Percutaneous Intervertebral-Vacuum Polymethylmethacrylate Injection for Foraminal Stenosis with Degenerative Lumbar Scoliosis.

BACKGROUND: Percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI) is a minimally invasive procedure for low back pain in elderly patients with degenerative lumbar scoliosis (DLS). Patients with DLS often have radiculopathy as a result of foraminal stenosis in addition to low back pain. The purpose of this study was to evaluate the clinical and radiologic results of PIPI for foraminal stenosis with radiculopathy in elderly patients with DLS. METHODS: We included patients with de novo DLS aged 65 years or older who underwent PIPI. The presence of an intervertebral vacuum on computed tomography and bone marrow edema on magnetic resonance imaging was required for inclusion. The intersegmental radiologic parameters on plain radiographs and computed tomography and the extent of bone marrow edema on magnetic resonance imaging were measured. The clinical outcomes were evaluated using the visual analog scale (VAS) and Oswestry Disability Index (ODI). RESULTS: We enrolled 40 patients with DLS who underwent PIPI. There were 16 men and 24 women, and the mean age was 79.0 ± 6.3 years. The mean foraminal height and extent of bone marrow edema showed a significant increase and reduction, respectively, after PIPI (P < 0.05). VAS score for radiculopathy and ODI significantly improved after PIPI (P < 0.01). The minimum clinically important differences in VAS score for radiculopathy and ODI at the final follow-up were 73.9% and 63.6%, respectively. CONCLUSIONS: PIPI is a minimally invasive procedure not only for low back pain but also for radiculopathy in elderly patients with DLS. It leads to intervertebral stabilization and indirect decompression of the foramen.

Long-term outcome of targeted therapy for low back pain in elderly degenerative lumbar scoliosis.

PURPOSE: Treatment of low back pain (LBP) associated with elderly degenerative lumbar scoliosis (DLS) remains controversial. We have developed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI) targeting to the intervertebral vacuum as a minimally invasive surgery. The present study compared the long-term clinical outcomes of PIPI to that of nonoperative treatment. METHODS: Patients with de novo DLS, aged ≥ 65 years, who had LBP with visual analog scale (VAS) of ≥ 50 for ≥ 6 months with intervertebral vacuum on computed tomography and bone marrow edema (BME) on magnetic resonance imaging were included. The clinical outcomes were evaluated using VAS and the Oswestry Disability Index (ODI) at baseline, 1, 6, 12, 24 months, and at the final follow-up. The course of BME was also evaluated. RESULTS: One hundred and one patients underwent PIPI and 61 received nonoperative treatment. The mean follow-up duration after PIPI and nonoperative treatment was 63.7 ± 32.4 and 43.9 ± 20.9 months, respectively. VAS and ODI after PIPI were significantly improved compared to post-nonoperative treatment. BME decreased substantially in the PIPI group and it was significantly correlated with VAS and ODI improvement. Following PIPI, LBP recurred in 28 patients (35%). LBP recurrence was identified at the same level of PIPI in 10 patients, at the adjacent level of PIPI in 11 patients, and at the non-adjacent level of PIPI in seven patients. Eighteen patients underwent additional PIPIs, and both VAS and ODI were significantly improved after additional PIPIs. CONCLUSION: Bone marrow lesions of the endplate are strongly associated with the presence of LBP. PIPI can be considered as an effective, safe and repeatable treatment for LBP in elderly DLS patients.

Translational Studies on Biologic Fusion of a Vertebral Segment as a Novel Treatment Modality for Low Back Pain.

