Treatment of Symptomatic Spinal Muscular Atrophy with Nusinersen: A Prospective Longitudinal Study on Scoliosis Progression.

Background: Nusinersen treatment has demonstrated efficacy in improving clinical outcomes for spinal muscular atrophy (SMA), yet its impact on scoliosis progression remains unclear. Objective: This study aimed to assess the progression of scoliosis in pediatric patients with SMA undergoing nusinersen treatment. Methods: In this prospective study, data were systematically collected from Hong Kong pediatric SMA patients receiving nusinersen between 2018 and 2023. All patients had longitudinal radiographic studies pre-nusinersen, and at half-yearly or yearly intervals during treatment based on the scoliosis severity. Motor function evaluations were conducted pre-nusinersen, and after starting treatment at 6- and 12-month intervals. Results: Twenty-three patients ((SMA type 1 (SMA1) = 8, SMA type 2 (SMA2) = 7, SMA type 3 (SMA3) = 8)) with a median age of 5.8 years (range: 0.4-17.5 years) at nusinersen initiation, and median follow-up duration of 3.4 years (range: 1.1-5.2 years) were included. During the study period, motor scores remained stable or improved in 83% of patients. However, scoliosis progressed across all subtypes, with mean annual progression rates of 5.2, 11.9, and 3.6 degrees in SMA1, SMA2, and SMA3 respectively. Patients initiating nusinersen between ages 5 and 11 years exhibited the most rapid progression, with rates of 11.8, 16.5, and 7.3 degrees per year in SMA1, SMA2, and SMA3 respectively. Positive correlations were observed between the difference in CHOP-INTEND score post-nusinersen and scoliosis progression in SMA1 (rs = 0.741, p = 0.041). Conversely, negative correlations were found between the difference in HFMSE score post-nusinersen and scoliosis progression in SMA2 (rs =-0.890, p = 0.012) and SMA3 (rs =-0.777, p = 0.028). Conclusions: This study reveals that nusinersen treatment in symptomatic pediatric SMA patients with motor improvement is linked to increased scoliosis progression in SMA1, whereas it is associated with decreased progression in SMA2 and SMA3. Age, baseline Cobb angle, and motor milestone improvement are influential factors in scoliosis progression.

Ultrasound-guided interlaminar approach for nusinersen administration in patients with spinal muscular atrophy with spinal fusion or severe scoliosis.

BACKGROUND: Intrathecal injection of medications can be challenging in spinal muscular atrophy (SMA) patients with severe scoliosis or after spine surgery. Here we report our experience with real-time ultrasound (US)-guided intrathecal administration of nusinersen in patients with SMA. METHODS: Seven patients (six children and one adult) with either spinal fusion or severe scoliosis were enrolled. We performed intrathecal injections of nusinersen under US guidance. The efficacy and safety of US-guided injection were explored. RESULTS: Five patients had undergone spinal fusion, while the other two presented severe scoliosis. Success was achieved in 19/20 lumbar punctures (95%), 15 of which were performed through the near-spinous process approach. The intervertebral space with a designated channel was selected for the five postoperative patients, while the interspaces with the smallest rotation angle were chosen for the other two patients with severe scoliosis. In 89.5% (17/19) of the punctures, the number of insertions was no more than two. No major adverse events were observed. CONCLUSION: Given its safety and efficacy, real-time US guidance is recommended for SMA patients with spine surgery or severe scoliosis, and the near-spinous process view can be used as a interlaminar puncture approach for US guidance.

Nusinersen for spinal muscular atrophy types II and III: a retrospective single-center study in South Korea.

