Thoracic Spinal Canal Stenosis Research Articles

IL-6 is involved in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is a heterotopic ossification of spinal ligaments. TOLF is the major cause of thoracic spinal canal stenosis and myelopathy, and its underlying mechanisms are not clear. Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts, and regulated by BMP2, RUNX2, Osterix (OSX), etc. In this study, we continue to further characterize properties of TOLF. Our immunohistochemistry experiments showed that expressions of osteoblastic factors such as BMP2 and RUNX2 increased in TOLF. According to flow cytometry analysis the proportion of S phase of cell cycle in primary TOLF cells was 9% higher than the control. Alizarin red staining and ALP staining observations were consistent with immunohistochemistry results. It was also observed that inflammatory cytokine IL-6 level dramatically increased in the culture supernatant of primary TOLF cells. We propose the hypothesis that IL-6 is involved in TOLF. To testify the hypothesis, we examined the effect of IL-6. Our results showed that IL-6 was able to activate expressions of osteoblastic factors such as BMP2, RUNX2, OSX, OCN and ALP, and that expressions of cell proliferation factors cyclin D1 and cyclin C increased in the presence of IL-6. Moreover, IL-6-induced BMP2 expression was inhibited by p38 inhibitor SB203580, indicating that IL-6 regulated the osteogenic BMP2 activation through p38 MAPK pathway. These data suggest that IL-6 is involved in TOLF.

Multiple Segments Thoracal Spinal Canal Stenosis Caused by Ossification of Ligamentum Flavum: A Case Report

Background: Thoracal spinal canal stenosis (SCS) that refers to multiple segments of the thoracic spine is a peculiar clinical condition. Various factors can cause thoracic SCS, including ossification of the ligamentum flavum (OLF). The aim of this study is to explain about the diagnosis for multiple segment thoracal spinal canal stenosis and management properly to prevent further complications. Case Presentation: A 58-year-old male came to Orthopaedic Outpatient Clinic in Prof. I.G.N.G Ngoerah Hospital, complaining back pain since one year prior to admission. Pain aggravated when he was bending his back. The patient was diagnosed with Thoracal Spinal Canal Stenosis Th 8-9, Th9-10, Th10-11. Patient underwent decompression, stabilization, fusion and biopsy surgery. Results: Patient underwent decompression, stabilization, fusion and biopsy surgery at RSUP Prof. I.G.N.G Ngoerah. In durante operation, already done laminectomy and eight pieces of pedicle screw was applied in Th8-Th11 (55mm x 40 mm Monoaxial on right side Th8, 55mm x 40 mm Polyaxial on left side Th8; 55mm x 40 mm Monoaxial on right side Th9, 55mm x 35 mm Monoaxial on left side Th9; 55mm x 40 mm Monoaxial on right and left side Th10; 55mm x 40 mm Monoaxial on right and left side Th11). There were no complications found in this patient after 4th day following surgery. Conclusion: The goal of surgical intervention for SCS is decompression by removing the calcific areas that are responsible for the spinal canal narrowing and subsequent cord compression. Although the diagnosis and choice of intervention can be difficult, early detection and management are critical to postoperative success. Postoperative results are variable and often unsatisfactory. Keywords: Spinal canal stenosis, ligamentum flavum, spine, surgery Correspondence: I Gusti Lanang Ngurah Artha Wiguna. Division of Spine, Department of Orthopaedic and Traumatology, Prof. I.G.N.G Ngoerah Hospital, Faculty of Medicine, Udayana University, Bali, Indonesia. Email:lanangwiguna20021979@gmail.com. Mobile: 0811388859. Indonesian Journal of Medicine (2022), 07(03): 278-288 https://doi.org/10.26911/theijmed.2022.07.03.04

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway.

