D. Greg Anderson

Comparative Gene Expression Profiling of Normal and Degenerative Discs : Analysis of a Rabbit Annular Laceration Model

Study Design. A rabbit annular laceration model was used to investigate intervertebral disc gene expression in normal and lacerated discs. Objectives. To determine and compare the pattern of expression of potentially important genes in normal and lacerated discs and to determine if the changes in gene expression were similar to human degenerative discs. Summery of Background Data. Little is known regarding gene expression in normal or degenerating disc tissue. Methods. Eighteen rabbits were subjected to annular laceration of the L1–L2 and L2–L3 discs while two rabbits served as sham controls. Control and lacerated discs were harvested 1 week, 3 weeks, and 6 weeks following surgery and subjected to histologic examination and gene expression analysis using the reverse transcription–polymerase chain reaction (RT-PCR). The genes studied included collagen Type I (Col I), collagen Type II (Col II), decorin, fibronectin (FN), interleukin-1a (IL-1&agr;), bone morphogenetic protein 2 (BMP-2), Fas, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 13 (MMP-13), and tumor necrosis factor (TNF). Expression levels of each gene were normalized to that of glyceraldehyde-3-phosphate dehydrogenase (GADPH), a constitutively expressed gene. Results. Histology confirmed progressive degeneration of the discs over the 6-week study period. Different patterns of gene expression were observed in control and lesioned discs. Annular laceration caused a marked upregulation (two- to eightfold) of the expression of Col I, Col II, FN, MMP-1, MMP-9, MMP-13, and Fas genes, whereas that of BMP-2, IL-1&agr;, and TNF genes was unaffected. Expression of the decorin gene was downregulated approximately sixfold after annular laceration. Conclusion. Annular laceration in this animal model resulted in marked changes in gene expression. Upregulation of gene expression was observed for some molecules found at high concentration in human degenerated discs, suggesting similarities to human disc degeneration at the molecular level. This supports the need for further study of the genes found to be activated by annular laceration.

TNF-α and IL-1β Promote a Disintegrin-like and Metalloprotease with Thrombospondin Type I Motif-5-mediated Aggrecan Degradation through Syndecan-4 in Intervertebral Disc

Background: Disc degeneration is characterized by elevated levels of cytokines, TNF-α and IL-1β and an increase in aggrecan-rich matrix degradation. Results: Cytokine-dependent syndecan-4 expression regulate ADAMTS-5/aggrecanse2 activation in disc cells. Conclusion: Syndecan-4 may play a key role in pathogenesis of degenerative disc disease. Significance: Syndecan-4 may offer a potential therapeutic target for controlling progression of degenerative disc disease. Elevated levels of TNF-α, IL-1β and a resultant increase in ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type I motifs) expression is seen during disc degeneration. However, if these pro-inflammatory cytokines control ADAMTS activity is not definitively known. The goal of the investigation was to study if TNF-α and IL-1β regulate syndecan-4 (SDC4) expression, and if SDC4 was responsible for promoting aggrecan degradation through controlling ADAMTS activity in nucleus pulposus cells of the intervertebral disc. Cytokine treatment increased SDC4 expression and promoter activity. Use of inhibitor, SM7368 and co-transfections with IκBα, RelA/p50 showed that NF-κΒ regulated both basal and cytokine-dependent SDC4 transcription. SDC4 promoter harboring RelA binding site mutation was unresponsive to the cytokines. Moreover, cytokines failed to increase SDC4 promoter activity in RelA-null cells. Cytokines increased ADAMTS-4/5 expression and aggrecan degradation and promoted SDC4 interaction with ADAMTS-5. Treatment with heparinase-III and p-nitrophenyl-β-d-xylopyranoside (PNPX), an inhibitor of heparan sulfate synthesis and transfection with SDC4-shRNA partially blocked cytokine mediated aggrecan degradation. Analysis of human tissues showed increased aggrecan degradation with a concomitant increase in SDC4 and ADAMTS-5 protein expression with severity of disc disease. Likewise, SDC4, TNF-α, IL-1β, ADAMTS-4, and ADAMTS-5 mRNA expression increased in degenerate tissues. We conclude that in nucleus pulposus, TNF-α and IL-1β regulate SDC4 expression, which plays a key role in pathogenesis of degenerative disc disease by promoting aggrecan degradation by ADAMTS-5.

