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Study Design. Retrospective cohort study. Objective. To clarify whether outcomes of anterior cervical discectomy and fusion (ACDF) differ according to the presence of posterior cord compression from the ligamentum flavum (CCLF) Summary of Background Data. Although ACDF effectively addresses anterior cord compression from disc material and bone spurs, it cannot address posterior compression. Whether ACDF could result in favorable outcomes when CCLF is present remains unclear. Patients and Methods. A total of 195 consecutive patients who underwent ACDF and were followed up for >2 years were included. CCLF was graded based on magnetic resonance imaging findings. Patients with CCLF grade 2 were classified as such, whereas patients with CCLF grades 0 to 1 were classified as the no- CCLF group. Patient characteristics, cervical sagittal parameters, neck pain visual analog scale, arm pain visual analog scale, and Japanese Orthopedic Association (JOA) score were assessed. Categorical variables were analyzed using a χ² test, whereas continuous variables were analyzed using the Student t test. Multivariable logistic regression analysis was performed to elucidate factors associated with JOA recovery rates of > 50%. Results. One hundred sixty-seven patients (85.6%) were included in the no-CCLF group, whereas the remaining 28 patients (14.4%) were included in the CCLF group. Among patients in the CCLF group, 14 patients (50.0%) achieved clinical improvement. JOA score significantly improved in the no-CCLF group after the operation (P < 0.001), whereas improvement was not appreciated in the CCLF group (P = 0.642). JOA scores at 3 months (P = 0.037) and 2 years (P = 0.001) postoperatively were significantly higher in the no-CCLF group. Furthermore, the JOA recovery rate at 2 years after surgery was significantly higher in the no-CCLF group (P = 0.042). Logistic regression demonstrated that CCLF was significantly associated with a JOA recovery rate of >50% at 2 years after surgery (odds ratio: 2.719; 95% CI: 1.12, 6.60). Conclusion. ACDF performed for patients with CCLF grade 2 showed inferior JOA score improvement compared with those with CCLF grade 0 or 1. ACDF cannot remove posterior compressive structures, which limits its utility when ligamentum flavum significantly contributes to cord compression. [ABSTRACT FROM AUTHOR]

Study Design. Histologic analysis of the ligamentum flavum (LF) in the lumbar spine. Objective. The objective of this study is to investigate the levels of glycogen synthase kinase-3β (GSK-3β) and β-catenin in the LF tissue of patients with lumbar spinal stenosis (LSS). Summary of Background Data. The hypertrophy of the LF is the primary cause of the progression of LSS. Recently, Wnt signaling has been proposed as one of the molecular processes contributing to LF hypertrophy. GSK-3β and β-catenin are recognized to play a crucial part in the control of this signaling pathway. Materials and Methods. From May 2020 to July 2022, LF from 51 LSS patients (LSS group) and 18 lumbar disc herniation patients (control group) were prospectively collected during surgery. Histologic analysis was investigated to confirm the progression of LF fibrosis. The levels of α-smooth muscle actin, phosphorylation of GSK-3β (p-GSK-3β; inactive form), and β-catenin were analyzed in LF withWestern blot analysis to reveal the GSK-3β/β-catenin signaling pathway. Continuous variables are expressed as mean±SD and compared using the student t test. Categorical variables are compared using the χ² test or Fisher exact test, as appropriate. To determine the association between p-GSK-3β and LF thickness, the Pearson correlation coefficient was calculated based on the results of Western blot analysis. Results. The LSS group was older and had thicker LF than the controls. The LSS group showed increased collagen fiber and cellularity than the controls. The levels of α-smooth muscle actin, p-GSK-3β, and β-catenin in the LF of the LSS group were significantly higher than that of the control group. There was a strong positive correlation between p-GSK-3β (Ser9) level and LF thickness in LSS patients (r=0.69, P= 0.01). Conclusion. This research proposes a molecular mechanism for the pathogenesis of LF hypertrophy in LSS. Specifically, GSK-3β/β-catenin signaling appears to be related to LF hypertrophy in LSS and a positive correlation exists between p-GSK-3β level and LF thickness. [ABSTRACT FROM AUTHOR]

