Nonpharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

BACKGROUND: A 2007 American College of Physicians guideline addressed nonpharmacologic treatment options for low back pain. New evidence is now available. PURPOSE: To systematically review the current evidence on nonpharmacologic therapies for acute or chronic nonradicular or radicular low back pain. DATA SOURCES: Ovid MEDLINE (January 2008 through February 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. STUDY SELECTION: Randomized trials of 9 nonpharmacologic options versus sham treatment, wait list, or usual care, or of 1 nonpharmacologic option versus another. DATA EXTRACTION: One investigator abstracted data, and a second checked abstractions for accuracy; 2 investigators independently assessed study quality. DATA SYNTHESIS: The number of trials evaluating nonpharmacologic therapies ranged from 2 (tai chi) to 121 (exercise). New evidence indicates that tai chi (strength of evidence [SOE], low) and mindfulness-based stress reduction (SOE, moderate) are effective for chronic low back pain and strengthens previous findings regarding the effectiveness of yoga (SOE, moderate). Evidence continues to support the effectiveness of exercise, psychological therapies, multidisciplinary rehabilitation, spinal manipulation, massage, and acupuncture for chronic low back pain (SOE, low to moderate). Limited evidence shows that acupuncture is modestly effective for acute low back pain (SOE, low). The magnitude of pain benefits was small to moderate and generally short term; effects on function generally were smaller than effects on pain. LIMITATION: Qualitatively synthesized new trials with prior meta-analyses, restricted to English-language studies; heterogeneity in treatment techniques; and inability to exclude placebo effects. CONCLUSION: Several nonpharmacologic therapies for primarily chronic low back pain are associated with small to moderate, usually short-term effects on pain; findings include new evidence on mind-body interventions. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).

Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis: A Systematic Review and Meta-analysis.

BACKGROUND: Use of epidural corticosteroid injections is increasing. PURPOSE: To review evidence on the benefits and harms of epidural corticosteroid injections in adults with radicular low back pain or spinal stenosis of any duration. DATA SOURCES: Ovid MEDLINE (through May 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, prior systematic reviews, and reference lists. STUDY SELECTION: Randomized trials of epidural corticosteroid injections versus placebo interventions, or that compared epidural injection techniques, corticosteroids, or doses. DATA EXTRACTION: Dual extraction and quality assessment of individual studies, which were used to determine the overall strength of evidence (SOE). DATA SYNTHESIS: 30 placebo-controlled trials evaluated epidural corticosteroid injections for radiculopathy, and 8 trials were done for spinal stenosis. For radiculopathy, epidural corticosteroids were associated with greater immediate-term reduction in pain (weighted mean difference on a scale of 0 to 100, -7.55 [95% CI, -11.4 to -3.74]; SOE, moderate), function (standardized mean difference after exclusion of an outlier trial, -0.33 [CI, -0.56 to -0.09]; SOE, low), and short-term surgery risk (relative risk, 0.62 [CI, 0.41 to 0.92]; SOE, low). Effects were below predefined minimum clinically important difference thresholds, and there were no longer-term benefits. Limited evidence showed no clear effects of technical factors, patient characteristics, or comparator interventions on estimates. There were no clear effects of epidural corticosteroid injections for spinal stenosis (SOE, low to moderate). Serious harms were rare, but harms reporting was suboptimal (SOE, low). LIMITATIONS: The review was restricted to English-language studies. Some meta-analyses were based on small numbers of trials (particularly for spinal stenosis), and most trials had methodological shortcomings. CONCLUSION: Epidural corticosteroid injections for radiculopathy were associated with immediate reductions in pain and function. However, benefits were small and not sustained, and there was no effect on long-term surgery risk. Limited evidence suggested no effectiveness for spinal stenosis.

Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin.

BACKGROUND: Repulsive guidance molecule c (RGMc or hemojuvelin), a glycosylphosphatidylinositol-linked glycoprotein expressed in liver and striated muscle, plays a central role in systemic iron balance. Inactivating mutations in the RGMc gene cause juvenile hemochromatosis (JH), a rapidly progressing iron storage disorder with severe systemic manifestations. RGMc undergoes complex biosynthetic steps leading to membrane-bound and soluble forms of the protein, including both 50 and 40 kDa single-chain species. RESULTS: We now show that pro-protein convertases (PC) are responsible for conversion of 50 kDa RGMc to a 40 kDa protein with a truncated COOH-terminus. Unlike related molecules RGMa and RGMb, RGMc encodes a conserved PC recognition and cleavage site, and JH-associated RGMc frame-shift mutants undergo COOH-terminal cleavage only if this site is present. A cell-impermeable peptide PC inhibitor blocks the appearance of 40 kDa RGMc in extra-cellular fluid, as does an engineered mutation in the conserved PC recognition sequence, while the PC furin cleaves 50 kDa RGMc in vitro into a 40 kDa molecule with an intact NH2-terminus. Iron loading reduces release of RGMc from the cell membrane, and diminishes accumulation of the 40 kDa species in cell culture medium. CONCLUSION: Our results define a role for PCs in the maturation of RGMc that may have implications for the physiological actions of this critical iron-regulatory protein.

