Adolescent Idiopathic Scoliosis: Fishy Tales of Crooked Spines.

Adolescent idiopathic scoliosis (AIS) is a common skeletal disorder, characterized by abnormal spine curvatures. In zebrafish, cilia-driven cerebrospinal fluid flow and urotensin II pathway activity are required for proper spine morphogenesis. Genetic studies with AIS patients now establish a conservation of the zebrafish findings in the etiology of the disease.

Continuous Hypodynamic Change of Cerebrospinal Fluid Flow as A Potential Factor Working for Experimental Scoliotic Formation.

Scoliosis is often associated with syringomyelia (SM). As an important role in SM formation, the influence from abnormal cerebrospinal fluid (CSF) flow is still unclear to scoliosis. The aim of this experimental work is to explore the connection between CSF flow and scoliosis through imaging and histological analysis on the basis of a kaolin-induced scoliotic rabbit model. For imaging observation, in 40 kaolin-induced rabbits by C7 spinal cord injection, through pre- and postoperative MRI and radiography, CSF flow and scoliosis formation were detected at consecutive phases. According to the final formation of scoliosis until postoperative week 12, the kaolin-induced rabbits were divided into 2 groups. Through comparing the 2 groups, the relationship between the changes of CSF flow velocity and scoliosis formation were reviewed and analyzed. For histological observation, another 20 kaolin-induced rabbits were used for consecutive histological observations of spinal cord at postoperative 3-day, 2-week, 4-week and 6-week. After kaolin-induction, abnormal spinal coronal curve was observed from postoperative week 6 in the 37 survived rabbits. At postoperative week 12, scoliosis formation was detected in 73.0% kaolin-induced rabbits and the mean Cobb angle was 27.4°. From the comparison between scoliotic and non-scoliotic groups, the difference of the velocities of CSF flow was more obviously from postoperative week 4 to 12, especially after week 6. In the scoliotic group, the peak velocity of CSF flow was diseased gradually following scoliosis formation after induction. Moreover, the decrease of the peak velocities of CSF flow from preoperation to postoperative 12 weeks (ΔVmax), including up-flow (ΔVUmax) and down-flow (ΔVDmax), were positively correlated to the final scoliotic Cobb angle (P < 0.01). Through histological observation at different phases, the distinctive pathological changes of the spinal cord included early inflammatory reaction, adhesion and blockage in the subarachnoid space and the central canal, perivascular space enlargement, central canal expansion, which suggested the CSF flow being blocked by multiple ways after kaolin-induction. In conclusion, experimental scoliosis can be successfully induced by intraspinal kaolin injection. In this model, continuous hypodynamic change of CSF flow was correlated to the formation of scoliosis, which could be an important factor of scoliotic pathogenesis being explored furtherly.

Preoperative Norepinephrine Levels in Cerebrospinal Fluid and Plasma Correlate With Pain Intensity After Pediatric Spine Surgery.

PURPOSE: Catecholamines were found to be involved in descending pain modulation and associated with perioperative pain. The purpose of the present study was to investigate the relationship between preoperative concentrations of catecholamines and postoperative pain intensity of pediatric patients. METHODS: Fifty adolescents with idiopathic scoliosis scheduled for elective spinal fusion surgery were enrolled in this prospective cohort study. Preoperative plasma and cerebrospinal fluid (CSF) samples were collected and analyzed by mass spectrometry. Pain intensity was assessed during the acute postoperative period and in the intermediate period. RESULTS: Preoperative plasma concentrations of norepinephrine (NE) and normetanephrine (NME), as well as the CSF concentration of NE, were significantly correlated with the presence of pain six weeks after surgery (r = 0.48, 0.50, and 0.50, respectively; p < .002). We also found that preoperative NE levels in CSF were significantly higher in patients reporting moderate to severe pain intensity than in patients with mild pain during the first day following surgery (0.268 ± 0.29 ng/mL vs. 0.121 ± 0.074 ng/mL, p = .01), as well as between patients reporting pain and painless patients at 6 weeks postsurgery (0.274 ± 0.282 ng/mL vs. 0.103 ± 0.046 ng/mL respectively, U = 69.5, p = .002). CONCLUSIONS: These results support the potential role of catecholamine levels in predicting postoperative pain intensity.

Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature.

Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the mechanisms underlying this spinal deformity remain unknown. Here we show that ptk7 mutant zebrafish, a faithful developmental model of IS, exhibit defects in ependymal cell cilia development and cerebrospinal fluid (CSF) flow. Transgenic reintroduction of Ptk7 in motile ciliated lineages prevents scoliosis in ptk7 mutants, and mutation of multiple independent cilia motility genes yields IS phenotypes. We define a finite developmental window for motile cilia in zebrafish spine morphogenesis. Notably, restoration of cilia motility after the onset of scoliosis blocks spinal curve progression. Together, our results indicate a critical role for cilia-driven CSF flow in spine development, implicate irregularities in CSF flow as an underlying biological cause of IS, and suggest that noninvasive therapeutic intervention may prevent severe scoliosis.

Changes in CSF flow after one-stage posterior vertebral column resection in scoliosis patients with syringomyelia and Chiari malformation type I.

OBJECT: Phase contrast-cine MRI (PC-cine MRI) studies in patients with syringomyelia and Chiari malformation Type I (CM-I) have demonstrated abnormal CSF flow across the foramen magnum, which can revert to normal after craniocervical decompression with syrinx shrinkage. In order to investigate the mechanisms leading to postoperative syringomyelia shrinkage, the authors studied the hydrodynamic changes of CSF flow in the craniocervical junction and spinal canal in patients with scoliosis associated with syringomyelia after one-stage deformity correction by posterior vertebral column resection. METHODS: Preoperative and postoperative CSF flow dynamics at the levels of the foramen magnum, C-7, T-7 (or apex), and L-1 were assessed by electrocardiogram-synchronized cardiac-gated PC-cine MRI in 8 adolescent patients suffering from severe scoliosis with syringomyelia and CM-I (scoliosis group) and undergoing posterior vertebral column resection. An additional 8 patients with syringomyelia and CM-I without spinal deformity (syrinx group) and 8 healthy volunteers (control group) were also enrolled. Mean values were obtained for the following parameters: the duration of a CSF cycle, the duration of caudad CSF flow (CSF downflow [DF]) and cephalad CSF flow (CSF upflow [UF]), the ratio of DF duration to CSF cycle duration (DF%), and the ratio of UF duration to CSF cycle duration (UF%). The ratio of the stationary phase (SP) duration to CSF cycle duration was calculated (SP%). The maximum downflow velocities (VD max) and maximum upflow velocities (VU max) were measured. SPSS (version 14.0) was used for all statistical analysis. RESULTS: Patients in the scoliosis group underwent one-stage posterior vertebral column resection for deformity correction without suboccipital decompression. The mean preoperative coronal Cobb angle was 102.4° (range 76°-138°). The mean postoperative Cobb angle was 41.7° (range 12°-75°), with an average correction rate of 59.3%. During the follow-up, 1 patient with hypermyotonia experienced a significant decrease of muscle tension and 1 patient with reduced anal sphincter tone manifested recovery. A total of 5 patients demonstrated a significant decrease (> 30%) in syrinx size. With respect to changes in CSF flow dynamics, the syrinx group was characterized by slower and shorter downflow than the control group, and the difference was more significant at the foramen magnum and C-7 levels. In patients with scoliosis, CSF downflow at the foramen magnum level was significantly restricted, and a prolonged stationary phase indicated increased obstruction of CSF flow. After posterior vertebral column resection, the peak velocity of CSF flow at the foramen magnum increased, and the downflow phase duration was markedly prolonged. The parameters showed a return to almost normal CSF dynamics at the craniocervical region, and this improvement was maintained for 6-12 months of follow-up. CONCLUSIONS: There were distinct abnormalities of CSF flow at the craniocervical junction in patients with syringomyelia. Abnormal dynamics of downflow could be aggravated by associated severe spinal deformity and improved by correction via posterior vertebral column resection.

Citramalic acid in cerebrospinal fluid of patients with bacterial meningitis.

Cerebrospinal fluid (CSF) from uninfected patients and from patients with bacterial and viral meningitis was analyzed by gas-liquid chromatography, with use of a flame ionization detector, and by gas chromatography-mass spectrometry. The resulting profiles were consistent and reproducible. Hydroxy acids were the compounds found in greatest abundance in both normal and infected CSF. Control experiments to establish the sensitivity and efficiency of the extraction and derivatization methods are also presented. Constituents of CSF from patients with bacterial meningitis differed quantitatively and qualitatively from those of CSF from uninfected patients or patients with nonbacterial infections. CSF from seven of eight patients with bacterial meningitis contained citramalic acid, a compound not previously identified in either normal or infected CSF. The implications of these findings are discussed.