- Email: [email protected]
Wednesday, October 30, 2001 8:24–9:07 am General Session 2: Basic Science
48S
Proceedings of the NASS 17th Annual Meeting / The Spine Journal 2 (2002) 47S–128S
Relationship between findings and existing knowledge: The findings suggest that use of internal fixation and PL fusion have increased, whereas use of pure autograft have decreased over the past 20 years. Specific techniques, such as instrumentation and posterior IB fusion appear to increase fusion rates, although their effects on clinical outcome remain in question. The limitations of analyzing pooled data from a large number of studies in meta-analyses are noted, which include nonuniform patient selection, randomization, surgical technique and outcome scoring. For the present study’s purpose, however, it appears to be a reasonable method to observe shifting trends and their influence on outcome over long time periods. Although the published literature cannot be absolutely correlated to the trends in clinical practice, it is certainly a general reflection of surgical decision making as a whole. Overall significance of findings: Significant shifts in trends of lumbar fusion for DDD have occurred over the past two decades. Despite these changes, the current data indicate that neither the overall fusion rate nor clinical outcomes have been statistically improved over time. These data may be useful in directing further attempts to improve the surgical results. More importantly, avancements in patient selection and surgical selection criteria must be more closely and uniformly scrutinized. Disclosures: No disclosures. Conflict of interest: No conflicts. PII: S1529-9430(02)00391-1
7:52 Recombinant human bone morphogenic protein–2 in a posterior lumbar interbody fusion construct: 2-year clinical and radiologic outcomes Joseph Alexander, MD1, Charles Branch, Jr., MD1; Wake Forest University, Winston-Salem, NC, USA Purpose of study: Recombinant human bone morphogenetic protein (rhBMP)-2 has been demonstrated to form bone in various spine fusion applications as effectively as autologous iliac crest bone, without the morbidity of the graft harvest. Posterior lumbar interbody fusion (PLIF) constructs are commonly used in the treatment of degenerative spinal disease. This study evaluates the use of rhBMP-2 in a PLIF construct. Methods used: This is a prospective, randomized, Food and Drug Administration–approved, IDE study comparing the outcome of PLIF using cylindrical titanium cages loaded with either InFuse Bone Graft (rhBMP-2 in a collagen sponge; Medtronic, Minneapolis, MN) or autologous iliac crest bone graft. Enrollment in the study was stopped at 67 patients after “excess” bone formation was noted posterior to the cage in some patients. Clinical and radiographic assessment of the patients has continued, with a minimum of 2-year follow-up now available. Radiographs were evaluated in a blinded fashion by a panel of surgeons and critically compared to the clinical data. Summary of findings: Recombinant human BMP-2 is at least as effective as autologous iliac bone in this PLIF construct, in terms of promoting radiographic fusion. However, 58% of the rhBMP-2 patients demonstrated “greater than expected bone formation” dorsal to the cage, a finding seen in none of the controls. In 30% of the rhBMP-2 cases, this bone compromised the central canal, the neural foramen or both. At a mean 2-year follow-up, there was no correlation between the clinical outcome (Oswestry, back pain, leg pain or neurological score) and the radiological outcome in either group. Relationship between findings and existing knowledge: Recombinant human BMP-2 is an effective substitute for autogenous iliac crest bone in PLIF constructs. This is the first clinical study to document “excessive” bone formation with the use of BMP, although there was no discernable effect on the clinical outcome. The cause of the bone formation seen in selected cases is not understood, and theories to explain this finding are currently being evaluated. Overall significance of findings: BMP should not be used in PLIF constructs outside of clinical trials at this time. Disclosures: Device or drug: recombinant human bone morphogenetic protein–2. Status: investigational. Conflict of interest: Joseph Alexander, Speaker’s Bureau, Mediatronic Sofamor Danek. PII: S1529-9430(02)00273-5
