ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes.

STUDY DESIGN: Cross-sectional cohort analysis of patients with Modic Changes (MC). OBJECTIVE: Our goal was to characterize the molecular and cellular features of MC bone marrow and adjacent discs. We hypothesized that MC associate with biologic cross-talk between discs and bone marrow, the presence of which may have both diagnostic and therapeutic implications. BACKGROUND DATA: MC are vertebral bone marrow lesions that can be a diagnostic indicator for discogenic low back pain. Yet, the pathobiology of MC is largely unknown. METHODS: Patients with Modic type 1 or 2 changes (MC1, MC2) undergoing at least 2-level lumbar interbody fusion with one surgical level having MC and one without MC (control level). Two discs (MC, control) and two bone marrow aspirates (MC, control) were collected per patient. Marrow cellularity was analyzed using flow cytometry. Myelopoietic differentiation potential of bone marrow cells was quantified to gauge marrow function, as was the relative gene expression profiles of the marrow and disc cells. Disc/bone marrow cross-talk was assessed by comparing MC disc/bone marrow features relative to unaffected levels. RESULTS: Thirteen MC1 and eleven MC2 patients were included. We observed pro-osteoclastic changes in MC2 discs, an inflammatory dysmyelopoiesis with fibrogenic changes in MC1 and MC2 marrow, and up-regulation of neurotrophic receptors in MC1 and MC2 bone marrow and discs. CONCLUSION: Our data reveal a fibrogenic and pro-inflammatory cross-talk between MC bone marrow and adjacent discs. This provides insight into the pain generator at MC levels and informs novel therapeutic targets for treatment of MC-associated LBP.

Results at 24 months from the prospective, randomized, multicenter Investigational Device Exemption trial of ProDisc-C versus anterior cervical discectomy and fusion with 4-year follow-up and continued access patients.

BACKGROUND: Cervical total disk replacement (TDR) is intended to address pain and preserve motion between vertebral bodies in patients with symptomatic cervical disk disease. Two-year follow-up for the ProDisc-C (Synthes USA Products, LLC, West Chester, Pennsylvania) TDR clinical trial showed non-inferiority versus anterior cervical discectomy and fusion (ACDF), showing superiority in many clinical outcomes. We present the 4-year interim follow-up results. METHODS: Patients were randomized (1:1) to ProDisc-C (PDC-R) or ACDF. Patients were assessed preoperatively, and postoperatively at 6 weeks and 3, 6, 12, 18, 24, 36, and 48 months. After the randomized portion, continued access (CA) patients also underwent ProDisc-C implantation, with follow-up visits up to 24 months. Evaluations included Neck Disability Index (NDI), Visual Analog Scale (VAS) for pain/satisfaction, and radiographic and physical/neurologic examinations. RESULTS: Randomized patients (103 PDC-R and 106 ACDF) and 136 CA patients were treated at 13 sites. VAS pain and NDI score improvements from baseline were significant for all patients (P < .0001) but did not differ among groups. VAS satisfaction was higher at all time points for PDC-R versus ACDF patients (P = .0499 at 48 months). The percentage of patients who responded yes to surgery again was 85.6% at 24 months and 88.9% at 48 months in the PDC-R group, 80.9% at 24 months and 81.0% at 48 months in the ACDF group, and 86.3% at 24 months in the CA group. Five PDC-R patients (48 months) and no CA patients (24 months) had index-level bridging bone. By 48 months, approximately 4-fold more ACDF patients required secondary surgery (3 of 103 PDC-R patients [2.9%] vs 12 of 106 ACDF patients [11.3%], P = .0292). Of these, 6 ACDF patients (5.6%) required procedures at adjacent levels. Three CA patients required secondary procedures (24 months). CONCLUSIONS: Our 4-year data support that ProDisc-C TDR and ACDF are viable surgical options for symptomatic cervical disk disease. Although ACDF patients may be at higher risk for additional surgical intervention, patients in both groups show good clinical results at longer-term follow-up.

Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis.

STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To characterize the increase in gelatinase A (MMP2) activity after spinal cord injury (SCI) in the mouse model, and the effects of MMP2/MMP9 inhibition on apoptotic cells. SUMMARY OF BACKGROUND DATA: Clinical consequences of SCI are due to a series of secondary injury cascades. Matrix metalloproteinases are thought play a key role in this, leading to apoptotic cell death. METHODS: SCI via a drop tower in mice was used. MMP2 beta-gal reporter mice were used to quantify the level of MMP2 after SCI. In a follow-up experiment, mice which underwent SCI were randomized to daily SQ injections of MMP2/MMP9 inhibitor versus placebo. MMP2 levels were quantified and histology was performed with TUNEL and Luxol fast blue staining. RESULTS: MMP2 transcription was significantly upregulated after SCI, by the beta-gal assay. Inhibition of MMP2/MMP9 activity after SCI led to statistically significant decreases in apoptosis within the zone of injury. There was a trend towards preservation of myelin by preserved luxol fast blue staining. CONCLUSION: After SCI, MMP2 is upregulated along with neuron and glial cells apoptosis. The level of apoptosis could be reduced with MMP2/MMP9 inhibition. This supports MMP2 as cause for apoptosis after SCI with the potential for therapeutic intervention as apoptosis can be reduced with MMP2 inhibition.

Biomechanics of the anterior longitudinal ligament during 8 g whiplash simulation following single- and contiguous two-level fusion: a finite element study.

STUDY DESIGN: A computational study of anterior longitudinal ligament (ALL) strain in the cervical spine following single- and 2-level fusion during simulated whiplash. OBJECTIVE: To evaluate how cervical fusion alters the peak strain of the ALL in the adjacent motion segments. SUMMARY OF BACKGROUND DATA: Although an in vitro study of ALL strain during whiplash has been conducted in healthy cervical spines, no such study has been performed in a cervical spine with fused segments. It has been demonstrated that the loss of motion following fusion results in increased strain in the adjacent motion segments. However, the biomechanics of the adjacent motion segments during high energy acceleration-deceleration simulations have not been widely reported. Accordingly, we investigated the peak strain of the ALL following single- and 2-level fusion during simulated whiplash. METHODS: A detailed finite element (FE) model of the human body in the driver-occupant position was used to investigate cervical hyperextension injury. The cervical spine was subjected to simulated whiplash at 8 g acceleration and peak ALL strains were computed. The results were validated against published experimental data. This validated FE model was then modified to simulate single- and 2-level fusion and tested under identical loading conditions. RESULTS: The mean increase in peak ALL strain at the motion segment immediately adjacent to the level of fusion was 15.5% for single-level fusion when compared with 40.8% in 2-level contiguous fusion (P = 0.019). CONCLUSION: Cervical arthrodesis increases peak ALL strain in the adjacent motion segments. Two-level fusion increased ALL strain in the adjacent motion segments, on average, greater than single-level fusion did. Disc arthroplasty and other techniques that provide stability without loss of flexibility may be beneficial in patients undergoing multiple-level fusion. Detailed FE models such as ours can provide strong correlation with experimentally determined data.

Intervertebral disc replacement maintains cervical spine kinetics.