BACKGROUND: This study investigated the efficacy and safety of nusinersen, an antisense oligonucleotide, in patients with spinal muscular atrophy (SMA) types II (OMIM: 253,550) or III (OMIM: 253,400), including those with severe scoliosis or requiring respiratory support via mechanical ventilation. METHODS: Data from 40 patients with genetically confirmed SMA who were treated with nusinersen at our institute from March 2019 to April 2022 were retrospectively analyzed. Of these, 30 patients with an age of onset < 3 years and not on permanent ventilation were selected. Clinical and genetic characteristics were investigated, and motor function was evaluated based on the Hammersmith Functional Motor Scale-Expanded (HFMSE) score. RESULTS: The mean age of symptom onset was 1.2 years. Most patients were diagnosed with SMA type II (27/30, 90%). Nusinersen was administered via computed tomography-guided or direct intrathecal injection in 87% (26/30) and 13% (4/30) of the patients, respectively. At the 6-, 14-, 22-, and 26-month follow-ups, 72%, 71%, 88%, and 86% of patients showed motor improvement, respectively, with mean changes in HFMSE scores of 2.10, 2.88, 4.21, and 5.29, respectively. Multivariable analysis showed that the use of noninvasive ventilation was associated with poorer outcomes of motor function. CONCLUSIONS: Patients with SMA type II or III who received nusinersen treatment showed significant improvement in motor function. A longer treatment duration led to a higher number of patients with improved motor function. No significant side effects of nusinersen were observed. Patients with SMA, even those with severe scoliosis or on respiratory support, can be safely treated using nusinersen.

A microbiology study on the wounds of pediatric patients undergoing spinal fusion for scoliosis.

PURPOSE: Surgical site infection is a significant complication in posterior spinal fusion for scoliosis in pediatric and adolescent patients. Current literature demonstrates a lack of consensus regarding best prophylactic systemic and topical antibiotic regimens for reducing infection rates. This study aims to identify which common microbes are present at particular locations in the spine, and whether these are covered by our current systemic and topical antibiotic prophylaxis regimens. METHODS: A prospective observational study at a National Children's Hospital was conducted on 21 consecutive patients who underwent elective surgery for spinal deformity. Swabs were taken from four layers of the spine, including the superficial skin surface at the start of the case (after surgical site preparation with povidone-iodine), the deep dermis, and the deep surgical bed at the end of exposure and again after the corrective maneuver prior to closure. At each layer, swabs were taken from the proximal, middle, and distal portion of the wound. Swabs were sent to the laboratory for culture and susceptibility testing. RESULTS: Thirteen (62%) of patients had positive microbial growth. Two microbes were identified, Staphylococcus epidermidis (9.5% of patients) and Cutibacterium acnes (Propionibacterium acnes) (52% of patients). 100% of these microbes were sensitive to cefazolin and vancomycin. 3% of patients had positive growth at the skin layer, 32% positive at the dermal layer, 17% positive after exposure, and 40% positive at the conclusion of the case (p = 0.006). No difference was observed in microbial presence in the upper thoracic, lower thoracic and lumbar spine. CONCLUSION: Despite adequate surgical site preparation and sterile procedure, microbial contamination remains abundant in the dermal layer and deeper in the spinal wound throughout the case.

[Clinical follow-up analysis of nusinersen in the disease-modifying treatment of pediatric spinal muscular atrophy].

Objective: To explore the clinical efficacy of disease-modifying drug nusinersen on children with spinal muscular atrophy. Methods: The baseline and longitudinal clinical data of 15 children who were treated with nusinersen in the Children's Hospital, Zhejiang University School of Medicine from October 2019 to October 2021 were retrospectively collected. The general data (gender, age, genotype, and clinical classification, etc.), motor function, nutritional status, scoliosis and respiratory function were analyzed. Wilcoxon rank-sum test was used for comparing multi-system conditions before and after treatment. Results: The age of 15 cases (7 males, 8 females) was 6.8 (2.8, 8.3) years, with 2 cases of type 1, 6 cases of type 2, and 7 cases of type 3 respectively, and the course of disease was 55.0 (21.0, 69.0) months. After 9.0 (9.0, 24.0) months of treatment, the motor function scale evaluations of the Hammersmith neurological examination section 2 (13.0 (7.0, 23.0) vs. 18.0 (10.0, 25.0) scores, Z=-2.67, P=0.018) of 15 children, the Hammersmith functional motor scale expanded (38.0 (18.5, 45.5) vs. 42.0 (23.0, 51.0) scores, Z=-2.38, P=0.018), and the revised upper limb module (27.0 (19.5, 32.0) vs. 33.0 (22.5, 35.5) scores, Z=-2.52, P=0.012) of children with type 2 and 3 had significantly improved. Thirteen patients achieved clinically significant motor function improvement, and 2 of them had kept stable scale scores. Subjective reports also indicated that the muscle strength and daily exercise ability of these children improved after treatment, and no serious adverse reactions were reported. Supplemented by the multi-disciplinary team management, the levels of some indicators such as Cobbs angle of scoliosis and forced vital capacity all had significantly improved (all P<0.05). Conclusions: Nusinersen can improve the motor function of patients with 5q spinal muscular atrophy, which is also proved safe to be used in children. The drug treatment supplemented by the multi-disciplinary team management is helpful to improve the multi-system function of the children with spinal muscular atrophy.

