Previous research in Hong Kong introduced a redefined MRI reference level at the foramen magnum (at and below the basion-opisthion line) to diagnose asymptomatic Chiari 1 malformation [32, Moderator see 33]. In 164 patients with AIS, tonsillar ectopia was found in 33% of patients with abnormal SSEPs and 2.9% of patients with normal SSEPs 34 pointing to a neural origin. In AIS, tonsillar ectopia significantly different from normal is established 3536. Abnormal SSEPs were found in 17/147 (11%) of AIS patients [37, see 38]. SSEPs reflect the presence of disturbed standing balance control when the subject relies on somatosensory input 39 with functional delay above the cervical level in most patients 40. But there is evidence that SSEPs do not correlate significantly with Cobb angle changes after one year of rehabilitation 41. The conus medullaris is at a normal position 42 in AIS 43, Dr Chu and colleagues speculate that 1) subjects with severe scoliosis could have subclinical cord tethering without clinically detectable neurological deficit, and 2) AIS is a disorder of wide spectrum with neuroanatomical changes and/or abnormal neural function only emerging with severe scoliosis.

Not only is linear vertebral column growth abnormally increased in AIS, but Dr Chu and colleagues report morphological evidence 234 of altered spinal cord shape about the curve apex suggesting that the cord is also affected ie a 'double pathology' may exist involving spine and cord (Figure 2). Consideration is required for the cause of each of 1) vertebral column overgrowth, and 2) putative impaired spinal cord growth. Dr Chu and colleagues address these aspects further in recent papers 34. The vertebral overgrowth of AIS may be explained by the concept of primary skeletal change 44 as it affects the sagittal plane of the spine with anterior increments and posterior decrements as pathogenesis and, as histogenesis,uncoupled, or asynchronous, endochondral-membranous bone growth 67. Roth explained AIS pathogenesis as an exaggeration of the normal differential growth of the cord and spine by hormonal abnormality ['vertebro-neural growth theory', 23242545]. Porter 28 stated that the putative impaired growth of the spinal cord in AIS may result from an abnormal response to stretch including: 1) inadequate cord growth from deficient hormonal environment; 2) cell membrane defect with abnormal function of contractile proteins in cells of the spinal cord as part of a systemic disorder; 3) abnormality of the elastin fibre system, 4) failure of melatonin to scavenge free radicals resulting in spinal cord stretch injury; and 5) hypoxia.

There is a lack of research on the biomechanical properties of the spinal cord in scoliosis specimens. Dr Chu and colleagues have a biomechanical model in hand to test the asynchronous neuro-osseous growth concept of AIS. There is research on the biomechanical properties of the normal spinal cord in relation in vivo kinematics caused by spinal movements 16174647484950, viscoelastic properties 515253545556 and, some evidence for the development of an anterior component of force in spinal forward flexion 16; the latter which may be relevant to scoliosis pathogenesis is not debated in this EFG.

From the biomechanical standpoint the continuous axial neural tract (neuraxis) of pons, medulla oblongata, spinal cord and cauda equina is a functional unit between mesencephalon and lumbo-sacral ganglia 1747. When the normal adult spinal canal is elongated by forward flexion, the neuraxis is axially stretched between its cranial and caudal points of fixation and, when backward extended, is slackened 161746474849. Breig 17 examined cadavers and living subjects and found that in spinal flexion/extension the spinal cord: 1) unfolds and folds; 2) does not move up and down axially in the spinal canal but adapts to the varying length of the canal by plastic deformation – lengthening in flexion and shortening in extension; 3) cross-sectional area decreases in flexion and increases in extension (Figure 2); and 4) resistance to further cord elongation in pronounced flexion is taken up primarily by pia mater and to a lesser extent by cord substance. In lateral flexion, both spinal canal and neuraxis elongate on the convexity and shorten on the concavity. During spinal flexion, or lateral flexion, there is slight elastic tension with cord lengthening limited by an unyielding pia mater. Breig 17 suggested that processes which increase axial tension in the neuraxis namely, changes in relative lengths of spinal canal and cord, can lead to pathologic axial tension and damage the cord and spinal nerves by overstretching. In health, cord function, synaptic transmission, and metabolism all continue undisturbed within dynamically changing cord tissue 4650.