Reliability of a novel classification system for thoracolumbar injuries: the Thoracolumbar Injury Severity Score.

Study Design. Prospective study of 5 spine surgeons rating 71 clinical cases of thoracolumbar spinal injuries using the Thoracolumbar Injury Severity Score (TLISS) and then re-rating the cases in a different order 1 month later. Objective. To determine the reliability of the TLISS system. Summary of Background Data. The TLISS is a recently introduced classification system for thoracolumbar spinal column injures designed to simplify injury classification and facilitate treatment decision making. Before being widely adopted, the reliability of the TLISS must be studied. Methods. A total of 71 cases of thoracolumbar spinal trauma were distributed on CD-ROM to 5 attending spine surgeons, including clinical/radiographic data, details of the TLISS, and a scoring sheet in which cases would be scored using the system. The surgeons were later assigned the task with the cases reordered. Intraobserver and interobserver reliability was calculated for TLISS components, total score, and surgeons treatment decision using the Cohen unweighted kappa coefficients and Spearman rank-order correlation. Results. Interrater reliability assessed by generalized kappa coefficients was 0.33 ± 0.03 for injury mechanism, 0.91 ± 0.02 for neurologic status, 0.35 ± 0.03 for posterior ligamentous complex status, 0.29 ± 0.02 for TLISS total, and 0.52 ± 0.03 for treatment recommendation. Respective results using the Spearman correlation were 0.35 ± 0.04, 0.94 ± 0.01, 0.48 ± 0.04, 0.65 ± 0.03, and 0.51 ± 0.04. Surgeons agreed with the TLISS recommendation 96.4% of the time. Intrarater kappa coefficients were 0.57 ± 0.04 for injury mechanism, 0.93 ± 0.02 for neurologic status, 0.48 ± 0.04 for posterior ligamentous complex status, 0.46 ± 0.03 for TLISS total, and 0.62 ± 0.04 for treatment recommendation. Respective results using the Spearman correlation were 0.70 ± 0.04, 0.95 ± 0.02, 0.59 ± 0.05, 0.77 ± 0.04, and 0.59 ± 0.05. Conclusions. The TLISS has good reliability and compares favorably to other contemporary thoracolumbar fracture classification systems.

Collagen and Proteoglycan Abnormalities in the GDF-5-Deficient Mice and Molecular Changes When Treating Disk Cells With Recombinant Growth Factor

Study Design. A magnetic resonance image, histologic, biochemical, and gene expression study was conducted to characterize the effects of growth and development factor-5 (GDF-5) deficiency on the health of the intervertebral disc. Objective. To determine the effect of GDF-5 deficiency on extracellular matrix and gene expression on the intervertebral disc. Summary of Background Data. Developmental and degenerative changes in intervertebral disc are not fully understood. Molecular abnormalities and spontaneous mutations that lead to the deficiency in a normal protein have been useful in understanding the function of certain molecules and the role they play in the structure and health of certain tissues. Although the role of GDF-5 in the disc has not been elucidated, this factor may have an important role in the disc as a result of the well-documented effect of GDF-5 in other chondrogenic tissues. Methods. Intervertebral discs of 20-week-old GDF-5 (−/−) and (+/+) mice were examined radiographically, histologically, biochemically, and with gene expression studies. Cells isolated from GDF-5-deficient mouse discs were treated with recombinant GDF-5 and gene expression was subsequently analyzed. Results. GDF-5 (−/−) mice demonstrated significantly lower T2-weighted signal intensity in the central region of their lumbar discs, and disc histology revealed loss of the normal lamellar architecture of the anulus fibrosus and a shrunken, disorganized nucleus pulposus. Biochemical analysis revealed decreased proteoglycan content but no appreciable change in total collagen content of the discs. Significant downregulation of both aggrecan and type II collagen mRNA, without an appreciable change in type I collagen expression, was noted on gene expression studies. Recombinant GDF-5 treatment of disc cells from the GDF-5-deficient mice resulted in a dose-dependent upregulation of the aggrecan and type II collagen genes. Conclusion. The intervertebral disc is markedly affected by GDF-5 deficiency. This relatively simple (single gene) system with a known molecular defect may be useful in studies designed to define the response of the intervertebral disc to treatment with growth factor in vivo.