Prednisone and deflazacort in Duchenne muscular dystrophy: a patient perspective and plain language summary publication of the Cincinnati study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about the Cincinnati study, which was published in the Journal of Comparative Effectiveness Research in January 2020. The Cincinnati study reviewed data from 435 males with Duchenne muscular dystrophy, also known as DMD, who were treated at the Cincinnati Children's Hospital Medical Center. DMD is a rare disease that worsens over time. People with DMD experience inflammation in their muscles and muscle loss over time. They also experience bone problems such as an abnormally bent spine, also known as scoliosis, as well as heart and lung problems. WHAT HAPPENED IN THE CINCINNATI STUDY?: Prednisone and deflazacort are steroids that help to reduce muscle inflammation and are used as treatments for DMD. The study researchers wanted to further understand the differences between using prednisone and deflazacort in males with DMD by reviewing data from past medical records of patients seen in clinics rather than in clinical studies. This is known as gathering real-world evidence. In the Cincinnati study, the researchers compared males with DMD who started taking prednisone as their first steroid treatment with males who started taking deflazacort as their first steroid treatment. WHAT WERE THE RESULTS?: Overall, the researchers found that the participants who took deflazacort were able to walk until a later age before they needed to use a wheelchair, compared with those who took prednisone. They also had a lower risk of scoliosis and developed it at a later age. WHAT DO THE RESULTS OF THE STUDY MEAN?: These results helped the researchers to learn more about the differences between how well prednisone and deflazacort work in males with DMD based on their medical records.

Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Population-based estimates of survival among individuals with Duchenne muscular dystrophy (DMD) living in the United States are lacking. It is also unclear whether the association between glucocorticoid use and all-cause mortality persists in the context of other common treatments (cardiac medication, cough-assist, bilevel positive airway pressure, and scoliosis surgery) observed to delay mortality. Among 526 individuals identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network, the estimated median survival time from birth was 23.7 years. Current glucocorticoid users had a lower hazard of mortality than non-users. Individuals who ever had scoliosis surgery had a lower hazard of mortality than individuals who did not have scoliosis surgery. Individuals who ever used cough assist had a lower hazard of mortality than individuals who never used cough assist. Non-Hispanic Black individuals had a higher hazard of mortality than non-Hispanic White individuals. No differences in hazards of mortality were observed between ever versus never use of cardiac medication and ever versus never use of bilevel positive airway pressure. The glucocorticoid observation is consistent with the 2018 Care Considerations statement that glucocorticoid use continues in the non-ambulatory phase. Our observations may inform the clinical care of individuals living with DMD.

A six years longitudinal cohort study on the changes in bone density and bone quality up to peak bone mass in adolescent idiopathic scoliosis (AIS) with and without 2 years of Calcium and Vit-D supplementation.

