Unraveling the neuroimmune interface in chronic pain-the association between cytokines in the cerebrospinal fluid and pain in patients with lumbar disk herniation or degenerative disk disease.

ABSTRACT: Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.

Ozone as Modulator of Resorption and Inflammatory Response in Extruded Nucleus Pulposus Herniation. Revising Concepts.

Ozone therapy has been used to treat disc herniation for more than four decades. There are several papers describing results and mechanism of action. However, it is very important to define the characteristics of extruded disc herniation. Although ozone therapy showed excellent results in the majority of spinal diseases, it is not yet fully accepted within the medical community. Perhaps it is partly due to the fact that, sometimes, indications are not appropriately made. The objective of our work is to explain the mechanisms of action of ozone therapy on the extruded disc herniation. Indeed, these mechanisms are quite different from those exerted by ozone on the protruded disc herniation and on the degenerative disc disease because the inflammatory response is very different between the various cases. Extruded disc herniation occurs when the nucleus squeezes through a weakness or tear in the annulus. Host immune system considers the nucleus material to be a foreign invader, which triggers an immune response and inflammation. We think ozone therapy modulates this immune response, activating macrophages, which produce phagocytosis of extruded nucleus pulposus. Ozone would also facilitate the passage from the M1 to M2 phase of macrophages, going from an inflammatory phase to a reparative phase. Further studies are needed to verify the switch of macrophages.

Revealing the Immune Infiltration Landscape and Identifying Diagnostic Biomarkers for Lumbar Disc Herniation.

Intervertebral disc (IVD) degeneration and its inflammatory microenvironment ultimately led to discogenic pain, which is thought to originate in the nucleus pulposus (NP). In this study, key genes involved in NP tissue immune infiltration in lumbar disc herniation (LDH) were identified by bioinformatic analysis. Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. The CIBERSORT algorithm was used to analyze the immune infiltration into NP tissue between the LDH and control groups. Hub genes were identified by the WGCNA R package in Bioconductor and single-cell sequencing data was analyzed using R packages. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction. The immune infiltration profiles varied significantly between the LDH and control groups. Compared with control tissue, LDH tissue contained a higher proportion of regulatory T cells and macrophages, which are associated with the macrophage polarization process. The most significant module contained three hub genes and four subclusters of NP cells. Functional analysis of these genes was performed, the hub gene expression pattern was confirmed by PCR, and clinical features of the patients were investigated. Finally, we identified TGF-ß and MAPK signaling pathways as crucial in this process and these pathways may provide diagnostic markers for LDH. We hypothesize that the hub genes expressed in the specific NP subclusters, along with the infiltrating macrophages play important roles in the pathogenesis of IVD degeneration and ultimately, disc herniation.

[Serum biomarkers in acute low back pain and sciatica]. / Szérumbiomarkerek akut lumbalis-lumbosacralis fájdalomban.

Inflammation contributes to the pathogenesis of low back pain and sciatica. Growing evidence suggests that elevated levels of some inflammatory biomarkers are associated with these conditions. Much of the research evaluating the association between pro- and anti-inflammatory cytokines, chemokines, other regulatory molecules, and low back pain and sciatica, focused on patients with chronic low back pain, while fewer studies addressed the issue of detectable biomarkers in the acute phase. Previous studies suggest that pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8 and anti-inflammatory IL-4 and IL-10 play an important role in the inflammatory response following intervertebral disc herniation. According to the approach of personalized medicine it is important to identify subsets of patients within the acute patient group regarding etiology, prognosis and treatment. In addition, if we can identify subgroups based on levels of pro-inflammatory biomarkers, where inflammation may be the leading cause of pain, we assume that this subgroup would likely be effectively treated with anti-inflammatory medication. The efficacy of TNF-α inhibitors and IL-6 inhibitors in treating low back pain and sciatica has already been tested in clinical trials, but further studies are required. Overall, identification of circulating biomarkers of acute low back pain and sciatica may assist in refining personalized diagnosis and treatment. Further research is needed to evaluate the role of inflammation in acute low back pain and sciatica, to identify what methods are appropriate for evaluation in clinical practice, and whether there are biomarkers of prognostic value in these patients. Orv Hetil. 2020; 161(13): 483-490.