STUDY DESIGN: Preclinical studies: Efficacy and toxicological studies on lactic acid (LA)-induced sclerozation in pig lumbar discs. Clinical study: Prospective, randomized, double-blinded, placebo-controlled, single ascending dose study investigating the safety and local tolerability of LA. OBJECTIVE: To determine if LA produces sclerozation of the porcine nucleus pulposus (NP) followed by a phase Ib study to evaluate preliminary safety, tolerability, and efficacy of LA in patients with chronic discogenic low back pain. SUMMARY OF BACKGROUND DATA: Surgical stabilization of a motion segment harboring a painful degenerated disc often affords symptomatic relief. In the present study, the hypothesis was tested that LA can produce sclerozation and stabilization of the NP. METHODS: LA (0.2 mL; 60, 120, or 240 mg/mL) or vehicle was injected into the NP or close to the extra spinal region of spinal nerves of young female pigs. The size of the NP, MRI changes, flexural stiffness, and histology of the disc was studied after up to 84 days of survival. Fifteen patients injected intra discally with placebo (iohexol, 1.5 mL, n = 6) or iohexol plus LA (30, 60, or 120 mg/mL; three patients in each group) were followed for up to 12 months. RESULTS: Injection of LA in the pig reproducibly induced sclerozation of the NP and increased flexural rigidity. Histological changes included generation of connective tissue and increased expression of collagen I. No safety concerns were raised. Adverse events in patients were limited to transiently increased low back pain with no obvious difference between treatment groups. There was indication of lower water content of NP injected with the two highest doses of LA. CONCLUSION: LA has a sclerozing effect on the NP in pigs and patients and is therefore a candidate for further clinical studies powered to determine its potential as a treatment of chronic discogenic low back pain. LEVEL OF EVIDENCE: 2.

Structural Analysis of Experimentally Induced Disc Herniation-Like Changes in the Rat.

INTRODUCTION: A disc herniation has traditionally been considered as disc tissue that has slipped out from an intervertebral disc. However, it was recently suggested that the disc herniation mass is a product of bioactive substances from the disc and that the disc hernia would more likely be scar tissue than herniated disc material. In this study, we aimed to analyze the structural components of experimentally induced disc herniations and compare with scar tissue and nucleus pulposus, in the rat. METHODS: Twenty-eight rats had their L4-5 discs punctured. After three weeks, the nodule that had been formed over the puncture site, scar tissue from the spine musculature, and normal nucleus pulposus were harvested and processed for further analysis. RESULTS: Proteomics analysis demonstrated that the formed nodule was more similar to scar tissue than to nucleus pulposus. Gene expression analysis showed that there was no resemblance between any tissues when looking at inflammatory genes but that, there was a clear resemblance between the nodule and scar tissue when analyzing extracellular matrix-related genes. Analysis of the GAG and polysaccharide size distribution revealed that only the nodule and scar tissue contained the shorter versions, potentially short chain hyaluronic acid that is known to induce inflammatory responses. The hematoxylin and eosin stained sections of the nodule, disc tissue, and scar tissue indicated that the morphology of the nodule and scar tissue was very similar. CONCLUSIONS: The nodule formed after experimental disc puncture, and that resembles a disc hernia, has a more structural resemblance to scar tissue than disc tissue. The nodule is, therefore, more likely to be induced by disc-derived bioactive substances than being formed by herniated disc material.

Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.

Relationship between clinical symptoms of osteoporotic vertebral fracture with intravertebral cleft and radiographic findings.

BACKGROUND: With aging of the population, the numbers of osteoporotic vertebral fractures with intravertebral cleft have been increasing. However, the details of clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft are poorly understood. The purpose of this study was to evaluate the relationship between clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft and radiographic findings. METHODS: Two hundred seventeen patients with single-level osteoporotic vertebral fractures with intravertebral cleft were examined. Clinical symptoms were evaluated using Numerical Rating Scale for back pain and the Oswestry Disability Index for physical disability. The presence of delayed neurologic deficit was also detected. Radiography and computed tomography were used to measure local kyphotic angle and vertebral instability and to detect the presence of posterior wall fracture of the vertebral body. Correlations between clinical symptoms of osteoporotic vertebral fractures with intravertebral cleft and radiographic findings were investigated. RESULTS: Mean Numerical Rating Scale and Oswestry Disability Index were 7.4 and 58.0%, respectively. Delayed neurologic deficit occurred in 41 patients (19%). The mean local kyphotic angle, vertebral instability, and rate of posterior wall fracture of the vertebral body were 19.4°, 7.3°, and 91%, respectively. Numerical Rating Scale and Oswestry Disability Index were statistically correlated with vertebral instability but not with local kyphotic angle and presence of posterior wall fracture. In the patients with delayed neurologic deficit, vertebral instability was significantly higher and posterior wall fractures were significantly more frequent than in the patients without delayed neurologic deficit. Local kyphotic angle was not correlated with delayed neurologic deficit. CONCLUSIONS: Vertebral instability is a factor causing symptoms of osteoporotic vertebral fractures with intravertebral cleft. In addition, vertebral instability may be the predominant cause of delayed neurologic deficit. To manage osteoporotic vertebral fractures with intravertebral cleft and delayed neurologic deficit efficiently, it may be important to control vertebral instability of osteoporotic vertebral fractures.