7:58 Adjacent segment failure above lumbosacral fusions instrumented to L1 or L2 Michael Swank MD, Cincinnati, OH, USA Purpose of study: Adjacent segment degeneration has been recognized as a problem in lumbar fusion surgery. Several studies have evaluated the radiographic changes adjacent to fusions, but very little has been reported on adjacent segment degeneration as it relates to the level of lumbar fusion. During routine follow-up of adult patients with long instrumented lumbar fusions, we noticed an unexpectedly high number of complications at the cephalad end of the fusion construct. This review was designed to evaluate the rate of adjacent segment problems in patients with instrumented lumbar fusions from the sacrum to L1 or L2. Methods used: From 1994 to 2000, 20 adult patients, with an average age of 56 years, who underwent lumbosacral fusions from the sacrum to L1 or L2 for a variety of spinal pathologies, including degenerative spinal stenosis, scoliosis, postlaminectomy syndrome, pseudarthrosis and spondylolisthesis, were retrospectively reviewed from a prospectively gathered computerized database. Clinical outcomes, pain scores, Short Form (SF)-36 scores, satisfaction scores, reoperation rates and radiographic analysis were performed for all patients at a minimum 2-year follow-up. Summary of findings: Overall, the clinical results for these patients after their index surgery were poor with only two patients having a good or excellent clinical result. Nine patients had adjacent segment failure, usually within the first 2 years postoperatively. Reoperations were required in seven patients, four for fracture at or above the most superior instrumented vertebra, two for adjacent segment degeneration and spinal stenosis and one for infection. One other patient had a pedicle fracture above his fusion treated nonperatively, and two more patients have developed symptomatic adjacent segment degeneration requiring further nonoperative care and are being considered for reoperation. Relationship between findings and existing knowledge: Although the effects of fusion on the acceleration of degenerative changes at levels adjacent to lumbar fusions have been recognized, little has been published about the need for reoperations for symptomatic degeneration, and very few publications have evaluated the effects of number of fusion levels on adjacent segment failure. This study supported the initial clinical observation that instrumented lumbosacral fusions in the adult degenerative population that included the L1 or L2 vertebra resulted in high incidence of adjacent segment failure. Overall significance of findings: Fractures or rapid disc degeneration with subsequent stenosis occurred in half of the patients within the first 2 years of surgery. Because of this unacceptably high rate of early adjacent segment failure, we cannot recommend to L1 or L2 in the adult degenerative population. Disclosures: Device or drug: lumbar pedicle screws. Status: approved. Conflict of interest: No conflicts. PII: S1529-9430(02)00274-7
Wednesday, October 30, 2001 8:24–9:07 am General Session 2: Basic Science 8:24 Locomotor recovery after treatment with neurotrophic factors in a rat model of spinal cord injury Johannes A. Bernbeck, MD1, Eric M. Aldrich, MD2, Parveen Sra, MPH3, I. Sharon Nagakawa, MPH3, Linda E.A. Kanim, MA3, Rick B. Delamarter, MD3; 1Kaiser Permanente, Department of Orthopaedics, Baldwin Park, CA, USA; 2Johns Hopkins University, Department of Neurology and Neurosurgery, Baltimore, MD, USA; 3Spine Institute at Saint John’s Health Center, Santa Monica, CA, USA
Proceedings of the NASS 17th Annual Meeting / The Spine Journal 2 (2002) 47S–128S Purpose of study: Lumbar spinal cord injury (SCI) involves the spinal nerve roots of the cauda equina resulting in flaccid paralysis of lower motor neurons. Neurotrophic factors have been implicated in the maintenance of neurons and prevention of cell death after spinal cord injury. The purpose of this study was to evaluate treatment with neurotrophic factors after lumbar SCI. Methods used: Brain-derived neurotrophic factor (BDNF), saline or nothing was randomly infused in 51 Sprague-Dawley rats (240 to 260 g) undergoing compression injury. A laminectomy at L2 was performed. A silk suture was passed around the conus medullaris, cauda equina and nerve roots, tied in a knot with 200-g weights applied to the ends for 20 minutes. An intrathecal catheter was inserted into the dura by means of laminectomy at L6 and attached to a microosmotic pump implanted subcutaneously, allowing continuous infusion for 28 days. Locomotor function was recorded for 10 weeks using the BBB 21-point scale (Basso, Beattie, and Bresnahan, 1995). Differences in mean recovery between treatments was assessed by analysis of variance. Summary of findings: Concentric compressions resulted in severe neurologic dysfunction affecting lower extremities and bladder. There was no significant difference in the attrition rate among treatments. Rats surviving the 10-week observation period (n12 BDNF, n13 saline, n14 crush only) never regained full function. The greatest recovery occurred in the initial weeks after compression. BDNF had greater early recovery; however, this difference was not maintained long term. The greatest difference between groups was at 3 weeks (p.06).