Synthetic bone graft versus autograft or allograft for spinal fusion: a systematic review.

The purpose of this review was to compare the efficacy and safety of synthetic bone graft substitutes versus autograft or allograft for the treatment of lumbar and cervical spinal degenerative diseases. Multiple major medical reference databases were searched for studies that evaluated spinal fusion using synthetic bone graft substitutes (either alone or with an autograft or allograft) compared with autograft and allograft. Randomized controlled trials (RCT) and cohort studies with more than 10 patients were included. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. The search yielded 214 citations with 27 studies that met the inclusion criteria. For the patients with lumbar spinal degenerative disease, data from 19 comparative studies were included: 3 RCTs, 12 prospective, and 4 retrospective studies. Hydroxyapatite (HA), HA+collagen, ß-tricalcium phosphate (ß-TCP), calcium sulfate, or polymethylmethacrylate (PMMA) were used. Overall, there were no differences between the treatment groups in terms of fusion, functional outcomes, or complications, except in 1 study that found higher rates of HA graft absorption. For the patients with cervical degenerative conditions, data from 8 comparative studies were included: 4 RCTs and 4 cohort studies (1 prospective and 3 retrospective studies). Synthetic grafts included HA, ß-TCP/HA, PMMA, and biocompatible osteoconductive polymer (BOP). The PMMA and BOP grafts led to lower fusion rates, and PMMA, HA, and BOP had greater risks of graft fragmentation, settling, and instrumentation problems compared with iliac crest bone graft. The overall quality of evidence evaluating the potential use and superiority of the synthetic biological materials for lumbar and cervical fusion in this systematic review was low or insufficient, largely due to the high potential for bias and small sample sizes. Thus, definitive conclusions or recommendations regarding the use of these synthetic materials should be made cautiously and within the context of the limitations of the evidence.

Biological substitutes/extenders for spinal arthrodesis: which agents are cost-effective?

STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the cost-effectiveness of lumbar or cervical spinal arthrodesis using biological substitutes and extenders compared with iliac crest autograft for the treatment of degenerative spinal conditions. SUMMARY OF BACKGROUND DATA: The cost-effectiveness of using bone graft substitutes and extenders for spinal fusion compared with using iliac crest autograft is not yet well established. METHODS: A systematic search of PubMed/MEDLINE, the Cochrane Collaboration Library, EMBASE, the CRD (Centre for Reviews and Dissemination) database, and Tuft's CEA registry for literature published through December 2013 was performed to identify full formal economic analyses comparing the use of biological grafts with iliac crest bone graft in spinal fusion for thoracolumbar or cervical degenerative, deformity, and traumatic spinal conditions. Economic outcomes such as cost per improved outcome or cost per quality-adjusted life year were reported in the context of the model type, analytic perspective clinical comparisons, and sensitivity analyses employed. RESULTS: The search strategy yielded 88 citations, and 6 full economic analyses ultimately met our inclusion criteria. For the comparison of recombinant human bone morphogenetic protein-2 to iliac crest bone graft in the lumbar spine, data from 4 cost-effectiveness studies and 1 cost-utility study provided discordant conclusions that varied with type of data used, cost-measurement methods, and study design. In the cervical spine, one study suggested that from a societal perspective, anterior cervical discectomy and fusion (ACDF) with allograft is similarly cost-effective as ACDF with autograft. CONCLUSION: The results suggest that compared with use of iliac crest bone graft in lumbar spinal fusion, use of recombinant human bone morphogenetic protein is not cost-effective from a payer perspective with higher upfront costs, but it may be cost-effective from a societal perspective due to a decrease in lost productivity. The data in this study also suggest that from a societal perspective, ACDF with allograft is similarly cost-effective to ACDF with autograft. LEVEL OF EVIDENCE: 3.

