R Geoffrey Burwell

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.

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 environment s. 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.

Changes in surface and radiographic deformity after universal spine system for right thoracic adolescent idiopathic scoliosis: is rib-hump reassertion a mechanical problem of the thoracic cage rather than an effect of relative anterior spinal overgrowth

Study Design. Analysis of preoperative, 8-week, 1-year, and 2-year data from patients with right thoracic adolescent idiopathic scoliosis treated by posterior Universal Spine System (Stratec Medical, Oberdorf, Switzerland). Objective. Report 2-year results and the association between back surface and radiographic assessments. Summary of Background Data. Few longitudinal studies have related surface and radiographic data in the follow-up of surgical patients. Methods. Of 34 patients with right thoracic adolescent idiopathic scoliosis having posterior Universal Spine System instrumentation, 27 had complete prospective back surface and radiographic appraisal. Results. Cobb angle corrected from 58° to 34° (41%), apical vertebral rotation from 26° to 20° (23%), apical vertebral translation from 4.5 to 2.4 cm (47%), and maximum angle of trunk inclination from 17° to 13° (22%) (preoperative to 2 years). Rib-hump reassertion occurred between 8 weeks and 1 year, regardless of age, and correlated with changes in vertebral translation (for 10 vertebral levels corresponding to 10 back surface levels between C7 and S1, P = 0.001 MANOVA). Preoperative frontal tilt of L1 with concave fifth rib-spinal angle predicted the percentage correction of maximum angle of trunk inclination, and the concave ninth rib-spinal angle predicted reassertion of maximum angle of trunk inclination. Conclusions. Almost half of initial back surface correction is lost by 2 years. Segmental vertebral translation measurements most strongly correlate with segmental angle of trunk inclination measurements during follow-up. Rib-hump reassertion is best explained by unwinding of the thoracic cage tensioned by surgery rather than through relative anterior spinal overgrowth. Spine and thoracic cage factors determine rib-hump correction, so surgical disruption of the latter by costoplasty may prevent rib-hump reassertion. Results of scoliosis sur-gery should include surface data.

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.

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?

BackgroundIn 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).Methods5953 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.ResultsIn 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.DiscussionBMI 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.

Body mass index in relation to truncal asymmetry of healthy adolescents, a physiopathogenetic concept in common with idiopathic scoliosis: summary of an electronic focus group debate of the IBSE

There is no generally accepted scientific theory for the cause of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE).introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr TB Grivas. It is based on published research from Athens, Greece evaluating schoolchildren age 11–17 years for the relation of body mass index (BMI) to each of truncal asymmetry (TA) and menarcheal status. Girls with relatively lower BMI were found to have a significant excess of severe TAs and significantly later menarche confirming the well-known relation of BMI to menarche. Together with other evidence linking nutritional status to skeletal growth, the observations suggest energy balance via the hypothalamus is related to trunk asymmetry. As with a recent speculative hypothesis for the pathogenesis of AIS in girls, Grivas et al. suggest that the severe TAs involve a genetically-determined selectively increased sensitivity (up-regulation) of the hypothalamus to circulating leptin with asymmetry as an adverse response to stress (hormesis). The TA is expressed bilaterally via the sympathetic nervous system to produce left-right asymmetry in ribs and/or vertebrae leading to severe TAs when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion in the trunk. This EFG discusses the findings and interpretations of the paper by Grivas and colleagues as research at the borderland between the genesis of TA (physiogenesis) and AIS (pathogenesis). It is suggested that TAs, here regarded in common with AIS, result from the combination of secondary sexual development affecting body composition, adolescent skeletal growth velocity, and an asymmetry process. The possible involvement of epigenetic factors is not considered.

Scoliogeny of adolescent idiopathic scoliosis: inviting contributions for a discussion based on evidence and theoretical interpretations aiming ultimately to prevention or aetiological treatment

This Editorial initiates a Thematic Series on the aetiology, pathogenesis and pathomechanisms (scoliogeny) of adolescent idiopathic scoliosis (AIS). It introduces the Series and invites contributions from researchers in the field and from interested parties. The aim is to develop a wideranging online discussion based on evidence and theoretical interpretations, In doing this, it will extend the role of the electronic focus group of the International Federated Body on Scoliosis Etiology (IBSE) which discussed nine selected topics from 2003 to 2013 [1,2]. While the relationship between scoliosis and growth was recognized forty years ago [3], progress in understanding the causation of AIS was fettered by a relative paucity of basic biological and biomechanical scientific data. Since then and subsequent to emphasis in pathogenesis on sagittal spinal plane [4] and relative anterior spinal overgrowth [5], advances in biological knowledge have enabled scoliogenic understanding to progress particularly after the year 2000 [6-8]. Knowledge limtation still restricts scoliogenic understanding for example in relation to the biochemistry and endocrinology of AIS [9] and the abnormal extra-spinal skeletal length asymmetries of AIS girls which are of unknown pathogenetic significance [2,10,11]. Research on the genetic variant hypothesis of disease for AIS has led to significant achievements [12]. Within the research forum of the British Scoliosis Research Foundation [13] there is a separate, private forum for the International Scoliosis Genetics Interest Group (ISGIG), a specialist group formed at the 2011 International Phillip Zorab Symposium. A possible role for environmental and epigenetic factors in AIS scoliogeny is