Early complications of surgical versus conservative treatment of isolated type II odontoid fractures in octogenarians: A retrospective cohort study

Study Design A retrospective cohort study of operative versus nonoperative treatment of isolated type II odontoid fractures in patients aged 80 years and more without neurologic deficit admitted to a level 1 spinal cord injury center between June 1985 and July 2006. Objective To assess the presentation and acute complications of operatively and nonoperatively managed type II odontoid fractures in the octogenarian population. Summary of Background Data Type II odontoid fractures are the most common cervical spine fracture in the elderly. Studies suggest acute in-hospital complication rates in type II odontoid fractures in the elderly exceed 50%. Few studies have examined the acute in-hospital outcomes of isolated type II odontoid fractures in the octogenarian population. Methods The medical records of 223 consecutive C2 fractures from June 1985 to July 2006 over the age of 80 years were reviewed retrospectively. Patients with associated cervical spine fractures were excluded. Eighty neurologically intact patients over age 80 were identified with isolated acute type II odontoid fractures. The charts were reviewed and mechanism of injury, comorbidities, date of injury, date of admission, date of discharge, radiology reports, discharge disposition, associated injuries, fracture management, type of surgical fixation (if any), and documented complications were abstracted. Results Thirty-two patients received operative treatment (10 anterior and 22 posterior) and 40 patients received nonsurgical treatment. Eight patients were excluded because the medical record could not be located. The mean age was 85.5±3.5 years in the surgical and 87.3±4.7 years in the nonsurgical group (P>0.05); mean length of acute hospital stay was 11.2±8.5 days in the nonsurgical and 22.8±28.3 days in the surgical group (P<0.05); mean comorbidity score was 2.3±1.2 in the nonsurgical and 2.0±1.0 in the surgical group (P>0.5); mean fracture displacement was 4.1±3.5 mm in the nonsurgical and 3.9±3.4 mm in the surgical group (P>0.5). Acute in-hospital mortality rate was 15% in the nonsurgical group and 12.5% in the surgical group (P>0.05). The percentage of patients experiencing at least one significant complication was higher in the operative group than the nonoperative group (62% vs. 35%, respectively, P<0.05). Conclusions Type II odontoid fractures in the octogenarian population are associated with substantial morbidity and mortality, irrespective of management method. Prospective studies are needed to better elucidate management strategies for this difficult clinical problem.

Surgical Decision Making for Unstable Thoracolumbar Spine Injuries: Results of a Consensus Panel Review by the Spine Trauma Study Group