Outcomes after laminoplasty compared with laminectomy and fusion in patients with cervical myelopathy: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine the effectiveness and safety of cervical laminoplasty versus laminectomy and fusion for the treatment of cervical myelopathy, and to identify any patient subgroups for whom one treatment may result in better outcomes than the other. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty and cervical laminectomy plus fusion are both procedures that treat cervical stenosis induced myelopathy by expanding the space available for the spinal cord. Although there are strong proponents of each procedure, the effectiveness, safety, and differential effectiveness and safety of laminoplasty versus laminectomy and fusion remains unclear. METHODS: A systematic search of multiple major medical reference databases was conducted to identify studies that compared laminoplasty with laminectomy and fusion. Studies could include either or both cervical myelopathic spondylosis (CSM) and ossification of the posterior longitudinal ligament. Randomized controlled trials and cohort studies were included. Case reports and studies with less than 10 patients in the comparative group were excluded. Japanese Orthopaedic Association, modified Japanese Orthopaedic Association, and Nurick scores were the primary outcomes measuring myelopathy effectiveness. Reoperation and complication rates were evaluated for safety. Clinical recommendations were made through a modified Delphi approach by applying the Grading of Recommendations Assessment, Development and Evaluation/Agency for Healthcare Research and Quality criteria. RESULTS: The search strategy yielded 305 citations, and 4 retrospective cohort studies ultimately met our inclusion criteria. For patients with CSM, data from 3 class of evidence III retrospective cohort studies suggest that there is no difference between treatment groups in severity of myelopathy or pain: 2 studies reported no significant difference between treatment groups in severity of myelopathy, and 3 studies found no significant difference in pain outcomes between treatment groups. For patients with ossification of the posterior longitudinal ligament, one small class of evidence III retrospective cohort study reported significant improvements in myelopathy severity after laminectomy and fusion compared with laminoplasty, but no differences in long-term pain between treatment groups. The overall evidence on the comparative safety of laminoplasty compared with laminectomy and fusion is inconsistent. Reoperation rates were lower after laminoplasty in 2 of 3 studies reporting. However, the incidence of debilitating neck pain was higher after laminoplasty as reported by one study; results on neurological complications were inconclusive, with 2 studies reporting. Results on kyphotic deformity were inconsistent, with opposite results in the 2 studies reporting. After laminectomy and fusion, 1% to 38% of patients had pseudarthrosis. Infection rates were slightly lower after laminoplasty, but the results are not likely to be statistically significant. CONCLUSION: For patients with CSM, there is low-quality evidence that suggests that laminoplasty and laminectomy and fusion procedures are similarly effective in treating CSM. For patients with ossification of the posterior longitudinal ligament, the evidence regarding the effectiveness of these procedures is insufficient. For both patient populations, the evidence as to whether one procedure is safer than the other is insufficient. Higher-quality research is necessary to more clearly delineate when one procedure is preferred compared with the other. EVIDENCE-BASED CLINICAL RECOMMENDATIONS: RECOMMENDATION: For CSM, evidence suggests that laminoplasty and laminectomy-fusion procedures can be similarly effective. We suggest that surgeons consider each case individually and take into account their own familiarity and expertise with each procedure. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Weak.

Cervical spondylotic myelopathy: methodological approaches to evaluate the literature and establish best evidence.

STUDY DESIGN: Review of methods. OBJECTIVE: To provide a detailed description of the methods undertaken in the articles in this focus issue pertaining to cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL) and to describe the process used to develop summary statements and clinical recommendations regarding factors associated with the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. SUMMARY OF BACKGROUND DATA: We present methods used in conducting the systematic, evidence-based reviews and development of expert panel summary statements and clinical recommendations of the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Our intent is that clinicians will combine the information from these systematic reviews, narrative reviews, and primary research studies with an understanding of their own capacities and experience to better manage patients with CSM or OPLL and consider future research for the diagnosis and treatment of these diseases. METHODS: For the systematic reviews, which make up the bulk of the studies in this focus issue, a systematic search and critical review of the English language literature was undertaken for articles published on the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Articles were screened for relevance using a priori criteria and relevant articles were critically reviewed. Whether an article was included for review depended on whether the study question was descriptive, one of therapy, or one of prognosis. The strength of evidence for the overall body of literature in each topic area was determined by 2 independent reviewers considering risk of bias, consistency, directness, and precision of results using a modification of the Grading of Recommendation Assessment, Development and Evaluation criteria. Disagreements were resolved by consensus. Findings from articles meeting inclusion criteria were summarized. From these summaries, summary statements or clinical recommendations were formulated among subject experts through a modified Delphi process using the Grading of Recommendation Assessment, Development and Evaluation approach. Methods for the 2 primary research studies and the narrative reviews are also reviewed. RESULTS: Because of the nature of questions that needed to be addressed, not all studies in this focus issue were amenable to systematic review. As a result, this focus issue consists of several different article types, including 1 research protocol, 2 primary research studies, 2 narrative literature reviews, 7 systematic reviews, and 3 articles that combine a systematic review component with either a narrative section (n = 2) or a provider survey (n = 1). In general, the strength of evidence ratings ranged from insufficient to moderate. Summary statements or clinical recommendations were made according to available evidence and study type: 16 summary statements were made across 8 articles, and 17 clinical recommendations were made across 9 articles. Three articles had both summary statements and clinical recommendations, 5 had summary statements only, 6 had clinical recommendations only, and 1 (the research protocol) was not amenable to either. CONCLUSION: Systematic reviews, narrative reviews, and primary research studies were undertaken to understand the mechanisms, diagnosis, progression, and treatment of CSM and OPLL and to provide summary statements and clinical recommendations. This article reports the methods used in the studies in this focus issue. SUMMARY STATEMENTS: The objectives of this focus issue were met using a variety of article and study designs, each of which has some unique methodological aspects associated with it. The reader should refer to the full article in this issue for additional details specific to that topic. The methods for systematic review follow accepted standards for rigor and, together with the application of Grading of Recommendation Assessment, Development and Evaluation, are intended to allow for transparency in the process for creating the clinical recommendation.

