Outcome of intradiscal condoliase injection therapy for patients with recurrent lumbar disc herniation.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to compare data from patients who received intradiscal condoliase (chondroitin sulfate ABC endolyase) injection for primary lumbar disc herniation (LDH) and recurrent LDH. OVERVIEW OF LITERATURE: Chemonucleolysis with condoliase for LDH is a treatment with relatively good results and a high safety profile; however, few studies have reported recurrence after LDH surgery. METHODS: The study participants were 249 patients who underwent intradiscal condoliase injection for LDH at nine participating institutions, including 241 patients with initial LDH (group C) and eight with recurrent LDH (group R). Patient characteristics including age, sex, body mass index, disease duration, intervertebral LDH level, smoking history, and diabetes history were evaluated. Low back pain/leg pain Numerical Rating Scale (NRS) scores and the Oswestry Disability Index (ODI) were used to evaluate clinical symptoms before treatment and at 6 months and 1 year after treatment. RESULTS: Low back pain NRS scores (before treatment and at 6 months and 1 year after treatment, respectively) in group C (4.9 → 2.6 → 1.8) showed significant improvement until 1 year after treatment. Although a tendency for improvement was observed in group R (3.5 → 2.8 → 2.2), no significant difference was noted. Groups C (6.6 → 2.4 → 1.4) and R (7.0 → 3.1 → 3.2) showed significant improvement in the leg pain NRS scores after treatment. Group C (41.4 → 19.5 → 13.7) demonstrated significant improvement in the ODI up to 1 year after treatment; however, no significant difference was found in group R (35.7 → 31.7 → 26.4). CONCLUSIONS: Although intradiscal condoliase injection is less effective for LDH recurrence than for initial cases, it is useful for improving leg pain and can be considered a minimally invasive and safe treatment method.

Patient-Reported Outcomes and Patient Satisfaction Following Surgery for Thoracic Myelopathy.

Introduction: The association between postoperative patient-reported outcomes (PROs) and patient satisfaction remains poorly defined in patients undergoing surgery for thoracic myelopathy. This study aimed to investigate PROs and patient satisfaction following surgical intervention for thoracic myelopathy. Methods: A prospective cohort of 133 patients who underwent surgery for thoracic myelopathy at 13 hospitals between April 2017 and August 2021 was enrolled. Patient demographics and perioperative complications were recorded. PROs were assessed using questionnaires administered preoperatively and 1 year postoperatively, including the EuroQol-5 dimension, physical and mental component summaries of the 12-item Short-Form Health Survey, Oswestry Disability Index, and numerical rating scales for low back, lower extremity, and plantar pain. Patients were categorized into two groups: satisfied (very satisfied, satisfied, and slightly satisfied) and dissatisfied (neither satisfied nor dissatisfied, slightly dissatisfied, dissatisfied, and very dissatisfied). Results: The mean age of the patients was 66.5 years, comprising 87 men and 46 women. The most common diagnoses were ossification of the ligamentum flavum (48.8%) and thoracic spondylotic myelopathy (26.3%). Seventy-four (55.6%) and 59 (44.3%) patients underwent decompression surgery and underwent decompression with fusion, respectively. Eight patients required reoperation due to postoperative surgical site infection, hematoma, and insufficient decompression in four, three, and one patient. Ninety (67.7%) patients completed both the preoperative and postoperative PRO questionnaires, all of which demonstrated significant improvement. Among them, 58 (64.4%) and 32 (35.6%) reported satisfaction and dissatisfaction with their treatment, respectively. The satisfied group showed superior improvement in PROs than the dissatisfied group, although there were no significant differences in complication rates between the two groups. Conclusions: The 64.4% satisfaction rate observed in patients undergoing surgery for thoracic myelopathy was lower than that reported in previous studies on cervical or lumbar spine surgery. The dissatisfied group exhibited significantly poorer quality of life (QOL) and higher pain scores than the satisfied group.

Comparison of surgical outcomes for cervical radiculopathy by nerve root level.