Targeted Therapy for Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cohort Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To compare the novel treatment procedure with nonoperative treatment for low back pain (LBP) in elderly patients with degenerative lumbar scoliosis (DLS). SUMMARY OF BACKGROUND DATA: Treatment of LBP associated with elderly DLS is controversial. We developed a novel treatment procedure, termed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI). METHODS: We included patients with de novo DLS aged ≥65 years who had LBP with a visual analogue scale (VAS) score of >50 for ≥6 months with intervertebral vacuum and vertebral bone marrow edema (BME) defined on fat-saturated T2-weighted or gadolinium-enhanced T1-weighted magnetic resonance imaging. The primary outcomes were evaluated using the VAS score and modified Oswestry Disability Index (ODI). As an objective measurement, we scored BME on magnetic resonance imaging. RESULTS: Between August 2004 and July 2011, 109 patients underwent PIPI and 53 received nonoperative treatment. At 1 month, mean improvements in VAS scores were -55.3 (95% CI, -60.5 to -50.1) and -1.9 (CI, -7.7 to 3.8) and mean improvements in ODI were -22.7 (CI, -27.3 to -18.2) and -0.6 (CI, -6.6 to 5.4) for the PIPI and nonoperative groups, respectively. At 2 years, mean improvements in VAS scores were -52.2 (CI, -59.9 to -44.4) and -4.0 (CI, -10.9 to 3.0) and mean improvements in ODI were -20.7 (CI, -27.3 to -14.5) and -1.0 (CI, -7.7 to 5.7) for the PIPI and nonoperative groups, respectively. BME substantially decreased in the PIPI group compared with the nonoperative group (P <0.001) and correlated with VAS score and ODI improvements (VAS score: r = 0.502, P <0.001; ODI: r = 0.372, P <0.001). CONCLUSION: PIPI improved treatment for LBP, with a sustained clinical benefit for at least 2 years. LEVEL OF EVIDENCE: 3.

Bone Marrow Edema and Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cross-Sectional Study.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine whether bone marrow edema is associated with low back pain in elderly patients with degenerative lumbar scoliosis. SUMMARY OF BACKGROUND DATA: The cause of low back pain in degenerative lumbar scoliosis is unclear. METHODS: A total of 120 degenerative lumbar scoliosis patients 65 years of age or older were evaluated. Radiography, computed tomography (CT), magnetic resonance imaging (MRI), and tender point examination in the lumbar spine were performed. On MRI, coronal gadolinium-contrasted T1- or T2-weighed fat-saturated images were used to score the size of bone marrow edema. The prevalence of bone marrow edema in patients with and without low back pain was compared; in patients with low back pain, we tested whether the locations of lumbar tender point were consistent with that of bone marrow edema. RESULTS: Bone marrow edema was found in 62 of 64 (96.9%) patients with low back pain compared with 21 of 56 (37.5%) patients without it (P < 0.001). Bone marrow edema located more frequently on the concave side than on the convex side of scoliosis (P < 0.001). Among patients with low back pain, bone marrow edema score was associated with low back pain severity (r = 0.724; P < 0.001), and the location of lumbar tender point were consistent with that of bone marrow edema (κ value = 0.745; P < 0.001). CONCLUSION: Bone marrow edema on MRI was closely associated with the presence of low back pain in elderly degenerative lumbar scoliosis. LEVEL OF EVIDENCE: 4.

Efficacy of Percutaneous Vertebroplasty in the Treatment of Osteoporotic Vertebral Compression Fractures with Intravertebral Cleft.