Thoracic ossification of the ligamentum flavum (TOLF) is heterotopic ossification of spinal ligaments, which may cause serious thoracic spinal canal stenosis and myelopathy. However, the underlying etiology remains inadequately understood. In this study, the ossification patterns of TOLF were analyzed by micro-computer tomography (micro-CT). The expression profile of genes associated with angiogenesis was analyzed in thoracic ligamentum flavum cells at sites of different patterns of ossification using RNA sequencing. Significant differences in the expression profile of several genes were identified from Gene Ontology (GO) analysis. Angiopoietin-2 (ANGPT2) was significantly up-regulated in primary thoracic ligamentum flavum cells during osteogenic differentiation. To address the effect of ANGPT2 on Notch signaling and osteogenesis, ANGPT2 stimulation increased the expression of Notch2 and osteogenic markers of primary thoracic ligamentum flavum cells of immature ossification, while inhibition of ANGPT2 exhibited opposite effect on Notch pathway and osteogenesis of cells of mature ossification. These findings provide the first evidence for positive regulation of ANGPT2 on osteogenic differentiation in human thoracic ligamentum flavum cells via modulating the Notch signaling pathway.

The efficacy and safety of tranexamic acid in reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis

Study Design:A retrospective study.Objective:To investigate the effectiveness and safety of intravenous tranexamic acid for reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis (TSS).Methods:This is a retrospective observational study of 42 patients with multilevel TSS admitted from December 2016 to October 2017 to the spine department of Honghui Hospital who underwent posterolateral bone graft fusion with posterior laminectomy and decompression fixation. The patients were divided into 2 groups. All the surgeries were completed by the same surgeon. Group A received an intravenous infusion of 15 mg/kg 15 min prior to surgery. Continuous infuse on of tranexamic acid (TXA) at a dose of 1 mg/kg/h was provided throughout the operation until the skin was closed. Group B received no TXA as a blank control group. Group A comprised 10 males and 10 females with an average age of 53.41 ± 7.93 years; group B comprised 11 males and 11 females with an average age of 55.10 ± 8.43 years. The need for blood transfusion, volume of blood transfusion, blood coagulation function, extubation time, postoperative hospital stay and incidence of postoperative deep venous thrombosis (DVT) were recorded during and after the operation for the 2 groups.Results:There was no significant difference between the 2 groups in general characteristics, such as age, sex and body mass index (BMI) (P > .05). There was no significant difference between the 2 groups in the levels are instrumented and the laminectomy levels in each group. The average postoperative blood loss, need for blood transfusion, time to postoperative extubation and length of postoperative hospital stay in group A were lower than those in group B, and there was a significant difference between the 2 groups (P < .05). The preoperative and postoperative coagulation, and postoperative DVT did not occur 48 h after operation.Conclusion:In the treatment of multilevel thoracic spinal canal stenosis using trabeculectomy with posterior laminectomy and posterolateral bone graft fusion, TXA can reduce the amount of blood transfused and the need for blood transfusion and can shorten the extubation time and the length of postoperative hospital stay without increasing the incidence of postoperative coagulation dysfunction or postoperative DVT.Level of Evidence: 4

MiR-490-3p inhibits osteogenic differentiation in thoracic ligamentum flavum cells by targeting FOXO1.

Thoracic ossification of the ligamentum flavum (TOLF) is a rare heterotopic ossification of spinal ligaments, which is the major cause of thoracic spinal canal stenosis and myelopathy. In this study, the roles of miR-490-3p and forkhead box O1 (FOXO1) in osteogenesis of human thoracic ligamentum flavum cells were investigated. MiR-490-3p was found to be down-regulated during osteogenic differentiation of thoracic ligamentum flavum cells, while their overexpression inhibited osteogenic differentiation. In addition, the analysis of target prediction and dual luciferase reporter assays supported that miR-490-3p directly targeted FOXO1 and suppressed the expression of FOXO1. Moreover, FOXO1 knockdown was displayed to attenuate the effect of miR-490-3p inhibition. ChIP assays showed that miR-490-3p negatively regulated the interaction of FOXO1 and RUNX2. These findings suggest that miR-490-3p performs an inhibitory role in osteogenic differentiation of thoracic ligamentum flavum cells by potentially targeting FOXO1.

The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-α) in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-α increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-α on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-α stimulation. To address the effect of TNF-α on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-α. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-α stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-α. TNF-α activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-α activation of Osx expression. This suggests that TNF-α activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-α involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx.

Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF)is a common cause of thoracic spinal canal stenosis and has been reported almost exclusively in East Asian countries. In this study, we established a relationship between bone morphogenic protein 2 (BMP-2) and TOLF. We divided patients into two groups according to severity of ossification and identified susceptible loci through exome sequencing. We identified 39 novel likely pathogenic variants in 29 genes in the transforming growth factor-beta (TGF-β) superfamily or TGF-β/BMPs signaling pathway, including two missense variants in BMP-2 (NM_001200.3) exon region, c.460C>G:p.(R154G) and c.584G>T:p.(R195M). Further Sanger sequencing and genotyping suggested the variants were only found in patients with long regional OLF. Bioinformatic assays predicted the two BMP-2 variants to cause significant alterations to gene and protein expression. Functional assays showed upregulation of BMP-2 expression, increased osteogenic marker expression, and enhanced osteogenic differentiation. Collectively, these results suggest a genetic contribution to the pathogenesis of TOLF, particularly in patients with long segment disease, and that nucleotide substitutions associated with increased BMP-2 expression may be involved in TOLF pathogenesis.

MiR-199b-5p inhibits osteogenic differentiation in ligamentum flavum cells by targeting JAG1 and modulating the Notch signalling pathway.

Ossification of the ligamentum flavum (OLF) is a pathology almost only reported in East Asian countries. The leading cause of OLF is thoracic spinal canal stenosis and myelopathy. In this study, the role of miR‐199b‐5p and jagged 1 (JAG1) in primary ligamentum flavum cell osteogenesis was examined. MiR‐199b‐5p was found to be down‐regulated during osteogenic differentiation in ligamentum flavum cells, while miR‐199b‐5p overexpression inhibited osteogenic differentiation. In addition, JAG1 was found to be up‐regulated during osteogenic differentiation in ligamentum flavum cells, while JAG1 knockdown via RNA interference caused an inhibition of Notch signalling and osteogenic differentiation. Moreover, target prediction analysis and dual luciferase reporter assays supported the notion that JAG1 was a direct target of miR‐199b‐5p, with miR‐199b‐5p found to down‐regulate both JAG1 and Notch. Further, JAG1 knockdown was demonstrated to block the effect of miR‐199b‐5p inhibition. These findings imply that miR‐199b‐5p performs an inhibitory role in osteogenic differentiation in ligamentum flavum cells by potentially targeting JAG1 and influencing the Notch signalling pathway.

MiR-132-3p Regulates the Osteogenic Differentiation of Thoracic Ligamentum Flavum Cells by Inhibiting Multiple Osteogenesis-Related Genes.

Ossification of the ligamentum flavum (OLF) is a disorder of heterotopic ossification of spinal ligaments and is the main cause of thoracic spinal canal stenosis. Previous studies suggested that miR-132-3p negatively regulates osteoblast differentiation. However, whether miR-132-3p is involved in the process of OLF has not been investigated. In this study, we investigated the effect of miR-132-3p and its target genes forkhead box O1 (FOXO1), growth differentiation factor 5 (GDF5) and SRY-box 6 (SOX6) on the osteogenic differentiation of ligamentum flavum (LF) cells. We demonstrated that miR-132-3p was down-regulated during the osteogenic differentiation of LF cells and negatively regulated the osteoblast differentiation. Further, miR-132-3p targeted FOXO1, GDF5 and SOX6 and down-regulated the protein expression of these genes. Meanwhile, FOXO1, GDF5 and SOX6 were up-regulated after osteogenic differentiation and the down-regulation of endogenous FOXO1, GDF5 or SOX6 suppressed the osteogenic differentiation of LF cells. In addition, we also found FOXO1, GDF5 and SOX6 expression in the ossification front of OLF samples. Overall, these results suggest that miR-132-3p inhibits the osteogenic differentiation of LF cells by targeting FOXO1, GDF5 and SOX6.

Clinical outcomes after decompressive laminectomy for symptomatic ossification of ligamentum flavum at the thoracic spine