In monkeys 46, the cervical cord in flexion stretches most (24%) and least in the caudal cord (4%). Below the mid-cervical level, movements in flexion are toward the head and above this level are away from it. In human cadavers, Reid 16 found that the length of the spinal canal increased up to 18 mm at C8-T5 roots on forward flexion. In AIS girls the mean sitting height lengthening is 20 mm 13. In the thoracic kyphosis of human cadavers in the normal erect posture, the cord and dura (theca) are closely apposed to the anterior wall of the spinal canal and loosely tied by fibrous bands to the posterior longitudinal ligament 16. In different degrees of spinal flexion, Reid 16 measured the anterior component of a force exerted by the cord and dura at different levels (C3-T12) and found physiological lengthening of cord and dura, chiefly between C2-T1 up to a maximum of 17.6%; and the anterior component of the force which reached maximum values of 30–40 lb/sq inch (207–276 kilopascals) (Figures 1 &2).

These data suggest a mechanism for thoracic AIS by which the hypokyphosis about the curve apex may come about. A spinal cord of normal length stretched by linear vertebral overgrowth may create an anterior component of force that exerts pressure on, and flattens, the kyphos. Mid-thoracic vertebrae have a pre-existing rotation to the right 57. In Dr Chu's concept for AIS the lateral spinal curve and axial vertebral rotation evolve together, by the cord tether restraining linear vertebral overgrowth – as in the spring model of Roth 2425. Scoliosis evolution with its lateral spinal flexion – by analogy with Reid's 16 findings of cord lengthening in forward flexion – should lead to structural lengthening of cord and dura, despite the move to a posterior centre of axial rotation 2658. This lengthening of the cord in a scoliotic spine suggests that where Dr Chu and colleagues measured the cord length as normal in the deformed spine, before curve initiation the cord was short in absolute terms. In normal children, asynchronous growth of cord and column in early adolescence may contribute to the flattening of the kyphosis in normal girls 5960. In progressive infantile idiopathic scoliosis, the cord axial rotation may not always adjust to the change in anatomy of the vertebral column 61, an observation confirmed for AIS 31.

The biomechanical properties of the human cadaveric spinal cord within physiological levels of loading have been studied under axial tension and longitudinal elongation in isolated specimens freed from dura mater 5354. Uniaxial tension applied at moderate strain rates showed a non-linear stress-strain response with increasing strain increasing the tangent modulus; and a significant relaxation over 1 minute 53. The pia mater gives the isolated human spinal cord its tensile strength in the axial direction 54. In animals, uniaxial biomechanical properties of the spinal cord have been reported for anesthetised puppies 51 and cats 52, cattle 56 and rats 55. The rat spinal cord subjected to moderate strain rates showed non-linear viscoelastic characteristics commonly seen with biological tissues, fitted to an integral non-linear viscoelastic model 55. We are aware of no studies on the mechanical properties of the spinal cord specimens from either experimental scoliosis 6263, or scoliotic subjects. One difficulty with human spinal cords if and when available is the rapid deterioration in the quality of the tissue after excision 56.

Restriction of neck flexion with AIS has not been reported except for a special group of boys 6465: twelve adolescent males had mild thoracic scoliosis of unknown pathogenesis and markedly restricted neck flexion with no other anomalies detected, and described as a distinct type of adolescent "idiopathic" scoliosis. The most prominent feature in 9/12 subjects was the presence of mild thoracic or neck pain. To explain the thoracic scoliosis, limited neck flexion, and pain, local or distant cord tethering 64 and a short spinal cord 65 are suggested. Neck flexion/extension alters spinal cord shape 17 (Figure 2).