Cervical radiculopathy might affect finger movement and dexterity. Postoperative features and clinical outcomes comparing C8 radiculopathies with other radiculopathies are unknown. This prospective multicenter study analyzed 359 patients undergoing single-level surgery for pure cervical radiculopathy (C5, 48; C6, 132; C7, 149; C8, 30). Background data and pre- and 1-year postoperative neck disability index (NDI) and numerical rating scale (NRS) scores were collected. The C5-7 and C8 radiculopathy groups were compared after propensity score matching, with clinical significance determined by minimal clinically important differences (MCID). Postoperative arm numbness was significantly higher than upper back or neck numbness, and arm pain was reduced the most (3.4 points) after surgery among the C5-8 radiculopathy groups. The C8 radiculopathy group had worse postoperative NDI scores (p = 0.026), upper back pain (p = 0.042), change in arm pain NRS scores (p = 0.021), and upper back numbness (p = 0.028) than the C5-7 group. NDI achieved MCID in both groups, but neck and arm pain NRS did not achieve MCID in the C8 group. In conclusion, although arm numbness persisted, arm pain was relieved after surgery for cervical radiculopathy. Patients with C8 radiculopathy exhibited worse NDI and change in NRS arm pain score than those with C5-7 radiculopathy.

Post-operative shift in pain profile following fusion surgery for adult spinal deformity: a cluster analysis.

PURPOSE: Adult spinal deformity (ASD) is associated with a combination of back and leg pain of various intensities. The objective of the present study was to investigate the diverse reaction of pain profiles following ASD surgery as well as post-operative patient satisfaction. METHODS: Multicenter surveillance collected data for patients ≥ 19 years old who underwent primary thoracolumbar fusion surgery at > 5 spinal levels for ASD. Two-step cluster analysis was performed utilizing pre-operative numeric rating scale (NRS) for back and leg pain. Radiologic parameters and patient-reported outcome (PRO) scores were also obtained. One-year post-operative outcomes and satisfaction rates were compared among clusters, and influencing factors were analyzed. RESULTS: Based on cluster analysis, 191 ASD patients were categorized into three groups: ClusterNP, mild pain only (n = 55); ClusterBP, back pain only (n = 68); and ClusterBLP, significant back and leg pain (n = 68). ClusterBLP (mean NRSback 7.6, mean NRSleg 6.9) was the oldest 73.4 years (p < 0.001) and underwent interbody fusion (88%, p < 0.001) and sacral/pelvic fixation (69%, p = 0.001) more commonly than the other groups, for the worst pelvis incidence-lumbar lordosis mismatch (mean 43.7°, p = 0.03) and the greatest sagittal vertical axis (mean 123 mm, p = 0.002). While NRSback, NRSleg and PRO scores were all improved postoperatively in ClustersBP and BLP, ClusterBLP showed the lowest satisfaction rate (80% vs. 80% vs. 63%, p = 0.11), which correlated with post-operative NRSback (rho = -0.357). CONCLUSIONS: Cluster analysis revealed three clusters of ASD patients, and the cluster with the worst pain back and leg pain had the most advanced disease and showed the lowest satisfaction rate, affected by postoperative back pain.

Evaluation of crankshaft phenomenon after posterior fusion for early onset scoliosis using an inverse trigonometric function: a multicenter retrospective cohort study.

PURPOSE: The crankshaft phenomenon (CSP) is a corrective loss after posterior surgery for early onset scoliosis (EOS). However, an accurate method for CSP evaluation has yet to be developed. In this study, we evaluated pedicle screw (PS) length and rotation angle using an inverse trigonometric function and investigated the prevalence of the CSP. METHODS: Fifty patients from nine institutions (mean age 10.6 years, male/female ratio 4:46) who underwent early definitive fusion surgery at ≤ 11 years of age were included. The rotation angle was calculated as arctan (lateral/frontal PS length) using radiography. Measurements were taken at the apex and lower instrumented vertebra (LIV) immediate, 2-, and 5-year postoperatively. CSP was defined as a rotation angle progression ≥ 5°. We divided patients into CSP and non-CSP groups and measured the demographic parameters, Risser grade, state of the triradiate cartilage, major coronal Cobb angle, T1-T12 length, T1-S1 length, and presence of distal adding-on (DAO). We compared these variables between groups and investigated the correlation between the measured variables and vertebral rotation. Logistic regression analysis investigated factors associated with CSP. RESULTS: The rotation angle progressed by 2.4 and 1.3° over 5 years for the apex and LIV, respectively. CSP occurred in 15 cases (30%), DAO in 11 cases (22%), and CSP and DAO overlapped in 4 cases (8%). In the CSP group, the T1-T12 length was low immediate postoperatively. The rotation angle was negatively correlated with preoperative height (r = - 0.33), T1-T12 length (r = - 0.35), and T1-S1 length (r = - 0.30). A lower preoperative T1-T12 length was associated with CSP (odds ratio: 0.996, p = 0.048). CONCLUSIONS: CSP occurred in 30% of patients with EOS who underwent definitive fusion. The presence of CSP was associated with a lower preoperative T1-T12 length. LEVEL OF EVIDENCE: Diagnosis, level IV.