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments.

Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO- versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, known as pro-inflammatory (PRO), and soluble diclofenac, a non-steroidal anti-inflammatory drug (ANTI), were intradiscally administered in a rat IVD injury model, 24 h after lesion. Two weeks after administration, a reduction of disc height accompanied by hernia formation was observed. In the PRO-inflammatory treated group, IL-1ß, IL-6 and COX-2 IVD gene expression were upregulated, and loss of nucleus pulposus (NP) structure and composition was observed. Systemically, lower T-cell frequency was observed in the lymph nodes (LN) and spleen (SP) of the PRO group, together with an increase in CD4+ T cells subset in the blood (BL) and LN. In contrast, the ANTI-group had higher proteoglycans/collagen ratio and collagen type 2 content in the NP, while an increase in the frequency of myeloid cells, M1 macrophages and activated macrophages (MHCII+) was observed at the systemic level. Overall, this study illustrates the dynamics of local and systemic inflammatory and immune cell responses associated with intradiscal therapies, which will contribute to designing more successful immunomodulatory treatments for IVD degeneration.

Investigation of resident and recruited macrophages following disc injury in mice.

Macrophages, particularly M1 macrophages, produce proinflammatory cytokines and contribute to the degenerative process in injured intervertebral discs (IVDs). We previously showed that macrophages in both intact and injured IVDs increased following IVD injury. Resident macrophages and macrophages recruited from the peripheral blood have distinct roles in tissue. However, it remains to be determined whether increased macrophages derive from resident or recruited macrophages. We investigated the origin of M1 macrophages in injured IVDs using green fluorescent protein (GFP) transgenic bone marrow chimeric mice. The M1 macrophage marker, CD86, increased in both disc-derived resident macrophages and bone marrow-derived macrophages (BMMs) after lipopolysaccharide/interferon γ stimulation in vitro. Following IVD injury, the proportion of cells positive for the CD86 ligand, the F4/80 antigen, and the surface glycoprotein CD11b (CD86+ CD11b+ F4/80+) significantly increased in GFP+ populations at days 3, 7, and 14. In contrast, CD86+ CD11b+ F4/80+ cells in GFP- populations significantly increased on day 3, and thereafter decreased on days 7 and 14. The proportion of CD86+ CD11b+ F4/80+ cells in the GFP+ populations was significantly higher than that in the GFP- populations at days 1, 3, 7, and 14. Monocyte chemoattractant protein-1 expression in disc-derived macrophages, but not in BMMs, increased following interleukin-1ß stimulation. Our results suggest M1 macrophages following IVD injury originate from recruited macrophages. Resident macrophages may behave differently in IVD injury. The role of resident macrophages needs to be clarified. Further investigation is needed.

Effect of Preoperative Uric Acid Level and Neutrophil / Lymphocyte Ratio on Preoperative and Postoperative Visual Analogue Pain Scores in Patients with Lumbar Disc Herniation: A Cross-Sectional Study.