Study Design.: We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL). Objective.: To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL. Summary of Background Data.: Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear. Methods.: Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors. Results.: Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9 , Runx2 , and SIRT1. In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front. Conclusions.: IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL. [ABSTRACT FROM AUTHOR]

Study Design: Sequencing and experimental analysis of the expression profile of circular RNAs (circRNAs) in hypertrophic ligamentum flavum (LFH).Objectives: The aim of this study was to identify differentially expressed circRNAs between LFH and nonhypertrophic ligamentum flavum tissues from lumbar spinal stenosis (LSS) patients.Summary Of Background Data: Hypertrophy of the ligamentum flavum (LF) can cause LSS. circRNAs are important in various diseases. However, no circRNA expression patterns related to LF hypertrophy have been reported.Methods: A total of 33 patients with LSS participated in this study. LF tissue samples were obtained when patients underwent decompressive laminectomy during surgery. The expression profile of circRNAs was analyzed by transcriptome high-throughput sequencing and validated with quantitative real-time polymerase chain reaction (PCR). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed for the differentially expressed circRNA-associated genes and related pathways. The connections between circRNAs and microRNAs were explored using Cytoscape. The role of hsa_circ_0052318 on LF cell fibrosis was assessed by analyzing the expression of collagen I and collagen III.Results: The results showed that 2439 circRNAs of 4025 were differentially expressed between the LFH and nonhypertrophic ligamentum flavum tissues, including 1276 upregulated and 1163 downregulated circRNAs. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these differentially expressed circRNAs functioned in biological processes, cellular components, and molecular functions. Autophagy and mammalian target of rapamycin were the top two signaling pathways affected by these circRNAs. Five circRNAs (hsa_circ_0021604, hsa_circ_0025489, hsa_circ_0002599, hsa_circ_0052318, and hsa_circ_0003609) were confirmed by quantitative real-time PCR. The network indicated a strong relationship between circRNAs and miRNAs. Furthermore, hsa_circ_0052318 overexpression decreased mRNA and protein expression of collagen I and III in LF cells from LFH tissues.Conclusion: This study identified circRNA expression profiles characteristic of hypertrophied LF in LSS patients, and demonstrated that hsa_circ_0052318 may play an important role in the pathogenesis of LF hypertrophy.Level of Evidence: N/A. [ABSTRACT FROM AUTHOR]