Motion Capture-based 3-dimensional Measurement of Range of Motion in Patients Undergoing Cervical Laminoplasty.

STUDY DESIGN: A prospective study. OBJECTIVE: To measure 3-dimensional cervical range of motion (ROM) by noninvasive optical tracking-based motion-capture technology in patients undergoing laminoplasty, and to elucidate the postoperative effects of laminoplasty on cervical mobility. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is a motion-sparing decompression surgery for degenerative cervical myelopathy. Unlike cervical laminectomy and fusion, the true postoperative impact of laminoplasty on neck motion has not been well studied. METHODS: Participants comprised 25 patients undergoing double-door cervical laminoplasty for degenerative cervical myelopathy in a single center. Maximum flexion/extension, left/right rotation, and left/right side bending were recorded using the motion-capture device preoperatively and 3 months postoperatively. ROMs in 3 orthogonal axes were calculated. Preoperative differences in C2-7 Cobb angles on lateral flexion/extension x-rays were also measured as the radiologic ROM to assess reliability. Preoperative and 1-year postoperative Japanese Orthopaedic Association score, Neck Disability Index [NDI], and Euro-QOL were recorded, and correlations with ROMs were assessed. RESULTS: Preoperative mean (±SD) ROMs for flexion/extension, rotation, and side bending were 90±17, 107±16, and 53±17 degrees, respectively. Although radiologic sagittal ROM measurement showed a smaller range than motion capture, averaging 36±13 degrees, a moderate to strong correlation between radiologic and motion capture values was observed (R=0.57, P=0.003). Preoperative NDI showed a negative correlation with coronal ROM (rho=-0.547, P=0.02). Postoperative ROM showed a significant reduction in rotation (95±16 degrees, P=0.002) but not in flexion/extension or side bending. CONCLUSIONS: Three-dimensional motion-capture analysis allowed reliable measurement of cervical ROM. Rotational ROM was significantly reduced after laminoplasty, showing that cervical kinematics are still significantly altered.

Postoperative Complications of Surgery for Cervical Spondylotic Myelopathy with and Without Athetoid Cerebral Palsy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: With the aging of the Japanese population, patients with athetoid cerebral palsy (ACP) are getting older, and the rate of surgery for CSM is increasing in ACP patients. However, postoperative complications of such surgery among adult patients with ACP have not been reported yet. We investigated postoperative complications of surgery for CSM with ACP and compared them with those of surgery for CSM without ACP using a national inpatient database of Japan. METHODS: Using the Diagnosis Procedure Combination database, we identified 61382 patients who underwent surgery for CSM from July 2010 to March 2018. We examined patient backgrounds, surgical procedures, and type of hospital, and a 4:1 propensity score matching was performed to compare the outcomes between the non-ACP and ACP groups. RESULTS: There were 60 847 patients without ACP and 535 patients with ACP. The mean age was 68.5 years in the non-ACP group and 55 years in the ACP group. The percentages of patients who underwent fusion surgery were 21.6% and 68.8% in the non-ACP and ACP groups, respectively. The 4:1 propensity score matching selected 1858 in the non-ACP group and 465 in the ACP group. The ACP group was more likely to have postoperative urinary tract infection (.4% vs 2.8%, P < .001), postoperative pneumonia (.4% vs 2.4%, P < .001), and 90-day readmission for reoperation (1.9% vs 4.3%, P = .003). CONCLUSIONS: We found that ACP patients were more vulnerable to postoperative complications and reoperation after CSM than non-ACP patients.