AIM: To determine the relationship between the serum urate (SU) level, neutrophil / lymphocyte ratio (NLR), and pain severity using preoperative and postoperative visual analogue scale (VAS) scores in patients with lumbar disc herniation (LDH). MATERIAL AND METHODS: This single-center, cross-sectional study included 20 consecutive patients who were operated for LDH by the same surgeon. The patients'pre- and postoperative UA levels, NLRs, and intensity severity VAS scores were investigated. Preoperative magnetic resonance imaging (MRI) findings, serum UA levels, and neutrophil and lymphocyte counts were recorded. Pain severity was recorded preoperatively and at 6 months postoperatively. Effects of the preoperative SU levels and NLRs on the pre- and postoperative VAS scores were statistically assessed. RESULTS: Statistically significant positive correlation coefficients were determined between NLR and the preoperative and postoperative VAS scores. Negative correlation coefficients were found between the SU levels and preoperative VAS scores; in contrast, positive correlation coefficients were found between the SU levels and the postoperative VAS scores. CONCLUSION: Our results demonstrate the importance of not ignoring the serum UA level and NLR in pre- and postoperative pain in patients with LDH. Nevertheless, further extensive studies are warranted.

The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

Characterization of neuroinflammation and periphery-to-CNS inflammatory cross-talk in patients with disc herniation and degenerative disc disease.

The aim of the study was to identify inflammatory cytokines/chemokines associated with neuroinflammation and periphery-to-CNS inflammatory cross-talk in degenerative disc disease (DDD) and lumbar disc herniation (LDH), common causes of low back pain (LBP). A secondary aim was to investigate the associations between cytokines and symptom severity. METHODS: In total, 40 DDD and 40 LDH patients were recruited from a surgical waiting list, as well as 39 healthy controls (HC) and 40 cerebrospinal fluid (CSF) controls. The subjects completed questionnaires and pressure algometry was performed at the lumbar spine and forearm. The CSF, serum and disc tissues were collected during surgery. Inflammatory mediators TNF, INFg, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and MCP1 were analysed by immunoassay (Meso Scale Discovery) and quantitative real-time polymerase chain reaction (qPCR) was used for analysis of IL-6, IL-8, MCP1 and TSPO expression in intervertebral discs (IVDs). RESULTS: In the LDH group, we found elevated IL-8 concentrations in CSF indicating neuroinflammation, while IL-8 and MCP1 concentrations in serum were lower compared to HC. The IVD expression of IL-6, IL-8 and TSPO was lower in LDH patients compared to DDD. LDH patients had a positive correlation between IL-8 concentrations in CSF and serum and IL-8 in CSF was associated with higher pain intensity and increased spinal pressure pain sensitivity. The MCP1 concentration in serum was associated with higher global pain ratings and increased spinal pressure pain sensitivity, while IL-6 serum concentration correlated with the intensity of the neuropathic pain component (leg pain) in LDH patients. IVD expression of TSPO in LDH patients was associated with increased intensity of back pain. No differences were found in cytokine CSF concentrations between DDD patients and CSF controls, but DDD patients had lower IL-8 and MCP1 serum concentrations than HC. In female DDD patients, IL-8 and MCP1 concentrations in serum were associated with increased intensity of back pain. CONCLUSION: Our results suggest that neuroinflammation mediated by elevated IL-8 concentrations in CSF and IL-8 mediated periphery-to-CNS inflammatory cross-talk contributes to pain in LDH patients and suggest a link between TSPO expression in discs and low back pain.

The inflammatory response in the regression of lumbar disc herniation.

Lumbar disc herniation (LDH) is highly associated with inflammation in the context of low back pain. Currently, inflammation is associated with adverse symptoms related to the stimulation of nerve fibers that may lead to pain. However, inflammation has also been indicated as the main factor responsible for LDH regression. This apparent controversy places inflammation as a good prognostic indicator of spontaneous regression of LDH. This review addresses the molecular and cellular mechanisms involved in LDH regression, including matrix remodeling and neovascularization, in the scope of the clinical decision on conservative versus surgical intervention. Based on the evidence, a special focus on the inflammatory response in the LDH context is given, particularly in the monocyte/macrophage role. The phenomenon of spontaneous regression of LDH, extensively reported in the literature, is therefore analyzed here under the perspective of the modulatory role of inflammation.

The effect of percutaneous endoscopic lumbar discectomy under different anesthesia on pain and immunity of patients with prolapse of lumbar intervertebral disc.

