2.22], n=8), history of anxiety symptoms (OR 1.22 [95% CI 1.09 to 1.36], n=10), sleep difficulties (OR 2.32 [95% CI 1.46 to 3.69], n=2), higher body mass index (OR 1.02 [95% CI 1.01 to 1.03], n=2), presence of preoperative pain (OR 1.21 [95% CI 1.10 to 1.32], n=13) and use of preoperative analgesia (OR 1.54 [95% CI 1.18 to 2.03], n=6). Pain catastrophising, American Society of Anesthesiologists status, chronic pain, marital status, socioeconomic status, education, surgical history, preoperative pressure pain tolerance and orthopaedic surgery (vs abdominal surgery) were not associated with increased odds of poor pain control. Study quality was generally high, although appropriate blinding of predictor during outcome ascertainment was often limited. CONCLUSIONS: Nine predictors of poor postoperative pain control were identified. These should be recognised as potentially important factors when developing discipline-specific clinical care pathways to improve pain outcomes and to guide future surgical pain research. PROSPERO REGISTRATION NUMBER: CRD42017080682.

Intrathecal Morphine Following Lumbar Fusion: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Despite the potential for faster postoperative recovery and the ease of direct intraoperative injection, intrathecal morphine is rarely provided in lumbar spine surgery. OBJECTIVE: To evaluate the safety and efficacy of intrathecal morphine following lumbar fusion. METHODS: We randomly assigned 150 patients undergoing elective instrumented lumbar fusion to receive a single intrathecal injection of morphine (0.2 mg) or placebo (normal saline) immediately prior to wound closure. The primary outcome was pain on the visual-analogue scale during the first 24 h after surgery. Secondary outcomes included respiratory depression, treatment-related side effects, postoperative opioid requirements, and length of hospital stay. An intention-to-treat, repeated-measures analysis was used to estimate outcomes according to treatment in the primary analysis. RESULTS: The baseline characteristics of the 2 groups were similar. Intrathecal morphine reduced pain both at rest (32% area under the curves [AUCs] difference, P < .01) and with movement (22% AUCs difference, P < .02) during the initial 24 h after surgery. The risk of respiratory depression was not increased by intrathecal morphine (hazard ratio, 0.86; 95% confidence interval, 0.44 to 1.68; P = .66). Although postoperative opioid requirements were reduced with intrathecal morphine (P < .03), lengths of hospital stay were similar (P = .32). Other than a trend towards increased intermittent catheterization among patients assigned to intrathecal morphine (P = .09), treatment-related side effects did not significantly differ. The early benefits of intrathecal morphine on postoperative pain were no longer apparent after 48 h. CONCLUSION: A single intrathecal injection of 0.2 mg of morphine safely reduces postoperative pain following lumbar fusion.

Effect of preoperative symptom duration on outcome in lumbar spinal stenosis: a Canadian Spine Outcomes and Research Network registry study.

BACKGROUND CONTEXT: Lumbar degenerative stenosis is one of the most common spine pathologies for which surgical intervention is indicated. There is some evidence that a prolonged duration of neurological compression could lead to a failure of surgery to alleviate symptoms. PURPOSE: Determination of whether longer symptom duration was associated with worse postoperative disability outcomes after decompressive surgery for lumbar degenerative stenosis. STUDY DESIGN/SETTING: The Canadian Spine Outcomes and Research Network (CSORN) prospective database includes pre- and postoperative data from 18 tertiary care hospitals. PATIENT SAMPLE: The CSORN database was queried for all cases of degenerative lumbar stenosis receiving surgical decompression for neurogenic claudication or radiculopathy. Patients with tumor, infection, fracture, or previous surgery were excluded. Patients were divided into groups based on symptom duration (<6 weeks, 6-12 weeks, 3-6 months, 6-12 months, 1-2 years, and >2 years). OUTCOME MEASURES: Change between preoperative and 12-month postoperative Oswestry Disability Index (ODI) was compared between symptom duration groups. Secondary outcomes included SF12 physical component score (PCS), and numeric rating scales for leg and back pain. Outcomes were also assessed at 3 months and 24 months postoperatively. METHODS: Change in ODI, and secondary outcome measures, were compared between different symptom duration groups. Multiple regression analysis was used to identify factors interacting with symptom duration to predict change in ODI. RESULTS: Four hundred and seventy-eight cases of lumbar stenosis with 12-month postoperative data were identified. Longer symptom duration correlated with less improvement in ODI (p<.001). Patients with >1 year of symptoms were less likely to achieve a Minimal Clinically Significant Difference in ODI (54.4% vs. 66.1%; p=.03) and were more likely to experience no improvement or worse disability, postoperatively (22.1% vs. 11.3%; p=.008). Similar results were found at 3- and 24-month timepoints. Smaller postoperative improvements in SF12 PCS and leg pain scales were also correlated with longer symptom duration (p<.05). CONCLUSIONS: Multicenter registry data provides important real-world evidence to guide consent, surgical planning, and health resource management. Longer symptom duration was found to correlate with less improvement in pain and disability after lumbar stenosis surgery suggesting that these patients may benefit from earlier treatment.