Adolescent idiopathic scoliosis (AIS) is associated with osteopenia which could persist into adulthood affecting attainment of Peak Bone Mass thus resulting in osteoporosis in late adulthood. We previously reported a randomized double-blinded placebo-controlled trial(the Cal study) showing significant bone health improvement with 2-year calcium(Ca)+Vit-D supplementation for AIS girls. This study addressed the important issue whether bone health improvement from the initial 2-year Ca+Vit-D supplementation could persist as subjects approached towards Peak Bone Mass at 6-year ie after 4-year of supplement discontinuation. This was an extension of the Cal study on AIS girls (11-14 years old, mean age=12.9 years, Tanner stage

Ultra-low radiation dose protocol for CT-guided intrathecal nusinersen injections for patients with spinal muscular atrophy and severe scoliosis.

PURPOSE: Intrathecal injection of nusinersen is an approved treatment of spinal muscular atrophy (SMA). CT-guided injection is a method of nusinersen administration in patients with severe scoliosis, in whom standard lumbar puncture is not feasible. The injections are repeated every 4 months for life, and accumulated radiation doses absorbed by the patient can increase the risk of cancer. In this study, we present the results of CT-guided intrathecal nusinersen injections with an ultra-low radiation dose protocol. METHODS: Eighteen patients (15 adults and three children) in whom standard lumbar puncture was not feasible due to severe scoliosis or spinal stabilization were included in this retrospective study. The first 23 injections were performed with a standard radiation dose protocol and the next 42 injections with an ultra-low-dose protocol. The radiation doses, measured as total dose length product (DLP), were acquired and compared between the protocols. RESULTS: Injections were successful in 100% of patients with both ultra-low-dose and standard protocols. The radiation dose, measured as DLP, was 111.2-1100.7 (Me = 248.1) mGy*cm for the standard protocol. For the ultra-low-dose protocol, the dose range was 5.0-54.4 (Me = 26.7) mGy*cm, which was significantly lower than with the standard protocol (p < 0.001, η2 = 0.67). CONCLUSION: Radiation doses can be significantly decreased in the CT-guided injection of nusinersen. The proposed protocol allows for effective CT-guided intrathecal nusinersen administration in patients with SMA and severe scoliosis.

Targeting miR-10a-5p/IL-6R axis for reducing IL-6-induced cartilage cell ferroptosis.

BACKGROUND: Intervertebral disc degeneration (IDD) causes lower back pain, and is often accompanied with robust inflammation. However, whether inflammation plays a role in IDD remains controversial, and the mechanism is ill-elucidated. METHODS: Cartilage specimens from patients with scoliosis (control) and IDD were examined for IL-6 and its receptor expression by qPCR and western blot. Primary human articular chondrocyte was employed as a model for in vitro assessment of IL-6 effects in cell viability, cellular oxidative stress and iron homeostasis by MTT, MDA, ROS and Iron Colorimetric assays. The underlying mechanism was explored by qPCR, western blot, RIP in combination with bioinformatics analysis. RESULTS: We found in this study that IL-6 and its receptor were aberrantly expressed in cartilage tissues of IDD patients. IL-6 down-regulated miR-10a-5p, which subsequently derepressed IL-6R expression. IL-6 exposure caused cartilage cell ferroptosis by inducing cellular oxidative stress and disturbing iron homeostasis. Overexpressing miR-10a-5p suppressed IL-6R expression, and partially abolished IL-6-induced ferroptosis. CONCLUSION: Results from current study suggests that inflammatory cytokine IL-6 appeared in IVD aggravates its degeneration by inducing cartilage cell ferroptosis. This is caused partially by inhibiting miR-10a-5p and subsequently derepressing IL-6R signaling pathway. Our study provides a novel mechanism explaining inflammatory cytokine-caused cartilage cell death in degenerative IVD, and makes IL-6/miR-10a-5p/IL-6R axis a potential therapeutic target for intervention of IDD.

The first case report of Kyphoscoliotic Ehlers-Danlos syndrome of chinese origin with a novel PLOD1 gene mutation.

BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population. CASE PRESENTATION: A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol and nifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up. CONCLUSIONS: This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1, extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients with congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed by mutation analysis of PLOD1.