Intravertebral cleft (IVC) is frequently observed in patients with painful osteoporotic vertebral compression fracture (OVCF). Some studies reported the usefulness of percutaneous vertebroplasty (PVP) for treating OVCF with IVC. However, systematic studies are scarce, and their results are conflicting. The purpose of this study was to evaluate the clinical and radiographic results of PVP in the treatment of painful OVCF with IVC. Two hundred ninety-one patients with OVCF with IVC underwent PVP. Back pain was measured using a visual analog scale (VAS), and physical disability was assessed using the Oswestry Disability Index (ODI). Three radiological parameters were assessed: the local kyphotic angle, percentage spinal canal cross-sectional area of compromise, and intravertebral instability of the affected vertebra. The mean follow-up period was 28 months. The mean values for the VAS and ODI were 8.4 and 60.0%, respectively, before PVP, versus 3.9 and 35.4%, respectively, at the final follow-up. The average local kyphotic angle, percentage spinal canal cross-sectional area of compromise, and intravertebral instability were 10.5°, 17.9% and 6.1°, respectively, before PVP and 8.1°, 15.2%, and 0.8°, respectively, at the final follow-up. There were no neurological or systemic complications due to cement leakage. PVP is an effective and safe intervention for treating OVCF with IVC.

Experimental Disc Herniation in the Rat Causes Downregulation of Serotonin Receptor 2c in a TNF-dependent Manner.

BACKGROUND: During recent decades, the knowledge of the pathophysiology of disc herniation and sciatica has drastically improved. What previously was considered a strict biomechanical process is now considered a more complex interaction between leaked nucleus pulposus and the tissue in the spinal canal. An inflammatory reaction, with tumor necrosis factor (TNF) playing an essential role, has been demonstrated. However, the exact mechanisms of the pathophysiology of disc herniation remain unknown. QUESTIONS/PURPOSES: In this study we use an animal model to investigate (1) if and/or how experimental disc herniation affects gene expression in the early phase (24 hours postsurgery) in the dorsal root ganglion; and (2) if TNF inhibition can reduce any observed changes. METHODS: A rat model of disc herniation was used. Twenty rats were evenly divided into four groups: naïve, sham, disc herniation, and disc herniation with TNF inhibition. The dorsal root ganglion of the affected nerve root was harvested 24 hours after surgery and analyzed with a TaqMan Low Density Array(®) quantitative polymerase chain reaction assay. Gene expression levels in sham were compared with disc herniation to assess question 1 and disc herniation to disc herniation with TNF inhibition to assess question 2. RESULTS: Experimental disc herniation caused a decrease in the expression of the serotonin receptor 2c gene (p = 0.022). TNF inhibition was found to reduce the observed decrease in expression of serotonin receptor 2c (p = 0.037). CONCLUSIONS: Our results suggest that a decrease in the expression of the serotonin receptor 2c gene may contribute to the pathophysiology of disc herniation. Further research on its involvement is warranted. CLINICAL RELEVANCE: This pilot study gives a brief insight into cellular changes that may contribute to the pathophysiology of disc herniation. This knowledge may contribute to the development of more and better treatment options for patients with disc herniation and sciatica.

Increase of sodium channels (nav 1.8 and nav 1.9) in rat dorsal root ganglion neurons exposed to autologous nucleus pulposus.

PURPOSE: It has been assumed that nucleus pulposus-induced activation of the dorsal root ganglion (DRG) may be related to an activation of sodium channels in the DRG neurons. In this study we assessed the expression of Nav 1.8 and Nav 1.9 following disc puncture. METHOD: Thirty female Sprague-Dawley rats were used. The L4/L5 disc was punctured by a needle (n=12) and compared to a sham group without disc puncture (n=12) and a naive group (n=6). At day 1 and 7, sections of the left L4 DRG were immunostained with anti-Nav 1.8 and Nav 1.9 antibodies. RESULT: At day 1 after surgery, both Nav 1.8-IR neurons and Nav 1.9-IR neurons were significantly increased in the disc puncture group compared to the sham and naive groups (p<0.05), but not at day 7. CONCLUSION: The findings in the present study demonstrate a neuronal mechanism that may be of importance in the pathophysiology of sciatic pain in disc herniation.

New, clinically more relevant model for nerve root injury in the rat.

