Spinal height for growth guidance treatment in early onset idiopathic scoliosis: analysis through final surgical treatment.

BACKGROUND: The growth guidance (GG) method for treatment of early onset scoliosis has as its primary goal the restoration of apical spinal alignment, facilitating normal spinal growth to achieve a suitable adult thoracic height. PURPOSE: To evaluate whether GG surgical treatment achieves comparable thoracic and spinal height to distraction-based treatment (DBT) in idiopathic early onset scoliosis (I-EOS) patients. We hypothesized that GG would prove superior to DBT at the time of definitive fusion surgery. METHODS: All I-EOS patients who underwent GG at a single center were reviewed. T1-L1 and T1-S1 heights were measured using the traditional coronal method as well as the Halifax sagittal spinal length (SSL) technique. The same measurements were obtained from a comparable control group obtained from a multi-center pediatric early onset scoliosis database who underwent treatment with traditional growing rods (TGR) or magnetically controlled growing rods (MCGR). RESULTS: Of the I-EOS patients who underwent GG 2004-2019, 15 patients underwent final fusion after GG completion, with a mean 5.5 years of GG treatment prior to fusion (range 2.0-11.4 years). Mean age at GG implantation was 8.4 years (range 2.0-11.7 years); 7 were male and 8 female. GG patients experienced a mean coronal thoracic height increase of 6.2 cm during treatment through final fusion, and a mean coronal spinal height increase of 8.8 cm. At the time of final fusion, GG patients achieved greater significant mean increases than DBT patients by 2.9 cm in coronal thoracic height (p = 0.0023), 4.5 cm in coronal spinal height (p = 0.001), and 4.0 cm in SSL spinal height (p = 0.01). No GG patient concluded treatment with a thoracic height less than 18 cm in either coronal or sagittal plane. CONCLUSIONS: Not only did 100% of GG patients reach minimum thoracic height of 18 cm at time of final fusion, but GG also proved to be superior to distraction-based constructs in a comparison cohort on 3 of 4 spinal elongation measures. LEVEL OF EVIDENCE: 3.

Analysis of three-dimensional spine growth for vertebral body tethering patients at 2 and 5 years post operatively.

PURPOSE: Scoliosis can be treated with vertebral body tethering (VBT) as a motion-sparing procedure. However, the knowledge of how growth is affected by a tether spanning multiple levels is unclear in the literature. Three-dimensional true spine length (3D-TSL) is a validated assessment technique that accounts for the shape of the spine in both the coronal and sagittal planes. This study aimed to assess if 3D-TSL increases over a five-year period after VBT implantation in thoracic curves for idiopathic scoliosis. METHODS: Prospectively collected radiographic data from an international pediatric spine registry was analyzed. Complete radiographic data over three visits (post-operative, 2 years, and 5 years) was available for 53 patients who underwent VBT. RESULTS: The mean age at instrumentation of this cohort was 12.2 (9-15) years. The average number of vertebrae instrumented was 7.3 (SD 0.7). Maximum Cobb angles were 50° pre-op, which improved to 26° post-op (p < 0.001) and was maintained at 5 years (30°; p = 0.543). Instrumented Cobb angle was 22° at 5 years (p < 0.001 vs 5-year maximum Cobb angle). An accentuation was seen in global kyphosis from 29° pre-operative to 41° at 5 years (p < 0.05). The global spine length (T1-S1 3D-TSL) started at 40.6 cm; measured 42.8 cm at 2 years; and 44.0 cm at the final visit (all p < 0.05). At 5 years, patients reached an average T1-S1 length that is comparable to a normal population at maturity. Immediate mean post-operative instrumented 3D-TSL (top of UIV-top of LIV) was 13.8 cm two-year length was 14.3 cm; and five-year length was 14.6 cm (all p < 0.05). The mean growth of 0.09 cm per instrumented level at 2 years was approximately 50% of normal thoracic growth. Patients who grew more than 0.5 cm at 2 years had a significantly lower BMI (17.0 vs 19.0, p < 0.05) and smaller pre-operative scoliosis (48° vs 53°, p < 0.05). Other subgroup analyses were not significant for age, skeletal maturity, Cobb angles or number of spanned vertebras as contributing factors. CONCLUSIONS: This series demonstrates that 3D-TSL increased significantly over the thoracic instrumented levels after VBT surgery for idiopathic scoliosis. This represented approximately 50% of expected normal thoracic growth over 2 years.

Palmitoylation of the small GTPase Cdc42 by DHHC5 modulates spine formation and gene transcription.

The small GTPase Cdc42 exists in the form of two alternatively spliced variants that are modified by hydrophobic chains: the ubiquitously expressed Cdc42-prenyl and a brain-specific isoform that can be palmitoylated, Cdc42-palm. Our previous work demonstrated that Cdc42-palm can be palmitoylated at two cysteine residues, Cys188 and Cys189, while Cys188 can also be prenylated. We showed that palmitoylation of Cys188 is essential for the plasma membrane localization of Cdc42-palm and is critically involved in Cdc42-mediated regulation of gene transcription and neuronal morphology. However, the abundance and regulation of this modification was not investigated. In the present study, we found that only a minor fraction of Cdc42 undergoes monopalmitoylation in neuroblastoma cells and in hippocampal neurons. In addition, we identified DHHC5 as one of the major palmitoyl acyltransferases that could physically interact with Cdc42-palm. We demonstrate that overexpression of dominant negative DHHC5 mutant decreased palmitoylation and plasma membrane localization of Cdc42-palm. In addition, knockdown of DHHC5 significantly reduced Cdc42-palm palmitoylation, leading to a decrease of Cdc42-mediated gene transcription and spine formation in hippocampal neurons. We also found that the expression of DHHC5 in the brain is developmentally regulated. Taken together, these findings suggest that DHHC5-mediated palmitoylation of Cdc42 represents an important mechanism for the regulation of Cdc42 functions in hippocampus.