49S
8:30 PH and anti-inflammatory agents modulate nucleus pulposus cytokine secretion P.J. Moroney1, R.W.G. Watson1, J.G. Burke1, J. O’Byrne1, J.M. Fitzpatrick1; 1 Mater Misericordiae Hospital, University College, Dublin, Ireland Purpose of study: Increased levels of interleukin (IL)-6 and IL-8 have been found in intervertebral disc (IVD) tissue from patients undergoing fusion for discogenic low back pain. The stimuli that induce these mediators in degenerate discs remain unknown. Impaired diffusion of nutrients and wastes to and from the nucleus pulposus (NP) is believed to be an important factor in the degenerative process. The oxygen tension and pH in the NP of degenerating discs are significantly decreased. The aims of this study were to 1) demonstrate the ability of porcine NP to respond to a proinflammatory stimulus (lipopolysaccharide [LPS]) in vitro, 2) investigate the effects of pH, pO2 and glucose concentration on NP proinflammatory mediator secretion and 3) determine if methylprednisolone (MP) or indomethacin (IND) can block NP proinflammatory mediator secretion. Methods used: IVDs were harvested from 6-month-old pigs and dissected under sterile conditions in the laboratory. Two hundred milligram samples of NP were cultured under optimal conditions (control), in a 1% O2 environment, at pH 6 and in culture medium without glucose for 72 hours. Blocking experiments were performed by culturing LPS-stimulated samples with either methylprednisolone or indomethacin for 24 hours. IL-6 and IL-8 levels were estimated by ELISA. Summary of findings: See Tables 1 and 2. Table 1 Control
LPS (5 ug/ml)
Hypoxia
IL-6 pg/ml 6.2 1.3 371 101 IL-8 pg/ml 13.9 1.4 2068 745†
3.3 4
Glucosefree
pH 6
2.3 3
27.5 1*
12.4 2.1 3.7 3.6
559 8‡
Datamean SD. Statistical analysis was by Students t test. A significant result between control and stimulated groups is indicated by *p.024, † p.0007 or ‡p.012.
Table 2 Control
Fig. 1. BBB scores.
Relationship between findings and existing knowledge: Although neurotrophic factors, cell translation and gene therapy have been studied in various animal models of spinal cord injury, the observational periods have varied. In this study, the recovery curve of BDNF-treated rats was steeper initially during the first 5 weeks, after which all treatments were comparable. These findings suggest observational periods should be at least 5 weeks after injury. Overall significance of findings: Lumbar compression resulted in substantial locomotor dysfunction over the 10-week period. Solution was infused for 4 weeks, possibly corresponding to the higher recovery in BDNFtreated rats during that initial period. This simple, reproducible and costefficient rat model of lumbar SCI is currently being used to screen the effectiveness of various neurotrophic factors. Disclosures: No disclosures. Conflict of interest: No conflicts. PII: S1529-9430(02)00275-9
IL-6 pg/ml IL-8 pg/ml
7.5 6.3 9.1 9.3
LPS (5 ug/ml) 59 66 3,212 998
LPS MP 2 2.4* 10 11.2‡
LPS IND 0.5 1† 21.5 14.3‡
LPS MP LPS-stimulated tissue incubated with 2 mg/ml MP; LPS IND LPS-stimulated tissue incubated with 500 uM IND. Data mean SD. Statistical analysis was by Students t test. A significant result between control and stimulated groups is indicated by *p.044, †p.04 or ‡ p.00004.