Instrumentation failure following pediatric spine deformity growth-sparing surgery using traditional growing rods or vertical expandable prosthetic titanium ribs.

BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.

Patients with a large ossification of the posterior longitudinal ligament have a higher incidence of arteriosclerosis in the carotid artery.

PURPOSE: This study aimed to investigate the impact of the severity of cervical ossification of the posterior longitudinal ligament (OPLL) on the incidence of arteriosclerosis in the carotid artery. METHODS: Patients with OPLL-induced cervical myelopathy were prospectively enrolled. The study involved analyzing patient characteristics, blood samples, computed tomography scans of the spine, and intima-media thickness (IMT) measurements of the common carotid artery. Patients were divided into two groups based on the size of the cervical OPLL to compare demographic data, comorbidities, and the presence of thickening of the carotid intima-media (max IMT ≥ 1.1 mm). RESULTS: The study included 96 patients (mean age: 63.5 years; mean body mass index: 26.9 kg/m2; 71.8% male; 35.4% with diabetes mellitus). The mean maximum anteroposterior (AP) diameter of the OPLL was 4.9 mm, with a mean occupancy ratio of 43%. The mean maximum IMT was 1.23 mm. Arteriosclerosis of the carotid artery was diagnosed in 62.5% of the patients. On comparing the two groups based on OPLL size, the group with larger OPLL (≥ 5 mm) had a higher BMI and a greater prevalence of carotid intima-media thickening. This significant difference in the prevalence of carotid intima-media thickening persisted even after adjusting for patient backgrounds using propensity score matching. CONCLUSIONS: Patients with a larger cervical OPLL showed a higher frequency of intima-media thickening in the carotid artery.

Coexisting Lower Back Pain in Patients With Cervical Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of the present study is to investigate the coexisting lower back pain (LBP) in patients with cervical myelopathy and to evaluate changes in LBP after cervical spine surgery. SUMMARY OF BACKGROUND DATA: Only a few studies with a small number of participants have evaluated the association between cervical myelopathy surgery and postoperative improvement in LBP. METHODS: Patients who underwent primary cervical decompression surgery with or without fusion for myelopathy and completed preoperative and 1-year postoperative questionnaires were reviewed using a prospectively collected database involving 9 tertiary referral hospitals. The questionnaires included the patient-reported Japanese Orthopaedic Association (PRO-JOA) score and Numerical Rating Scales (NRS). The minimum clinically important difference (MCID) for NRS-LBP was defined as >30% improvement from baseline. Patient demographics, characteristics, and PRO-JOA score were compared between patients with and without concurrent LBP, and the contributor to achieving the MCID for LBP was analyzed using logistic regression analysis. RESULTS: A total of 786 consecutive patients with cervical myelopathy were included, of which 525 (67%) presented with concurrent LBP. LBP was associated with a higher body mass index ( P <0.001) and worse preoperative PRO-JOA score ( P <0.001). Among the 525 patients with concurrent LBP, the mean postoperative NRS-LBP significantly improved from 4.5±2.4 to 3.4±2.7 ( P <0.01) postoperatively, with 248 (47%) patients reaching the MCID cutoff. Patients with a PRO-JOA recovery rate >50% were more likely to achieve MCID compared with those with a recovery rate <0% (adjusted odd ratio 4.02, P <0.001). CONCLUSIONS: More than 50% of patients with myelopathy reported improvement in LBP after cervical spine surgery, and 47% achieved the MCID for LBP, which was positively correlated with a better PRO-JOA recovery rate. Treating cervical myelopathy in patients with concomitant LBP may be sufficient to mitigate concomitant LBP. LEVEL OF EVIDENCE: Level III.

Bone Turnover Markers in Patients With Ossification of the Posterior Longitudinal Ligament in the Thoracic Spine.