The asynchronous neuro-osseous growth concept of Dr Chu and colleagues does not explain higher level CNS disturbances in AIS including vestibular function 6667686970. This led Dr Chu and colleagues to scan the brain, search for and find 1) volumetric regional brain volume differences between AIS subjects and normal controls [7172 Moderator see 7374], and 2) abnormalities of the skull base 89 and vault 10. This EFG debates the brain asymmetries, a possible primary deficit of interhemispheric coordination, skull abnormalities (of vault and base) and the larger foramen magnum 35. It raises questions about the embryology, particularly of neural crest 75, and the evolution of the normal human gracile skull and possibly gracile human spine in relation to the inactivated MYH16 gene 76.

The research engenders controversy, including:

1. Why don't all children with cord tethering develop scoliosis?

2. A cause-and-effect relationship has not been demonstrated, only an association.

3. Should thoracic AIS be caused by spinal cord tethering of the adjacent growing spine, how can cord tethering initiate thoracolumbar and lumbar AIS?

4. If the neural axis tethers the anterior spinal column, how can this determine the laterality patterns of AIS?

5. Cord tethering in syringomyelia does not cause a predominant laterality for the associated scoliosis 77, so how can a short spinal cord explain the laterality patterns of AIS?

6. Why neck flexion is not restricted in thoracic AIS apart from a distinct type of adolescent 'idiopathic' scoliosis in males 6465. A neuraxis under pathologic axial tension in AIS should limit spinal cord elongation in forward flexion 1617474849 which evidently it does not.

7. Mechanical properties of spinal cord relative to physiological forces created by traction from linear vertebral growth 515253545556.

8. Can the 'double pathology' concept be validated in a biomechanical test model?

9. Whether the altered apical spinal cord shape of thoracic AIS results from an abnormal spinal cord or, is secondary to the apical hypokyphosis with its local structural spinal extension (Figure 2).

9. How to account for extra-spinal left-right skeletal length asymmetries 131415787980818283 and disproportions by asychronous neuro-osseous growth

10. Speculation that a process producing left-right spinal asymmetry (? from end-plate physes, osseous, discal, or neuromuscular tissues) together with rapid spinal elongation, brain maturation delay, upright posture and trunk movements 84 may contribute to the initiation and progression of AIS [85, Moderator see 8687].

11. Might the results of applying gadolinium-enhanced MR imaging 888990 to vertebral growth plates in AIS shed light on the mechanism of any uncoupled, asynchronous, neuro-osseous growth?

12. Whether spinal nerve roots may develop 'insufficiency' and, with it, left-right asymmetries to induce spinal root neuro-osseous tethers [2391 Moderator see 92].

13. Neural abnormalities for a minority of AIS groups being used to interpret the findings for the majority.

14. Does the lower position of cerebellar tonsils result from spinal cord tether? Or, in some subjects, from a relatively small posterior cranial fossa (as in Chiari I malformation) leading to overcrowding of the hind brain causing the cerebellar tonsils to be pushed down? 93.

15. The view that pontine and hindbrain regions are the likely sites of primary pathology that lead to idiopathic scoliosis 94.

16. The concept does not explain higher level CNS disturbances including vestibular dysfunction 666768697071727374.

17. Anecdotal evidence that prolonged rest in bed halts the progress of scoliosis 9596.

18. Whether different mechanisms are involved in the initiation and progression of AIS 152167979899100101102103104.

19. Whether systemic melatonin-signaling pathway dysfunction in AIS 105106107108109110111 may affect the spinal cord and meninges.

20. Five other concepts that attempt to explain the pathogenesis for AIS are debated: a) relative anterior spinal overgrowth 6718192021; b) right thoracic curves in adolescent girls as a pediatric nosological entity 80112113114 involving the autonomic nervous system and expressed through the ribcage [Moderator see 92115;] c) scoliosis as a biomechanical abnormality arising in hip movement asymmetry [116117118119120121, Moderator see 122123]; d) a neurodevelopmental concept [85, Moderator see 8687]; and e) biomechanical spinal growth modulation [101102103, Moderator see 104124].

21. Whether the concept of subclinical cord tethering has relevance to the pathogenesis of non-idiopathic scoliosis 29 and scoliosis associated with abnormal CNS findings [93125126, Moderator see 127].