Objectives: The optimal surgical approach and treatment of unstable thoracolumbar spine injuries are poorly defined owing to a lack of widely accepted level I clinical literature. This lack of evidence-based standards has led to varied practice patterns based on individual surgeon preferences. The purpose of this study was to survey the leaders in the field of spine trauma to define the major characteristics of thoracolumbar injuries that influence their surgical decision making. In the absence of good scientific data, expert consensus opinions may provide surgeons with a practical framework to guide therapy and to conduct future research. Methods: A panel of 22 leading spinal surgeons from 20 level I trauma centers in seven countries met to discuss the indications for surgical approach selection in unstable thoracolumbar injuries. Injuries were presented to the surgeons in a case scenario survey format. Preferred surgical approaches to the clinical scenarios were tabulated and comments weighed. Results: All members of the panel agreed that three independent characteristics of thoracolumbar injuries carry primary importance in surgical decision making: the injury morphology, the neurologic status of the patient, and the integrity of the posterior ligaments. Six clinical scenarios based on the neurologic status of the patient (intact, incomplete, or complete) and on the status of the posterior ligamentous complex (intact or disrupted) were created, and consensus treatment approaches were described. Additional circumstances capable of altering the treatments were acknowledged. Conclusions: Decision making for the surgical treatment of thoracolumbar injuries is largely dependent on three patient characteristics: injury morphology, neurologic status, and posterior ligament integrity. A logical and practical decision-making process based on these characteristics may guide treatment even for the most complicated fracture patterns.

Thoracolumbar injury classification and severity score: a new paradigm for the treatment of thoracolumbar spine trauma

BackgroundContemporary understanding of the biomechanics, natural history, and methods of treating thoracolumbar spine injuries continues to evolve. Current classification schemes of these injuries, however, can be either too simplified or overly complex for clinical use.MethodsThe Spine Trauma Group was given a survey to identify similarities in treatment algorithms for common thoracolumbar injuries, as well as to identify characteristics of injury that played a key role in the decision-making process.ResultsBased on the survey, the Spine Trauma Group has developed a classification system and an injury severity score (thoracolumbar injury classification and severity score, or TLICS), which may facilitate communication between physicians and serve as a guideline for treating these injuries. The classification system is based on the morphology of the injury, integrity of the posterior ligamentous complex, and neurological status of the patient. Points are assigned for each category, and the final total points suggest a possible treatment option.ConclusionsThe usefulness of this new system will have to be proven in future studies investigating inter- and intraobserver reliability, as well as long-term outcome studies for operative and nonoperative treatment methods.

The adoption of a new classification system: time-dependent variation in interobserver reliability of the thoracolumbar injury severity score classification system.

Study Design. Prospective clinical assessment of the interobserver reliability of the Thoracolumbar Injury Classification and Severity Score (TLISS) in a series of consecutive patients. Objective. To evaluate the time-dependent changes in interobserver reliability of the TLISS system. Summary of Background Data. Reliability of an injury classification system is fundamental to its usefulness. A system that can be taught and implemented effectively will be highly reliable. Vaccaro et al recently introduced a novel thoracolumbar injury classification and treatment recommendation system called the “Thoracolumbar Injury Classification and Severity Score.” An improvement over previous traumatic thoracolumbar systems, it has been designed to be both descriptive as well as prognostic. To define better the benefits of this system, the purpose of our study was to assess the time-dependent changes associated with implementation of the TLISS system at 1 institution. Methods. Seventy-one consecutive patients presenting with acute thoracolumbar injury were prospectively assessed at a single training institution. Plain radiographs, computed tomography, and magnetic resonance imaging were independently reviewed, and each case was classified according to the TLISS system. Seven months later, 25 consecutive patients presenting with acute thoracolumbar injuries were prospectively assessed at the same institution. TLISS classification criteria were again applied after reviewing plain radiographs, computed tomography, and magnetic resonance imaging. The unweighted Cohen kappa coefficient and Spearman correlation values were calculated to assess interobserver reliability at each assessment time. Interobserved reliability at the time of the first assessment was then compared with interobserver reliability from the second assessment. Results. Statistically significant (P < 0.05) improvements in interobserver reliability were observed. Both the unweighted Cohen kappa coefficient and Spearman correlation values increased across all comparable fields: TLISS subscores (mechanism of injury, posterior ligamentous complex), total TLISS, and TLISS management scores. Conclusions. The significant improvements observed in interobserver reliability of the TLISS system suggest that the classification system can be taught effectively and be readily incorporated into daily practice. The strong correlation values obtained at the second assessment time suggest that the TLISS system may be reproducibly used to describe thoracolumbar injuries.