STUDY DESIGN: An in vitro biomechanical study of C4-C5 intervertebral disc replacement using a cadaveric model. OBJECTIVES: To investigate the degree of motion afforded by a ball-and-socket cervical intervertebral disc prosthesis design. SUMMARY OF BACKGROUND DATA: Intervertebral disc prostheses designs attempt to restore or maintain cervical disc motion after anterior cervical discectomy and reduce the likelihood of accelerated degeneration in adjacent discs by maintaining normal motion at the affected disc level. Surprisingly, the actual kinetic and biomechanical effects that cervical disc arthroplasty imparts on the spine have not been widely reported. Accordingly, we investigated what effect implanting a cervical disc prosthesis has on the range of motion at the affected level as well as how it changes the coupled motion patterns at the level of implantation. METHODS: Six fresh-frozen human cadaveric cervical spines (C2-C7) were used in this study. We evaluated two different spinal conditions: intact and after disc replacement at C4-C5. Compression (using the follower load concept) and pure moment loading were applied to the specimen. Range of motion was measured using an optical tracking system. Statistical differences between the intact and replaced condition range of motion was determined using analysis of variance with post hoc comparisons (alpha = 0.05). RESULTS: The data indicate that the intervertebral disc prosthesis approximated the intact motion in all three rotation planes at the affected level. Finally, changes in cervical coupled rotations, specifically lateral bending during axial rotation loading and axial rotation during lateral bending loading, were not statistically significant between the two tested conditions. CONCLUSIONS: Our data demonstrate that a ball-and-socket design can replicate physiologic motion at the affected and adjacent levels. More importantly, the data indicate that motion coupling, which is most dramatic in the cervical spine and plays an important biomechanical role, is maintained.

Percutaneous plasma decompression alters cytokine expression in injured porcine intervertebral discs.

BACKGROUND CONTEXT: Discectomy is a surgical technique commonly used to treat bulging or herniated discs causing nerve root compression. Clinical data suggest discectomy may also help patients with contained discs and no clear neural compromise. However, the mechanisms of clinical efficacy are uncertain, and consequently bases for treatment optimization are limited. PURPOSE: To determine the effect of percutaneous plasma decompression on the histologic, morphologic, biochemical and biomechanical features of degenerating intervertebral discs. STUDY DESIGN: An adult porcine model of disc degeneration was used to establish a degenerative baseline against which to evaluate discectomy efficacy. OUTCOME MEASURES: Cytokines interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha were measured from tissue samples using enzyme-linked immunosorbent assay. Histology and morphology images were rated for degenerative findings (of cells and matrix) in both the nucleus and annulus. Proteoglycan content was determined, and intact specimen stiffness and flexibility were measured biomechanically. Magnetic resonance images were collected for biomechanical specimens. METHODS: Using a retroperitoneal surgical approach, stab incisions were made in four or five lumbar discs per spine in 12 minipigs. Animals were allocated into one of three groups: 6-week recovery, 12-week recovery and percutaneous plasma decompression using an electrosurgical device at 6 weeks with recovery for 6 additional weeks. Four additional animals served as controls. RESULTS: Discs treated with discectomy had a significant increase in IL-8 and a decrease in IL-1 as compared with the 12-week, nontreated discs. There were no significant differences in morphologic and biomechanical parameters or proteoglycan content between treated discs and time-matched, nontreated discs. CONCLUSIONS: Our results demonstrate that percutaneous plasma discectomy alters the expression of inflammatory cytokines in degenerated discs, leading to a decrease in IL-1 and an increase in IL-8. Whereas both IL-1 and IL-8 have hyperalgesic properties, IL-1 is likely to be a more important pathophysiologic factor in painful disc disorders than IL-8. Therefore, the alteration in cytokine expression that we observed is consistent with this effect as a mechanism of pain relief after discectomy. In addition, given that IL-1 is catabolic in injured tissue and IL-8 is anabolic, our results suggest that a percutaneous plasma discectomy may be capable of initiating a repair response in the disc.

Spinal infections.

Spinal infections can occur in a variety of clinical situations. Their presentation ranges from the infant with diskitis who is unwilling to crawl or walk to the adult who develops an infection after a spinal procedure. The most common types of spinal infections are hematogenous bacterial or fungal infections, pediatric diskitis, epidural abscess, and postoperative infections. Prompt and accurate diagnosis of spinal infections, the cornerstone of treatment, requires a high index of suspicion in at-risk patients and the appropriate evaluation to identify the organism and determine the extent of infection. Neurologic function and spinal stability also should be carefully evaluated. The goals of therapy should include eradicating the infection, relieving pain, preserving or restoring neurologic function, improving nutrition, and maintaining spinal stability.