STUDY DESIGN: Exposure to nucleus pulposus and displacement of intraspinal nervous structures with assessment of spontaneous behavioral changes in rats. OBJECTIVE: To develop a controlled, experimental model for nerve root injury. SUMMARY OF BACKGROUND DATA: There are a number of experimental models presented for studies on radiculopathies. One frequently used model is based on exposure to nucleus pulposus and displacement of the dorsal root ganglion (DRG). However, it is clinically more common that the nerve roots are displaced/compressed than the DRG. In this study, we developed a model for displacement of the nerve root by modifying the DRG model. METHODS: After removing the left L3-L4 facet joint, the underlying disc was punctured, and the L4 nerve root was displaced laterally by an injection needle (n = 10). In sham experiments, the same procedure was performed without disc puncture and displacement (n = 10). In 10 rats, the left L4-L5 facet joint was removed. The underlying disc was punctured and the L4 DRG was displaced medially by an injection needle. Assessment of spontaneous behavioral changes was performed on days 1, 3, 7, 14, and 21, postsurgery. RESULTS: There was a clear increase in duration of the behavior "unloading of the paw" after displacement of the DRG that was most pronounced on day 1 and then gradually declined. There was a similar pattern for this behavior induced by nerve root displacement, although the duration was higher than that for the DRG displacement. No apparent trends in behavioral changes were observed for the other behaviors studied. CONCLUSION: Displacement of the nerve root induced more changes in the pain behavior than displacement of the DRG, but only for the behavior unloading of the paw. Because nerve root injury is more common than DRG injury, this model may be more clinically relevant than the DRG model. LEVEL OF EVIDENCE: N/A.

Effect of lactoferrin peptide (PXL01) on rabbit digit mobility after flexor tendon repair.

PURPOSE: Restoration of digital function after flexor tendon injuries remains a clinical challenge. Complications such as adhesion formation and tendon rupture can lead to limited hand function. The aim of this study was to compare the effects of the lactoferrin-derived peptide, PXL01, formulated in sodium hyaluronate (SH), with SH alone on joint mobility as an indirect measure of postsurgical adhesion prevention and healing strength of the tendon and to elucidate the most optimal concentration of PXL01. METHODS: Using a rabbit flexor tendon repair model, in which the deep flexor tendon was fully transected and repaired, PXL01 in SH or SH alone was administered between the repaired tendon and the tendon sheath before closure of the surgical wound. Three concentrations of PXL01 in SH (5, 20, or 40 mg/mL) were compared to determine the lowest effective concentration. The repaired tendons were evaluated 7 weeks after surgery by measuring the proximal interphalangeal joint mobility by full range of flexion assessment and the tendon repair strength. RESULTS: Treatment with PXL01 formulated in SH resulted in improved mobility of the proximal interphalangeal joint with an average of 10°, corresponding to improvement of approximately 25% to 60% of the flexion of nonoperated toes at the different measuring points compared with SH alone. The difference was statistically significant in 5 out of 6 measuring points (0.5, 1, 2, 3, and 4 N; P < .05). The dose-response study indicated that the lowest effective concentration of PXL01 was 20 mg/mL. There was no difference in healing strength of the tendon between the groups as assessed by load-to-failure breaking strength. CONCLUSIONS: PXL01 in SH significantly improved the mobility compared with the carrier SH alone, without any negative effect on healing strength, and PXL01 at 20 mg/mL was the lowest effective concentration. CLINICAL RELEVANCE: The result provides a valuable basis for a clinical trial to assess efficacy and safety of PXL01 in clinical hand surgery.

Local application of nucleus pulposus induces expression OF P2X3 in rat dorsal root ganglion cells.

The P2X(3) receptor is a ligand-gated cation channel that is activated by extra cellular adenosine triphosphate (ATP) found in the dorsal root, trigeminal and nodose ganglia. It is one of the receptors transmitting nociceptive information of injuries and inflammation of the periphery by endogenous ATP released from damaged cells. The present study was performed in order to evaluate if there was an increased expression of P2X(3)-immunoreactivity in dorsal root ganglion (DRG) neurons after experimental disc herniation. There were four groups: exposure of the left L4 dorsal root ganglion and incision of the L4-L5 disc, exposure and slight displacement of the left L4 dorsal ganglion, sham exposure of the L4 dorsal root ganglion, and normal. Seven days after surgery, the DRG's were collected, sectioned and stained immunohistochemically for the P2X(3) receptor. The expression of P2X(3) increased significantly following incision of the L4-5 disc compared to the normal group. Sham surgery induced a minor, although statistically significant increase. Mechanical displacement did not induce any increased expression of the receptors. The study demonstrates that expression of the P2X(3)receptors in the DRG may be induced by local application of nucleus pulposus. This may increase our understanding of the pathophysiologic mechanisms related to disc herniation and sciatica.