Relationship between findings and existing knowledge: In recent years evidence has accumulated that biochemical events play an integral role in IVD degeneration and discogenic low back pain. Kang et al. have reported increased levels of nitric oxide, IL-6 and PGE2 in herniated IVDs. Burke et al. have linked IVD production of elevated levels of IL-6 and IL-8 with discogenic low back pain. The stimuli responsible for proinflammatory mediator production in degenerating disc tissue remain unknown. This study has demonstrated that decreased pH stimulates NP proinflammatory mediator secretion at values that have been recorded in vivo. This study confirms the findings of Takahashi et al. that corticosteroids reduce disc proinflamma-
Proceedings of the NASS 17th Annual Meeting / The Spine Journal 2 (2002) 47S–128S
Relationship between findings and existing knowledge: The findings suggest that use of internal fixation and PL fusion have increased, whereas use of pure autograft have decreased over the past 20 years. Specific techniques, such as instrumentation and posterior IB fusion appear to increase fusion rates, although their effects on clinical outcome remain in question. The limitations of analyzing pooled data from a large number of studies in meta-analyses are noted, which include nonuniform patient selection, randomization, surgical technique and outcome scoring. For the present study’s purpose, however, it appears to be a reasonable method to observe shifting trends and their influence on outcome over long time periods. Although the published literature cannot be absolutely correlated to the trends in clinical practice, it is certainly a general reflection of surgical decision making as a whole. Overall significance of findings: Significant shifts in trends of lumbar fusion for DDD have occurred over the past two decades. Despite these changes, the current data indicate that neither the overall fusion rate nor clinical outcomes have been statistically improved over time. These data may be useful in directing further attempts to improve the surgical results. More importantly, avancements in patient selection and surgical selection criteria must be more closely and uniformly scrutinized. Disclosures: No disclosures. Conflict of interest: No conflicts. PII: S1529-9430(02)00391-1
7:52 Recombinant human bone morphogenic protein–2 in a posterior lumbar interbody fusion construct: 2-year clinical and radiologic outcomes Joseph Alexander, MD1, Charles Branch, Jr., MD1; Wake Forest University, Winston-Salem, NC, USA Purpose of study: Recombinant human bone morphogenetic protein (rhBMP)-2 has been demonstrated to form bone in various spine fusion applications as effectively as autologous iliac crest bone, without the morbidity of the graft harvest. Posterior lumbar interbody fusion (PLIF) constructs are commonly used in the treatment of degenerative spinal disease. This study evaluates the use of rhBMP-2 in a PLIF construct. Methods used: This is a prospective, randomized, Food and Drug Administration–approved, IDE study comparing the outcome of PLIF using cylindrical titanium cages loaded with either InFuse Bone Graft (rhBMP-2 in a collagen sponge; Medtronic, Minneapolis, MN) or autologous iliac crest bone graft. Enrollment in the study was stopped at 67 patients after “excess” bone formation was noted posterior to the cage in some patients. Clinical and radiographic assessment of the patients has continued, with a minimum of 2-year follow-up now available. Radiographs were evaluated in a blinded fashion by a panel of surgeons and critically compared to the clinical data. Summary of findings: Recombinant human BMP-2 is at least as effective as autologous iliac bone in this PLIF construct, in terms of promoting radiographic fusion. However, 58% of the rhBMP-2 patients demonstrated “greater than expected bone formation” dorsal to the cage, a finding seen in none of the controls. In 30% of the rhBMP-2 cases, this bone compromised the central canal, the neural foramen or both. At a mean 2-year follow-up, there was no correlation between the clinical outcome (Oswestry, back pain, leg pain or neurological score) and the radiological outcome in either group. Relationship between findings and existing knowledge: Recombinant human BMP-2 is an effective substitute for autogenous iliac crest bone in PLIF constructs. This is the first clinical study to document “excessive” bone formation with the use of BMP, although there was no discernable effect on the clinical outcome. The cause of the bone formation seen in selected cases is not understood, and theories to explain this finding are currently being evaluated. Overall significance of findings: BMP should not be used in PLIF constructs outside of clinical trials at this time. Disclosures: Device or drug: recombinant human bone morphogenetic protein–2. Status: investigational. Conflict of interest: Joseph Alexander, Speaker’s Bureau, Mediatronic Sofamor Danek. PII: S1529-9430(02)00273-5