Marking fin spine of juvenile sturgeon (Acipenseriformes: Acipenseridae) using oxytetracycline and the comparing of growth performance / [Marcação da espinha da nadadeira de esturjão juvenil (Acipenseriformes: Acipenseridae) usando-se oxitetraciclina e comparação do desempenho de crescimento]

This study aimed to describe and validate the formation of the rings in the spine of the pectoral fin and to determine the coherence of the OTC mark with the rings of three species of Caspian Sea sturgeon, the Persian sturgeon (Acipenser persicus), the Starry sturgeon (Acipenser stellatus) and Ship sturgeon (Acipenser nudiventris). Validation was achieved by comparing the total radius of the fin spine of fish of known age after one and two years of growth with the measured radius of the first and second rings in the zone. There was no overlap between the measured radius for the first year and the increase for the second. The Ship sturgeon showed the largest width of the second ring followed by the Persian sturgeon and Stellate sturgeon. The results indicate that the highest growth parameter belongs to the juvenile Ship sturgeon. This research showed that chemically marking the fin spines of juvenile Acipenseridae leads to unbiased estimates and contributes to the knowledge of the population dynamics of these species. The study found that the combination of the dial ring of the pectoral fin spine with growth validated the age estimation in juvenile sturgeon Ship, Persian, and Starry sturgeon.(AU)

O objetivo deste estudo foi descrever e validar a formação dos anéis na espinha da nadadeira peitoral de três espécies de esturjão do mar Cáspio: o esturjão-persa (Acipenser persicus), o esturjão-estrelado (Acipenser stellatus) e o esturjão-de-navio (Acipenser nudiventris), bem como determinar a coerência da marca OTC com os anéis dessas três espécies. A validação foi alcançada comparando-se o raio total da espinha da nadadeira de peixes de idade conhecida, após um e dois anos de crescimento, com o raio medido do primeiro e segundo anéis na zona. Não houve sobreposição entre o raio medido no primeiro ano e o aumento no segundo. O esturjão-de-navio mostrou a maior largura do segundo anel, seguido pelo esturjão-persa e pelo esturjão-estrelado. Os resultados indicam que o maior parâmetro de crescimento pertence ao esturjão-de-navio juvenil. Esta pesquisa mostrou que a marcação química dos espinhos das nadadeiras de juvenis de Acipenseridae leva a estimativas imparciais e contribui para o conhecimento da dinâmica populacional dessas espécies. O estudo descobriu que a combinação do anel do mostrador da barbatana peitoral espinhal com o crescimento validou a estimativa de idade em esturjão-de-navio juvenil, esturjão-persa e esturjão-estrelado.(AU)

Does the Use of Sanders Staging and Distal Radius and Ulna Classification Avoid Mismatches in Growth Assessment with Risser Staging Alone?

