Idiopathic and normal lateral lumbar curves: muscle effects interpreted by 12th rib length asymmetry with pathomechanic implications for lumbar idiopathic scoliosis.

BACKGROUND: The historical view of scoliosis as a primary rotation deformity led to debate about the pathomechanic role of paravertebral muscles; particularly multifidus, thought by some to be scoliogenic, counteracting, uncertain, or unimportant. Here, we address lateral lumbar curves (LLC) and suggest a pathomechanic role for quadrates lumborum, (QL) in the light of a new finding, namely of 12th rib bilateral length asymmetry associated with idiopathic and small non-scoliosis LLC. METHODS: Group 1: The postero-anterior spinal radiographs of 14 children (girls 9, boys 5) aged 9-18, median age 13 years, with right lumbar idiopathic scoliosis (IS) and right LLC less that 10°, were studied. The mean Cobb angle was 12° (range 5-22°). Group 2: In 28 children (girls 17, boys 11) with straight spines, postero-anterior spinal radiographs were evaluated similarly to the children with the LLC, aged 8-17, median age 13 years. The ratio of the right/left 12th rib lengths and it's reliability was calculated. The difference of the ratio between the two groups was tested; and the correlation between the ratio and the Cobb angle estimated. Statistical analysis was done using the SPSS package. RESULTS: The ratio's reliability study showed intra-observer +/-0,036 and the inter-observer error +/-0,042 respectively in terms of 95 % confidence limit of the error of measurements. The 12th rib was longer on the side of the curve convexity in 12 children with LLC and equal in two patients with lumbar scoliosis. The 12th rib ratios of the children with lumbar curve were statistically significantly greater than in those with straight spines. The correlation of the 12th rib ratio with Cobb angle was statistically significant. The 12th thoracic vertebrae show no axial rotation (or minimal) in the LLC and no rotation in the straight spine group. CONCLUSIONS: It is not possible, at present, to determine whether the 12th convex rib lengthening is congenitally lengthened, induced mechanically, or both. Several small muscles are attached to the 12th ribs. We focus attention here on the largest of these muscles namely, QL. It has attachments to the pelvis, 12th ribs and transverse processes of lumbar vertebrae as origins and as insertions. Given increased muscle activity on the lumbar curve convexity and similar to the interpretations of earlier workers outlined above, we suggest two hypotheses, relatively increased activity of the right QL muscle causes the LLCs (first hypothesis); or counteracts the lumbar curvature as part of the body's attempt to compensate for the curvature (second hypothesis). These hypotheses may be tested by electrical stimulation studies of QL muscles in subjects with lumbar IS by revealing respectively curve worsening or correction. We suggest that one mechanism leading to relatively increased length of the right 12 ribs is mechanotransduction in accordance with Wolff's and Pauwels Laws.

Erratum to: Physical activities of Patients with adolescent idiopathic scoliosis (AIS): preliminary longitudinal case-control study historical evaluation of possible risk factors.

[This corrects the article DOI: 10.1186/s13013-015-0029-8.].

Adolescent idiopathic scoliosis (AIS): a multifactorial cascade concept for pathogenesis and embryonic origin.