Postoperative Pain Management in Pediatric Spinal Fusion Surgery for Idiopathic Scoliosis.

This article reviews and summarizes current evidence and knowledge gaps regarding postoperative analgesia after pediatric posterior spine fusion for adolescent idiopathic scoliosis, a common procedure that results in severe acute postoperative pain. Inadequate analgesia may delay recovery, cause patient dissatisfaction, and increase chronic pain risk. Despite significant adverse effects, opioids are the analgesic mainstay after scoliosis surgery. However, growing emphasis on opioid minimization and enhanced recovery has increased adoption of multimodal analgesia (MMA) regimens. While opioid adverse effects remain a concern, MMA protocols must also consider risks and benefits of adjunct medications. We discuss use of opioids via different administration routes and elaborate on the effect of MMA components on opioid/pain and recovery outcomes including upcoming regional analgesia. We also discuss risk for prolonged opioid use after surgery and chronic post-surgical pain risk in this population. Evidence supports use of neuraxial opioids at safe doses, low-dose ketorolac, and methadone for postoperative analgesia. There may be a role for low-dose ketamine in those who are opioid-tolerant or have chronic pain, but the evidence for preoperative gabapentinoids and intravenous lidocaine is currently insufficient. There is a need for further studies to evaluate pediatric-specific optimal MMA dosing regimens after scoliosis surgery. Questions remain regarding how best to prevent acute opioid tolerance, opioid-induced hyperalgesia, and chronic postsurgical pain. We anticipate that this timely update will enable clinicians to develop efficient pain regimens and provide impetus for future research to optimize recovery outcomes after spine fusion.

Advanced Progression of Scoliosis After Intrathecal Baclofen in an Adult With Stiff Person Syndrome: A Case Report.

Stiff person syndrome is a neuroimmunological disorder characterized by progressive muscular rigidity and spasms that affect axial/limb muscles, resulting in severe pain and functional limitations. When refractory to conservative treatments, intrathecal baclofen is a viable option to treat the increased tone. Intrathecal baclofen has been shown to accelerate underlying neuromuscular scoliosis in the pediatric population with cerebral palsy. This adverse effect has never been reported in adults with stiff person syndrome. We report a case of an adult with stiff person syndrome and underlying scoliosis who experienced accelerated progression of scoliosis after initiation of intrathecal baclofen, subsequently requiring neurosurgical intervention.

Safety and Effectiveness of Antifibrinolytics in Posterior Scoliosis Surgery for Adolescent Idiopathic Scoliosis: An Analysis of the NSQIP-Pediatric Database.

STUDY DESIGN: This was a retrospective study of prospectively collected data. OBJECTIVE: To utilize a large national database with prospectively collected data [National Surgical Quality Improvement Program Pediatric (NSQIP-Pediatric)] to study the safety and effectiveness of antifibrinolytic use during multilevel posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: There is currently a lack of consensus and evidence regarding the safety and effectiveness of antifibrinolytic use for pediatric patients undergoing corrective surgery for AIS. MATERIALS AND METHODS: Patients who underwent multilevel PSF for AIS in the 2016 NSQIP-Pediatric database were identified. Preoperative and procedural characteristics were compared between patients who received antifibrinolytics versus those who did not. Multivariate regressions were used to compare perioperative transfusion rates and postoperative outcomes, such as rate of return to the operating room, 30-day readmission, and intensive care unit and hospital length of stay between the 2 treatment groups. RESULTS: This study included 975 patients who received antifibrinolytics and 223 patients who did not. Patients who received these agents tended to have more levels fused, osteotomies performed, and longer operative times. After controlling for these variances, there were no statistical differences in rate and volume of transfusion, rate of return to the operating room, 30-day readmission, 30-day postoperative complications, or intensive care unit or hospital length of stay between the 2 treatment groups. CONCLUSIONS: This study did not demonstrate transfusion reduction in the group that received antifibrinolytics. This finding may be, in part, secondary to nonoptimized or nonstandardized protocols for antifibrinolytic use in pediatric deformity surgery or the inability to adequately control for selection bias, as those with greater surgical invasiveness may be more likely to receive antifibrinolytics. Nonetheless, using antifibrinolytics in this population appears safe and not associated with increased perioperative complications. LEVEL OF EVIDENCE: Level III.