BACKGROUND: Although Risser stages are visible on the same radiograph of the spine, Risser staging is criticized for its insensitivity in estimating the remaining growth potential and its weak correlation with curve progression in patients with adolescent idiopathic scoliosis. Risser staging is frequently accompanied by other skeletal maturity indices to increase its precision for assessing pubertal growth. However, it remains unknown whether there is any discrepancy between various maturity parameters and the extent of this discrepancy when these indices are used concurrently to assess pubertal growth landmarks, which are important for the timing of brace initiation and weaning. QUESTIONS/PURPOSES: (1) What is the chronologic order of skeletal maturity grades based on the growth rate and curve progression rate in patients with adolescent idiopathic scoliosis? (2) What are the discrepancies among the grades of each maturity index for indicating the peak growth and start of the growth plateau, and how do these indices correspond to each other? (3) What is the effectiveness of Risser staging, Sanders staging, and the distal radius and ulna classification in assessing peak growth and the beginning of the growth plateau? METHODS: Between 2014 and 2017, a total of 13,536 patients diagnosed with adolescent idiopathic scoliosis were treated at our tertiary clinic. Of those, 3864 patients with a radiograph of the left hand and wrist and a posteroanterior radiograph of the spine at the same visits including initial presentation were considered potentially eligible for this study. Minimum follow-up was defined as 6 months from the first visit, and the follow-up duration was defined as 2 years since initial consultation. In all, 48% (1867 of 3864) of patients were eligible, of which 26% (485 of 1867) were excluded because they were prescribed bracing at the first consultation. These patients visited the subsequent clinics wearing the brace, which might have affected body height measurement. Six percent (117 of 1867) of eligible patients were also excluded as their major coronal Cobb angle reached the surgical threshold of 50° and had undergone surgery before skeletal maturity. Another 21% (387 of 1867) of patients were lost before minimum follow-up or had incomplete data, leaving 47% (878) for analysis. These 878 patients with 1139 skeletal maturity assessments were studied; 74% (648 of 878) were girls. Standing body height was measured in a standardized manner by a wall-mounted stadiometer. Several surgeons measured curve magnitude as per routine clinical consultation, skeletal maturity was measured according to the distal radius and ulna classification, and two raters measured Risser and Sanders stages. Reliability tests were performed with satisfaction. Data were collected for the included patients at multiple points when skeletal maturity was assessed, and only up to when brace wear started for those who eventually had bracing. The growth rate and curve progression rate were calculated by the change of body height and major coronal Cobb angle over the number of months elapsed between the initial visit and next follow-up. At each skeletal maturity grading, we examined the growth rate (in centimeters per month) and curve progression rate (in degrees per month) since the skeletal maturity assessment, as well as the mean age at which this maturity grading occurred. Each patient was then individually assessed for whether he or she was experiencing peak growth and the beginning of growth plateau at each timepoint by comparing the calculated growth rate with the previously defined peak growth rate of ≥ 0.7 cm per month and the beginning of growth plateau rate of ≤ 0.15 cm per month in this adolescent idiopathic scoliosis population. Among the timepoints at which the peak growth and the beginning of growth plateau occurred, the median maturity grade of each maturity index was identified as the benchmark grade for comparison between indices. We used the McNemar test to investigate whether pubertal growth landmarks were identified by specific maturity grades concurrently. We assessed the effectiveness of these skeletal maturity indices by the difference in proportions (%) between two benchmark grades in indicating peak growth and the growth plateau. RESULTS: For girls, the chronological order of maturity grades that indicated peak growth was the radius grade, ulna grade, Sanders stage, and Risser stage. Curve progression peaked between the age of 11.6 and 12.1 years at a similar timing by all maturity indices for girls but was inconsistent for boys. For both sexes, radius (R) grade 6, ulna (U) grade 5, Sanders stage (SS) 3, and Risser stage 0+ were the median grades for peak growth, whereas Risser stage 4, R8/9, U7/8, and SS6/7 indicated the beginning of the growth plateau. The largest discrepancy between maturity indices was represented by Risser stage 0+, which corresponded to six grades of the Sanders staging system (SS2 to SS7) and to R6 in only 41% (62 of 152) of girls in the whole cohort. Despite Risser stage 0+ corresponding to the wide range of Sanders and distal radius and ulna grades, none of the R6, U5, SS3, and Risser stage 0+ was found more effective than another grade in indicating the peak growth in girls. R6 most effectively indicated the peak growth in boys, and Risser stage 0+ was the least effective. For the beginning of the growth plateau in girls, SS6/7 was the most effective indicator, followed by U7/8. Risser stage 4 was the least effective because it indicated 29% (95% CI 21% to 36%; p < 0.001) fewer patients who reached the beginning of the growth plateau than did those with R8/9. Risser stage 4 also indicated 36% (95% CI 28% to 43%; p < 0.001) fewer patients who reached the beginning of the growth plateau than those indicated by U7/8, and it identified 39% fewer patients than SS6/7 (95% CI 32% to 47%; p < 0.001). For boys, similarly, R8/9, U7/8, and SS6/7 were all more effective than Risser stage 4 in identifying when the growth plateau began. CONCLUSION: Risser stage 0+ corresponds to a wide range of Sanders and distal radius and ulna grades. Risser stage 0+ is least effective in indicating the peak growth in boys, and Risser stage 4 is the least effective maturity grade for indicating when the growth plateau starts in both sexes. The concurrent use of R6 and SS3 can be useful for detecting the peak growth, and SS6/7 in conjunction with U7/8 is most effective in indicating the beginning of the growth plateau. Using a combination of specific grades of Sanders staging and the distal radius and ulna classification can indicate pubertal growth landmarks with reduced risk of underestimating or overestimating skeletal maturity. These findings may aid in refining clinical decision-making of brace initiation and weaning at a more precise timing. Among Risser stage 0, the appearance of R6, U5, and SS3 provide the most effective assessment of peak growth that can indicate the most effective bracing period within which curve progression occurs. For initiation of the growth plateau, Risser 4 is not useful, and SS6/7, R8/9 and U7/8 should be used instead. LEVEL OF EVIDENCE: Level III, diagnostic study.

Unveiling the tale of the tail: an illustration of spinal dysraphisms.

Spinal dysraphism is an umbrella term describing herniation of meninges or neural elements through defective neural arch. They can be broadly categorized into open and closed types. MRI is the investigation of choice to study neural abnormalities and to assess the severity of hydrocephalus and Chiari malformation. Knowledge of the embryology of these disorders is valuable in correctly identifying the type of dysraphism. The aim of surgery is untethering and dural reconstruction. Accurate depiction of the abnormal anatomy in cases of spinal dysraphism is of utmost importance for surgical management of these patients. MRI makes this possible due to its excellent soft tissue contrast resolution and multiplanar capability, allowing the radiologist to evaluate the intricate details in small pediatric spinal structures. Imaging enlightens the surgeons about the status of spinal cord and other associated abnormalities and helps detect re-tethering in operated cases. Besides, antenatal surgery to repair myelomeningoceles has made detection of open dysraphisms on fetal MRI and antenatal ultrasound critical. The purpose of this review is to describe the development of spine, illustrate the myriad imaging features of open and closed spinal dysraphisms, and enlist the reporting points the operating surgeon seeks from the radiologist.