Predictive factors affecting outcome after cervical laminoplasty.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine whether various preoperative factors affect patient outcome after cervical laminoplasty for cervical spondylotic myelopathy (CSM) and/or ossification of posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is a procedure designed to decompress the spinal cord by enlarging the spinal canal while preserving the lamina. Prior research has identified a variety of potential predictive factors that might affect outcomes after this procedure. METHODS: A systematic search of multiple major medical reference databases was conducted to identify studies explicitly designed to evaluate the effect of preoperative factors on patient outcome after cervical laminoplasty for CSM or OPLL. Studies specifically designed to evaluate potential predictive factors and their associations with outcome were included. Only cohort studies that used multivariate analysis, enrolled at least 20 patients, and adjusted for age as a potential confounding variable were included. JOA (Japanese Orthopaedic Association), modified JOA, and JOACMEQ-L (JOA Cervical Myelopathy Evaluation Questionnaire lower extremity function section) scores were the main outcome measures. Clinical recommendations and consensus statements were made through a modified Delphi approach by applying the GRADE (Grading of Recommendation Assessment, Development and Evaluation)/AHRQ (Agency for Healthcare Research and Quality) criteria. RESULTS: The search strategy yielded 433 citations, of which 1 prospective and 11 retrospective cohort studies met our inclusion criteria. Overall, the strength of evidence from the 12 studies is low or insufficient for most of the predictive factors. Increased age was not associated with poorer JOA outcomes for patients with CSM, but there is insufficient evidence to make a conclusion for patients with OPLL. Increased severity of disease and a longer duration of symptoms might be associated with JOA outcomes for patients with CSM. Hill-shaped lesions might be associated with poorer JOA outcomes for patients with OPLL. There is insufficient evidence to permit conclusions regarding other predictive factors. CONCLUSION: Overall, the strength of evidence for all of the predictive factors was insufficient or low. Given that cervical myelopathy due to CSM tends to be progressive and that increased severity of myelopathy and duration of symptoms might be associated with poorer outcomes after cervical laminoplasty for CSM, it is preferable to perform laminoplasty in patients with CSM earlier rather than waiting for symptoms to get worse. Further research is needed to more clearly identify predictive factors that affect outcomes after cervical laminoplasty because there were relatively few studies identified that used multivariate analyses to control for confounding factors and many of these studies did not provide a detailed description of the multivariate analyses or the magnitude of effect estimates. EVIDENCE-BASED CLINICAL RECOMMENDATIONS: RECOMMENDATION 1: For patients with CSM, increased age is not a strong predictor of clinical neurological outcomes after laminoplasty; therefore, age by itself should not preclude cervical laminoplasty for CSM. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Strong. RECOMMENDATION 2: For patients with CSM, increased severity of disease and a longer duration of symptoms might be associated with poorer clinical neurological outcomes after laminoplasty; therefore, we recommend that patients be informed about this. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Strong. SUMMARY STATEMENTS: For patients with OPLL, hill-shaped lesions might be associated with poorer clinical neurological outcomes after laminoplasty; therefore, surgeons might consider potential benefits and risks of alternative or additional surgery.

Total disc replacement in the cervical spine: a systematic review evaluating long-term safety.