Study Design: Experimental animal study.Objective: The aim of this study was to clarify chronological effects of mechanical stress on ligamentum flavum (LF) using a long-term fusion rabbit model.Summary Of Background Data: LF hypertrophy is a major pathology of lumbar spinal stenosis (LSS), but its mechanism remains unclear. We previously demonstrated mechanical-stress-induced LF hypertrophy with a rabbit model. However, we only investigated LFs at a single time point in the short-term; the effects of long-term mechanical stress have not been elucidated.Methods: Eighteen-week-old male New Zealand White rabbits were randomly divided into two groups: the mechanical stress group underwent L2-3 and L4-5 posterolateral fusion and resection of the L3-4 supraspinal muscle, whereas the control group underwent only surgical exposure. Rabbits were sacrificed 16 and 52 weeks after the procedure. Axial specimens of LFs at L3-4 were evaluated histologically. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) was performed to assess the numbers of vessels and myofibroblasts.Results: In the mechanical stress group, LFs at the L3-4 level exhibited hypertrophy with elastic fiber disruption and cartilage matrix production at 16 and 52 weeks. A trend test indicated that mechanical stress induced LF hypertrophy, elastic fiber disruption, and cartilage matrix production in a time-dependent manner, with the lowest levels before treatment and the highest at 52 weeks. Immunostaining for α-SMA showed similar numbers of vessels in both groups, whereas the percentage of myofibroblasts was significantly larger at 16 and 52 weeks in the mechanical stress group than in the control group.Conclusion: We demonstrated that long-term mechanical stress caused LF hypertrophy with progressive elastic fiber disruption and cartilage matrix production accompanied by enhanced myofibroblasts. In addition, the reported rabbit model could be extended to elucidate the mechanism of LF hypertrophy and to develop new therapeutic strategies for LSS by preventing LF hypertrophy.Level of Evidence: SSSSS. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective cohort study.Objectives: To report the feasibility, nuances, technical tips as well as outcomes of managing single-level grade D (extreme stenosis) and to compare the outcomes with nonextreme stenosis using the tubular retractor system.Summary Of Background Data: Minimally invasive decompression in extreme stenosis is a challenge due to technical difficulty, feasibility of adequate decompression, and a steep learning curve.Methods: Consecutive patients from January 2007 to January 2017 presenting with neurogenic claudication secondary to single-level spinal stenosis operated using tubular retractors were included in the study. The patients were divided into two groups; extreme-stenosis and nonextreme stenosis. The outcomes of surgery were evaluated and compared using visual analogue score (VAS) for leg and back pain, Oswestry disability index (ODI), and MacNab's criteria.Results: A total of 325 patients (out of 446 patients after excluding the multilevel cases) fulfilled the inclusion criteria. One hundred forty patients were cases of extreme stenosis and 185 were nonextreme stenosis. The mean VAS for back and leg pain for extreme stenosis improved from 3.23 ± 1.30 to 2.15 ± 0.91 and 7.33 ± 0.78 to 1.66 ± 1.03 respectively as compared with nonextreme stenosis where the mean VAS for back and leg pain improved from 3.01 ± 1.15 to 1.86 ± 1.10 and 6.57 ± 1.00 to 1.54 ± 1.12 respectively. The mean ODI changed from 66.47 ± 7.53 to 19.95 ± 2.90 in extreme stenosis as compared with nonextreme stenosis where mean ODI changed from 59.05 ± 5.08 to 19.88 ± 2.67. As per MacNab's criteria 102 (of 120 patients) and 139 (of 157 patients) reported excellent and good outcomes in extreme and nonextreme stenosis respectively.Conclusion: Tubular decompression is feasible in patients with extreme-stenosis with no difference in the outcomes as well as complication rates when compared with a cohort of nonextreme stenosis.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Study Design. Case-control study of an animal model. Objective. To investigate the factors that are upregulated and potentially related to degenerative changes in the ligamentum flavum (LF) upon mechanical stress concentration. Summary of Background Data. LF hypertrophy is reported to be associated with mechanical stress. However, few studies, using exhaustive analysis with control subjects, on the molecular mechanisms of LF hypertrophy have been published. Methods. Fourteen rabbits were used for this study. The first group underwent L2-3 and L4-5 posterolateral fusion with instrumentation and resection of the L3-4 supraspinal muscle to concentrate the mechanical stress on L3-4, whereas the other group underwent a sham operation. The deep layer of the LF from L2-3 to L4-5 in both groups was harvested after 16 weeks. Gene expression was evaluated exhaustively using DNA microarray and real-time polymerase chain reaction (RT-PCR). Fibroblast growth factor 9 (FGF9) protein expression was subsequently examined by immunohistological staining. Results. A total of 680 genes were found to be upregulated upon mechanical stress concentration and downregulated upon mechanical shielding compared with those in the sham group. Functional annotation analysis revealed that these genes not only included those related to the extracellular matrix but also those related to certain FGF families. On RT-PCR validation and immunohistological analysis, we identified that the FGF9 protein increases in the LF upon mechanical stress, especially in the area wherein degenerative changes were frequently identified in the previous literature. Conclusion. FGF9 and its pathway are suggested to contribute to the degenerative changes in the LF following mechanical stress. This finding will be helpful in further understanding the molecular mechanism of human LF degeneration. Level of Evidence: N/A [ABSTRACT FROM AUTHOR]