This paper formulates a novel multifactorial Cascade Concept for the pathogenesis of adolescent idiopathic scoliosis (AIS). This Concept stems from the longitudinal findings of Clark et al. (J Bone Miner Res 29(8):1729-36, 2014) who identified leptin body composition factors at 10 years of age associated with a scoliosis deformity found at 15 years. We interpret these findings in the light of some concepts for AIS pathogenesis. In particular, we speculate that the leptin body composition effect is linked to central nervous system development and the initiation of the asynchronous neuro-osseous growth mechanism that involves the creation of a neuraxis tether of relative anterior vertebral overgrowth. The latter mechanism in combination with age and gender-related anatomical variants of vertebral backward tilt (dorsal shear concept), human upright posture, adolescent growth factors, Hueter-Volkmann effect in vertebrae and vertebral bone mass abnormalities, lead to AIS, possibly both initiation and progression of scoliosis curvatures. Being multifactorial, while the Cascade Concept cannot be tested for all its components, some components should be testable by the method of numerical simulation. Clark et al. (J Bone Miner Res 29(8):1729-36, 2014) also suggested the origin of scoliosis was in the embryonic stages of life from cell types, including adipocytes and osteoblasts, derived from the same progenitor cells, and myoblasts from mesodermal somites. The involvement of cell types from different developmental origins suggests a process acting in embryonic life at a similar time, probably environmental, as previously proposed from anthropometric studies. As a Complex disease, AIS will involve genetic, environmental and life style factors operating in development and growth; this possibility needs evaluating in epidemiological studies.

Physical activities of Patients with adolescent idiopathic scoliosis (AIS): preliminary longitudinal case-control study historical evaluation of possible risk factors.

To our knowledge there are no publications that have evaluated physical activities in relation to the etiopathogenesis of adolescent idiopathic scoliosis (AIS) other than sports scolioses. In a preliminary longitudinal case-control study, mother and child were questioned and the children examined by one observer. The aim of the study was to examine possible risk factors for AIS. Two study groups were assessed for physical activities: 79 children diagnosed as having progressive AIS at one spinal deformity centre (66 girls, 13 boys) and a Control Group of 77 school children (66 girls, 11 boys), the selection involving six criteria. A structured history of physical activities was obtained, every child allocated to a socioeconomic group and examined for toe touching. Unlike the Patients, the Controls were not X-rayed and were examined for surface vertical spinous process asymmetry (VSPA). Statistical analyses showed progressive AIS to be positively associated with social deprivation, early introduction to indoor heated swimming pools and ability to toe touch. AIS is negatively associated with participation in dance, skating, gymnastics or karate and football or hockey classes, which might suggest preventive possibilities. There is a significantly increased independent odds of AIS in children who went to an indoor heated swimming pool within the first year of life (odds ratio 3.88, 95% CI 1.77-8.48; p = 0·001). Furthermore fourteen (61%) Controls with VSPA compared with 9 (17%) Controls without VSPA had been introduced to the swimming pool within their first year of life (P < 0.001). Early exposure to indoor heated swimming pools for both AIS and VSPA, suggests that the AIS findings do not result from sample selection.

Adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common form of structural spinal deformities that have a radiological lateral Cobb angle - a measure of spinal curvature - of ≥10(°). AIS affects between 1% and 4% of adolescents in the early stages of puberty and is more common in young women than in young men. The condition occurs in otherwise healthy individuals and currently has no recognizable cause. In the past few decades, considerable progress has been made towards understanding the clinical patterns and the three-dimensional pathoanatomy of AIS. Advances in biomechanics and technology and their clinical application, supported by limited evidence-based research, have led to improvements in the safety and outcomes of surgical and non-surgical treatments. However, the definite aetiology and aetiopathogenetic mechanisms that underlie AIS are still unclear. Thus, at present, both the prevention of AIS and the treatment of its direct underlying cause are not possible.

Whither the etiopathogenesis (and scoliogeny) of adolescent idiopathic scoliosis? Incorporating presentations on scoliogeny at the 2012 IRSSD and SRS meetings.