7:58 Adjacent segment failure above lumbosacral fusions instrumented to L1 or L2 Michael Swank MD, Cincinnati, OH, USA Purpose of study: Adjacent segment degeneration has been recognized as a problem in lumbar fusion surgery. Several studies have evaluated the radiographic changes adjacent to fusions, but very little has been reported on adjacent segment degeneration as it relates to the level of lumbar fusion. During routine follow-up of adult patients with long instrumented lumbar fusions, we noticed an unexpectedly high number of complications at the cephalad end of the fusion construct. This review was designed to evaluate the rate of adjacent segment problems in patients with instrumented lumbar fusions from the sacrum to L1 or L2. Methods used: From 1994 to 2000, 20 adult patients, with an average age of 56 years, who underwent lumbosacral fusions from the sacrum to L1 or L2 for a variety of spinal pathologies, including degenerative spinal stenosis, scoliosis, postlaminectomy syndrome, pseudarthrosis and spondylolisthesis, were retrospectively reviewed from a prospectively gathered computerized database. Clinical outcomes, pain scores, Short Form (SF)-36 scores, satisfaction scores, reoperation rates and radiographic analysis were performed for all patients at a minimum 2-year follow-up. Summary of findings: Overall, the clinical results for these patients after their index surgery were poor with only two patients having a good or excellent clinical result. Nine patients had adjacent segment failure, usually within the first 2 years postoperatively. Reoperations were required in seven patients, four for fracture at or above the most superior instrumented vertebra, two for adjacent segment degeneration and spinal stenosis and one for infection. One other patient had a pedicle fracture above his fusion treated nonperatively, and two more patients have developed symptomatic adjacent segment degeneration requiring further nonoperative care and are being considered for reoperation. Relationship between findings and existing knowledge: Although the effects of fusion on the acceleration of degenerative changes at levels adjacent to lumbar fusions have been recognized, little has been published about the need for reoperations for symptomatic degeneration, and very few publications have evaluated the effects of number of fusion levels on adjacent segment failure. This study supported the initial clinical observation that instrumented lumbosacral fusions in the adult degenerative population that included the L1 or L2 vertebra resulted in high incidence of adjacent segment failure. Overall significance of findings: Fractures or rapid disc degeneration with subsequent stenosis occurred in half of the patients within the first 2 years of surgery. Because of this unacceptably high rate of early adjacent segment failure, we cannot recommend to L1 or L2 in the adult degenerative population. Disclosures: Device or drug: lumbar pedicle screws. Status: approved. Conflict of interest: No conflicts. PII: S1529-9430(02)00274-7
Wednesday, October 30, 2001 8:24–9:07 am General Session 2: Basic Science 8:24 Locomotor recovery after treatment with neurotrophic factors in a rat model of spinal cord injury Johannes A. Bernbeck, MD1, Eric M. Aldrich, MD2, Parveen Sra, MPH3, I. Sharon Nagakawa, MPH3, Linda E.A. Kanim, MA3, Rick B. Delamarter, MD3; 1Kaiser Permanente, Department of Orthopaedics, Baldwin Park, CA, USA; 2Johns Hopkins University, Department of Neurology and Neurosurgery, Baltimore, MD, USA; 3Spine Institute at Saint John’s Health Center, Santa Monica, CA, USA
Proceedings of the NASS 17th Annual Meeting / The Spine Journal 2 (2002) 47S–128S Purpose of study: Lumbar spinal cord injury (SCI) involves the spinal nerve roots of the cauda equina resulting in flaccid paralysis of lower motor neurons. Neurotrophic factors have been implicated in the maintenance of neurons and prevention of cell death after spinal cord injury. The purpose of this study was to evaluate treatment with neurotrophic factors after lumbar SCI. Methods used: Brain-derived neurotrophic factor (BDNF), saline or nothing was randomly infused in 51 Sprague-Dawley rats (240 to 260 g) undergoing compression injury. A laminectomy at L2 was performed. A silk suture was passed around the conus medullaris, cauda equina and nerve roots, tied in a knot with 200-g weights applied to the ends for 20 minutes. An intrathecal catheter was inserted into the dura by means of laminectomy at L6 and attached to a microosmotic pump implanted subcutaneously, allowing continuous infusion for 28 days. Locomotor function was recorded for 10 weeks using the BBB 21-point scale (Basso, Beattie, and Bresnahan, 1995). Differences in mean recovery between treatments was assessed by analysis of variance. Summary of findings: Concentric compressions resulted in severe neurologic dysfunction affecting lower extremities and bladder. There was no significant difference in the attrition rate among treatments. Rats surviving the 10-week observation period (n12 BDNF, n13 saline, n14 crush only) never regained full function. The greatest recovery occurred in the initial weeks after compression. BDNF had greater early recovery; however, this difference was not maintained long term. The greatest difference between groups was at 3 weeks (p.06).