Study Design: Cross-sectional study.Objective: To investigate if adding a lumbar pillow in supine position during magnetic resonance imaging (MRI) is superior to standing positional MRI for diagnosing lumbar spinal stenosis (LSS).Summary Of Background Data: The upright standing position and especially extension of the lumbar spine seem to worsening symptoms of LSS. However, it is unclear whether a forced lumbar extension by a pillow in the lower back during conventional supine MRI may improve the diagnostics of LSS compared with standing MRI.Methods: Patients suspected for LSS and referred to conventional MRI were included to an additional positional MRI scan (0.25T G-Scan) performed in: (1) conventional supine, (2) standing, (3) supine with a lumbar pillow in the lower back. LSS was evaluated for each position in consensus on a 0 to 3 semi-quantitative grading scale. Independently, L2-S1 lordosis angle, spinal cross-sectional diameter (SCSD), dural cross-sectional diameter (DCSD), and dural cross-sectional diameter (DCSA) were measured. The smallest dural diameter was defined as stenosis level and the largest control level for comparison.Results: Twenty-seven patients (60.6 years; ±9.4) were included. The lordosis angle increased significantly from supine to standing (3.2° CI: 1.2-5.2) and with the lumbar pillow (12.8° CI: 10.3-15.3). One-way analysis of variance (ANOVA) showed significant differences between positions (P < 0.001). When compared with the supine position, pairwise comparisons showed decreased SCSD, DCSD, DCSA, and increasing semi-quantitative grading, during both standing and supine with the lumbar pillow. A difference in the semi-quantitative grades was only found between standing and supine with a lumbar pillow, and the scan with a lumbar pillow was significantly more painful.Conclusion: Standing MRI and supine MRI with a lumbar pillow resulted in equal changes in the lumbar spine, although standing MRI may be more sensitive in the assessment of patients suspected for LSS.Level Of Evidence: 2. [ABSTRACT FROM AUTHOR]

Study Design: Longitudinal case-control animal model.Objective: To investigate effects of mesenchymal stem cell (MSC) treatment on multifidus muscle remodeling after intervertebral disc (IVD) lesion.Summary Of Background Data: Lesion and degeneration of IVDs cause structural remodeling of the multifidus muscle. Proinflammatory cytokines are thought to contribute. MSC treatment restores IVD health after lesion but its effects on surrounding tissues remains unknown. Using an animal model of IVD degeneration, we assessed the effects of MSC treatment of IVDs on the structural remodeling and cytokine expression within the multifidus muscle.Methods: An anterolateral lesion was performed on the L1-2, L3-4, and L5-6 IVDs in sheep. At either 4 (early treatment) or 12 (late treatment) weeks after IVD lesion, MSCs were injected into the lesioned IVD. Multifidus muscle was harvested from L2 (gene expression analysis) and L4 (histological analysis) at 3 or 6 months after IVD lesion and naïve controls for histological analysis of muscle, adipose, and connective tissue cross-sectional areas, and immunohistochemistry to study muscle fiber types. Real-time polymerase chain reactions quantified expression of tumor necrosis factor, interleukin-1β, and transforming growth factor-β1.Results: MSC treatment of IVD lesion prevented the increased adipose and connective tissue cross-sectional area expected after IVD lesion. MSC treatment did not prevent slow-to-fast muscle fiber type transformation. Gene expression of proinflammatory cytokines within the muscle was altered by the MSC treatment of IVD. Increased interleukin-1β expression was prevented in the early treatment group and tumor necrosis factor and transforming growth factor-β1 expression was upregulated at 6 months.Conclusion: Results show that although MSC treatment prevents fatty infiltration and fibrosis of the multifidus muscle after IVD lesion, it cannot prevent a muscle inflammatory response and muscle fiber transformation. These findings highlight the potential role of MSC therapy after IVD injury, but reveals that other interventions may also be necessary to optimize recovery of muscle.Level Of Evidence: 4. [ABSTRACT FROM AUTHOR]