STUDY DESIGN: A prospective, single-center, observational study. OBJECTIVE: To explore the association between serum levels of bone turnover markers and ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine. SUMMARY OF BACKGROUND DATA: The relationship between bone turnover markers, such as N-terminal propeptide of type I procollagen (PINP) or tartrate-resistant acid phosphate 5b (TRACP-5b), and OPLL has previously been examined. However, the correlation between these markers and thoracic OPLL, which is more severe than cervical-only OPLL, remains unclear. METHODS: This prospective study included 212 patients from a single institution with compressive spinal myelopathy and divided them into those without OPLL (Non-OPLL group, 73 patients) and those with OPLL (OPLL group, 139 patients). The OPLL group was further subdivided into cervical OPLL (C-OPLL, 92 patients) and thoracic OPLL (T-OPLL, 47 patients) groups. Patients' characteristics and biomarkers related to bone metabolism, such as calcium, inorganic phosphate (Pi), 25-hydroxyvitamin D, 1α,25 dihydroxyvitamin D, PINP, and TRACP-5b, were compared between the Non-OPLL and OPLL groups, as well as the C-OPLL and T-OPLL groups. Bone metabolism biomarkers were also compared after adjusting for age, sex, body mass index, and the presence of renal impairment using propensity score-matched analysis. RESULTS: The OPLL group had significantly lower serum levels of Pi and higher levels of PINP versus the Non-OPLL group as determined by propensity score-matched analysis. The comparison results between the C-OPLL and T-OPLL groups using a propensity score-matched analysis showed that T-OPLL patients had significantly higher concentrations of bone turnover markers, such as PINP and TRACP-5b, compared with C-OPLL patients. CONCLUSIONS: Increased systemic bone turnover may be associated with the presence of OPLL in the thoracic spine, and bone turnover markers such as PINP and TRACP-5b can help screen for thoracic OPLL.

Comparative Analysis of Microendoscopic and Open Laminectomy for Single-Level Lumbar Spinal Stenosis at L1-L2 or L2-L3.

BACKGROUND: Several reports have highlighted comparable surgical outcomes between microendoscopic laminectomy (MEL) and open laminectomy (open) for lumbar spinal stenosis. However, the unilateral approach in MEL may present challenges for the upper lumbar levels, where facet joints are located deeper inside. Our objective was to compare surgical outcomes and radiographic evaluations for single-level decompression cases at L1-L2 or L2-L3 between MEL and open laminectomy. METHODS: We analyzed patients who underwent single-level decompression for upper lumbar spinal stenosis at 12 distinguished spine centers from April 2017 to September 2021. Baseline demographics, preoperative, and 1-year postoperative patient-reported outcomes, along with imaging parameters, were compared between the MEL and open groups. To account for potential confounding, patients' backgrounds were adjusted using the inverse probability weighting method based on propensity scores. RESULTS: Among the 2487 patients undergoing decompression surgery, 118 patients (4.7%) underwent single-level decompression at L1-L2 or L2-L3. Finally, 80 patients (51 in the MEL group, 29 in the open group) with postoperative data were deemed eligible for analysis. The MEL group exhibited significantly improved postoperative EuroQol 5-Dimension values compared to the open group. Additionally, the MEL group showed a lower facet preservation rate according to computed tomography examination, whereas the open group had a higher incidence of retrolisthesis. CONCLUSIONS: Although overall surgical outcomes were similar, the MEL group demonstrated potential advantages in enhancing EuroQol 5-Dimension scores. The MEL group's lower facet preservation rate did not translate into a higher postoperative instability rate.

Impact of the COVID-19 pandemic on surgical volume and outcomes in spine surgery: a multicentre retrospective study in Tokyo.