This paper aims to integrate into current understanding of AIS causation, etiopathogenetic information presented at two Meetings during 2012 namely, the International Research Society of Spinal Deformities (IRSSD) and the Scoliosis Research Society (SRS). The ultimate hope is to prevent the occurrence or progression of the spinal deformity of AIS with non-invasive treatment, possibly medical. This might be attained by personalised polymechanistic preventive therapy targeting the appropriate etiology and/or etiopathogenetic pathways, to avoid fusion and maintain spinal mobility. Although considerable progress had been made in the past two decades in understanding the etiopathogenesis of adolescent idiopathic scoliosis (AIS), it still lacks an agreed theory of etiopathogenesis. One problem may be that AIS results not from one cause, but several that interact with various genetic predisposing factors. There is a view there are two other pathogenic processes for idiopathic scoliosis namely, initiating (or inducing), and those that cause curve progression. Twin studies and observations of family aggregation have revealed significant genetic contributions to idiopathic scoliosis, that place AIS among other common disease or complex traits with a high heritability interpreted by the genetic variant hypothesis of disease. We summarize etiopathogenetic knowledge of AIS as theories of pathogenesis including recent multiple concepts, and blood tests for AIS based on predictive biomarkers and genetic variants that signify disease risk. There is increasing evidence for the possibility of an underlying neurological disorder for AIS, research which holds promise. Like brain research, most AIS workers focus on their own corner and there is a need for greater integration of research effort. Epigenetics, a relatively recent field, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Research on the role of environmental factors, epigenetics and chronic non-communicable diseases (NCDs) including adiposity, after a slow start, has exploded in the last decade. Not so for AIS research and the environment where, except for monozygotic twin studies, there are only sporadic reports to suggest that environmental factors are at work in etiology. Here, we examine epigenetic concepts as they may relate to human development, normal life history phases and AIS pathogenesis. Although AIS is not regarded as an NCD, like them, it is associated with whole organism metabolic phenomena, including lower body mass index, lower circulating leptin levels and other systemic disorders. Some epigenetic research applied to Silver-Russell syndrome and adiposity is examined, from which suggestions are made for consideration of AIS epigenetic research, cross-sectional and longitudinal. The word scoliogeny is suggested to include etiology, pathogenesis and pathomechanism.

Whither the etiopathogenesis (and scoliogeny) of adolescent idiopathic scoliosis?

Although considerable progress had been made in the past two decades in understanding the etiopathogenesis of adolescent idiopathic scoliosis (AIS), it still lacks an agreed theory of etiopathogenesis. One problem may be that AIS results not from one cause, but several that interact with various genetic predisposing factors. There is a view there are two other pathogenic processes for idiopathic scoliosis namely, initiating (or inducing), and those that cause curve progression. Twin studies and observations of family aggregation have revealed significant genetic contributions to idiopathic scoliosis, that place AIS among other common disease or complex traits with a high heritability interpreted by the genetic variant hypothesis of disease. We summarize etiopathogenetic knowledge of AIS as theories of pathogenesis including recent multiple concepts, and blood tests for AIS based on predictive biomarkers and genetic variants that signify disease risk. There is increasing evidence for the possibility of an underlying neurological disorder for AIS, research which holds promise. Like brain research, most AIS workers focus on their own corner and there is a need for greater integration of research effort. Epigenetics, a relatively recent field, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Research on the role of environmental factors, epigenetics and chronic non-communicable diseases (NCDs) including adiposity, after a slow start, has exploded in the last decade. Not so for AIS research and the environment where, except for monozygotic twin studies, there are only sporadic reports to suggest that environmental factors are at work in etiology. Here, we examine epigenetic concepts as they may relate to human development, normal life history phases and AIS pathogenesis. Although AIS is not regarded as an NCD, like them, it is associated with whole organism metabolic phenomena, including lower body mass index, lower circulating leptin levels and other systemic disorders. Some epigenetic research applied to Silver-Russell syndrome and adiposity is examined, from which suggestions are made for consideration of AIS epigenetic research, cross-sectional and longitudinal. The word scoliogeny is suggested to include etiology, pathogenesis and pathomechanism.

Maternal age at birth: does it dictate the epigenotypic expression of the trunkal asymmetry of a child?