Ossification of the ligamentum flavum (OLF) is a rare disease that causes acquired thoracic spinal canal stenosis and thoracic myelopathy. The aim of this study was to investigate clinical outcomes of symptomatic thoracic OLF treated using posterior decompressive laminectomy. We retrospectively analyzed the medical records of 22 patients who underwent posterior decompressive laminectomy for symptomatic thoracic OLF. The surgical results were evaluated using the modified Japanese Orthopaedic Association (JOA) scoring system and Hirabayashi recovery rate. The intensity of pain was evaluated using a visual analog scale (VAS). The mean duration of follow-up was 35.6months. The mean JOA score was significantly improved at final follow-up (9.18±standard deviation of 1.53 points [range, 6–11 points]) compared with before surgery (5.64±2.04 points [range, 3–9 points]) (P<0.001). The mean Hirabayashi recovery rate was 65.49% (range, 20–100%). Recovery outcomes were excellent in nine patients, good in eight patients, fair in four patients and unchanged in one patient. No patient was classified as deteriorated. The VAS scores were 2.82±3.08 before surgery and 0.59±1.05 at final follow-up (P=0.001). Surgical complications, which resolved after appropriate and prompt treatment, included dural tear in five patients, cerebrospinal fluid leakage in one patient, immediate postoperative neurologic deterioration in one patient, epidural hematoma in one patient, and wound infection in one patient. Our findings suggest that posterior decompressive laminectomy is an effective treatment for symptomatic thoracic OLF and provides satisfactory clinical improvement, but surgery for thoracic OLF is associated with a relatively high incidence of complications.

Relation between cervical and thoracic spinal canal stenosis and the development of spinal cord decompression sickness in recreational scuba divers

Retrospective case-control study. The intent of this study was to investigate the relationships between vertebral degenerative changes resulting in spinal canal stenosis, spinal cord lesions and the development of spinal cord decompression sickness (DCS) in scuba divers. Referral hyperbaric facility, Toulon, France. We examined 33 injured divers less than 50 years old by cervical and thoracic MRI and compared them with 34 matched control divers. The number of intervertebral disk abnormalities and the degree of canal compression were analyzed on T2-weighted sagittal images using a validated grading system developed recently. The presence and the distribution of hyperintense cord lesions in relation with the accident and the recovery status at 6 months were also assessed. Canal spinal narrowing was more common in injured divers than in controls (79% vs. 50%, OR=3.7 [95% CI, 1.3-10.8], P=0.021). We found a significant linear association between the extent of canal stenosis, multisegmental findings and the development of spinal cord decompression sickness. MRI intramedullary lesions were significantly more frequent in divers with incomplete recovery (OR=16 [95% CI, 2.6-99], P=0.0014), but statistical analysis failed to demonstrate a significant relationship between canal compression, signal cord abnormalities and a negative clinical outcome. These results suggest that divers with cervical and thoracic spinal canal stenosis, mainly due to disk degeneration, are at increased risk for the occurrence of spinal cord decompression sickness.

Clinical characteristics and surgical outcome of the symptomatic ossification of ligamentum flavum at the thoracic level with combined lumbar spinal stenosis

Retrospective study. To identify the clinical significance of coexistence of lumbar spinal stenosis (LSS) with thoracic ossification of ligamentum flavum (OLF), and to study the surgical outcome of the thoracic OLF patients with or without LSS. The OLF at the thoracic level (thoracic OLF) is a rare disease that causes acquired thoracic spinal canal stenosis. Thoracic OLF is frequently combined with other spinal disorders, such as LSS, and it is not uncommon for thoracic OLF to be misdiagnosed as LSS, resulting in delayed diagnosis. However, clinical impacts of the coexistence of LSS with thoracic OLF remain unknown. In the present study, 36 patients who underwent posterior decompression for OLF-induced thoracic myelopathy were retrospectively reviewed, and the adverse influence of the copresence of LSS with thoracic OLF was studied with regard to clinical features such as clinical symptoms and surgical outcome. Out of 36 patients, 18 patients had LSS (combined group: C-group), and the remaining 18 patients had thoracic OLF only (thoracic group: T-group). No significant inter-group differences were found in terms of gender, age, follow-up period, and preoperative duration of symptoms. Regarding the etiology of LSS in the C-group, 12 cases had degenerative LSS, two cases had lumbar OLF, one case had degenerative LSS with lumbar OLF, one case had had degenerative LSS with lumbar OPLL, and two cases had traumatic LSS due to lumbar kyphosis after vertebral fracture. Clinical examination revealed that the T-group was significantly more likely to demonstrate Achilles hyper-reflexia, while the C-group was significantly more likely to demonstrate Achilles hypo-reflexia. The mean preoperative and postoperative JOA scores were not statistically different between the two groups. However, the mean recovery rate of the JOA score was 17.3% in the C-group, and 30.4% in the T-group. Statistical analysis revealed that the recovery rate of the C-group was significantly lower than that of the T-group. Thoracic OLF with LSS will show a more severe clinical manifestation than that without LSS. In this study, we clearly indicated that the coexisting LSS in thoracic OLF will have adverse effects on the surgical results in thoracic OLF.