In summation, this EFG aims to explore what may be learnt about the pathogenesis of AIS by IBSE members debating via e-mail the findings of Dr Chu and colleagues revealed by applying a new MR imaging technique to progressive adolescent idiopathic scoliosis [Moderator see 128]. Clinical, biological and biomechanical issues relating to the concept of uncoupled, or asynchronous, neuro-osseous growth in the initiation and progression of AIS are discussed with new concepts emerging. Recent relevant research on AIS pathogenesis is considered.

The observations relate to lengths of the vertebral column and spinal cord in two groups of so-called idiopathic scoliosis, 14 girls AIS (<30 degrees) and 14 girls AIS (>40 degrees) in comparison with 14 normal girls are good and proper. The article is very interesting.

The authors present the results of a morphometric MRI study of the spine in right thoracic AIS in girls (Rcx-T-F-AS) using the multiplanar reconstruction MRI technique. It is the second of two MRI studies on thoracic AIS from that centre. Guo et al 67 had used MRI vertebral morphometry of the thoracic spine in AIS which was stated to confirm and support the consensus of the relatively faster growth of anterior than posterior elements of the thoracic vertebrae. In both studies 16 different parameters of vertebrae have been measured and compared between scoliotic and normal subjects.

Dr Chu and colleagues

a) Support the concept of uncoupled neuro-osseous growth, namely that "...longitudinal growth of the spinal cord fails to keep pace with growth of the vertebral column."

b) Support the concept that idiopathic scoliosis is a consequence of maladaptation of the growing immature spine to a tether created by a relatively short spinal cord.

c) Speculate that relative low position of the cerebellar tonsil is related to relative shortening and functional tethering of the spinal cord.

d) Suggest that patients with severe scoliosis could have subclinical cord tethering.

The AIS study population comprises 14 girls with mild scoliosis (<30 degrees Cobb angle) and 14 girls with severe scoliosis >40 degrees Cobb angle).

a) What are the curve types?

b) What is the reproducibility of measuring cerebellar tonsillar ectopia?

There is controversy on methods to analyse stature and sitting height 13132. Standing height is reported as uncorrected for the loss of height due to the lateral spinal curvature.

a) Do you have figures for corrected heights (standing and sitting) for the AIS girls with mild and severe curves?

b) If not, can the corrected heights be calculated from the data generated by the multiplanar reconstruction MRI technique?

Dr Chu and colleagues explain the localization of anterior column lengthening to the thoracic vertebrae by growth plate closure later than in the cervical and lumbar spines, quoting Ganey and Ogden 134. But this quote relates to the neurocentral synchondroses closure with the last closure about 6–7 years and not the vertebral endplate physeal closure which determines the relative anterior spinal overgrowth during adolescence.

After the CT scanning method was applied to the scoliotic spine 136137 in the early 1990s the principles were applied in a series of morphometric studies using different skeletal parameters of scoliotic and normal vertebrae published by a Swedish group 138139140141142.

a) In what respect is the multiplanar reconstruction MR method superior to the earlier morphometric radiological studies?

b) Were they any important differences between the results of studied parameters obtained by the use of the two methods?

The uncoupled, or asynchronous, neuro-osseous growth hypothesis for AIS as postulated by Dr Chu and colleagues has several requirements (Figure 1 and reference 1 Figure 6]:

1) Appendicular skeleton – taller standing height (corrected), sitting height (corrected), arm span, sub-ischial height and body mass index.

2) Vertebral column – relative overgrowth of thoracic anterior spinal column.

3) Spinal cord – normal length (but shortening relative to spine).

4) Tethering of cord anatomically.- low lying tonsil, Chiari I, syringomyelia.

5) Tethering of cord functionally – abnormal neurology.

Do you consider the vertebral and extra-spinal skeletal length overgrowth, apparently seamless, to have a common origin?

In connection with asymptomatic Chiari I malformation and AIS, Sun et al 36149 used MRI to examine 205 AIS patients with a Cobb angle above 40 degrees and 86 age-matched healthy adolescents all of whom were neurologically normal on physical examination. The prevalence of tonsillar ectopia in AIS subjects (0 to 5.2 mm below the BO line) was higher than in healthy adolescents (0 to 1.8 mm). No significant correlations were found between cerebellar tonsil position and age or sex in AIS or control subjects. In AIS patients, cerebellar tonsil position was not statistically significant by curve severity or pattern except for double thoracic curves which had a greater prevalence of tonsillar ectopia. It was concluded that a lower cerebellar tonsil position may play an important role in pathogenesis but not in the development of AIS. Tonsillar ectopia of 2 mm or more in AIS subjects was regarded as abnormal.