STUDY DESIGN: Systematic review.Clinical questions: What are the rates and causes of subsequent surgeries? What is the long-term complication rates following cervical artificial disc replacement (C-ADR)? How do these rates change over time? METHODS: A systematic review was undertaken for articles published up to October 2011. Electronic databases and reference lists of key articles were searched to identify comparative and non-comparative studies reporting long-term (≥ 48 months) complications of C-ADR. Two independent reviewers assessed the strength of evidence using the GRADE criteria and disagreements were resolved by consensus. RESULTS: Two RCTs reporting outcomes following C-ADR (Bryan disc, Prestige disc) versus anterior cervical discectomy and fusion (ACDF) at follow-ups of 4 to 5 years were found; five case series reporting outcomes following C-ADR at follow-ups of 4 to 8 years were identified. Secondary surgery rates were similar or slightly lower following C-ADR compared with fusion at 4 to 5 years postoperatively. In one small subset of an RCT, rates of adjacent disc heterotopic ossification were lower in C-ADR patients than in those treated with fusion. Rates of other adverse events were similar between treatment groups. CONCLUSIONS: There is low evidence on the long-term safety outcomes following C-ADR. Additional comparative studies with follow-up of at least 4 years are needed to fully understand the long-term safety outcomes of C-ADR compared with fusion.

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury.

There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.

Kinematics of the cervical adjacent segments after disc arthroplasty compared with anterior discectomy and fusion: a systematic review and meta-analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To determine the kinematics of the adjacent segments and global cervical spine after cervical arthroplasty compared with anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Adjacent segment pathology after ACDF is a significant concern. Arthroplasty may decrease the risk of adjacent segment degeneration by maintaining normal spinal kinematics compared with fusion. However, the differences in the in vivo kinematics of the adjacent segments after cervical fusion versus arthroplasty have not been clearly established. METHODS: A systematic literature review of studies comparing adjacent segment kinematic changes between fusion and arthroplasty was performed. We included randomized controlled trials and cohort studies that compared cervical arthroplasty with ACDF in adults with degenerative disease and reported on at least 1 outcome of interest. Meta-analysis was performed using a random-effects model where appropriate. The standardized mean difference of changes from baseline to follow-up between treatment groups was determined. Recommendations were made using Grades of Recommendation Assessment, Development, and Evaluation criteria. RESULTS: We identified 12 studies, including 7 randomized controlled trials, 4 cohort studies, and 1 case-control study that evaluated kinematic measurements at the adjacent segments or the global cervical spine (C2-C7) after cervical arthroplasty compared with ACDF. We found no statistically significant differences between treatment groups in the change in range of motion (ROM) at the cranial or caudal adjacent segments from baseline to 2 years of follow-up. However, there was low evidence that the global cervical spine (C2-C7) had significantly greater change in ROM after arthroplasty compared with ACDF: patients had a greater angular ROM as measured up to 2 years after arthroplasty. We found no statistically significant differences between treatment groups in the change in the horizontal or vertical centers of rotation at the adjacent segments as measured up to 2 years after surgery. Regarding sagittal alignment, the cranial and caudal adjacent segments both became significantly more lordotic after arthroplasty compared with fusion at 1 to 2 years after surgery. However, there was no statistically significant difference between treatment groups in the change in global cervical sagittal alignment from baseline to 2 years. CONCLUSION.: There is no statistically or clinically significant difference in the adjacent segment ROM or centers of rotation after cervical arthroplasty compared with ACDF. However, the change in sagittal alignment at the cranial and caudal adjacent segments was significantly more lordotic after arthroplasty compared with fusion. In addition, although we found that there was no statistically significant difference between treatment groups in the change in global cervical (C2-C7) sagittal alignment, there was a significantly greater change in the angular ROM of the cervical spine at up to 2 years after arthroplasty than occurred after fusion. CONSENSUS STATEMENT: Patients can be advised that single-level arthroplasty and ACDF result in clinically similar kinematic changes at short-term follow-up. Strength of Statement: Strong.

A systematic review of definitions and classification systems of adjacent segment pathology.

