Published papers

Background: Postoperative shoulder imbalance (PSI) has a negative impact on the surgical outcomes of patients with adolescent idiopathic scoliosis. This study aimed to evaluate the risk factors of PSI in patients with Lenke type 5C curves. Methods: This study included 100 patients who underwent posterior correction surgery using pedicle screw constructs for Lenke type 5C curves. The mean age of the patients at surgery was 15.5 ± 2.3 years, and the mean follow-up period was 36.6 ± 15.0 months. The subjects were classified into the following two groups: PSI and non-PSI. Radiographic parameters, including the preoperative and 2-year postoperative coronal and sagittal profiles, were compared between the two groups. Result: PSI was found in eight patients (8.0%). The preoperative Cobb angles were 47.3° ± 8.7° and 48.0° ± 3.9° in the non-PSI and PSI groups, respectively. The correction rate in the PSI group was significantly higher than that in the non-PSI group (81.0% ± 17.7% vs. 67.7% ± 14.7%; p = 0.018). The preoperative T1 tilt angle in the PSI group was significantly larger than that in the non-PSI group (6.1° ± 3.3° vs. 3.1° ± 2.8°; p = 0.005). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.769 (p = 0.012, 95% confidence interval [CI], 0.556–0.982) and 0.763 (p = 0.014, 95% CI, 0.598–0.928) for the correction rate and preoperative T1 tilt, respectively. The cut-off value was 73% and 4° for the correction rate and preoperative T1, respectively. Conclusion: PSI was found in 8.0% of Lenke type 5C curves. Excessive correction of the lumbar curve of >73% and preoperative T1 tilt of >4° can be risk factors for PSI in patients with Lenke type 5C curve.

© 2018 Wolters Kluwer Health, Inc. All rights reserved. Study Design. Case-only study. Objective. The aim of this study was to confirm the association of rs11190870 with adolescent idiopathic scoliosis (AIS) severity in Japanese patients with AIS. Summary of Background Data. Although the association of rs11190870 with AIS susceptibility is replicated in multiple ethnics, the association of rs11190870 with curve severity is controversial. Since the previous studies are of small, we performed a replication study using far larger number of patients than previous studies. Methods. A total of 1860 Japanese patients with AIS who had reached skeletal maturity or undergone surgical fusion were included in the study. We evaluated the association between rs11190870 and AIS progression for the entire group, and then for patients grouped according to a severe curve (a Cobb angle of ≥40°) or mild curve (a Cobb angle <30°). Because braces could affect the results of the present study, patients in the mild-curve group were divided according to whether or not they had worn a brace. We then evaluated associations between rs11190870 genotype and curve severity in these groups. Results. The mean Cobb angles were 54.8° ± 12.1° in the severe-curve group and 24.4° ± 4.0° in the mild-curve group. The difference in rs11190870 risk-allele frequency between the severe- and mild-curve groups was evaluated. No significant differences were observed. We then examined the association of rs11190870 risk-allele frequency between patients in the mild- and severe-curve groups using the χ 2 test for three models, and found a marginal association between rs11190870 and curve severity in the dominant model (P = 0.035, odds ratio = 1.51). Conclusion. We found no association between rs11190870 and curve severity using the criteria of previous study. However, we found a marginal association between rs11190870 and curve severity. Large-scale replication studies that consider skeletal maturity and brace history, including replication studies in other ethnic groups, would be helpful for clarifying the association. Level of Evidence: 4.