OBJECTIVE: To explore the effect of percutaneous transforaminal endoscopic discectomy under different anesthesia on pain and immunity of patients with lumbar disc herniation. PATIENTS AND METHODS: 92 cases of patients with lumbar disc herniation in the Affiliated Hospital of Qingdao University from February 2015 to January 2016 were collected. These patients were randomly divided into control group and observation group (n = 46). Patients in the control group underwent percutaneous transforaminal endoscopic discectomy with the use of local anesthesia, while patients in the observation group used continuous epidural anesthesia. Oswestry Disability Index (ODI) and Visual Analogue Scale of Pain (VAS) were used to compare the surgical effect and the degree of pain of patients in the two groups. Adverse reactions (nausea, vomiting, dizziness, drowsiness) of patients in two groups were compared. T lymphocytes subset level (CD4+, CD8+) and inflammatory cytokines (IL-2, TNF) in the immune system were compared on the 1st, 3rd, and 10th day post-operatively. RESULTS: The pain degree of patients in the two groups had no significant difference before their operations (p > 0.05). The intraoperative pain rate of patients in the observation group was significantly lower than the control group (p < 0.05). Patients in both groups achieved a remarkable decrease of pain intensity on month 1 and month 3 post-operatively (p < 0.05). There is no significant difference between the two groups (p > 0.05). ODI scores of patients in the two groups had no significant difference pre-operatively (p > 0.05). Patients in both groups achieved a remarkable decrease of ODI scores after surgery (p < 0.05), and there is no significant difference between the two groups (p > 0.05). The occurrence of adverse reactions in the observation group was significantly lower than the control group (p < 0.05). On day 1 and 3 post-operatively, CD4+ and CD8+ levels of patients in both groups were lower than before operation, and data in the control group decreased more than the observation group (p < 0.05). IL-2 and TNF-α levels of patients in the two groups were significantly higher than pre-operatively, and data in the control group was higher than the observation group (p < 0.05). On day 10 post-operatively, all the indexes returned to the preoperative level. CONCLUSIONS: Both continuous epidural anesthesia and local anesthesia can reduce or avoid perioperative pain, but continuous epidural anesthesia has more advantages than local anesthesia, and it can improve the immune function for patients undergoing PTED for LDH.

Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain.

Lumbar radicular pain after disc herniation may be associated with release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN-γ expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the dorsal nerve roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN-γ SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN-γ close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation.

Endothelin-1 Immunoreactivity and its Association with Intramedullary Hemorrhage and Myelomalacia in Naturally Occurring Disk Extrusion in Dogs.

BACKGROUND: The pathophysiology of ascending/descending myelomalacia (ADMM) after canine intervertebral disk (IVD) extrusion remains poorly understood. Vasoactive molecules might contribute. HYPOTHESIS/OBJECTIVES: To investigate the immunoreactivity of endothelin-1 (ET-1) in the uninjured and injured spinal cord of dogs and its potential association with intramedullary hemorrhage and extension of myelomalacia. ANIMALS: Eleven normal control and 34 dogs with thoracolumbar IVD extrusion. METHODS: Spinal cord tissue of dogs retrospectively selected from our histopathologic database was examined histologically at the level of the extrusion (center) and in segments remote from the center. Endothelin-1 immunoreactivity was examined immunohistochemically and by in situ hybridization. Associations between the immunoreactivity for ET-1 and the severity of intramedullary hemorrhage or the extension of myelomalacia were examined. RESULTS: Endothelin-1 was expressed by astrocytes, macrophages, and neurons and only rarely by endothelial cells in all dogs. At the center, ET-1 immunoreactivity was significantly higher in astrocytes (median score 4.02) and lower in neurons (3.21) than in control dogs (3.0 and 4.54) (P < .001; P = .004) irrespective of the grade of hemorrhage or myelomalacia. In both astrocytes and neurons, there was a higher ET-1 immunoreactivity in spinal cord regions remote from the center (4.58 and 4.15) than in the center itself (P = .013; P = .001). ET-1 mRNA was present in nearly all neurons with variable intensity, but not in astrocytes. CONCLUSION AND CLINICAL IMPORTANCE: Enhanced ET-1 immunoreactivity over multiple spinal cord segments after IVD extrusion might play a role in the pathogenesis of ADMM. More effective quantitative techniques are required.