INTRODUCTION: Trunkal back asymmetry is considered very important for the selection of children at risk of developing scoliosis. Traditionally, this asymmetry as thoracic or lumbar hump is the main indicator for referral of subjects with idiopathic scoliosis (IS) to clinics from school-screening programs. This asymmetry is also used as the most important sign for further assessment at scoliosis clinics. There are reports suggesting that an epigenetic risk factor for IS is maternal age at birth. However, the influence of maternal age on the development of trunkal asymmetry during growth has not been reported. This report aims to assess if maternal age at birth impacts trunkal asymmetry, and how this parameter may dictate the epigenotypic expression of the trunkal asymmetry of a child. MATERIAL AND METHODS: The sample examined: 11832 (5855 males and 5977 females) children and adolescents (5-17 years old, mean age: 11.34±2.79) were screened at their school for back trunkal asymmetry and/or scoliosis. The measurements: The Prujis scoliometer was used to examine the students in standing and sitting forward bending positions. If at least one of child's measured angles was equal to or exceeded 6 or 7 degrees of scoliometer reading, it was labelled as "Asymmetry-6" and "Asymmetry-7" respectively. The age, standing height and body weight of children and maternal age were also documented, among other parameters. The maternal age at birth and children's BMI were subsequently calculated. The statistical analysis: Asymmetries were tested for correlation with maternal age at birth which was transformed to a categorical variable using 5-year intervals. Pearson's χ2 test was used for the univariate analysis, while logistic regression was used for quantitative univariate and multivariate analysis. Statistical significance level was set to p<.05. SPSS and STATA TM v. 11.0 statistical packages were used for the analysis. RESULTS: Univariate analysis: Univariate analysis showed that the prevalence of asymmetry-6 in boys tended to significantly decrease as mother's age at birth increased (mother's age at birth: <19, 20-24, 25-29, 30-34, 35-39, >40 years, % of asymmetry-6: 11.5%, 9.5%, 8.5%, 7.6%, 5.2%, 5.3%, respectively, (p=0.026). This trend, although present, was not significant in girls. The prevalence of asymmetry-7 also showed a decreasing trend, which was only significant in boys (mother's age at birth: <19, 20-24, 25-29, 30-34, 35-39, >40 years, % of asymmetry-7: 8.7%, 5.9%, 5.9%, 4.6%, 2.6%, 3.5%, respectively, p=0.010). Maternal age at birth, as a continuous variable, was inversely associated with the appearance of asymmetry-6 in both boys and girl s (OR: 0.966, 0.982, 95%CIs: 0.947-0.985, 0.965-0.999, p: 0.001, 0.040, respectively). This was also the case for asymmetry-7 only in boys: (OR: 0.961, 0.982, 95%CIs: 0.938-0.985, 0.962-1.003, p: 0.001, 0.088, respectively). Multivariate analysis: The significant and inverse effect of maternal age at birth on the appearance of asymmetry in boys remained even after adjusting for child's BMI and age. For one year increase of maternal age at birth, the odds of the boys being asymmetrical6 were reduced by 2.8% (OR:0.972, 95% CIs: 0.953-0.992, p: 0.005), adjusting for child's age and BMI. For one year increase of maternal age at birth, the odds of the boys being asymmetrical7 were reduced by 3.2% (OR:0.968, 95% CIs: 0.945-0.992, p: 0.010), adjusting for child's age and BMI. However, the aforementioned correlations were not significant for girls in both cases. DISCUSSION AND CONCLUSIONS: The influence of maternal age at birth on the development of trunkal asymmetry during growth has not been previously assessed, as evidenced from literature review. The findings of this report indicate that maternal age as an environmental factor in the general population, may possibly influence epigenetically, the occurrence of the initial presentation of trunkal asymmetry in males more than females, as well as IS during growth. Consistent findings reported from the USA, Edinburgh and Sweden reveal increased maternal age as a risk factor for AIS, suggesting maternal factors can predispose to it. It seems that males are more affected by this factor but, unexpectedly in this study, by younger and not older mothers, as reported for AIS in the literature. Low-birth weight associated with younger parental age may also be associated with increased trunkal asymmetry particularly of boys, an hypothesis that need testing. The importance our findings is based on the belief that the intra-uterine environment is crucial in programming the fetus for various health and disease outcomes throughout life.