© 2017, Springer-Verlag GmbH Germany. Purpose: Information about the cost-effectiveness of surgical procedures for adult spinal deformity (ASD) is critical for providing appropriate treatments for these patients. The purposes of this study were to compare the direct cost and cost-effectiveness of surgery for ASD in the United States (US) and Japan (JP). Methods: Retrospective analysis of 76 US and 76 JP patients receiving surgery for ASD with ≥2-year follow-up was identified. Data analysis included preoperative and postoperative demographic, radiographic, health-related quality of life (HRQOL), and direct cost for surgery. An incremental cost-effectiveness ratio (ICER) was determined using cost/quality-adjusted life years (QALY). The cost/QALY was calculated from the 2-year cost and HRQOL data. Results: JP exhibited worse baseline spinopelvic alignment than the US (pelvic incidence and lumbar lordosis: 35.4° vs 22.7°, p OpenSPiltSPi 0.01). The US had more three-column osteotomies (50 vs 16%), and shorter hospital stay (7.9 vs 22.7 days) (p OpenSPiltSPi 0.05). The US demonstrated worse postoperative ODI (41.3 vs. 33.9%) and greater revision surgery rate (40 vs 10%) (p OpenSPiltSPi 0.05). Due to the high initial cost and revision frequency, the US had greater total cost ($92,133 vs. $49,647) and cost/QALY ($511,840 vs. $225,668) at 2-year follow-up (p OpenSPiltSPi 0.05). Conclusion: Retrospective analysis comparing the direct costs and cost-effectiveness of ASD surgery in the US vs JP demonstrated that the total direct costs and cost/QALY were substantially higher in the US than JP. Variations in patient cohort, healthcare costs, revision frequencies, and HRQOL improvement influenced the cost/QALY differential between these countries.

© 2018, The Author(s). Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity and has a significant genetic background. Genome-wide association studies (GWASs) identified several susceptibility loci associated with AIS. Among them is a locus on chromosome 6q24.1 that we identified by a GWAS in a Japanese cohort. The locus is represented by rs6570507 located within GPR126. To ensure the association of rs6570507 with AIS, we conducted a meta-analysis using eight cohorts from East Asia, Northern Europe and USA. The analysis included a total of 6,873 cases and 38,916 controls and yielded significant association (combined P = 2.95 × 10 −20 ; odds ratio = 1.22), providing convincing evidence of the worldwide association between rs6570507 and AIS susceptibility. In silico analyses strongly suggested that GPR126 is a susceptibility gene at this locus.

© 2018 The Japanese Orthopaedic Association Background: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC. Methods: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC. Results: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area. Conclusions: We established an effective screening method based on physical examinations and MRI findings.

CASE: A 74-year-old woman presented with severe trunk deformity. Radiographs revealed severe sagittal and coronal imbalance with spinal canal stenosis at L4 to L5. Anterior cages were placed at L2 to L3, L3 to L4, and L4 to L5. Three days later, posterior correction surgery from T5 to the ilium with decompression at L4 to L5 was performed. At 30 minutes after surgery, leg muscle strength severely deteriorated. Emergency surgery revealed disc fragments protruding into the spinal canal at L2 to L3. CONCLUSION: Because posteriorly placed extreme lateral interbody fusion (XLIF) cages can be a risk factor for disc protrusion into the spinal canal, computed tomographic evaluation or prophylactic posterior decompression should be considered before the correction procedure.

© BMJ Publishing Group Limited 2018. A 23-year-old man presented with difficulty walking and leg pain and numbness. MRI revealed a cystic mass at Th11-12 and a pineal-region tumour. The patient underwent surgery to resect the thoracic-level mass. The tumour adhered strongly to the neural tissue and could only be partially resected. On pathological examination, the resected tumour was diagnosed as a mature teratoma. The tumour regrew and disseminated within 3 months after resection. Both the spinal cord tumour and the tumour in the pineal region shrank significantly after chemotherapy and radiotherapy. Although the tumour was pathologically diagnosed as a mature teratoma, we suspect that the residual tumour contained an immature or malignant component. Thus, careful follow-up observation is mandatory after partial resection of a mature teratoma. In addition, because teratomas can disseminate in the central nervous system, the presence of teratoma should prompt an examination of both the spinal cord and brain.

© 2018 The Author(s). Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-Analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 × 10 -18 (odds ratio = 1.19, 95% confidence interval = 1.14-1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. Methods: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. Results: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Conclusions: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis. Controlling its curve progression is the most important clinical task. Although recent genome-wide association studies (GWASs) identified several susceptibility loci associated with the development of AIS, the etiology of curve progression has been still unknown. Our previous GWAS has identified that rs12946942 showed significant association with severe AIS. To confirm the association, we conducted an international meta-analysis using four cohorts with different ethnicity. We analyzed 2272 severe AIS cases and 13,859 controls in total, and found the replication of significant association of rs12946942 (combined P = 7.23×10 −13 ; odds ratio = 1.36, 95% confidence interval = 1.25−1.49). In silico analyses suggested that SOX9 is the most likely susceptibility gene for AIS curve progression in the locus.