Plasmacytoid dendritic cells and memory T cells infiltrate true sequestrations stronger than subligamentous sequestrations: evidence from flow cytometric analysis of disc infiltrates.

PURPOSE: Herniated nucleus pulposus has been considered to induce an adaptive immune response. Antigen recognition by antigen-presenting-cells (APCs) represents an important step within manifestation of an adaptive immune response. Macrophages have been assumed to function as APC, while importance of plasmacytoid dendritic cells for initiation of an immune response directed towards herniated nucleus pulposus has never been examined. The aim of the present study was to assess importance of plasmacytoid dendritic cells for initiation of immune response directed towards herniated discs. METHODS: Fifteen patients with true sequestrations and three patients with subligamentous sequestrations underwent surgery after their neurological examinations. Disc material was harvested, weighted and digested for 90 min. Separated single cells were counted, stained for plasmacytoid dendritic cells (CD123(+)CD4(+)), macrophages (CD14(+)CD11c(+)) and memory T cells (CD4(+)CD45RO(+)) and analysed by flow cytometry. Both patient groups were compared in cell proportions. Furthermore, patients with true sequestrations (TRUE patients) were subdivided into subgroups based on severity of muscle weakness and results in straight leg raising (SLR) test. Subgroups were compared in cell proportions. RESULTS: Plasmacytoid dendritic cells and memory T cells infiltrated true sequestrations stronger than the subligamentous sequestration and plasmacytoid dendritic cells predominated over macrophages in true sequestrations. Highest proportions of plasmacytoid dendritic cells were detected in infiltrates of patients having true sequestrations, severe muscle weakness and negative result in SLR test. CONCLUSIONS: The findings of the present study indicate that plasmacytoid dendritic cells are involved in initiation of an immune response directed towards herniated nucleus pulposus, while macrophages may reinforce the manifested immune response and mediate disc resorption.

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.

Herniated intervertebral disk induces hypertrophy and ossification of ligamentum flavum.

STUDY DESIGN: In vitro experiment using degenerated human ligamentum flavum (LF) and herniated intervertebral disk (IVD). OBJECTIVES: To investigate the role and effect of degenerated and herniated IVDs on LF hypertrophy and ossification. SUMMARY OF BACKGROUND DATA: Spinal stenosis is caused, in part, by hypertrophy and ossification of the LF, which are induced by aging and degenerative process. It is well known that degenerated IVDs spontaneously produce inflammatory cytokines. Therefore, we hypothesized that degenerated IVD may affect adjacent LF through secreted inflammatory cytokines. METHODS: LF and herniated lumbar IVD tissues were obtained during surgical spinal procedures. LF fibroblasts were isolated by enzymatic digestion of LF tissue. LF cell cultures were treated with disk supernatant from herniated IVDs. Secreted cytokines from IVD tissue culture were detected by enzyme-linked immunosorbent assay. After analysis of cytotoxicity, DNA synthesis was measured. Reverse transcription-polymerase chain reaction for mRNA expressions of types I, II, III, V, and XI collagen and osteocalcin, and histochemical stains were performed. RESULTS: Supernatant from tissue culture of herniated IVD showed increased production of interleukin-1α, interleukin-6, tumor necrosis factor-α, prostaglandin E2, and nitric oxide compared with disk tissue culture from traumatic condition. There was no cytotoxicity in LF cells treated with disk supernatant from herniated IVDs. There was significant increase in DNA synthesis, upregulation in mRNA expression of types III, XI collagen and osteocalcin, whereas variable expression pattern of type I and V, and strong positive stains for Von Kossa and alkaline phosphatase in LF cultures with disk supernatant. CONCLUSIONS: Degenerated and herniated IVDs provide an important pathomechanism in hypertrophy and ossification of the LF through inflammatory cytokines.