Upper arm length model suggests transient bilateral asymmetry is associated with right thoracic adolescent idiopathic scoliosis (RT-AIS) with implications for pathogenesis and estimation of linear skeletal overgrowth.

INTRODUCTION: In girls with adolescent idiopathic scoliosis (AIS) the finding of abnormal extra-spinal bilateral skeletal length asymmetries in upper limbs, periapical ribs, and ilia begs the question whether these bilateral asymmetries are connected in some way with pathogenesis. MATERIAL AND METHODS: We investigated upper arm length (UAL) asymmetries in two groups of right-handed girls aged 11-18 years with right thoracic adolescent idiopathic scoliosis (RT-AIS, n=95) from preoperative and screening referrals (mean Cobb angle 46°) and healthy controls (n=240). Right and left UAL were measured with a Harpenden anthropometer of the Holtain equipment, Asymmetry was calculated as UAL difference, right minus left, in mm. Repeatability of the measurements was assessed as technical error of the measurement and coefficient of reliability. RESULTS: In girls with RT-AIS, UAL asymmetry was greater than in healthy girls, regressed negatively with age and correlated significantly with Cobb angle and apical vertebral rotation. In healthy girls, UAL asymmetry was unrelated to age. Plotted against years after estimated menarcheal age, UAL asymmetry decreased significantly for girls with RT-AIS but not for healthy girls. DISCUSSION AND CONCLUSIONS: The apparent transience of the abnormal UAL asymmetry suggests it is not secondary to spinal deformity but pathogenetically associated with it. We suggest two hypotheses to account for these changes: (1) a transient asymmetry process with growth velocity; and (2) in the light of subsequent research, early skeletal overgrowth with catch-down growth affecting right but not left upper arm. The relation of the upper arm length asymmetry to the increased length of periapical left ribs reported for RT-AIS is unknown. Right upper arm length may provide a more simple model than arm span, for estimating linear skeletal overgrowth of girls with RT-AIS.

Abnormal cerebral cortical thinning pattern in adolescent girls with idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a 3-D spinal deformity with uncertain etiology; abnormalities in brain development represent one of the possible explanatory concepts for its pathogenesis. The objective of this study is to investigate the brain maturation by thickness of cerebral cortex among female adolescents with and without idiopathic scoliosis. Fifty AIS patients with a typical right-thoracic curve pattern were compared with 40 age-matched healthy controls. Based on the T1-weighted magnetic resonance images, the thickness of cortical gray-matter was calculated using a well-validated surface measurement method. Focusing on adolescent participants within the age range with the frequent occurrences of AIS cases (i.e., 12 to 17 years), we observed that the cortical thickness declined significantly in almost all cortical lobes in normal subjects (Spearman correlation<-0.4; P ≤ 0.05) except temporal lobe in LH, while in AIS patients this decline was weakly correlated with age (Spearman correlation>-0.4) and largely insignificant (P ≥ 0.05). Quadratic regression results expressed the detailed difference in the age-related cortical changing pattern between the two groups. In addition, focal cortical thickness was significantly different in AIS patients compared with healthy controls in areas involved in motor and vestibular functions as well as object recognition. The findings from this study imply a different thinning pattern of the cerebral cortex during adolescence in patients with AIS; this may be primary (i.e. etiopathogenetic) or secondary (i.e. adaptation) to the development of scoliosis.

Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy.

Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy.

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans.

Relatively lower body mass index is associated with an excess of severe truncal asymmetry in healthy adolescents: Do white adipose tissue, leptin, hypothalamus and sympathetic nervous system influence truncal growth asymmetry?