Comparison of the Coagulation Profile of Adolescent Idiopathic Scoliosis Patients Undergoing Posterior Spinal Fusion With and Without Tranexamic Acid.

STUDY DESIGN: Prospective, observational cohort study. OBJECTIVE: To improve the understanding of coagulation and bleeding mechanisms during spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Fibrinolysis is the mechanism of bleeding for adolescent idiopathic scoliosis undergoing posterior spinal fusion. Antifibrinolytics have become popular; however, literature to support their use remains mixed. The mechanism of action has not been demonstrated. METHODS: The coagulation profile of 88 adolescent idiopathic scoliosis patients undergoing posterior spinal fusion was analyzed. Standard coagulation laboratory investigations and thromboelastograms were drawn hourly through the case. Fifty-eight patients received no antifibrinolytic, whereas 30 patients received tranexamic acid by standardized protocol. The coagulation parameters, estimated blood loss, and transfusion requirements were compared in the two groups. RESULTS: The two cohorts had no differences in demographic or surgical characteristics. Mean age was 13.6 years, 83% were female, a mean of 11.1 levels were fused, and the mean duration of surgery was 209 minutes. The tranexamic acid cohort did not demonstrate a decrease in blood loss. The transfusion rate, however, dropped from 47% in the non-tranexamic acid cohort to 23% in the tranexamic acid cohort (p = .03). Standard coagulation parameters did not differ between the groups. Fibrinolysis was diminished in the tranexamic acid cohort as measured by a Fibrinolysis score (mean maximum value 2.0 without tranexamic acid vs. 0.7 with tranexamic acid, p < .0001) and the lysis percent at 30 minutes by thromboelastogram (elevated to 3.9% without tranexamic acid vs. 1.2% with tranexamic acid at the 3-hour mark, p = .05). CONCLUSIONS: This study provides confirmation of antifibrinolytic activity during posterior spinal fusion for adolescent idiopathic scoliosis. The presented data of fibrinolysis are proposed as standard measurements for future work on controlling blood loss during scoliosis surgery. LEVEL OF EVIDENCE: Level 2, prospective comparative study.

Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: Transforaminal versus conventional approach.

Spinal deformities and surgical correction of scoliosis can make intrathecal delivery of nusinersen very challenging. We aim to evaluate the feasibility and safety of intrathecal administration of nusinersen either via interlaminar or transforaminal approach in a cohort of adult and adolescent patients with spinal muscular atrophy (SMA). Twelve patients were treated with nusinersen in our center under CT-guidance; after a CT scan of the lumbar column, we identified a safe virtual trajectory for the needle and defined patients to address to the transforaminal approach (seven patients) or the interlaminar approach (five patients). Out of 47 procedures, all injections but one were successful. There was one adverse event (post-lumbar puncture syndrome) in the interlaminar approach group (out of 20 procedures) and four adverse events in TFA group (out of 27 procedures) including one serious adverse event, a subarachnoid hemorrhage that required hospitalization. Transforaminal approach can be considered an effective option for nusinersen administration but potentially associated with serious complications, therefore it should be recommended in very selected patients.