A Review of Clinical Trials in Spinal Cord Injury Including Biomarkers.

Acute traumatic spinal cord injury (SCI) entered the arena of prospective, randomized clinical trials almost 40 years ago, with the undertaking of the National Acute Spinal Cord Study (NASCIS) I trial. Since then, a number of clinical trials have been conducted in the field, spurred by the devastating physical, social, and economic consequences of acute SCI for patients, families, and society at large. Many of these have been controversial and attracted criticism. The current review provides a critical summary of select past and current clinical trials in SCI, focusing in particular on the findings of prospective, randomized controlled trials, the challenges and barriers encountered, and the valuable lessons learned that can be applied to future trials.

First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury.

BACKGROUND: Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. OBJECTIVE: This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. METHODS: Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). RESULTS: ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. CONCLUSIONS: ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury.

BACKGROUND: Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). OBJECTIVE: To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. METHODS: Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. RESULTS: Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. CONCLUSION: A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Lumbar Fusion for Degenerative Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Due to uncertain evidence, lumbar fusion for degenerative indications is associated with the greatest measured practice variation of any surgical procedure. OBJECTIVE: To summarize the current evidence on the comparative safety and efficacy of lumbar fusion, decompression-alone, or nonoperative care for degenerative indications. METHODS: A systematic review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (up to June 30, 2016). Comparative studies reporting validated measures of safety or efficacy were included. Treatment effects were calculated through DerSimonian and Laird random effects models. RESULTS: The literature search yielded 65 studies (19 randomized controlled trials, 16 prospective cohort studies, 15 retrospective cohort studies, and 15 registries) enrolling a total of 302 620 patients. Disability, pain, and patient satisfaction following fusion, decompression-alone, or nonoperative care were dependent on surgical indications and study methodology. Relative to decompression-alone, the risk of reoperation following fusion was increased for spinal stenosis (relative risk [RR] 1.17, 95% confidence interval [CI] 1.06-1.28) and decreased for spondylolisthesis (RR 0.75, 95% CI 0.68-0.83). Among patients with spinal stenosis, complications were more frequent following fusion (RR 1.87, 95% CI 1.18-2.96). Mortality was not significantly associated with any treatment modality. CONCLUSION: Positive clinical change was greatest in patients undergoing fusion for spondylolisthesis while complications and the risk of reoperation limited the benefit of fusion for spinal stenosis. The relative safety and efficacy of fusion for chronic low back pain suggests careful patient selection is required (PROSPERO International Prospective Register of Systematic Reviews number, CRD42015020153).

Design limitations of Bryan disc arthroplasty.

BACKGROUND CONTEXT: Disc arthroplasty is gaining momentum as a surgical procedure in the treatment of spinal degenerative disease. Results must be carefully scrutinized to recognize benefits as well as limitations. PURPOSE: The aim of this study was to investigate factors associated with segmental kyphosis after Bryan disc replacement. STUDY DESIGN/SETTING: Prospective study of a consecutively enrolled cohort of 10 patients treated in a single center using the Bryan cervical disc prosthesis for single-level segmental reconstruction in the surgical treatment of cervical radiculopathy and/or myelopathy. Radiographic and quality of life outcome measures. METHODS: Static and dynamic lateral radiographs were digitally analyzed in patients undergoing Bryan disc arthroplasty throughout a minimum 3-month follow-up period. Observations were compared with preoperative studies looking for predictive factors of postoperative spinal alignment. RESULTS: Postoperative end plate angles through the Bryan disc in the neutral position were kyphotic in 9 of 10 patients. Compared with preoperative end plate angulation there was a mean change of -7 degrees (towards kyphosis) in postoperative end plate alignment (p=.007, 95% confidence interval [CI] -6 degrees to -13 degrees). This correlated significantly with postoperative reduction in posterior vertebral body height of the caudal segment (p=.011, r2=.575) and postoperative functional spine unit (FSU) kyphosis (p=.032, r2=.46). Despite intraoperative distraction, postoperative FSU height was significantly reduced, on average by 1.7 mm (p=.040, 95% CI 0.5-2.8 mm). CONCLUSIONS: Asymmetrical end plate preparation occurs because of suboptimal coordinates to which the milling jig is referenced. Although segmental motion is preserved, Bryan disc arthroplasty demonstrates a propensity towards kyphotic orientation through the prosthesis likely as a result of intraoperative lordotic distraction. FSU angulation tends towards kyphosis and FSU height is decreased in the postoperative state from lack of anterior column support. Limitations of Bryan cervical disc arthroplasty should be carefully considered when reconstruction or maintenance of cervical lordosis is desirable.