The uncoupled, or asynchronous, neuro-osseous growth concept accommodates -

a) the general skeletal overgrowth abnormality as applied to the spine,

b) the left-right asymmetries of the appendicular skeleton, and

c) speculates that a spinal cord abnormality with growth 'insufficiency' leads to 'a stretching tethering force from the two ends, both cranially and caudally' which causes the initiation and progression of thoracic AIS (see Comment no. 12, Response).

To explain with AIS each of the lower position of cerebellar tonsils an alternative view is that some subjects may have a relatively small posterior cranial fossa (PCF) with normal-sized hind brain leading to hind brain overcrowding causing the tonsils to be pushed down similar to that suggested for Chiari I malformation 150151("push" hypothesis, see Comment no. 14).

a) Is the concept of spinal cord abnormality testable ("pull" hypothesis)? [Moderator see 152].

b) Are the 'morphological changes of cross-sectional shape and relative position of the cord' especially in the apical region not just adaptive to the deformity from whatever cause? (see Figure 2 and Comment no. 10, Response).

c) Is the concept of asynchronous nerve root growth testable? (see Comment no. 28, Response b).

d) In AIS subjects should PCF volume be measured in relation to each of the lower position of cerebellar tonsils, tonsillar ectopia, syringomyelia, abnormal SSEPs and the scoliosis? ("push" hypothesis)150151.

e) In any AIS subjects with PCF hypoplasia, should reciprocity be sought with supratentorial brain abnormalities? [66676869707172, Moderator see 7374].

f) Do you relate the smaller skull vault posteriorly in AIS subjects 10 to PCF hypoplasia?

Stedman et al 76 formulated the hypothesis that a disabling mutation of the gene MYH16 produced a decrease in jaw-muscle size that removed a barrier to the gracile remodelling of the human cranium which consequently allowed an increase in the size of the brain. The hypothesis is controversial 160161162163164. The MYH16 gene encodes the predominant myosin heavy chain, a critical protein component of sarcomeres, expressed in powerful masticatory muscles found in most primates. This gene is inactivated in humans. Stredman et al estimate that the MYH16 mutation as a coding sequence deletion appeared approximately 2.4 million years ago (MYA), predating the appearance of modern human body size and the emigration of Homo from Africa. Perry et al 163 date the deletion to 5.3 MYA. Because of -

a) the close parallel between neuro-cranial and neuro-spinal morphogenesis 24134, and.

a) the low or nil prevalence of idiopathic scoliosis in non-human primates 165.

- is it reasonable to suggest that the inactivated MYH16 gene in humans may have relevance to the difference between humans and non-human primates with respect to -

a) spinal morphology 166, and

b) the prevalence of idiopathic scoliosis?

To our knowledge there are no reports of blood vessels supplying the growth plates of vertebral bodies in AIS. Mineiro 167 reported dilated vessels and vascular 'lakes' at each end of normal vertebral bodies from 9–13 years of age. It has been proposed 90 that dilated vessels and vascular 'lakes' adjacent to endplate physes of immature scoliotic vertebrae of living subjects might be sought by using gadolinium-enhanced MR imaging 88 and/or a serial study of diffusion characteristics in the spine after gadodiamide injection 89.

a) Can you apply such a radiological technique to the vertebrae of subjects with AIS?

b) Might the results of applying such techniques shed light on the mechanism of any uncoupled, or asynchronous, neuro-osseous growth?

c) May any positive findings with these radiological techniques in combination with the detection of:

i) platelet dysfunction 168169, and/or

ii) endothelial-derived marker plasma proteins in response to physical exercise 170 and/or exposure to vibration 171 to enable the discrimination of progressive from non-progressive curves 90?