The use of artificial intelligence (AI) as a tool supporting the diagnosis and treatment of spinal diseases is eagerly anticipated. In the field of diagnostic imaging, the possible application of AI includes diagnostic support for diseases requiring highly specialized expertise, such as trauma in children, scoliosis, symptomatic diseases, and spinal cord tumors. Moiré topography, which describes the 3-dimensional surface of the trunk with band patterns, has been used to screen students for scoliosis, but the interpretation of the band patterns can be ambiguous. Thus, we created a scoliosis screening system that estimates spinal alignment, the Cobb angle, and vertebral rotation from moiré images. In our system, a convolutional neural network (CNN) estimates the positions of 12 thoracic and 5 lumbar vertebrae, 17 spinous processes, and the vertebral rotation angle of each vertebra. We used this information to estimate the Cobb angle. The mean absolute error (MAE) of the estimated vertebral positions was 3.6 pixels (~5.4 mm) per person. T1 and L5 had smaller MAEs than the other levels. The MAE per person between the Cobb angle measured by doctors and the estimated Cobb angle was 3.42°. The MAE was 4.38° in normal spines, 3.13° in spines with a slight deformity, and 2.74° in spines with a mild to severe deformity. The MAE of the angle of vertebral rotation was 2.9° ± 1.4°, and was smaller when the deformity was milder. The proposed method of estimating the Cobb angle and AVR from moiré images using a CNN is expected to enhance the accuracy of scoliosis screening.

Background: Although diffuse idiopathic skeletal hyperostosis (DISH) is known to coexist with the ossification of spinal ligaments (OSLs), details of the radiographic relationship remain unclear. Methods: We prospectively collected data of 239 patients with symptomatic cervical ossification of the posterior longitudinal ligament (OPLL) and analyzed the DISH severity on whole-spine computed tomography images, using the following grades: grade 0, no DISH; grade 1, DISH at T3–T10; grade 2, DISH at both T3–T10 and C6–T2 and/or T11–L2; and grade 3, DISH beyond C5 and/or L3. Ossification indices were calculated as the sum of vertebral and intervertebral levels with OSL for each patient. Results: DISH was found in 107 patients (44.8%), 65 (60.7%) of whom had grade 2 DISH. We found significant associations of DISH grade with the indices for cervical OPLL (r = 0.45, p < 0.0001), thoracic ossification of the ligamentum flavum (OLF; r = 0.41, p < 0.0001) and thoracic ossification of the supra/interspinous ligaments (OSIL; r = 0.53, p < 0.0001). DISH grade was also correlated with the index for each OSL in the whole spine (OPLL: r = 0.29, p < 0.0001; OLF: r = 0.40, p < 0.0001; OSIL: r = 0.50, p < 0.0001). Conclusion: The DISH grade correlated with the indices of OSL at each high-prevalence level as well as the whole spine.

Study Design.Genetic case-control study of single nucleotide polymorphisms (SNPs).Objective.To examine the association of previously reported susceptibility genes for adolescent idiopathic scoliosis (AIS) and intervertebral disc (IVD) degeneration with adult spinal deformity (ASD).Summary of Background Data.ASD is a spinal deformity that develops and progresses with age. Its etiology is unclear. Several ASD susceptibility genes were recently reported using a candidate gene approach; however, the sample sizes were small and associations with ASD development were not determined.Methods.ASD was defined as structural scoliosis with a Cobb angle more than 15° on standing radiographs, taken of patients at age 40 to 75 years in this study. Subjects in whom scoliosis was diagnosed before age 20 were excluded. We recruited 356 Japanese ASD subjects and 3341 healthy controls for case-control association studies of previously reported SNPs. We genotyped four known AIS-associated SNPs (rs11190870 in LBX1, rs6570507 in GPR126, rs10738445 in BNC2, and rs6137473 in PAX1) and three IVD degeneration-associated SNPs (rs1245582 in CHST3, rs2073711 in CILP, and rs1676486 in COL11A1) by the Invader assay.Results.Among the AIS-associated SNPs, rs11190870 and rs6137473 showed strong and nominal associations with ASD (P=1.44×10-4, 1.00×10-2, respectively). Of the IVD degeneration-associated SNPs, rs1245582 and rs2073711 showed no association with ASD, while rs1676486 showed a nominal association (P=1.10×10-2). In a subgroup analysis, rs11190870 was significantly associated with a Cobb angle more than 20° in the minor thoracic curve (P=1.44×10-4) and with a left convex lumbar curve (P=6.70×10-4), and nominally associated with an apical vertebra higher than L1 (P=1.80×10-2).Conclusion.rs11190870 in LBX1, a strong susceptibility SNP for AIS, may also be a susceptibility SNP for ASD. Thus, ASD and AIS may share a common genetic background.Level of Evidence: 4.