OBJECTIVES: To investigate the effect of the COVID-19 pandemic on surgical volume and outcomes in spine surgery. DESIGN: A retrospective cohort study using prospectively collected data. SETTING AND PARTICIPANTS: A total of 9935 patients who underwent spine surgery between January 2019 and December 2021 at eight high-volume spine centres in the Greater Tokyo metropolitan area were included. OUTCOME MEASURES: The primary outcome measures were the number of surgical cases, perioperative complications and patient-reported outcomes, including numerical rating scales for each body part, Euro quality of life 5-dimension (EQ5D), Neck Disability Index and Oswestry Disability Index (ODI). RESULTS: The total number of surgeries in 2020 and 2021 remained lower than that of 2019, with respective percentages of 93.1% and 95.7% compared with the prepandemic period, with a marked reduction observed in May 2020 compared with the same period in 2019 (56.1% decrease). There were no significant differences between the prepandemic and postpandemic groups in the incidence of perioperative complications, although the frequency of reoperation tended to be higher in the postpandemic group (3.04% vs 3.76%, p=0.05). Subgroup analysis focusing on cervical spine surgery revealed significantly worse preoperative EQ5D scores in the postpandemic group (0.57 vs 0.54, p=0.004). Similarly, in lumbar spine surgery, the postpandemic group showed higher levels of leg pain (5.7 vs 6.1 to 0.002) and worse ODI scores (46.2 vs 47.7 to 0.02). However, postoperative outcomes were not different between pre and post-pandemic groups. CONCLUSIONS: The COVID-19 pandemic has significantly impacted spinal surgeries in Japan, leading to a decrease in surgical volumes and changes in patient characteristics and surgical procedures. However, surgical outcomes remained comparable between the pre and postpandemic periods, indicating the resilience and adaptability of healthcare systems.

Does surgical site infection affect patient-reported outcomes after spinal surgery? A multicenter cohort study.

BACKGROUND: Surgical site infections are common in spinal surgeries. It is uncertain whether outcomes in spine surgery patients with vs. without surgical site infection are equivalent. Therefore, we assessed the effects of surgical site infection on postoperative patient-reported outcomes. METHODS: We enrolled patients who underwent elective spine surgery at 12 hospitals between April 2017 and February 2020. We collected data regarding the patients' backgrounds, operative factors, and incidence of surgical site infection. Data for patient-reported outcomes, namely numerical rating scale, Neck Disability Index/Oswestry Disability Index, EuroQol Five-Dimensional questionnaire, and 12-Item Short-Form Health Survey scores, were obtained preoperatively and 1 year postoperatively. We divided the patients into with and without surgical site infection groups. Multivariate logistic regression analyses were performed to identify the risk factors for surgical site infection. Using propensity score matching, we obtained matched surgical site infection-negative and -positive groups. Student's t-test was used for comparisons of continuous variables, and Pearson's chi-square test was used to compare categorical variables between the two matched groups and two unmatched groups. RESULTS: We enrolled 8861 patients in this study; 74 (0.8 %) developed surgical site infections. Cervical spine surgery and American Society of Anesthesiologists physical status classification ≥3 were identified as risk factors; microendoscopy was identified as a protective factor. Using propensity score matching, we compared surgical site infection-positive and -negative groups (74 in each group). No significant difference was found in postoperative pain or dysesthesia of the lower back, buttock, leg, and plantar area between the groups. When comparing preoperative with postoperative pain and dysesthesia, statistically significant improvement was observed for both variables in both groups (p < 0.01 for all variables). No significant differences were observed in postoperative outcomes between the matched surgical site infection-positive and -negative groups. CONCLUSIONS: Patients with surgical site infections had comparable postoperative outcomes to those without surgical site infections.

A novel pathogenic variant located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif in SMAD3 causing Loeys-Dietz syndrome.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a heritable disorder of connective tissue closely related to Marfan syndrome (MFS). LDS is caused by loss-of-function variants of genes that encode components of transforming growth factor-ß (TGF-ß) signaling; nevertheless, LDS type 1/2 caused by TGFBR1/2 pathogenic variants is frequently found to have paradoxical increases in TGF-ß signaling in the aneurysmal aortic wall. Here, we present a Japanese LDS family having a novel SMAD3 variant. METHODS: The proband was tested via clinical, genetic, and histological analyses. In vitro analysis was performed for pathogenic evaluation. RESULTS: The novel heterozygous missense variant of SMAD3 [c.1262G>A, p.(Cys421Tyr)], located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif, was found in this instance of LDS type 3. This variant led to reduced phospho-SMAD3 (Ser423/Ser425) levels and transcription activity in vitro; however, a paradoxical upregulation of TGF-ß signaling was evident in the aortic wall. CONCLUSIONS: Our results revealed the presence of TGF-ß paradox in this case with the novel loss-of-function SMAD3 variant. The precise mechanism underlying the paradox is unknown, but further research is warranted to clarify the influence of the SMAD3 variant type and location on the LDS3 phenotype as well as the molecular mechanism leading to LDS3 aortopathy.