Ghrelin up-regulates cartilage-specific genes via the ERK/STAT3 pathway in chondrocytes of patients with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a severe spinal deformity that often occurs during puberty. The occurrence of AIS is suggested to be related to abnormal development of cartilage. Our previous study found increased serum ghrelin levels in AIS patients that may linked to the development of AIS. However, whether ghrelin affects cartilage in AIS patients is unclear. We used quantitative real-time PCR (qRT-PCR) and immunohistochemistry to detect the expression of cartilage-specific genes and the ghrelin receptor, growth hormone secretagogue receptor (GHSR). The mRNA and protein levels of collagen II (COLII), SOX9, AGGRECAN (ACAN) and GHSR were higher in AIS patients than in controls. In addition, the protein levels of GHSR downstream signaling pathway members p-STAT3 (Ser727), and p-ERK1/2 were increased. Furthermore, we treated chondrocytes from AIS patients with 100 nM ghrelin, the cell proliferation assay and Western blotting showed that ghrelin promotes chondrocyte proliferation and enhances COLII, SOX9, ACAN, p-ERK1/2 and p-STAT3 expression, respectively. Interestingly, all these observed alterations were abolished by ghrelin + [D-Lys3]-GHRP-6 (a ghrelin receptor inhibitor) treatment. And after U0126 (an inhibitor of ERK1/2 phosphorylation) treatment, ERK1/2 and STAT3 (Ser727) phosphorylation was simultaneously suppressed indicating that ERK1/2 is an upstream pathway protein of STAT3 (Ser727). In conclusion, ghrelin plays an important role in upregulating cartilage-specific genes on AIS primary chondrocytes by activating ERK/STAT3 signaling pathway.

Scoliosis and spinal muscular atrophy in the new world of medical therapy: providing lumbar access for intrathecal treatment in patients previously treated or undergoing spinal instrumentation and fusion.

This study describes a new procedure for a safer and easier access for the intrathecal injection of the recently approved nusinersen therapy in spinal muscular atrophy. This therapy changed the natural history of the disease, but, to date, scoliosis surgery was an excluding criteria for nusinersen therapy. The bone mass, due to the posterior spinal fusion of the scoliosis surgery, prevents the needle for the nusinersen administration from intervertebral access. This is a single-center, single-surgeon case series descriptive study. A laminotomy at the L3-L4 level was performed to provide safer access for the intrathecal injection. The procedure was carried out during the scoliosis surgery in patients who underwent posterior spinal fusion (PSF) after the nusinersen therapy was introduced, whereas for those who underwent PSF earlier, a second procedure was necessary to perform a laminotomy. A fat grafting was used to prevent bone overgrowth in the laminotomy. Markers were applied as radiographic references for the intrathecal injection. Five patients were enrolled, four females and one male. The mean age of the patients was 11 years. Three patients underwent PSF before the introduction of the nusinersen therapy. Two patients underwent PSF after the nusinersen therapy was available. All of them underwent a laminotomy with a fat grafting at the L3-L4 laminotomy level and received nusinersen therapy without complications. The procedure described is simple and effective in providing safe intrathecal access to make these patients eligible for such important therapy.

The effect of exogenous melatonin on reducing scoliotic curvature and improving bone quality in melatonin-deficient C57BL/6J mice.

It is well-documented that melatonin deficiency has been linked to the etiopathogenesis of adolescent idiopathic scoliosis. In this study, we intended to apply melatonin in melatonin-deficient mice to ascertain whether melatonin could reduce the incidence/severity of scoliosis, and investigate the role of melatonin on bone mineral density in scoliosis. A total of 80 mice were divided into 4 groups: 20 quadrupedal mice and 20 bipedal mice served as controls; 20 quadrupedal and 20 bipedal mice received oral melatonin (8 mg/kg BW) daily. After 5th, 10th, 15th and 20th weeks of treatment, radiographs and in vivo micro-CT were used to determine the incidence of scoliosis and bone qualities, respectively. Upon sacrifice, the levels of melatonin were measured in each group. At 20th week, the occurrence of scoliosis was 80%, 30%, 22% and 5% in bipedal, quadrupedal, bipedal + melatonin and quadrupedal + melatonin group, respectively. The trabecular bone quality of the vertebral body was significantly ameliorated in the melatonin-treated bipedal models. Likewise, the number of osteoclasts was significantly less in those treated with melatonin. Our results indicated that melatonin deficiency may be crucial for scoliotic development, and restoration of melatonin levels can prevent scoliotic development with the improvement in bone density.