Postembryonic screen for mutations affecting spine development in zebrafish.

The spine gives structural support for the adult body, protects the spinal cord, and provides muscle attachment for moving through the environment. The development and maturation of the spine and its physiology involve the integration of multiple musculoskeletal tissues including bone, cartilage, and fibrocartilaginous joints, as well as innervation and control by the nervous system. One of the most common disorders of the spine in human is adolescent idiopathic scoliosis (AIS), which is characterized by the onset of an abnormal lateral curvature of the spine of <10° around adolescence, in otherwise healthy children. The genetic basis of AIS is largely unknown. Systematic genome-wide mutagenesis screens for embryonic phenotypes in zebrafish have been instrumental in the understanding of early patterning of embryonic tissues necessary to build and pattern the embryonic spine. However, the mechanisms required for postembryonic maturation and homeostasis of the spine remain poorly understood. Here we report the results from a small-scale forward genetic screen for adult-viable recessive and dominant zebrafish mutations, leading to overt morphological abnormalities of the adult spine. Germline mutations induced with N-ethyl N-nitrosourea (ENU) were transmitted and screened for dominant phenotypes in 1229 F1 animals, and subsequently bred to homozygosity in F3 families; from these, 314 haploid genomes were screened for adult-viable recessive phenotypes affecting general body shape. We cumulatively found 40 adult-viable (3 dominant and 37 recessive) mutations each leading to a defect in the morphogenesis of the spine. The largest phenotypic group displayed larval onset axial curvatures, leading to whole-body scoliosis without vertebral dysplasia in adult fish. Pairwise complementation testing of 16 mutant lines within this phenotypic group revealed at least 9 independent mutant loci. Using massively-parallel whole genome or whole exome sequencing and meiotic mapping we defined the molecular identity of several loci for larval onset whole-body scoliosis in zebrafish. We identified a new mutation in the skolios/kinesin family member 6 (kif6) gene, causing neurodevelopmental and ependymal cilia defects in mouse and zebrafish. We also report multiple recessive alleles of the scospondin and a disintegrin and metalloproteinase with thrombospondin motifs 9 (adamts9) genes, which all display defects in spine morphogenesis. Our results provide evidence of monogenic traits that are essential for normal spine development in zebrafish, that may help to establish new candidate risk loci for spine disorders in humans.

Spinal changes after craniospinal irradiation in pediatric patients.

BACKGROUND: To evaluate long-term degenerative changes in bone and soft tissue after craniospinal irradiation (CSI). PROCEDURE: An analysis was performed for 892 vertebral bodies in 220 pediatric patients treated with CSI. To analyze vertebral growth, vertebral body height was calculated. Signal changes for vertebral bodies on MRI, scoliosis and kyphosis, degenerative changes of vertebral bones and discs, and wedging or vertebral height loss were analyzed on images, and factors that influenced these changes were investigated. RESULTS: Vertebral growth was significantly correlated with radiation dose and growth hormone (GH) deficiency. Growth rate was significantly worse at a dose >39 Gy. Fatty marrow change was found in 83% of patients, 31% had disc degenerative changes, 13% had degenerative changes of spinal bones, 17% had wedging or spinal height loss, and 27% had scoliosis. CONCLUSIONS: Vertebral bone growth was significantly reduced when high doses were administered, and adequate GH replacement was important for bone growth. Even with symmetrical irradiation, the risk of scoliosis is high after CSI. There was also frequent progression of spinal demineralization and degenerative changes after CSI. Therefore, careful attention should be paid to spinal symptoms as pediatric patients grow into adulthood.

Anterior Vertebral Body Growth-Modulation Tethering in Idiopathic Scoliosis: Surgical Technique.

The management of idiopathic scoliosis in the skeletally immature patient can be challenging. Posterior spinal fusion and instrumentation is indicated for severe scoliosis deformities. However, the skeletally immature patient undergoing posterior fusion and instrumentation is at risk for developing crankshaft deformities. Moreover, bracing treatment remains an option for patients who are skeletally immature, and although it was found to be effective, it does not completely preclude deformity progression. Recently, fusionless treatment options, such as anterior vertebral body growth modulation, have been developed to treat these patients while avoiding the complications of posterior rigid fusion. Good results have been shown in recent literature with proper indications and planning in the skeletally immature patient.

SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) affects 3% to 4% of children between the ages of 11 and 18 [1, 2]. This disorder, characterized by abnormal three-dimensional spinal curvatures that typically develop during periods of rapid growth, occurs in the absence of congenital vertebral malformations or neuromuscular defects [1]. Genetic heterogeneity [3] and a historical lack of appropriate animal models [4] have confounded basic understanding of AIS biology; thus, treatment options remain limited [5, 6]. Recently, genetic studies using zebrafish have linked idiopathic-like scoliosis to irregularities in motile cilia-mediated cerebrospinal fluid flow [7-9]. However, because loss of cilia motility in human primary ciliary dyskinesia patients is not fully associated with scoliosis [10, 11], other pathogenic mechanisms remain to be determined. Here, we demonstrate that zebrafish scospondin (sspo) mutants develop late-onset idiopathic-like spinal curvatures in the absence of obvious cilia motility defects. Sspo is a large secreted glycoprotein functionally associated with the subcommissural organ and Reissner's fiber [12]-ancient and enigmatic organs of the brain ventricular system reported to govern cerebrospinal fluid homeostasis [13, 14], neurogenesis [12, 15-18], and embryonic morphogenesis [19]. We demonstrate that irregular deposition of Sspo within brain ventricles is associated with idiopathic-like scoliosis across diverse genetic models. Furthermore, Sspo defects are sufficient to induce oxidative stress and neuroinflammatory responses implicated in AIS pathogenesis [9]. Through screening for chemical suppressors of sspo mutant phenotypes, we also identify potent agents capable of blocking severe juvenile spine deformity. Our work thus defines a new preclinical model of AIS and provides tools to realize novel therapeutic strategies.

Characterizing Use of Growth-friendly Implants for Early-onset Scoliosis: A 10-Year Update.

BACKGROUND: Growth-friendly treatment of early-onset scoliosis (EOS) has changed with the development and evolution of multiple devices. This study was designed to characterize changes in the use of growth-friendly implants for EOS from 2007 to 2017. METHODS: We queried the Pediatric Spine Study Group database for patients who underwent index surgery with growth-friendly implants from July 2007 to June 2017. In 1298 patients, we assessed causes of EOS; preoperative curve magnitude; age at first surgery; patient sex; construct type; lengthening interval; incidence of "final" fusion for definitive treatment; and age at definitive treatment. α=0.05. RESULTS: From 2007 to 2017, the annual proportion of patients with idiopathic EOS increased from 12% to 33% (R=0.58, P=0.006). Neuromuscular EOS was the most common type at all time points (range, 33% to 44%). By year, mean preoperative curve magnitude ranged from 67 to 77 degrees, with no significant temporal changes. Mean (±SD) age at first surgery increased from 6.1±2.9 years in 2007 to 7.8±2.5 years in 2017 (R=0.78, P<0.001). As a proportion of new implants, magnetically controlled growing rods increased from <5% during the first 2 years to 83% in the last 2 years of the study. Vertically expandable prosthetic titanium ribs decreased from a peak of 48% to 6%; growth-guidance devices decreased from 10% to 3%. No change was seen in mean surgical lengthening intervals (range, 6 to 9 mo) for the 614 patients with recorded lengthenings. Final fusion was performed in 88% of patients who had undergone definitive treatment, occurring at a mean age of 13.4±2.4 years. CONCLUSIONS: From 2007 to 2017, neuromuscular EOS was the most common diagnosis for patients treated with growth-friendly implants. Patient age at first surgery and the use of magnetically controlled growing rods increased during this time. Preoperative curve magnitude, traditional growing rod lengthening intervals, and rates of final fusion did not change. LEVEL OF EVIDENCE: Level II.

Comparison of Early Definitive Fusion and Traditional Growing Rods in Early-onset Dystrophic Scoliosis in Neurofibromatosis Type 1: A Preliminary Report.

BACKGROUND: Early definitive spinal fusion (EF) has been widely recommended to avoid spinal deformity progression for early-onset scoliosis (EOS) with neurofibromatosis type 1 (NF-1). In contrast, growing rod (GR) procedure has recently been recommended for EOS associated with the dystrophic type NF-1. However, no studies have compared the surgical outcomes between EF and GR procedure for EOS with NF-1. The purpose of this study was to compare the surgical outcomes of EF versus GR for early onset and dystrophic scoliosis with NF-1. METHODS: This was a retrospective multicenter study; 26 EOS patients with dystrophic type of NF-1 who underwent EF (16 patients) or GR (10 patients) were investigated. We compared age at first surgery, fused levels, total number of surgeries, coronal major curve, complication rates, spinal height (T1-T12 and T1-S1 length), and forced vital capacity between the 2 groups. RESULTS: The mean age at first surgery was 7.3 years in the EF and 5.8 years in the GR (P<0.05). The mean follow-up period was 12.8 and 10.5 years, respectively. The 2 groups did not show significant differences in preoperative major Cobb angle (75.1 vs. 83.1 degrees), complication rate (53% vs. 60%), and increase rate of T1-T12 (20.0% vs. 30.4%). However, significant differences (P<0.05) were recognized in fusion segments (13.9 vs. 15.8), total numbers of surgery (2.6 vs. 10.1), correction rate of major curve (59.0% vs. 40.6%), increase rate of T1-S1 (19.0% vs. 33.9%), body height at final follow-up (151 vs. 142 cm), and forced vital capacity at final follow-up (2.23 vs. 1.46 L). CONCLUSIONS: Early fusion is still a viable option for progressive EOS with dystrophic type of NF-1 even in the growth-friendly era. Surgeons should consider the best procedure for each patient taking into account the severity of dystrophic change when treating EOS with NF-1. LEVEL OF EVIDENCE: Level IV.

Serial Casting in Neuromuscular and Syndromic Early-onset Scoliosis (EOS) Can Delay Surgery Over 2 Years.