Puncture of a disc and application of nucleus pulposus induces disc herniation-like changes and osteophytes. An experimental study in rats.

It has been observed that puncture of a lumbar disc may induce formation of a nodule on the surface of the disc and osteophytes. It is not known if this is based on the presence of a foreign tissue or specifically by the presence of nucleus pulposus or on the disc injury. In this study these mechanisms were separated by comparing disc puncture with application of nucleus pulposus without disc injury, with superficial disc injury without nucleus pulposus and with application of fat. Fifty rats underwent facetectomy of the left L4-5 facet. Ten additional rats were used as donor rats. The rats were exposed to disc puncture (n=10), application of homologous nucleus pulposus (n=10), application of homologous fat tissue (n=10), superficial disc injury (n=10) and ten rats served as control. After 3 weeks the rats were examined macroscopically regarding presence of disc nodules and osteophytes. A limited histological analysis was performed to obtain a microscopic overview of any observed changes. In rats with application of fat, superficial disc injury and in sham controls there were almost no changes observed. However, in rats with disc puncture and applied nucleus pulposus there were clear disc nodules and osteophytes noted. Microscopically the nodules comprised granulation tissue and the osteophytes cortical bone. In conclusion, the data indicate that the presence of nucleus pulposus is more likely to be responsible for the formation of disc nodules and osteophytes than disc injury or the presence of a foreign tissue. This may provide new insights in the mechanisms regarding the formation of disc herniations and osteophytes.

Pain behavior changes following disc puncture relate to nucleus pulposus rather than to the disc injury per se: an experimental study in rats.

It has previously been demonstrated that disc puncture in the rat induced changes in grooming and wet dog shakes, two behavioral changes that may be linked to discomfort and neuropathic pain. In this study the aim was to separate the effects of disc injury and the epidural presence of nucleus pulposus. Following anesthesia, the L4-5 disc was exposed using a dorsal approach. Ten rats received a superficial disc injury without nucleus pulposus leakage and ten rats received nucleus pulposus from a donor rat without disc injury. In ten animals the L4-5 disc was punctured using a ventral approach, with 10 corresponding controls. Spontaneous behavior was assessed after surgery. The data was matched to historical control of dorsal sham surgery and disc puncture. The study showed that the effects of nucleus pulposus were more pronounced than the effects induced by the disc injury. Ventral disc puncture did not induce any behavioral changes different from sham exposure. In conclusion, the data from the study indicate that behavioral changes induced by disc puncture are more likely to relate to the epidural presence of nucleus pulposus than the disc injury per se.

Combination of two cytokine inhibitors reduces nucleus pulposus-induced nerve injury more than using each inhibitor separately.

Although recent experimental studies indicate that disc-derived cytokines, as for instance TNF, seems to be intimately involved in the pathophysiology of sciatica and low back pain, the clinical studies performed do not provide conclusive data on TNF-inhibition as a useful complement for treatment of such conditions to existing modalities. Based on the fact that TNF is merely one component in a complex network it was assumed that the combination of a TNF-inhibitor and an IL-1ß-inhibitor could potentiate the effects in a pig model on nucleus pulposus-induced nerve conduction velocity reduction. The data indicated that combination of two cytokine inhibitors seems to be more efficient in reducing the nucleus pulposus-induced effects on nerve conduction velocity than using each inhibitor separately. This may be considered if future clinical trials for the treatment of sciatica and low back pain using just a single inhibitor may continue to demonstrate inconclusive data.

Local application of interleukin-6 to the dorsal root ganglion induces tumor necrosis factor-α in the dorsal root ganglion and results in apoptosis of the dorsal root ganglion cells.