49S
8:30 PH and anti-inflammatory agents modulate nucleus pulposus cytokine secretion P.J. Moroney1, R.W.G. Watson1, J.G. Burke1, J. O’Byrne1, J.M. Fitzpatrick1; 1 Mater Misericordiae Hospital, University College, Dublin, Ireland Purpose of study: Increased levels of interleukin (IL)-6 and IL-8 have been found in intervertebral disc (IVD) tissue from patients undergoing fusion for discogenic low back pain. The stimuli that induce these mediators in degenerate discs remain unknown. Impaired diffusion of nutrients and wastes to and from the nucleus pulposus (NP) is believed to be an important factor in the degenerative process. The oxygen tension and pH in the NP of degenerating discs are significantly decreased. The aims of this study were to 1) demonstrate the ability of porcine NP to respond to a proinflammatory stimulus (lipopolysaccharide [LPS]) in vitro, 2) investigate the effects of pH, pO2 and glucose concentration on NP proinflammatory mediator secretion and 3) determine if methylprednisolone (MP) or indomethacin (IND) can block NP proinflammatory mediator secretion. Methods used: IVDs were harvested from 6-month-old pigs and dissected under sterile conditions in the laboratory. Two hundred milligram samples of NP were cultured under optimal conditions (control), in a 1% O2 environment, at pH 6 and in culture medium without glucose for 72 hours. Blocking experiments were performed by culturing LPS-stimulated samples with either methylprednisolone or indomethacin for 24 hours. IL-6 and IL-8 levels were estimated by ELISA. Summary of findings: See Tables 1 and 2. Table 1 Control
LPS (5 ug/ml)
Hypoxia
IL-6 pg/ml 6.2 1.3 371 101 IL-8 pg/ml 13.9 1.4 2068 745†
3.3 4
Glucosefree
pH 6
2.3 3
27.5 1*
12.4 2.1 3.7 3.6
559 8‡
Datamean SD. Statistical analysis was by Students t test. A significant result between control and stimulated groups is indicated by *p.024, † p.0007 or ‡p.012.
Table 2 Control
Fig. 1. BBB scores.
Relationship between findings and existing knowledge: Although neurotrophic factors, cell translation and gene therapy have been studied in various animal models of spinal cord injury, the observational periods have varied. In this study, the recovery curve of BDNF-treated rats was steeper initially during the first 5 weeks, after which all treatments were comparable. These findings suggest observational periods should be at least 5 weeks after injury. Overall significance of findings: Lumbar compression resulted in substantial locomotor dysfunction over the 10-week period. Solution was infused for 4 weeks, possibly corresponding to the higher recovery in BDNFtreated rats during that initial period. This simple, reproducible and costefficient rat model of lumbar SCI is currently being used to screen the effectiveness of various neurotrophic factors. Disclosures: No disclosures. Conflict of interest: No conflicts. PII: S1529-9430(02)00275-9
IL-6 pg/ml IL-8 pg/ml
7.5 6.3 9.1 9.3
LPS (5 ug/ml) 59 66 3,212 998
LPS MP 2 2.4* 10 11.2‡
LPS IND 0.5 1† 21.5 14.3‡
LPS MP LPS-stimulated tissue incubated with 2 mg/ml MP; LPS IND LPS-stimulated tissue incubated with 500 uM IND. Data mean SD. Statistical analysis was by Students t test. A significant result between control and stimulated groups is indicated by *p.044, †p.04 or ‡ p.00004.
Relationship between findings and existing knowledge: In recent years evidence has accumulated that biochemical events play an integral role in IVD degeneration and discogenic low back pain. Kang et al. have reported increased levels of nitric oxide, IL-6 and PGE2 in herniated IVDs. Burke et al. have linked IVD production of elevated levels of IL-6 and IL-8 with discogenic low back pain. The stimuli responsible for proinflammatory mediator production in degenerating disc tissue remain unknown. This study has demonstrated that decreased pH stimulates NP proinflammatory mediator secretion at values that have been recorded in vivo. This study confirms the findings of Takahashi et al. that corticosteroids reduce disc proinflamma-