Background: This study investigated how diffuse idiopathic skeletal hyperostosis (DISH) influences clinical characteristics in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Although DISH is considered unlikely to promote neurologic dysfunction, this relationship remains unclear. Methods: Patient data were prospectively collected from 16 Japanese institutions. In total, 239 patients with cervical OPLL were enrolled who had whole-spine computed tomography images available. The primary outcomes were visual analog scale pain scores and the results of other self-reported clinical questionnaires. Correlations were sought between clinical symptoms and DISH using the following grading system: 1, DISH at T3-T10; 2, DISH at both T3–10 and C6–T2 and/or T11–L2; and 3, DISH beyond the C5 and/or L3 levels. Results: DISH was absent in 132 cases, grade 1 in 23, grade 2 in 65, and grade 3 in 19. There were no significant correlations between DISH grade and clinical scores. However, there was a significant difference in the prevalence of neck pain (but not in back pain or low back pain) among the three grades. Interestingly, DISH localized in the thoracic spine (grade 1) may create overload at the cervical spine and lead to neck pain in patients with cervical OPLL. Conclusion: This study is the first prospective multicenter cross-sectional comparison of subjective outcomes in patients with cervical OPLL according to the presence or absence of DISH. The severity of DISH was partially associated with the prevalence of neck pain.

This study aimed to clarify whether ossification predisposition influences clinical symptoms including pain, restriction of activities of daily living, and quality of life in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Cervical ossification predisposition potentially causes neurologic dysfunction, but the relationship between clinical symptoms and radiologic severity of OPLL has not yet been investigated. Data were prospectively collected from 16 institutions across Japan. We enrolled 239 patients with cervical OPLL. The primary outcomes were patient-reported outcomes, including visual analog scale (VAS) pain scores and other questionnaires. Whole-spine computed tomography images were obtained, and correlations were investigated between clinical symptoms and radiologic findings, including the distribution of OPLL, the sum of the levels where OPLL was present (OP-index), and the canal narrowing ratio (CNR) grade. The cervical OP-index was Grade 1 in 113 patients, Grade 2 in 90, and Grade 3 in 36. No significant correlations were found between radiologic outcomes and VAS pain scores. The cervical OP-index was associated with lower extremity function, social dysfunction, and locomotive function. The CNR grade was not correlated with clinical symptoms, but Grade 4 was associated with lower extremity dysfunction. Thickness and extension of ossified lesions may be associated with lower extremity dysfunction in cervical OPLL.

Study design: Retrospective multicenter study. Objectives: To identify the usefulness of the baseline severity of myelopathy for predicting surgical outcomes for cervical spondylotic myelopathy (CSM). Setting: Seventeen institutions in Japan. Methods: This study included 675 persons with CSM who underwent posterior decompression. According to baseline severity, the individuals were divided into the mild (Japanese Orthopaedic Association [JOA] score ≥ 14.5), moderate (JOA score = 10.5–14), and severe (JOA score ≤ 10) groups. Surgical outcomes and clinical variables were compared between the groups. Logistic regression analysis was used to develop a prediction model for unsatisfactory symptom state (postoperative JOA score ≤ 14, residual moderate or severe myelopathy). Results: The mean (±standard deviation) age was 67 ± 12 years. The participants in the severe group were older than those in the mild group. Postoperative JOA scores were higher in the mild group than in the severe group. According to multivariate logistic regression analysis, the prediction model included preoperative JOA scores (odds ratio [OR] 0.60; 95% confidence interval [CI] 0.55–0.67) and age (OR 1.06, 95% CI 1.04–1.08). On the basis of the model, a representative combination of the thresholds to maximize the value of “sensitivity − (1 − specificity)” demonstrated a preoperative JOA score of 11.5 as a predictor of postoperative unsatisfactory symptom state in people around the mean age of the study cohort (67 years). Conclusions: The combination of the baseline severity of myelopathy and age can predict postoperative symptom states after posterior decompression surgery for CSM.