STUDY DESIGN: Systematic review. OBJECTIVE: To undertake a systematic review to determine how "adjacent segment degeneration," "adjacent segment disease," or clinical pathological processes that serve as surrogates for adjacent segment pathology are classified and defined in the peer-reviewed literature. SUMMARY OF BACKGROUND DATA: Adjacent segment degeneration and adjacent segment disease are terms referring to degenerative changes known to occur after reconstructive spine surgery, most commonly at an immediately adjacent functional spinal unit. These can include disc degeneration, instability, spinal stenosis, facet degeneration, and deformity. The true incidence and clinical impact of degenerative changes at the adjacent segment is unclear because there is lack of a universally accepted classification system that rigorously addresses clinical and radiological issues. METHODS: A systematic review of the English language literature was undertaken and articles were classified using the Grades of Recommendation Assessment, Development, and Evaluation criteria. RESULTS.: Seven classification systems of spinal degeneration, including degeneration at the adjacent segment, were identified. None have been evaluated for reliability or validity specific to patients with degeneration at the adjacent segment. The ways in which terms related to adjacent segment "degeneration" or "disease" are defined in the peer-reviewed literature are highly variable. CONCLUSION: On the basis of the systematic review presented in this article, no formal classification system for either cervical or thoracolumbar adjacent segment disorders currently exists. CONSENSUS STATEMENT: No recommendations regarding the use of current classification of degeneration at any segments can be made based on the available literature. A new comprehensive definition for adjacent segment pathology (ASP, the now preferred terminology) has been proposed in this Focus Issue, which reflects the diverse pathology observed at functional spinal units adjacent to previous spinal reconstruction and balances detailed stratification with clinical utility. A comprehensive classification system is being developed through expert opinion and will require validation as well as peer review. Strength of Statement: Strong.

Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: a systematic review.

OBJECT: Using a systematic approach, the authors evaluated the current utilization, safety, and effectiveness of cellular therapies for traumatic spinal cord injuries (SCIs) in humans. METHODS: A systematic search and critical review of the literature published through mid-January 2012 was performed. Articles included in the search were restricted to the English language, studies with at least 10 patients, and those analyzing cellular therapies for traumatic SCI. Citations were evaluated for relevance using a priori criteria, and those that met the inclusion criteria were critically reviewed. Each article was then designated a level of evidence that was developed by the Oxford Centre for Evidence-Based Medicine. RESULTS: The initial literature search identified 651 relevant articles, which decreased to 350 after excluding case reports and reviews. Evaluation of articles at the title/abstract level, and later at the full-text level, limited the final article set to 12 papers. The following cellular therapies employed in humans with SCI are reviewed: bone marrow mesenchymal and hematopoietic stem cells (8 studies), olfactory ensheathing cells (2 studies), Schwann cells (1 study), and fetal neurogenic tissue (1 study). Overall the quality of the literature was very low, with 3 Grade III levels of evidence and 9 Grade IV studies. CONCLUSIONS: Several different cellular-mediated strategies for adult SCI have been reported to be relatively safe with varying degrees of neurological recovery. However, the literature is of low quality and there is a need for improved preclinical studies and prospective, controlled clinical trials.

Spinal cord injury and quality of life: a systematic review of outcome measures.

STUDY DESIGN: Systematic review. STUDY RATIONALE: According to current estimates, there are more than 1 million people living with a spinal cord injury (SCI) in the United States alone. Given the potentially devastating impact of SCI on health-related quality of life (QoL), we sought to gain an improved understanding of QoL outcomes in SCI. OBJECTIVE: To identify and describe common QoL outcomes measures in patients with SCI. METHODS: A systematic review of the English-language literature was undertaken for articles published from 1998 through December 2010. Electronic databases and reference lists of key articles were searched to identify measures or indices used to evaluate QoL outcomes in patients with SCI. The titles and abstracts of the SCI peer-reviewed literature were searched to determine which of these outcome measures were most commonly used to evaluate QoL in patients with SCI. RESULTS: We identified 27 outcome measures used to evaluate QoL in patients with SCI. In SCI literature, the six most commonly used objective outcome measures were the Short-form 36 (SF-36); Craig Handicap Assessment and Reporting Technique (CHART); Short-form 12 (SF-12); Sickness Impact Profile (SIP68); Reintegration to Normal Living Index (RNL); and Community Integration Questionnaire (CIQ). The six subjective measures that were most frequently used were the Satisfaction with Life Scale (SWLS); Quality of Life Index (QLI); Life Satisfaction Questionnaire (LISAT-9/-1); World Health Organization Quality of Life-BREF scale (WHOQOL-BREF); Perceived Quality of Life (PQOL); and global QoL. All six objective measures have been validated in an SCI population, and four of the six subjective measures have been similarly validated. Three of each of the objective and subjective measures have been reliability tested in a population with SCI. CONCLUSION: In addition to neurological and functional changes after SCI, QoL outcomes should be routinely assessed. Choice of appropriate QoL measure should be influenced by the study objectives and design, as well as the psychometric properties of the particular measure within the context of SCI.

Does patient history and physical examination predict MRI proven cauda equina syndrome?