[Effects of sacral canal injection on nerve root local inflammatory factors in rat model with lumbar disc herniation].

OBJECTIVE: To explore the effects of sacral canal injection on nerve root local inflammatory factors in rat model with lumbar disc herniation, in order to identify its mechanism of treatment. METHODS: Forty-eight male SD rats were randomly divided into sham operation group(group A), model group (group B), Chinese medicine group(group C) and western medicine group(group D). There were 12 rats in each group. The model of lumbar disc herniation was established using compression and inflammatory stimulation in group B, C, D. All rats were given epidural catheterization and group A and B with physiological saline (1 ml/kg), group C with mixed liquor of 2% lidocaine and compound Danshen injections and physiological saline (2:2: 16) and group D with mixed liquor of 2% lidocaine and triamcinolone acetonide injection and physiological saline (2:2:16), once a week for a total of three treatments. Four rats were killed every 1 week after injection for once, and the inflammatory factors of tumor necrosis factor (TNF-alpha), prostaglandin E2 (PGE2), interleukin-l (IL-1) and interleukin-6 (IL-6) were detected by ELISA method. RESULTS: The levels of TNF-alpha, PGE2, IL-1 and IL-6 in compressed nerve tissues in group B were increased than those of group A (P < 0.01). The levels of PGE2, IL-1 and IL-6 in group C and D were decreased than those of group B, and group D was much less(P<0.05). There was no significant difference in level of TNF-alpha among group B, C, D (P > 0.05). CONCLUSION: Compound compression with inflammatory stimulation can lead to massive release of inflammatory mediators, such as TNF-alpha, PGE2, IL-1 and IL-6. Both injection with compound Danshen injections and triamcinolone acetonide injections by sacral canal can reduce the levels of part inflammatory mediators (PGE2, IL-1 and IL-6), and the effect of Glucocorticoid is better than Danshen (P < 0.05).

Association between baseline IL-6 and 1-year recovery in lumbar radicular pain.

BACKGROUND: In the present study, the influence of cytokines on 1-year recovery in lumbar radicular pain was examined. METHODS: In total, 110 patients with symptomatic lumbar disc herniation were followed for 1 year. Uni- and multivariate linear regression was used to assess the influence of interleukin (IL)-6, IL-8, disc degeneration and endplate changes (Modic changes) on the changes in the Oswestry Disability Index (ODI change; primary outcome) and visual analogue scale (VAS) for low back pain (LBP) and leg pain (secondary outcomes). RESULTS: Less favourable ODI outcome correlated with higher serum IL-6 levels (B = -3.41, 95% CI -5.52 to -1.30, p = 0.002), non-surgical treatment (B = -7.03, 95% CI 1.21 to 12.84, p = 0.018), higher baseline back pain intensity (B = -2.28, 95% CI -3.21 to -1.35, p < 0.001) and low educational level (B = -5.57, 95% CI 0.66 to 10.47, p = 0.027). High VAS for LBP and leg pain at 1 year was associated with high levels of serum IL-6, higher back pain intensity and longer duration of lumbar radicular pain at baseline. CONCLUSIONS: High serum IL-6 levels, but not disc degeneration or Modic changes, were associated with less favourable recovery in patients with lumbar radicular pain. Intense initial back pain, non-surgical treatment, lower educational level and longer duration of radicular pain before treatment also correlated with a slower recovery the first year after disc herniation.

Gadolinium enhancement in newly diagnosed patients with lumbar disc herniations are associated with inflammatory peridiscal tissue reactions--evidence of fragment degradation?