Evaluating Soluble EMMPRIN as a Marker of Disease Activity in Multiple Sclerosis: Studies of Serum and Cerebrospinal Fluid.

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is an inducer of matrix metalloproteinases and has roles in leukocyte activation and migration. We reported previously that in MS and its animal model, experimental autoimmune encephalomyelitis, cell surface-associated EMMPRIN was significantly elevated in leukocytes around inflammatory perivascular cuffs in the CNS. In this study we report that activated T-cells can secrete soluble form of EMMPRIN (sEMMPRIN) upon activation. As sEMMPRIN is also present in biological fluids, we determined whether sEMMPRIN is altered in the CSF and sera of MS subjects. Sera from individuals without neurological conditions served as controls, while CSFs collected from subjects undergoing discectomy, and without evidence of CNS pathology, were used as a comparator group. We found that serum levels of sEMMPRIN from clinically stable MS patients or other inflammatory conditions did not differ from control subjects. Paired serum and CSF samples demonstrated poor correlation of sEMMPRIN. Interestingly, sEMMPRIN levels were approximately 60% higher in CSFs compared to sera. sEMMPRIN CSF levels were significantly higher in secondary progressive compared to primary progressive subjects. Thus we conclude that measurement of sEMMPRIN in serum is not informative for disease activity in MS. The differential expression of sEMMPRIN in the CSF of primary and secondary progressive MS invites hypotheses of the still undefined roles of EMMPRIN in the CNS.

The promise of minocycline in neurology.

The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.

Clinical and radiological evaluation of the Codman semiconstrained load-sharing anterior cervical plate: prospective multicenter trial and independent blinded evaluation of outcome.

OBJECT: Semiconstrained load-sharing implants for spinal fixation accommodate change in the screw-plate interface as bone grafts shrink. The authors evaluated the clinical and radiological outcome in patients after placement of the Codman anterior cervical plate (ACP) system, which allows change in the screw-plate angle. METHODS: The authors undertook a 10-center prospective study with independent blinded evaluation. All patients underwent cervical fusion and placement of ACPs. Clinical and radiological evaluations were performed at 1, 3, 6, 12, and 24 months. Radiographs were examined for screw angles, construct height, fusion, and screw fracture or displacement. One hundred ninety-five patients were enrolled. The mean follow-up period was 17 months. At 24 months neurological improvement was demonstrated in 68.7% and pain improvement in 76.6% of the patients. Fusion was successful in 93.8%. Varying degrees (most minor) of hardware-related failure occurred in 10.4% of cases; however, reoperation was required in only four (2.1%). A significant change in screw angles occurred over time (mean 6.4 degrees in caudal screw angle [p < 0.001] and 2.4 degrees in the rostral screw angle [p = 0.003]). These changes plateaued by 6 months. A change in construct height (mean 3.48 mm) occurred by 6 months (p < 0.05). CONCLUSIONS: Based on an independent blinded evaluation, the Codman ACP provides effective fixation with load sharing and is effective in achieving fusion with a 94% success rate. Direct comparison with rigidly locked devices is required to establish definitively the optimal method for anterior cervical fixation.

Suspended laminoplasty for wide posterior cervical decompression and intradural access: results, advantages, and complications.

OBJECT: Cervical laminoplasty is a recognized technique commonly used for multilevel posterior cervical decompression, and it is favored over laminectomy for maintaining spinal stability. Traditional hinge techniques, however, limit lateral exposure on one side and can limit dural exposure. The authors present their experience with a modified laminoplasty technique incorporating complete laminectomy and placement of titanium miniplate instrumentation. This method allows wide bilateral posterior decompression and unobscured dural access. METHODS: Twenty-eight patients (mean age 57 years) underwent cervical laminoplasty during a 4-year period. Twenty-seven patients presented with progressive cervical myelopathy. Seventeen patients (61%) had degenerative spondylotic stenosis; nine (32%) underwent resection of an intradural neoplasm. A mean of 3.5 levels were exposed and reconstructed. The follow-up period ranged from 4 months to 4 years (mean 15 months). The mean angular extension-flexion displacement measured between C-1 and C-7 was unchanged postoperatively, with preserved mobility across laminoplasty-treated segments in all patients. The anteroposterior diameter of the spinal canal increased 3.6 mm (27.2%) postoperatively (p = 0.004). In one patient an asymptomatic postoperative kyphosis developed. There were five cases of postoperative infection. One superficial infection resolved after intravenous antibiotic therapy alone, and four deep infections required surgical reexploration. CONCLUSIONS: The advantages of this technique over other laminoplasty methods include wide lateral spinal canal and intradural access, as well as preserved motion with partial restoration of the posterior tension band.