BACKGROUND: In healthy adolescents normal back shape asymmetry, here termed truncal asymmetry (TA), is evaluated by higher and lower subsets of BMI. The study was initiated after research on girls with adolescent idiopathic scoliosis (AIS) showed that higher and lower BMI subsets discriminated patterns of skeletal maturation and asymmetry unexplained by existing theories of pathogenesis leading to a new interpretation which has therapeutic implications (double neuro-osseous theory). METHODS: 5953 adolescents age 11-17 years (boys 2939, girls 3014) were examined in a school screening program in two standard positions, standing forward bending (FB) and sitting FB. The sitting FB position is thought to reveal intrinsic TA free from back humps induced by any leg-length inequality. TA was measured in both positions using a Pruijs scoliometer as angle of trunk inclinations (ATIs) across the back at each of three spinal regions, thoracic, thoracolumbar and lumbar. Abnormality of ATIs was defined as being outside 2 standard deviations for each age group, gender, position and spinal region, and termed severe TA. RESULTS: In the sitting FB position after correcting for age,relatively lower BMIs are statistically associated with a greater number of severe TAs than with relatively higher BMIs in both girls (thoracolumbar region) and boys (thoracolumbar and lumbar regions).The relative frequency of severe TAs is significantly higher in girls than boys for each of the right thoracic (56.76%) and thoracolumbar (58.82%) regions (p = 0.006, 0.006, respectively). After correcting for age, smaller BMIs are associated with more severe TAs in boys and girls. DISCUSSION: BMI is a surrogate measure for body fat and circulating leptin levels. The finding that girls with relatively lower BMI have significantly later menarche, and a significant excess of TAs, suggests a relation to energy homeostasis through the hypothalamus. The hypothesis we suggest for the pathogenesis of severe TA in girls and boys has the same mechanism as that proposed recently for AIS girls, namely: severe TAs are initiated by a genetically-determined selectively increased hypothalamic sensitivity (up-regulation, i.e. increased sensitivity) to leptin with asymmetry as an adverse response to stress (hormesis), mediated bilaterally mainly to the growing trunk via the sympathetic nervous system (leptin-hypothalamic-sympathetic nervous system (LHS) concept). The putative autonomic dysfunction is thought to be increased by any lower circulating leptin levels associated with relatively lower BMIs. Sympathetic nervous system activation with asymmetry leads to asymmetries in ribs and/or vertebrae producing severe TA when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion of the trunk. A test of this hypothesis testing skin sympathetic responses, as in the Rett syndrome, is suggested.

Volume-based morphometry of brain MR images in adolescent idiopathic scoliosis and healthy control subjects.

BACKGROUND AND PURPOSE: Adolescent idiopathic scoliosis (AIS) is a spinal deformity with unknown cause. Previous studies have suggested that subclinical neurologic abnormalities are associated with AIS. The objective of this prospective study was to characterize systematically neuroanatomic changes in patients with left thoracic AIS vs right thoracic AIS and healthy control subjects by using volume-based morphometry. MATERIALS AND METHODS: Our current study involved 9 girls with left thoracic AIS and 20 girls with right thoracic AIS vs 11 and 17 matched female control subjects, respectively. Voxel-based morphometry (VBM), deformation-based morphometry (DBM), and tensor-based morphometry (TBM) were used to analyze the MR images aligned with a specific brain template of local adolescent girls. The statistical t test was used in VBM and TBM, and the Hotelling T(2) test was applied in DBM. RESULTS: Using VBM, we found statistically significant differences (P < .05) in the white matter attenuation of the genu of the corpus callosum and left internal capsule (left thoracic AIS < control subjects). In contrast, no significant differences were observed between patients with right thoracic AIS and control subjects. CONCLUSIONS: White matter attenuation in the corpus callosum and left internal capsule, responsible for interhemispheric communication and conduit of the corticothalamic projectional fibers, respectively, were found to be significantly lower in left thoracic AIS compared with control subjects; however, this was not the case in right thoracic AIS. Confirmation of the findings is required in future research, which needs to evaluate the relationship of white matter abnormality to curve laterality, pathogenesis, and prognosis in patients with AIS, with biologic significance and possible therapeutic correction.