In progressive AIS, Moreau et al 105 reported melatonin-signaling transduction to be impaired in vertebral osteoblasts, myoblasts and lymphocytes caused by the inactivation of Gi proteins [Moderator see 109]. In 2006 their presentations showed this to be associated with high levels of a circulating protein P factor that appears essential for the initiation and progression of AIS through a specific signalling action during a postnatal window 107108. In 2007, Moreau et al 111 reported the use of lymphocytes to develop a functional blood assay for the early detection of AIS and for the identification of children at risk of curve progression; this test can be performed without any prior knowledge of mutations in any defective genes causing AIS.

A systemic abnormality of cell differentiation is proposed as a novel mechanism in the pathogenesis of AIS 106. These findings suggest that the abnormality of AIS relates to the vertebrae rather than to the spinal cord and meninges. Considered with anthropometric findings for AIS showing widespread skeletal overgrowth 5131415 an abnormality of vertebral body growth plates (physes) is suggested that leads to skeletal overgrowth and growth conflicts [172, Moderator see 103173].

As a neuroradiologist I see many growing patients with proven spinal cord tethering, for instance by a thickened filim terminale or an intraspinal lipoma. Some develop neural disturbances but most do not have scoliosis and if so, often only a minimal scoliosis curve. Some fetuses develop spinal cord tethering again mostly without scoliosis. The suggestion that spinal cord tethering may of itself cause adolescent idiopathic scoliosis is theoretical. If so, why don't all patients with cord tethering develop scoliosis?

This is a very interesting description of the deformity of vertebrae in adolescent idiopathic scoliosis. However, it is just that: a description. We know the vertebrae are deformed and advanced imaging technology permits better visualisation and measurement. Chu et al then argue that this deformity is its own cause: because, in AIS, there is a disproportion between spinal and cord length, therefore the deformity was caused by this disproportion. They have not demonstrated a cause-and-effect relationship, only an association. They have not examined whether this proposed pathogenesis agrees with clinical observation or basic anatomy. How can the spinal cord, which has the consistency of cold porridge, tether anything against the powerful force of growth? Surely far greater clinical signs of cord tension would bring the patient to medical attention before the scoliosis was detected?

Does the concept of uncoupled neuro-osseous growth exist outside of scoliosis studies? A search of PubMed suggests not. They may be quite correct in their speculation, but surely solid evidence is necessary before anyone starts de-tethering the spinal cords of every mild scoliosis that presents in the hope of preventing progression?

Tether, thoracolumbar and lumbar scoliosis and curve laterality.

a) If the neuraaxis tethers the anterior spinal column to create thoracic AIS how can it also determine thoracolumbar and lumbar curves?

b) If the neuraaxis tethers the anterior spinal column, how can this determine the laterality patterns of AIS?

Have the investigators addressed the mechanical properties of the spinal cord relative to the physiological forces? If the hypothesis is that the cord mechanically resists, in part, the growth of the vertebral column, how much tension would the cord need to generate to affect the growth of the spine? Is there evidence to suggest that the tensile stiffness and strength of the cord, along its length as well as at the cranial and caudal boundaries, are sufficient to resist those loads?

To explain the extra-spinal left-right skeletal length asymmetries associated with AIS you speculate that the "....observations about asymmetry of skeletal growth might be part of the component in the process of asynchronous neuro-osseous growth in the pathogenesis of AIS." (see Response to Comment no. 34).

a) You invoke a new speculation namely 'asynchronous neuro-osseous growth'. Does this differ from the Porter concept of 'uncoupled neuro-osseous growth' 28 with vertebral growth tethered by spinal cord growth? If so, could you please define 'asynchronous neuro-osseous growth'.