STUDY DESIGN: Systematic review. STUDY RATIONALE: While magnetic resonance imaging (MRI) is used as the diagnostic gold standard for cauda equina syndrome (CES), many MRI scans obtained from patients presenting with signs and/or symptoms of CES do not reveal concordant pathology. As a result, the role of the history and physical examination remains unclear when determining which patients require emergent MRI.Objective or clinical question: Are there elements from the history or physical examination that are associated with CES as established by MRI? METHODS: A systematic review of the literature was undertaken for articles published through April 13, 2011. PubMed, Cochrane, National Guideline Clearinghouse Databases, and bibliographies of key articles were searched. Two independent reviewers reviewed articles. Inclusion and exclusion criteria were set and each article was subject to a predefined quality-rating scheme. RESULTS: We identified four articles meeting our inclusion criteria. All studies evaluated patients with symptoms suggestive of CES and compared symptoms and/or signs with findings at MRI. The mean prevalence of CES as diagnosed by MRI ranged from 14%-48% of patients. No symptoms or signs reported by more than one study showed high sensitivity and specificity, and all likelihood ratios were low. Symptoms included back/low back pain, bilateral sciatica, bladder retention, bladder incontinence, frequent urination, decreased urinary sensation, and bowel incontinence; signs included saddle numbness and reduced anal tone. CONCLUSIONS: There is low evidence that individual symptoms or signs from the patient history or clinical examination, respectively, can be used to diagnose CES. Additional prospective studies are needed to evaluate whether any single and/or combination of symptoms are associated with a positive diagnosis of CES.

Effectiveness of spinal fusion versus structured rehabilitation in chronic low back pain patients with and without isthmic spondylolisthesis: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine if the presence of isthmic spondylolisthesis modifies the effect of treatment (fusion vs. multidimensional supervised rehabilitation) in patients with chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Results of spinal surgery for CLBP are variable. It is unclear whether patients with CLBP and isthmic spondylolisthesis have more success with surgery versus a multidimensional supervised rehabilitation program when compared with those with CLBP but without spondylolisthesis. METHODS: A systematic search was conducted in MEDLINE and the Cochrane Collaboration Library for articles published through January 2011. Randomized controlled trials (RCTs) were included that compared spine fusion versus multidimensional supervised rehabilitation in patients with and without isthmic spondylolisthesis. Standardized mean differences (SMDs) and risk differences were calculated for common outcomes, and then compared to determine potential heterogeneity of treatment effect. The final strength of the body of literature was expressed as "high," "moderate," or "low" confidence that the evidence reflects the true effect. RESULTS: No studies were found that directly compared the two subgroups. Three RCTs compared fusion with supervised nonoperative care in patients with CLBP without isthmic spondylolisthesis; one RCT evaluated these treatments in patients with isthmic spondylolisthesis. There were study differences in patient characteristics, type of fusion, the nature of the rehabilitation, outcomes assessed, and length of follow-up. The SMDs for pain in favor of fusion were modest at 2 years for those without isthmic spondylolisthesis, but large in favor of fusion for those with isthmic spondylolisthesis compared with rehabilitation. Similarly, the SMDs for function in patients without isthmic spondylolisthesis compared with rehabilitation was small at 2 years, but appreciably higher in favor of fusion in patients with isthmic spondylolisthesis. CONCLUSION: The overall strength of evidence evaluating whether the presence of isthmic spondylolisthesis modifies the effect of fusion compared with rehabilitation patients with CLBP is "low." Fusion should be considered for patients with low back pain and isthmic spondylolisthesis who have failed nonoperative treatment. CLINICAL RECOMMENDATIONS: We recommend considering fusion for patients with isthmic spondylolisthesis and lower back pain who have failed nonoperative treatment. RECOMMENDATION: Weak.

Morbidity and mortality related to odontoid fracture surgery in the elderly population.