Body mass index of girls in health influences menarche and skeletal maturation: a leptin-sympathetic nervous system focus on the trunk with hypothalamic asymmetric dysfunction in the pathogenesis of adolescent idiopathic scoliosis?

Lower body mass index (BMI) and lower circulating leptin levels have been reported in girls with AIS. In this paper we evaluate skeletal sizes and asymmetries by higher and lower BMI subsets about the means for each of three groups of girls age 11-18 years: 1) normals, 2) school screening referrals, and 3) preoperative girls. Higher and lower BMI subsets, likely to have separated subjects with higher from those with lower circulating leptin levels, identify: 1) girls with relatively earlier and later menarche; 2) trunk width size greater in the higher than in the lower BMI subset, of all three groups; 3) abnormal upper arm length (UAL) asymmetries (right minus left) in the lower BMI subset of the preoperative girls; and 4) in thoracic AIS of screened and preoperative girls, Cobb angle and apical vertebral rotation each significantly and positively correlate with UAL asymmetry in the lower BMI subset but not in the higher BMI subset. In preoperative girls, the lower BMI subset shows the combination of relatively reduced pelvic width and abnormal UAL asymmetry, suggesting that both are linked to lower circulating leptin levels. An earlier puberty with hormonal changes provides a plausible explanation for the larger trunk width at the shoulders and pelvis especially at the younger ages in the higher BMI subsets. At the shoulders, this widening is driven by the ribcage which, in human evolution was acquired with decoupling of head and trunk movements required for efficient bipedal gait. The UAL asymmetry patterns within the groups and BMI subsets are not explained by hormonal mechanisms. It is hypothesized that 1) normal trunk widening of the thoracic cage by hormones in human adolescence is supplemented via the sympathetic nervous system under leptin-hypothalamic control influenced by energy stores (metabolic fuel); and 2) hypothalamic dysfunction with altered hypothalamic sensitivity to leptin through a SNS-driven asymmetric effect may create skeletal length asymmetries in upper arms, ribs, ilia and vertebrae, and initiate AIS. Additional mechanisms acting in the spine and trunk may be required for AIS to progress including 1) somatic nervous system dysfunction, 2) biomechanical spinal growth modulation, and 3) osteopenia.

Ultrasound femoral anteversion (FAV) relative to tibial torsion (TT) is abnormal after school screening for adolescent idiopathic scoliosis (AIS): evaluation by two methods.

In the scoliotic spine, torsion is generally evaluated in relation to axial rotation of the apical vertebra. In the lower limbs, the changes in torsion by age of femoral anteversion (FAV) relative to tibial torsion (TT) have been studied in dried bones, normal growing subjects and adults and subjects with osteoarthritis of the hip or the knee. This paper reports the application of real-time ultrasound to FAV and TT in normal children age 11-18 years and in scoliosis screening referrals with particular reference to how FAV relates to TT as 1) ratios, and 2) tibio-femoral index (TFI) of torsion, calculated as TT minus femoral FAV. The FAV/TT ratio findings show an abnormal normal relationship of FAV to TT both proximo-distally and in left-right asymmetry. These may express torsional abnormalities in femoral and/or tibial growth plates with left-right asynchrony suggesting the possibility of similar torsional abnormalities in vertebral end-plates and/or rib growth plates initiating the deformity of AIS. TFI of the right limb in the scoliosis girls is greater than in the normals that is interpreted as resulting from earlier skeletal maturation of FAV. FAV/TT ratios and TFI are unrelated to the spinal deformity (Cobb angle and apical vertebral rotation) except for boys where TFI is associated with apical vertebral rotation. FAV/TT ratios may be a more accurate method estimating the relationship of FAV to TT. than TFIs.