b) How do you explain the extra-spinal left-right skeletal length asymmetries of AIS by 'asychronous neuro-osseous growth'? Are you suggesting that some nerve roots and peripheral nerves develop left-right asymmetry in adolescent growth which in some way causes certain long bones to grow asymmetrically in AIS? In this connection Roth 23 concluded that the behaviour of the spinal cord and nerves in scoliosis suggests 'a primary growth insufficiency of the cord or the nerves, or of both', which account for the curvatures of the spine. Roth 23 wrote: "In other words, the spine cannot grow straight but is forced into curvatures." Some support for this view comes from Repko et al 91 who find that spinal peripheral nerves from the convexity and concavity of 9 patients with idiopathic scoliosis have morphological changes in myelin sheaths and axons compared with 2 patients without scoliosis that may help in the search for the pathogenesis of idiopathic scoliosis [Moderator see 92].

c) Might any asymmetries of rib 80112, upper arm 1314787981 and tibial length 82174 in AIS be explained by such left-right asymmetries of nerve roots and peripheral nerves?

d) If so, how would you account for the iliac length asymmetry 82 associated with each of lumbar and thoracolumbar AIS?

In connection with their uncoupled, or asynchronous, neuro-osseous growth concept would Dr Chu and colleagues respond to the following comments:

a) the view that pontine and hindbrain regions are the likely sites of primary pathology that could lead to idiopathic scoliosis 94,

b) speculation that a process producing left-right spinal asymmetry (? from end-plate physes, osseous, discal, or neuromuscular tissues) together with -

i) rapid spinal elongation

ii) brain maturation,

iii) upright posture and

iv) trunk movements -

may contribute to the initiation and progression of AIS [7185, Moderator see 8687](see Responses to Comments nos. 16 & 17).

c) anecdotal evidence that prolonged rest in bed halts the progress of scoliosis 9596. In over 30 patients in whom scoliosis was advancing, Cobb kept children in bed for 22 hours per day; except for one patient no progress was noted after three months.

The papers of Guo et al 67 address relative anterior spinal overgrowth and AIS in which the Roth-Porter hypothesis of uncoupled neuro-osseous growth was considered, but rejected. This was because knowledge of normal vertebral growth supports the view that the scoliosis deformity in AIS is related to longitudinal vertebral body growth rather than growth of the vertebral canal. As pathomechanism they adopted the concept of primary skeletal change affecting the sagittal plane of the spine, and in the pathogenesis they proposed a novel histogenetic hypothesis of uncoupled endochondral-membranous bone formation. The latter was viewed as part of an 'intrinsic abnormality of skeletal growth in patients with AIS which may be genetic.' The authors of the current paper state that the findings support the concept of uncoupled neuro-osseous growth in the pathogenesis of AIS 28.

a) Do Dr Chu and colleagues reject the primary RASO hypothesis of uncoupled endochondral- membranous bone formation in AIS pathogenesis?

b) Does RASO now provide a biological mechanism for a 'maladaptation of the growing immature spine to a tether created by a relatively short spinal cord'?

At the 2006 IRSSD meeting I presented the argument for girls with the condition of right thoracic adolescent scoliosis to be no longer termed idiopathic 114. These girls form a sub-group of AIS within the thoraco-spinal concept of the pathogenesis for which I proposed the acronym Rcx-T-F-AS 80112. The evidence for defining this sub-group separate from AIS is anthropometric, experimental and biomechanical. The features of this entity include: laterality and pattern of curve, height, weight, gender, menarche, sympathetic dysfunction, abnormalities of muscle fibres and platelets, and osteoporosis [113114, Moderator see 92115].

Our observations together with known and well-documented specific combination of morphological manifestations of the somatic deformity and physiological characteristics of the patients strengthen the recently propounded view that the right thoracic adolescent scoliosis in girls (Rcx-T-F-AS) is not just a spinal deformity but a neglected paediatric nosological entity probably with related extra-vertebral influences 114. We do not relate these observations to other types of adolescent scoliosis, i.e. Rcx in boys, or Lcx in girls and boys.

In the response to Comment no. 31 the authors agree that right convex thoracic adolescent scoliosis in females (Rcx-T-F-AS) may be a subset of AIS which "....probably should not be named 'idiopathic"'. Patients with this type of deformity comprise about 80 per cent of those referred to hospital with AIS apart from two or three small subset. How does your proposed pathogenetic hypothesis of 'asynchronous neuro-osseous growth' explain -

a) the complex of morphological and pathophysiological manifestations of Rcx-T-F-AS 113114, and

b) the simultaneous 3-D vertebral translation?