Study Design: A study of lumbar ligamentum flavum (LF).Objective: The aim of this study was to identify LF hypertrophy related microRNAs (miRNAs) expression profile and to investigate the role of miRNAs in the development of LF hypertrophy in lumbar spinal stenosis (LSS).Summary Of Background Data: Although histologic and biologic literature on LF hypertrophy is available, the pathomechanism is still unknown. Accumulating evidence suggests that microRNAs (miRNAs) participate in many physiologic processes, including cell proliferation, differentiation, and fibrosis, but the role of specific miRNAs involved in LF hypertrophy remains elusive.Methods: An initial screening of LF tissues miRNA expression by miRNA microarray was performed using samples from 10 patients and 10 controls, respectively. Subsequently, differential expression was validated using qRT-PCR. Then, functional analysis of the miRNAs in regulating collagens I and III expression was carried out. Western blotting and luciferase reporter assay were also used to detect the target gene. In addition, the thickness of the LF at the level of the facet joint was measured on axial T1-weighted magnetic resonance images.Results: We identified 18 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR-221 was significantly lower in LF tissues of patients than controls. The LF was significantly thicker in patients than that in controls. Bioinformatics target prediction identified tissue inhibitors of matrix metalloproteinase (TIMP)-2 as a putative target of miR-221. Furthermore, luciferase reporter assays demonstrated that miR-221 directly targets TIMP-2 and affects the protein expression of TIMP-2 in fibroblasts isolated from LF. Of note, miR-221 mimic reduced mRNA and protein expression of collagens I and collagen III in fibroblasts isolated from LF.Conclusion: The downregulation of miR-221 might contribute to LF hypertrophy by promoting collagens I and III expression via the induction of TIMP-2. Our study also underscores the potential of miR-221 as a novel therapeutic target in LSS.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Study Design. A histological, biological, and immunohistochemical study of human lumbar ligamentum flavum. Objective. To analyze changes in the hypertrophied ligamentum flavum and clarify their etiology. Summary of Background Data. Hypertrophy of the ligamentum flavum has been considered a major contributor to the development of lumbar spinal canal stenosis (LSCS). Although previous studies have reported some factors related to ligamentum flavum hypertrophy, its etiology is still unclear. Methods. Ligamentum flavum samples were collected from 20 patients with LSCS (LSCS group) and 10 patients with lumbar disc herniation (LDH group) as a control. The thickness of the ligamentum flavum was measured histologically. The amounts of elastic fibers and proteoglycans were assessed by Elastica-Masson staining and alcian blue staining, respectively. Gene and protein expressions related to fibrosis, inflammation, and chondrogenesis were analyzed by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The total genes of the 2 groups were compared by DNA microarray analysis. Results. The ligamentum flavum was significantly thicker in the LSCS group, which had a smaller amount of elastic fibers and a larger amount of proteoglycans. The gene expression related to fibrosis was significantly higher in the LSCS group; however, the immunoreactivities of collagen types I and III were weaker on the dorsal side of the ligamentum flavum in the LSCS group. The gene expression related to chondrogenesis and proteoglycan synthesis was significantly higher in the LSCS group. There was no significant difference in the gene expression related to inflammation between the 2 groups. Conclusion. Synthesis of the collagenous fibers and degradation of the elastic and collagenous fibers are both accelerated in the ligamentum flavum of patient with LSCS, which may be the reason for hypertrophy of the tissue. In addition, chondrogenesis and proteoglycan synthesis may have critical roles in the pathogenesis of the ligamentum flavum hypertrophy. [ABSTRACT FROM AUTHOR]

The article discusses the study that examines the Spine Patient Outcomes Research Trial lumbar stenosis observational cohort for the determination of baseline patient characteristics that predict the type of treatment to be chosen by patients. The analysis showed that patients who chose surgery were younger, experienced worse bodily pain (BP), worse physical function, worse Oswerty Disability Index (ODI), and worse Stenosis Bothersomeness Index, as well as those who had lateral recess stenosis.

The article presents a study which examines the impact of prolonged and repeated upright posture on the cartilage end plate of the lumbar vertebrae of rats. The study utilized 30 rats which were amputated to stand upright on their hind-limbs and were killed at 5, 7, and 9 months after the surgery to harvest their lumbar vertebrae samples for analysis. The study found that prolonged upright posture causes cartilage end plate calcification and hypertrophy in the lumbar spine of the rats.

The article determines the effect of posterior spinal fusion on paraspinal muscle by means of electrophysiological and histologic evaluation, using a rabbit model. The results have demonstrated that spinal fusion resultedin atrophy and reduced adjacent paraspinal muscle activity. The article shows that muscular activity was greater in the adjacent regions after spinal fusion, which may indicate muscle hypertrophy.

The article presents a study which investigates the pathomechanism of loss of elasticity and hypertrophy of the lumbar ligamentum flavum (LF) using biologic and histologic assessment in elderly patients with lumbar spinal canal stenosis. It founds that the decreased elasticity of LF is due to the loss of elastic fibers and increase of collagenous fibers in the dorsal aspect. LF hypertrophy, it notes, is due to the thickening of the normal elastic layer and of the abnormal collagenous layer.