Leg-arm length ratios correlate with severity of apical vertebral rotation in girls after school screening for adolescent idiopathic scoliosis (AIS): a dynamic pathomechanism in the initiation of the deformity?

There is increasing support for the view that the unique human bipedalism and the erect posture are prerequisites for the pathogenesis of adolescent idiopathic scoliosis (AIS). How human bipedalism may contribute to the pathogenesis of AIS is not clear. In normal humans, axial rotations and counter-rotations of the trunk are carried out frequently and forcibly in activities that are not performed by quadrupeds. Some workers have analysed gait in AIS subjects, others have studied torsions in lower limb bones, but there are only two reports on leg-arm ratios in relation to AIS. In this paper, leg-arm ratios studied in relation to the spinal deformity in scoliosis screening referrals, reveal a highly significant correlation with the apical vertebral rotation but not the Cobb angle of the scoliosis curves. We suggest that leg-arm proportions and movements during gait involving pelvi-spinal axial rotations and thoracic counter-rotations contribute a dynamic pathomechanism to early AIS from whatever cause and involving the thoracic cage. Curve progression needs other mechanisms that may include a central nervous system failure to control structural asymmetry of vertebral axial rotation, and biomechanical spinal growth modulation.

Etiologic theories of idiopathic scoliosis: autonomic nervous system and the leptin-sympathetic nervous system concept for the pathogenesis of adolescent idiopathic scoliosis.

The autonomic nervous system through its hypothalamic neuroendocrine control of puberty, skeletal growth and menarche contributes importantly to the pathogenesis of adolescent idiopathic scoliosis (AIS). Melatonin dysfunction detected in AIS subjects also involves the autonomic nervous system. The thoracospinal concept for the pathogenesis of right thoracic AIS in girls thought by some to result from dysfunction of the sympathetic nervous system (SNS), is supported by recent vascular and peripheral nerve studies. Lower body mass index (BMI).in girls with AIS is associated with decreased circulating leptin levels. Leptin, secreted by adipocytes, is a master hormone with many regulatory functions for growth and reproduction, including: 1) appetite repression, anorexigenic; 2) initiation of puberty in girls in a permissive action, and 3) in mice, longitudinal bone growth, chondrogenic and angiogenic, and in bone formation, antiosteogenic acting centrally through the SNS and possibly directly. In AIS girls, autonomic nervous system activity was reported to be higher than in controls. We suggest that in AIS susceptible girls, given adequate nutrition and energy stores, circulating leptin talks to the hypothalamus where dysfunction leads to an altered sensitivity to leptin resulting in increased SNS activity contributing with neuroendocrine mechanisms to: 1) earlier age at, and increased peak height velocity, 2) general skeletal overgrowth, 3) earlier skeletal maturation, 4) extra-spinal skeletal length asymmetries, including periapical ribs and ilia, 5) generalized osteopenia, and 6) lower BMI. The SNS-driven effects may also add adventitious changes to the spine including asymmetries complicating the neuroendocrine effects on adolescent spinal growth. In AIS pathogenesis, the leptin-SNS concept is complementary to our NOTOM escalator concept involving the somatic nervous system. Together these two concepts view AIS in girls as being initiated by a hypothalamic dysfunction of energy metabolism (bioenergetics) affecting skeletal growth in the trunk. Where, in susceptible girls, the postural mechanisms of the somatic nervous system fail to control the asymmetric spinal and/or rib growth changes in a rapidly enlarging adolescent spine; this failure becomes evident as mild back-shape shape asymmetry, or scoliosis. The environmentally-enhanced stature of normal subjects in the last 300 years, in girls susceptible to AIS, may have exaggerated any developmental dysharmony between the autonomic and somatic nervous systems being fought out in the spine and trunk of the girl - possibly making mild back-shape asymmetry, or scoliosis more prevalent today than hitherto.