BACKGROUND: The primary goal in managing early-onset scoliosis (EOS) is delaying/preventing surgical intervention while allowing improved spinal growth and chest wall and lung development to improve life expectancy. The effectiveness of serial casting for patients with neuromuscular and syndromic EOS is unclear. METHODS: Patients from 2 multicenter registries who underwent serial casting for nonidiopathic scoliosis (NIS) were reviewed retrospectively. Comparisons were made between precasting and postcasting major and compensatory curves and spine height. The need for surgical intervention and any treatment complications were documented. Risk factors for major curve progression from baseline to casting cessation were evaluated via univariate analysis. RESULTS: Forty-four patients (23 females; 21 males) with NIS (26 syndromic, 18 neuromuscular) and a mean age of 3.2 years at baseline were included. Mean follow-up and casting duration was 3.9 and 2.0 years, respectively. There were no statistically significant differences between mean precasting and postcasting major curve (55 vs. 60 degrees; P=0.348), minor curve (31 vs. 33 degrees; P=0.510), or rib-vertebra angle difference (18 vs. 29 degrees; P=0.840). However, thoracic height (15.5 vs. 16.8 cm; P=0.031) and lumbar height (8.9 vs. 9.8 cm; P=0.013) were significantly greater upon casting cessation. Currently, 13 patients (30%) have had successful casting (improvement of major curve ≥10 degrees) while 24 patients (55%) experienced major curve progression (worsening), and 19 patients (43%) required surgical intervention. Mean time from first casting to surgery was 34.5±15.1 months. There were no statistically significant predictors for major curve progression on univariate analysis. CONCLUSIONS: Spinal deformity progression despite casting and the subsequent need for surgical intervention for NIS were significantly higher compared with those reported for idiopathic EOS. However, serial casting did afford a substantial delay in surgical intervention. Ultimately, serial casting for neuromuscular or syndromic EOS is an effective strategy for delaying surgical intervention, despite suboptimal radiographic outcomes. LEVEL OF EVIDENCE: Level III.

Comparison of T1-S1 Spine Height of Postoperative Rib-based Implant Patients With Age-matched Peers.

BACKGROUND: Severe early-onset scoliosis leads to deficient spine height, thoracic growth inhibition, and ultimately pulmonary compromise. Rib-based growing instrumentation seeks to correct thoracic deformities, in part by correcting the spinal deformity, adding height, increasing thoracic volume, and allowing for continual spinal growth until maturity. However, the amount of growth in these patients relative to their peers is unknown. METHODS: Sixty patients who had undergone surgical intervention for the treatment of early-onset scoliosis were assessed via radiographic measurements of coronal T1-S1 height and major curve angle before implantation and again at most recent follow-up (minimum 2 years). T1-S1 measurements were then compared with age-matched peers to assess growth differences. Clinical information was examined for relevant parameters. RESULTS: The average age of our cohort at initial surgery and most recent follow-up was 4.4±3.8 and 10.0±4.4 years old, respectively. In this patient set, there was an average increase in T1-S1 height of 13.1±11.1 mm per year, with the majority of growth occurring in the first 2 years following implantation, and improvement in a major curve from 68±8 to 53±7 degrees. Overall, 77% of patients saw improvement in the major curve at most recent follow-up. Furthermore, a statistically significant greater percent of expected growth was seen in congenital compared with neuromuscular scoliosis (P<0.001). In addition, a weak negative correlation was observed between a number of surgical lengthenings and T1-S1 growth. CONCLUSIONS: Rib-based implant intervention has been shown to improve the major curve, but only improves growth potential to around 80% of expected growth. Scoliosis diagnosis type also influences growth rate potential, with congenital scoliosis patients being surgically treated earlier in life and having a growth rate approaching that of a healthy individual. LEVEL OF EVIDENCE: Level III-Case control.

Cyclically controlled vertebral body tethering for scoliosis: an in vivo verification in a pig model of the pressure exerted on vertebral end plates.

STUDY DESIGN: Experimental in vivo study of the pressure exerted on the spine of a pig by a new cyclic anterior vertebral body tethering (AVBT) prototype. OBJECTIVES: To evaluate the relationship between the tether tension and the pressures transmitted onto the vertebral end plates by a cyclic AVBT prototype. AVBT is a recent surgical technique for the treatment of pediatric scoliosis that compresses the convex side of the spine with a sustained tension, to modulate the growth to progressively correct the deformity over time. Previous studies demonstrated that cyclic compression has similar growth modulation capacity but with less detrimental effects on the integrity of the discs and growth plates. METHODS: A 3-month-old healthy Duroc pig was anesthetized and a lateral thoracotomy was performed. The T7-T10 segment was instrumented and compressed during 50 s with the load oscillating (0.2 Hz) from + 30 to - 30% of the following mean tensions: 29, 35, 40, 44, and 49 N. The pressure exerted on T9 superior vertebral end plate was monitored during the cyclic loading. Three repetitions of each test were performed. RESULTS: The resulting mean pressure exerted on the vertebral end plate was linearly correlated with the mean tether tension (r2 = 0.86). Each cycle translated in a hysteresis profile of the measured pressure and tension, with amplitudes varying between ± 11.5 and ± 29.9%. CONCLUSIONS: This experimental study documented the relationship between the tether tension and the pressure. This study confirmed the feasibility of cyclic AVBT principle to transfer varying pressures on the vertebral end plates, which is intended to control vertebral growth, while keeping the spine flexibility and preserving the health of soft tissues such as the intervertebral discs and the growth plate but remained to be further verified. LEVEL OF EVIDENCE: Level IV.