The "moustache" sign: Localized intervertebral disc fibrosis and panligamentous ossification in ankylosing spondylitis with kyphosis

Localized intervertebral disc and ligamentous ossification may precipitate neurological deficits at any time during the natural course of ankylosing spondylitis (AS). We report 2 patients with AS with "moustache' sign (localized intervertebral disc fibrosis and panligamentous ossification) and neurological deficits. One patient had syndesmophytosis (with paraparesis secondary to thoracic spinal canal stenosis), and the other had "bamboo spine" above and below the involved level. A laminectomy in the former relieved paraparesis, and posterior element excision in both the patients relieved focal tenderness and pain; and both of them could lie supine following surgery.

Nursing of patients with thoracic spinal canal stenosis

胸椎管狭窄症是一组以胸髓受压为主要临床表现的症候群,临床表现变化多样,主要表现为受压平面以下感觉减退,患者常是先出现胸背痛,随后是感觉障碍、无力和大小便功能障碍,手术减压是唯一有效的治疗手段[1]。

Vertebral Stabilization Using Positively Threaded Profile Pins and Polymethylmethacrylate, with or Without Laminectomy, for Spinal Canal Stenosis and Vertebral Instability Caused by Congenital Thoracic Vertebral Anomalies

To describe diagnostic findings, surgical technique, and outcome in dogs with thoracic spinal canal stenosis and vertebral instability secondary to congenital vertebral anomalies. Retrospective clinical study. Dogs (n=9) with thoracic spinal canal stenosis. Medical records (1995-1996; 2000-2006) of 9 dogs with a myelographic diagnosis of spinal canal stenosis and/or vertebral instability secondary to congenital vertebral anomaly that were surgically managed by vertebral stabilization with or without laminectomy were reviewed. Data on pre- and postoperative neurologic status, diagnostic findings, surgical techniques, and outcomes were retrieved. Follow-up evaluations were performed at 1, 2, and 6 months. Long-term outcome was assessed by means of clinical examination or owner telephone interviews. Spinal cord compression was confirmed by myelography, and in 2 dogs, dynamic compression by stress myelography. Eight dogs regained the ability to ambulate postoperatively. One dog with a partial recovery regained voluntary movement but did not become ambulatory. Spinal cord injury secondary to congenital vertebral anomaly may have a good outcome when treated by vertebral stabilization with or without laminectomy. Adequate stabilization of the vertebrae and improved neurologic outcome were achieved in most dogs. Vertebral stabilization using positively threaded profile pins and polymethylmethacrylate with or without laminectomy is an effective treatment for spinal canal stenosis and vertebral instability secondary to congenital thoracic vertebral anomalies.

Thoracic Myelopathy Caused by Ossification of the Ligamentum Flavum Clinicopathologic Study and Surgical Treatment

The authors reviewed 14 patients with thoracic myelopathy caused by ossification of the ligamentum flavum (OLF). The predominant locality of symptomatic OLF was at the thoracolumbar junction, particularly at T10-11 followed by T11-12. At the level of the thickest OLF in each patient, there were three types of OLF from computed tomography and operative findings: a lateral type in 3 patients, diffuse in 8, and thickened nodular in 3. The diagnosis of OLF-related thoracic spinal canal stenosis was best made by enhanced computed tomography. Histologic study revealed that the developmental mode of OLF was mainly endochondral ossification. Numerous fibrocartilaginous cells were found in the increased and swollen collagen fibers forming the hypertrophic ligamentum flavum (HLF). Ossification extended along the superficial layer of HLF. The size or extension of OLF was relevant to the corresponding diathesis of spinalhyperostosis. Results of laminectomy for OLF were poor because of the high occurrence of complications early on or later deterioration. Therefore, laminoplasty is recommended as a successful procedure for OLF-related thoracic myelopathy, avoiding further local mechanical stress due to tensile force.