Study Design.A retrospective study of consecutive collected data.Objective.To investigate risk factors for postoperative distal adding-on (DA) in Lenke Type 1B and 1C curves using intraoperative radiographs.Summary of Background Data.In adolescent idiopathic scoliosis (AIS), DA radiographic complication can negatively affect postoperative clinical results. However, few studies have focused on assessing risk factors for DA using intraoperative radiographs.Methods.We retrospectively evaluated 69 AIS patients with Lenke Type 1B or 1C curves who underwent posterior selective thoracic fusion. We divided patients into DA and non-DA groups based on radiograph data at 2-year follow-up using Wang et al (Spine 2011) definition of DA. We compared coronal radiographic parameters, including relative positions of end vertebra (EV), stable vertebra (SV), neutral vertebra (NV), and last touching vertebra (LTV) to lowest instrumented vertebra (LIV), and intraoperative radiographic parameters, between the two groups.Results.DA was present in 13 patients (18.8%) at 2-year follow-up. The mean LIV-EV, LIV-NV, LIV-SV, and LIV-LTV relative positions were significantly smaller in the DA group than in the non-DA group. Multivariate analysis showed that LIV-LTV was significantly associated with DA (DA: -0.2 ± 0.7, non-DA: 0.6 ± 0.7). Intraoperative radiographs showed that the mean angulation of the first disc below the LIV after final adjustment was significantly larger in the DA group (2.3° ± 1.1°) than in the non-DA group (0.9° ± 0.7°). Patients whose angulation of the first disc below the LIV was more than 3° were significantly associated with DA.Conclusion.The LIV selected at more cranial to the LTV may be a risk factor for postoperative DA in Lenke Type 1B and 1C curves. Moreover, it was suggested that LIV extension might be considered when the first disc's angulation below the LIV is >3° in intraoperative radiographs.Level of Evidence: 3.

Introduction: Intramedullary metastasis of Ewing sarcoma is extremely rare. Here, we report an adult case of cervical intramedullary recurrent Ewing sarcoma after a 10-year disease-free survival after the initial surgery for a thoracic lesion. Case presentation: A 39-year-old man with a history of surgery and chemoradiotherapy for thoracic Ewing sarcoma ten years ago presented with neck pain and incomplete motor paralysis in the right upper extremity, which had suddenly appeared three months before. Cervical magnetic resonance imaging revealed a tear-drop-shaped intramedullary lesion at the C3 level accompanied by diffuse edematous change. Because of the rapid progression of his myelopathy, he underwent surgery for this intramedullary lesion. Intraoperatively, the tumor exhibited an orangish exophytic appearance. The unclearness of the tumor boundary compelled us to perform a partial resection. The histopathology showed the tumor comprised small round atypical cells with immunoreactivity for Nkx2.2 and CD99, diagnosing a metastatic Ewing sarcoma. Postoperatively, although his myelopathy improved transiently and adjuvant chemotherapy radiation was undergone, he died of cranial dissemination of the tumor two months and a half later. Discussion: To our knowledge, 31 cases of primary and only 4 cases of recurrent intramedullary spinal Ewing sarcoma have been reported to date; however, this is the first case of recurrent intramedullary Ewing sarcoma with a 10-year disease-free survival. Sadly, the prognosis of the current case was extremely poor. There is no clear treatment guideline for recurrent intramedullary Ewing sarcoma because of its rarity, and further collection of similar cases would be required.