Is It Growth or Natural History? Increasing Spinal Deformity After Sanders Stage 7 in Females With AIS.

BACKGROUND: Accurate prognosis and treatment decisions in adolescent idiopathic scoliosis (AIS) demand a reliable radiographic marker of growth cessation. Specifically, Sanders Stage 7 (SS7) is a useful marker of spine growth cessation in females and is proposed as a bracing endpoint. The purpose of this study was to determine the amount of curve progression noted in female individuals with AIS after achieving SS7. We hypothesize that a subset of patients continues to progress at a greater rate than the natural history at SS7. METHODS: This retrospective review included female patients with AIS treated at a single institution from May 2008 to 2018. Patients required a hand radiograph demonstrating SS7 and concurrent spine radiograph measuring <50 degrees, plus 2-year follow-up spine radiograph. Curve types were categorized by the modified Lenke Classification. Risser grade, menarche, height, weight, and bracing data were collected. Progression was defined as an increase of the main curve ≥5 degrees. Comparison between groups was analyzed using independent t tests and χ or Fisher exact tests as appropriate. Binary logistic regressions were used to construct a model predictive of progressing beyond 50 degrees or undergoing surgery. RESULTS: A total of 89 patients met inclusion criteria, average main curve magnitude 33 degrees (SD 9) at SS7 and 38 degrees (SD 11) at 2-year follow-up. Forty-five (51%) patients progressed ≥5 degrees and 17 (19%) progressed at least 10 degrees. Seventy patients had curves <40 degrees at SS7 and 22 (31%) progressed to >40 degrees at 2 years. Eleven (12%) patients progressed to >50 degrees or had surgery at 2-year follow-up. Receiver operating characteristic curve analysis identified a threshold of 39.5 degrees curvature at SS7 associated with progression to >50 degrees or surgery (area under the curve=0.94, P<0.001, sensitivity=100%, specificity=87%). Patients with initial curves >40 degrees did have additional height gained (2.1 cm; SD 1.5), but this was not different than those <40 degrees, P>0.05. In addition, no other variables had statistically significant association with those that progressed (P>0.05). CONCLUSIONS: A curve >40 degrees at SS7 is at high risk for progressing to a curve measuring >50 degrees or requiring surgery. Those with curves below this threshold still have potential to make clinically significant progression after skeletal maturity. Follow-up of patients beyond SS7 is essential for curves measuring >40 degrees. Reaching SS7 with a curve <50 degrees may not be the endpoint for curve progression, even if predictive of the end of spinal growth. LEVEL OF EVIDENCE: Level III-retrospective research study.

Results of growth-friendly management of early-onset scoliosis in children with and without skeletal dysplasias: a matched comparison.

AIMS: The aim of this study was to compare the surgical and quality-of-life outcomes of children with skeletal dysplasia to those in children with idiopathic early-onset scoliosis (EOS) undergoing growth-friendly management. PATIENTS AND METHODS: A retrospective review of two prospective multicentre EOS databases identified 33 children with skeletal dysplasia and EOS (major curve ≥ 30°) who were treated with growth-friendly instrumentation at younger than ten years of age, had a minimum two years of postoperative follow-up, and had undergone three or more lengthening procedures. From the same registries, 33 matched controls with idiopathic EOS were identified. A total of 20 children in both groups were treated with growing rods and 13 children were treated with vertical expandable prosthetic titanium rib (VEPTR) instrumentation. RESULTS: Mean preoperative major curves were 76° (34° to 115°) in the skeletal dysplasia group and 75° (51° to 113°) in the idiopathic group (p = 0.55), which were corrected at final follow-up to 49° (13° to 113°) and 46° (12° to 112°; p = 0.68), respectively. T1-S1 height increased by a mean of 36 mm (0 to 105) in the skeletal dysplasia group and 38 mm (7 to 104) in the idiopathic group at the index surgery (p = 0.40), and by 21 mm (1 to 68) and 46 mm (7 to 157), respectively, during the distraction period (p = 0.0085). The skeletal dysplasia group had significantly worse scores in the physical function, daily living, financial impact, and parent satisfaction preoperatively, as well as on financial impact and child satisfaction at final follow-up, than the idiopathic group (all p < 0.05). The domains of the 24-Item Early-Onset Scoliosis Questionnaire (EOSQ24) remained at the same level from preoperative to final follow-up in the skeletal dysplasia group (all p > 0.10). CONCLUSION: Children with skeletal dysplasia gained significantly less spinal growth during growth-friendly management of their EOS and their health-related quality of life was significantly lower both preoperatively and at final follow-up than in children with idiopathic EOS. Cite this article: Bone Joint J 2019;101-B:1563-1569.

Spine Growth Modulation in Early Adolescent Idiopathic Scoliosis: Prospective US FDA IDE Pilot Study of Titanium Clip-Screw Implant at Two to Five Years.