STUDY DESIGN: The mechanisms of apoptosis behind the formation of tissue reactions at the surface of the dorsal root ganglion (DRG) exposed to the nucleus pulposus were studied with special reference to the role of interleukin-6 (IL-6), using electron microscopy and immunohistochemistry in rats. OBJECTIVE: To study the role of IL-6 on the DRG. SUMMARY OF BACKGROUND DATA: It has been reported that nucleus pulposus cells are capable to produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-6. Recently, it was observed that local application of nucleus pulposus induced a characteristic tissue reaction at the surface of the DRG. This change was due to apoptosis of DRG neurons. However, the role of IL-6 is not known regarding the apoptosis of the DRG neurons. METHODS: Recombinant IL-6 was applied between the L4 DRG and the dura to mimic a disc herniation of the L4-L5 disc in rats. The L4 DRGs were resected 24 hours after surgery. The sections were processed for immunohistochemistry using antisera to TNF-α. Furthermore, the sections of the specimens were observed using light and electron microscopy to confirm the induced apoptosis of the DRG neurons. The sections were also processed for immunohistochemistry, using antisera to single-stranded DNA (ssDNA) and Caspase 3. RESULTS: TNF-α immunoreactivity was observed in the peripheral area of DRG at the site of the application of IL-6. Typical changes of the cell nuclei were observed in the DRG by light and electron microscopy, indicating the presence of apoptosis. The presence of ssDNA and Caspase 3 further enhanced the impression that there was apoptosis of the DRG neurons. CONCLUSION: IL-6 seemed to induce TNF-α at the surface of DRG exposed to IL-6 and to induce a characteristic reaction at the surface of the DRG. IL-6 may thus play an important role in nucleus pulposus-induced apoptosis of the DRG neurons as well as TNF-α.

Pharmacological inhibition of tumor necrosis factor may reduce pain behavior changes induced by experimental disc puncture in the rat: an experimental study in rats.

STUDY DESIGN: Pain behavior assessment in rats following disc puncture (DP) and simultaneous tumor necrosis factor (TNF) inhibition. OBJECTIVE: To assess if treatment with TNF inhibition could reduce the pain behavior changes induced by DP in the rat. SUMMARY OF BACKGROUND DATA: Anular tears with leakage of nucleus pulposus have been suggested to be one possible cause of low back pain (LBP). In an experimental model, it was recently shown that DP might induce specific pain behavior changes. The aim of the present study was to a study if inhibition of TNF might reduce such pain behavior changes. METHODS: Sixty rats underwent facetectomy and puncture of the fourth lumbar disc. The rats were simultaneously treated with doxycycline locally at 0.3 and 3.0 mg/kg and systemically at 3.0 mg/kg, or infliximab locally at 0.5 and 5.0 mg/kg, and systemically at 5.0 mg/kg, (n ∇ 10 for each subseries). The rats were videotaped at 1, 3, 7, 14, and 21 days after surgery. The videos were analyzed regarding presence of wet-dog shakes (WDS). Data from a previous study with sham surgery and DP without treatment were included for comparison. RESULTS: All groups treated with doxycycline resulted in a statistically significant reduction of WDS compared to the group without treatment (DP). In infliximab treated animals, WDS decreased with statistically significance compared to the nontreated DP group at all analyzed days except for the group with high dose local treatment where a statistically significant reduction was obtained only at days 14 and 21. CONCLUSION: The present study showed that TNF inhibition induced a marked reduction of wet dog shakes. It is not fully understood if wet-dog shakes may relate to LBP, but in view of recent clinical findings one may consider clinical studies of TNF inhibition for the treatment of LBP.

Reduction of adhesion formation and promotion of wound healing after laminectomy by pharmacological inhibition of pro-inflammatory cytokines: an experimental study in the rat.

In a previous experiment using TNF inhibition in the rat it was accidentally found that adhesion and scar formation was reduced compared to previous experience. Wound and bone healing also seemed enhanced. The present study was conducted to assess if this observation could be verified in a controlled setting using a standardized laminectomy in the rat. Five rats received doxycycline and five other rats received saline and served as control. Macroscopic blinded evaluation 1 week after the laminectomy revealed that adhesion and scar formation was less in doxycycline-treated animals than in control animals. Wound and bone healing was found to be better in doxycycline-treated animals. The mechanisms for the observed effects cannot be fully understood but the data indicate that further research may lead to opportunities to design pharmacological modalities to reduce adhesion and scar formation, maybe in combination with suitable barriers.