STUDY DESIGN: Systematic analysis. OBJECTIVE: To determine the morbidity and mortality of surgical treatment of odontoid fractures in the elderly. SUMMARY OF BACKGROUND DATA: The prevalence of trauma in the elderly is increasing. There exists no consensus regarding the role of surgical treatment for odontoid fractures in the elderly and there exists significant variability in clinical practice. This variability may be related to a lack of robust information available to clinicians. Importantly, studies that define surgical risk are not available. METHODS: A systematic analysis of the English language literature was undertaken for articles published between January 1990 and June 2009. Electronic databases and reference lists of key articles were searched to identify articles examining complications and mortality following odontoid fracture surgery in subjects 65 years of age or older. Two independent reviewers assessed the level of evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, and disagreements were resolved by consensus. RESULTS: The initial literature search yielded 247 articles related to morbidity or mortality following surgery treatment of odontoid fractures in the elderly. After exclusion of articles based on title or abstract information, 48 remained to undergo full text review. Subsequent exclusions yielded 14 articles suited for this analysis. The most commonly reported major complications after odontoid fracture surgery in the elderly include cardiac failure (6.8%), DVT (3.2%), stroke (3.2%), pneumonia (9.9%), respiratory failure (7.7%), liver failure (6.7%), and severe infection (3.2%). Other site specific and minor complications were found to be reported consistently in the literature. The overall mortality rate after surgery is 10.1% (in-hospital, 6.2%; postdischarge, 8.8%). Similar mortality rates were found following anterior surgery (7% in-hospital; 9% overall) and posterior surgery (8% in-hospital; 9% overall); there were no differences in the rate of major airway complications between these groups (anterior: 17%; posterior: 18%). There was, however, a higher rate of site-specific complications, including nonunion, technical failure, and the need for revision surgery, following anterior surgery as compared with posterior surgery. CONCLUSION: Based on the summary of criteria results, future research evaluating complications following surgery for odontoid fractures in elderly patients is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate currently available in the literature.

Postoperative dysphagia in anterior cervical spine surgery.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine the incidence and prevalence and identify effective recommendations to minimize the incidence and prevalence of postoperative dysphagia after anterior cervical surgery. SUMMARY OF BACKGROUND DATA: The reported incidence and prevalence of postoperative dysphagia and risk factors associated with its development varies widely in the literature. METHODS: A systematic review of the English-language literature was undertaken for articles published between January 1990 and December 2008. Electronic databases and reference lists of key articles were searched to identify published studies examining the incidence and prevalence of dysphagia after anterior cervical spine surgery. Two independent reviewers assessed the strength of literature using the Grading of Recommendations Assessment, Development, and Evaluation criteria, assessing quality, quantity, and consistency of results. Disagreements were resolved by consensus. RESULTS: A total of 126 articles were initially screened, and 17 ultimately met the predetermined inclusion criteria. The rates of dysphagia found in the literature varied widely. Rates declined after surgery, but plateau at 1 year at a range of 13% to 21%. Risk factors identified were multilevel surgery and female sex. Specific preventive measures were not identified. CONCLUSION: A better understanding of dysphagia will require the development of better outcome measures.

Complications related to osteobiologics use in spine surgery: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: The objectives of this systematic review were to identify the character and rates of complications in patients after the use of BMP in spine fusion surgery and to determine whether there is a dose-response relationship of BMP with complications. SUMMARY OF BACKGROUND DATA: BMP is used on-label for ALIF with LT-CAGE and off-label for various spine fusion applications in the cervical, thoracic, and lumbar spines because of its effectiveness in promoting arthrodesis. Multiple studies published over the past several years have highlighted complications associated with BMP in a variety of clinical fusion scenarios. There are no systematic reviews on this topic, and thus, the complication profile of off-label use or physician directed use of BMP in spinal fusion surgery is not well characterized. Some of the reported complications are unique to BMP, which underscores the need for this thorough literature review. METHODS: A systematic review of the English language literature was performed for articles published between 1990 and June 2009. Electronic databases and reference lists of key articles were searched to identify articles examining the use of BMP in spine surgery. Two independent reviewers assessed the level of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria and disagreements were resolved by consensus. RESULTS: Two hundred forty-' articles that assessed outcomes after BMP use in spinal surgery were identified from the literature; of these, 31 articles were selected for inclusion. We determined that multiple complications are associated after the use of rhBMP-2 in both cervical and lumbar spine fusion surgery. There is a mean incidence of 44%, 25%, and 27% of resorption, subsidence, and interbody cage migration reported for lumbar spine interbody fusion surgery although reoperation or long-term detrimental effect was rare. Cervical studies report a mean 5.8% of postoperative soft tissue problems, including dysphagia, when rhBMP-2 is used for ventral cervical fusion. It was determined that the strength of evidence of the peer-reviewed literature that report on types of complications is high for the lumbar and low for the cervical spine, respectively, and that the current strength of evidence on rates of complications with BMP is moderate and low, respectively. CONCLUSION: The complication profile of BMP-2 for ALIF with LT-CAGE is well characterized. Because of the lack of substantive data, the same is not true for other types of lumbar fusions, or for cervical or thoracic fusion applications. BMP has been associated with a variety of unique complications in the ventral cervical and lumbar spines. The published data on BMP fail to precisely profile this product's use in fusion surgery; hence, it should be used only after a careful consideration of the relevant data. Well-designed and executed studies are necessary to completely define the incidence of various complications relative to type of BMP, type and region of fusion, surgical technique, dose, and carrier, and importantly, to define the natural history and management of associated complications.