OBJECTIVE: It is debatable whether a local inflammatory tissue response caused by herniated disc material contributes to sciatic pain and/or sensorimotor deficits. The impact of inflammatory changes on local tissue remodelling, the healing process and the clinical course of disease remains unclear. METHODS: In this prospective observational study, we included a total of 31 patients with a single-level, unilateral lumbar disc herniation. The diagnosis was confirmed by magnetic resonance imaging (MRI)±gadolinium. The presence of peridiscal contrast enhancement was correlated with the extent of inflammatory reactions in the herniated fragments as confirmed by immunohistochemistry; clinical symptoms, including the duration of radicular pain; and the incidence of sensorimotor deficits. RESULTS: Peridiscal contrast enhancement was found in 17 patients (55%) and was encasing the adjacent rootlet in 4 cases. There was no significant correlation between gadolinium uptake and the presence of sensorimotor deficits or the duration of radicular symptoms. Degenerative changes were observed in all 31 disc specimens. Overall, 18 cases exhibited increased cellularity in the marginal areas, which were mostly populated by CD68(+) macrophages and fibroblasts. Additionally, these areas displayed a limited number of CD3(+) T-lymphocytes and different degrees of concomitant neovascularisation, which represented a chronic and unspecific immune response. Peridiscal contrast enhancement on MRI was significantly correlated with the histopathological characteristics of tissue inflammation. However, no correlation was found between the histological evidence and the degree of inflammation and neurological symptoms. CONCLUSION: Gadolinium-enhanced MRI is a sensitive method to detect unspecific inflammatory reactions in therapy-naïve disc herniations. However, the neuroradiological and histological evidence of peridiscal inflammation was not correlated with the severity of pain or sensorimotor deficits in our patients. Additional research is needed because the occurrence of local inflammation may indicate an ongoing degradation of herniated fragments and thus be helpful in therapeutic decision-making.

Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation.

STUDY DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. OBJECTIVE: To examine the safety and efficacy of three different doses of the tumor necrosis factor alpha (TNF-α) inhibitor etanercept versus placebo for the treatment of symptomatic lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: TNF-α is considered to be a major cause of radicular leg pain associated with symptomatic LDH. Systemic administration of TNF-α inhibitors for sciatica has indicated a trend toward efficacy. METHODS: Forty-nine subjects aged between 18 and 70 years, with persistent lumbosacral radicular pain secondary to LDH, and an average leg pain intensity of 5/10 or more were randomized to 1 of 4 groups: 0.5-mg, 2.5-mg, 12.5-mg etanercept, or placebo. Subjects received 2 transforaminal epidural injections, 2 weeks apart, and were assessed for efficacy up to 26 weeks after the second injection. The primary outcome measure was the change in mean daily worst leg pain (WLP). Secondary outcomes included average leg pain, worst back pain, average back pain, in-clinic pain, Oswestry Disability Index, patient global impression of change, and tolerability. RESULTS: Forty-three of the 49 randomized patients completed the study. Patients receiving 0.5-mg etanercept showed a clinically and statistically significant (P< 0.1) reduction in mean daily WLP compared with the placebo cohort from 2 to 26 weeks for both the per protocol population (-5.13 vs. -1.95; P= 0.066) and the intention-to-treat population (-4.40 vs. -1.84; P= 0.058). Fifty percent of these subjects reported a 100% reduction in WLP 4 weeks post-treatment compared with 0% of subjects in the placebo cohort. Improvements in all secondary outcomes were also observed in the 0.5-mg etanercept cohort. The overall incidence of adverse events was similar in placebo and all etanercept cohorts. CONCLUSION: Two transforaminal injections of etanercept provided clinically significant reductions in mean daily WLP and worst back pain compared with placebo for subjects with symptomatic LDH. Epidural etanercept may offer patients with sciatica a safe and effective nonoperative treatment.