Reduced volume and altered composition of paraspinal muscles in Marfan syndrome: A retrospective cohort study.

Retrospective cohort study. Spinal deformities in patients with Marfan syndrome (MFS) are distinct from those in patients with idiopathic scoliosis (IS). It is more prone to progression and more likely to present with sagittal malalignment than IS. However, the etiology of this characteristic spinal deformity in MFS remains unclear. This study aimed to determine the spinal musculature characteristics in patients with MFS on the hypothesis that the paraspinal muscles of patients with MFS would be qualitatively or quantitatively different from those of patients with IS. Seventeen consecutive patients with MFS aged 25 years or younger undergoing surgery for scoliosis in our hospital were compared with age- and sex-matched patients with IS undergoing surgery for scoliosis. The body size-adjusted relative cross-sectional area (rCSA), fatty infiltration ratio (FI%), and relative functional cross-sectional area (rFCSA) of the psoas muscles (PM) and paravertebral muscles (PVM) at L3/4 and L4/5 were measured using preoperative T2-weighted magnetic resonance imaging. Functional CSA was defined as total CSA minus the fatty infiltration area of each muscle and rFCSA was calculated as the body size-adjusted functional CSA. The rCSA of the PM at L3/4 and L4/5 was significantly smaller in the MFS group than in the IS group (L3/4, P = .021; L4/5, P = .002). The FI% of the PM at L4/5 was significantly higher in the MFS group (P = .044). Consequently, the rFCSA of the PM at L3/4 and L4/5 and the rFCSA of the PVM at L3/4 in the MFS group were significantly smaller than those in the IS group (PM at L3/4, P = .021; PM at L4/5, P = .001; PVM at L3/4, P = .025). Compared with patients with IS, patients with MFS exhibited significantly decreased body-size-adjusted CSA of the PM and reduced body-size-adjusted functional CSA of the PVM and PM. These findings may partially explain the characteristics of distinctive spinal deformities in patients with MFS.

Genetic insights into ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated. Material and methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese. Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI. Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

A Novel Screening Method for Scoliosis Using a Bodysuit and 3-Dimensional Imaging.

STUDY DESIGN: A single-center prospective observational study. OBJECTIVE: To clarify the usefulness of a novel scoliosis screening method using a 3-dimensional (3D) human fitting application and a specific bodysuit. SUMMARY OF BACKGROUND DATA: Several scoliosis screening methods, such as scoliometer and Moiré topography, are available for detecting scoliosis. In the present study, a novel screening method for scoliosis using a 3D human fitting application and a specific bodysuit was developed. PATIENTS AND METHODS: Patients with scoliosis or suspected scoliosis, patients with non-scoliosis, and healthy volunteers were enrolled. They were divided into "non-scoliosis" and "scoliosis" groups. The scoliosis group was further subdivided into "mild," "moderate," and "severe-scoliosis" groups. Patients' characteristics and Z values, which were calculated by a 3D virtual human body model created by a 3D human fitting application and a specific bodysuit to evaluate trunk asymmetry caused by scoliosis, were compared between the non-scoliosis and scoliosis groups or among the non, mild, moderate and severe-scoliosis groups. Finally, the optimal cutoff of the Z value was determined to detect moderate to severe scoliosis using receiver operating characteristic curve analysis. RESULTS: A total of 101 patients were included. The non-scoliosis group consisted of 47 patients, and the scoliosis group included 54 patients, with 11, 31, and 12 patients in the mild, moderate, and severe-scoliosis groups, respectively. The scoliosis group showed a significantly higher Z value than the non-scoliosis group. The moderate or severe-scoliosis group had a significantly higher Z value than the non or mild-scoliosis group. The receiver operating characteristic curve analysis revealed that the optimal cutoff of the Z value was 19.9 mm (sensitivity, 95.3% and specificity, 58.6%). CONCLUSION: A novel scoliosis screening method consisting of a 3D human fitting application and a specific bodysuit may be useful for detecting moderate to severe scoliosis.