STUDY DESIGN: Prospective longitudinal study of growth modulation system for early adolescent idiopathic scoliosis (AIS), consecutive case series from first human use to skeletal maturity, fusion, or five years postoperation. OBJECTIVES: Determine adverse events and curvature changes to end of study; examine factors most likely to explain variability in curve changes. SUMMARY OF BACKGROUND: Pilot clinical safety study was performed under US Food and Drug Administration (FDA) Investigational Device Exemption (IDE). Safety and radiographic results were previously reported to 24 months postoperation. METHODS: Subjects with early AIS underwent thoracoscopic placement of titanium clip-screw devices designed to modify growth asymmetrically. Eligibility was based on high risk of progression to 50°: single major thoracic curve 25°-40°, Risser 0, open triradiate cartilages, and premenarchal if female. Six subjects, the maximum allowed, enrolled. Adverse events (AEs), clinical outcomes, and curvatures were systematically collected. Disc heights, vertebral heights, and implant-bone contact areas were assessed. RESULTS: Consecutive subjects enrolled, aged 12.1 years (±1.7), three were female. AEs from two to five years postoperation included deformity changes leading to a second surgery in three patients: two for posterior spinal fusion, and one for thoracoscopic removal of half the implants for overcorrection. In the latter case, overcorrection appeared halted for duration of study. One patient, whose curve exceeded 50° at age 18 years, did not choose fusion. Major thoracic curves were 34° (±3°) preoperatively and 42° (±20°) at end of study. CONCLUSIONS: In a study of spine growth modulation in patients with early AIS with high risk of progression, at skeletal maturity or five years postoperation, major thoracic curves of half progressed to >50°, whereas curves of the other half remained <40°, below fusion indications. Removal of selected implants may halt overcorrection. The next, pivotal, study phase was approved by FDA. LEVEL OF EVIDENCE: Level IV, prospective case series under stringent regulatory controls.

Eating Behavior Traits, Weight Loss Attempts, and Vertebral Dimensions Among the General Northern Finnish Population.

STUDY DESIGN: A population-based birth cohort study. OBJECTIVE: To evaluate the associations of eating behavior traits and weight loss attempts with vertebral size among the general Northern Finnish population. SUMMARY OF BACKGROUND DATA: Vertebral fragility fractures are a typical manifestation of osteoporosis, and small vertebral dimensions are a well-established risk factor for vertebral fracturing. Previous studies have associated cognitive eating restraint and diet-induced weight loss with deteriorated bone quality at various skeletal sites, but data on vertebral geometry are lacking. METHODS: This study of 1338 middle-aged Northern Finns evaluated the associations of eating behavior traits (flexible and rigid cognitive restraint of eating, uncontrolled eating, emotional eating; assessed by the Three-Factor Eating Questionnaire-18) and weight loss attempts (assessed by a separate questionnaire item) with magnetic resonance imaging-derived vertebral cross-sectional area (CSA). Sex-stratified linear regression models were used to analyze the data, taking body mass index, leisure-time physical activity, general diet, smoking, and socioeconomic status as potential confounders. RESULTS: Women with rigid or rigid-and-flexible cognitive eating restraints had 3.2% to 3.4% smaller vertebral CSA than those with no cognitive restraint (P ≤ 0.05). Similarly, the women who reported multiple weight loss attempts in adulthood and midlife had 3.5% smaller vertebral size than those who did not (P = 0.03). Other consistent findings were not obtained from either sex. CONCLUSION: Rigid cognitive eating restraint and multiple weight loss attempts predict small vertebral size and thus decreased spinal health among middle-aged women, but not among men. Future longitudinal studies should confirm these findings. LEVEL OF EVIDENCE: 3.

Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration.

Development of the skeleton is mediated through two distinct ossification mechanisms. Craniofacial bones are formed mainly through intramembranous ossification, a mechanism different from endochondral ossification required for development of the body skeleton. The skeletal structures are quite distinct between the two, thus they are likely to have their unique stem cell populations. The sutures serve as the growth center critical for healthy development of the craniofacial skeleton. Defects in suture morphogenesis cause its premature closure, resulting in development of craniosynostosis, a devastating disease affecting 1 in ~2,500 individuals. The suture mesenchyme has been postulated to act as the niche of skeletal stem cells essential for calvarial morphogenesis. However, very limited knowledge is available for suture biology and suture stem cells (SuSCs) have yet to be isolated. Here we report the first evidence for identification and isolation of a stem cell population residing in the suture midline. Genetic labeling of SuSCs shows their ability to self-renew and continually give rise to mature cell types over a 1-year monitoring period. They maintain their localization in the niches constantly produce skeletogenic descendants during calvarial development and homeostastic maintenance. Upon injury, SuSCs expand drastically surrounding the skeletogenic mesenchyme, migrate to the damaged site and contribute directly to skeletal repair in a cell autonomous fashion. The regeneration, pluripotency and frequency of SuSCs are also determined using limiting dilution transplantation. In vivo clonal expansion analysis demonstrates a single SuSC capable of generating bones. Furthermore, SuSC transplantation into injured calvaria facilitates the healing processes through direct engraftments. Our findings demonstrate SuSCs are bona fide skeletal stem cells ideally suited for cell-based craniofacial bone therapy as they possess abilities to engraft, differentiate.(Presented at the 1980th Meeting, April 16, 2019).