The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study.

Study Design. Randomized controlled trial comparing OP-1 (rhBMP-7) with iliac crest autograft in patients with symptomatic degenerative spondylolisthesis and spinal stenosis treated with decompression and uninstrumented posterolateral arthrodesis. Objective. To determine the safety and the clinical and radiographic efficacy of OP-1 (rhBMP-7) Putty as compared with an iliac crest bone autograft control in uninstrumented, single-level posterolateral spinal arthrodesis. Summary of Background Data. Preclinical and preliminary clinical data have demonstrated successful fusion and clinical outcomes with the use of OP-1 Putty in posterolateral spinal arthrodesis. No prior randomized controlled trial with adequate study power has been performed. Methods. A total of 335 patients were randomized in 2:1 fashion to receive either OP-1 Putty or autograft in the setting of an uninstrumented posterolateral arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis. Patients were observed serially with radiographs, clinical examinations, and appropriate clinical indicators, including ODI, Short-Form 36, and visual analog scale scores. Serum samples were examined at regular intervals to assess the presence of antibodies to OP-1. The primary end point, Overall Success, was analyzed at 24 months. The study was extended to include additional imaging data and long-term clinical follow-up at 36+ months. At the 36+ month time point, CT scans were obtained in addition to plain radiographs to evaluate the presence and location of new bone formation. Modified Overall Success, including improvements in ODI, absence of retreatment, neurologic success, absence of device-related serious adverse events, angulation and translation success, and new bone formation by CT scan (at 36+ months), was then calculated using the 24-month primary clinical endpoints, updated retreatment data, and CT imaging and radiographic end points. Results. OP-1 Putty was demonstrated to be statistically equivalent to autograft with respect to the primary end point of modified overall success. The use of OP-1 Putty when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. Although patients in the OP-1 Putty group demonstrated an early propensity for formation of anti-OP-1 antibodies, this resolved completely in all patients with no clinical sequelae. Conclusion. OP-1 Putty is a safe and effective alternative to autograft in the setting of uninstrumented posterolateral spinal arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis.

Mortality rates in geriatric patients with spinal cord injuries

OBJECT The authors undertook this study to evaluate the incidence of spinal cord injury (SCI) in geriatric patients (> or = 70 years of age) and examine the impact of patient age, extent of neurological injury, and spinal level of injury on the mortality rate associated with traumatic SCI. METHODS A prospectively maintained SCI database (3481 patients) at a single institution was retrospectively studied for the period from 1978 through 2005. Parameters analyzed included patient age, admission American Spinal Injury Association (ASIA) motor score, level of SCI, mechanism of injury, and mortality data. The data pertaining to the 412 patients 70 years of age and older were compared with those pertaining to the younger cohort using a chi-square analysis. RESULTS Since 1980, the number of SCI-related hospital admissions per year have increased fivefold in geriatric patients and the percentage of geriatric patients within the SCI population has increased from 4.2 to 15.4%. In comparison with younger patients, geriatric patients were found to be less likely to have severe neurological deficits (greater percentage of ASIA Grades C and D injuries), but the mortality rates were higher in the older age group both for the period of hospitalization (27.7% compared with 3.2%, p < 0.001) and during 1-year follow-up. The mortality rates in this older population directly correlate with the severity of neurological injury (1-year mortality rate, ASIA Grade A 66%, Grade D 23%, p < 0.001). The mortality rate in elderly patients with SCI has not changed significantly over the last two decades, and the 1-year mortality rate was greater than 40% in all periods analyzed. CONCLUSIONS Spinal cord injuries in older patients are becoming more prevalent. The mortality rate in this patient group is much greater than in younger patients and should be taken into account when aggressive interventions are considered and in counseling families regarding prognosis.