I cannot accept this hypothesis of uncoupled neuro-osseous growth namely that: "Such tethering could affect anterior spinal column growth leading to a progressive hypokyphosis and lordosis of the thoracic spine which coupled with the subtle neurological dysfunction can then initiate the process of lordoscoliosis deformity in the thoracic spine."

If a shortened spinal cord influences vertebral spinal growth in idiopathic scoliosis the neurological dysfunction cannot be subtle. My explanation for the initiation of the lordoscoliosis of the thoracic spine in idiopathic scoliosis is strictly biomechanical [116117118119120121, Moderator see 122123]. The origin lies in the 'syndrome of contractures' resulting from the left-sidedness of normal fetal positioning 121. This syndrome includes abductor muscle contracture of the right hip which leads to movement asymmetry of both hips transmitting asymmetrical loading from the 'missing' (restricted) movements of the right hip to the pelvis and spine. This produces rotational deformity of the spine with stiffness, and in some children a lordotic deformity, of the thoracic spine, making the anterior spinal column longer than the posterior spinal column (1^st etiological group of scoliosis 120). Hence, vertebral column deformity develops first, and relative shortening of the spinal cord occurs secondarily.

We identified skeletal growth abnormalities thought to be related to AIS pathogenesis and incorporated them into the Nottingham concept of pathogenesis [175, Moderator see 858687]. These include: a) widespread skeletal overgrowth 12131478176; b) extra-spinal left-right skeletal length asymmetries [1314787980818283174176177, Moderator see 178179]; c) proximo-distal lower limb skeletal length disproportion [83174, Moderator see also 177179]; and d) other skeletal disproportions 12. A novel neurodevelopmental mechanism was proposed for AIS pathogenesis [85, Moderator see 8687].

In connection with the widespread skeletal overgrowth, Cole 1314176 found an increase in each of 17 anthropometric components in 66 preoperative AIS girls compared with 693 age-matched healthy girl (5 unpaired and 12 paired components]; the regions included stature and sitting height (each corrected for Cobb angle), subischial height, biacromial width, biiliac width, total arm lengths, upper arm lengths, forearm-with-hand lengths, total leg lengths, tibial lengths and feet. There is controversy about overgrowth in relation to stature and AIS 14132. The skeletal overgrowth in AIS is more evident in younger than older subjects as judged by ranking in centiles, standard deviation scores and bone ageing 1314174179180.

It is not known whether the extra-spinal left-right skeletal length asymmetries and skeletal disproportions signify any local involvement in the spine. We speculate that they do 828385 as for the general skeletal overgrowth [67, Moderator see 8687173]. In this connection there is indirect evidence suggesting that in idiopathic scoliosis both the hypokyphotic and axial rotation components about the apex of the deformity may be determined by local processes in the spine not present in neurogenic scolioses 93124125126127. The CNS component of our neurodevelopmental concept 85 is speculative but accords with evidence that the pontine and hindbrain regions are the likely sites of primary pathology that could lead to idiopathic scoliosis 94. The initiating scoliogenic mechanisms in the trunk are unknown but may involve axial vertebral rotation 2257181, ribcage 1580112113114182183184185186 and trunk movements [8485, Moderator see 8687173187188189190 for the relation of skeletal maturity to curve progression see 191192].

a) How do Dr Chu and colleagues account for the association between thoracic apical rotation and upper arm length asymmetry in thoracic AIS subjects 81?

b) How does the uncoupled, or asynchronous, neuro-osseous growth concept explain the other patterns of extra-spinal left-right skeletal length asymmetries with AIS?

In a recent electronic focus group, Dr Stokes 103 addressed the concept of biomechanical spinal growth modulation in the pathogenesis of progressive AIS [Moderator see 104]. His 'vicious cycle' pathogenetic hypothesis requires a pre-existing scoliosis curve that initiates asymmetric muscle loading on vertebral bodies which in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically normal. How does your uncoupled, or asynchronous, neuro-osseous growth concept relate to biomechanical growth modulation concept proposed by Dr Stokes?