Aetiology of Idiopathic Scoliosis. Current Concepts, Burwell

PEDIATRIC REHABILITATION,
2003,
VOL.
6,
NO.
34, 137170
Aetiology of idiopathic scoliosis:

current concepts
R. G. BURWELL
Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

For personal use only.
Accepted for publication: October 2003
Keywords Scoliosis,
asymmetry
aetiology,
terminology
puberty,
spine,
thorax,
Summary
The aetiology of the three-dimensional spinal deformity of
idiopathic scoliosis (IS) is unknown. Progressive adolescent
idiopathic scoliosis (AIS) that mainly aects girls is generally
attributed to relative anterior spinal overgrowth from a
mechanical mechanism (torsion) during the adolescent growth
spurt. Established biological risk factors to AIS are growth
velocity and potential residual spinal growth assessed by
maturity indicators. Spine slenderness and ectomorphy in
girls are thought to be risk factors for AIS. Claimed
biomechanical susceptibilities are (1) a xed lordotic area
and hypokyphosis and (2) concave periapical rib overgrowth.
MRI has revealed neuroanatomical abnormalities in 20%
of younger children with IS. A neuromuscular cause for AIS
is probable but not established. Possible susceptibilities to
AIS in tissues relate to muscles, ligaments, discs, skeletal proportions and asymmetries, the latter also aecting soft tissues
(e.g. dermatoglyphics). AIS is generally considered to be
multi-factorial in origin. The many anomalies detected, particularly leftright asymmetries, have led to spatiotemporal
aetiologic concepts involving chronomics and the genome
altered by nurture without the necessity for a disease process.
Genetic susceptibilities dened in twins are being evaluated
in family studies; polymorphisms in the oestrogen receptor
gene are associated with curve severity. A neurodevelopmental
concept is outlined for the aetiology of progressive AIS. This
concept involves lipid peroxidation and, if substantiated, has
initial therapeutic potential by dietary anti-oxidants. Growth
saltations have not been evaluated in IS.
Introduction
The question of aetiology must be answered if logical
preventive and therapeutic measures are to be devised [1].
Author: R. G. Burwell, MD FRCS, Emeritus Professor,

University of Nottingham, UK; Honorary Consultant, The
Centre for Spinal Studies and Surgery, University Hospital,
Nottingham, UK. email: burwell@bun.com
The word aetiology strictly means the factor(s) causing the condition, pathogenesis its mode of origin and
pathomechanism the sequence of events in the evolution
of its structural and functional changes [2]. Although
the discussion here relates more to pathogenesis and
pathomechanisms than to the aetiology of AIS, the
term aetiology, or aetiopathogenesis, is used to embrace
all aspects of causation. Attention is directed mainly
to progressive AIS with a few comments on juvenile
idiopathic scoliosis (JIS) and infantile idiopathic scoliosis (IIS). Pelvic tilt scoliosis is not considered.
Torsion has two meanings [3]: (1) a local geometric
property of the vertebral body (geometric torsion or
tortuosity) and (2) axial plane angulations between specied vertebrae (mechanical torsion, or axial rotation).
historical
During the 19th century, three main concepts of
causation of IS emerged, namely (1) myopathic
(Guerin), (2) malpostural (Lovett) and (3) osteopathic
(Schulthess); the latter holding that rickets or endocrine
factors were important in causation [4, 5].
difficulties in deciphering the aetiology of

AIScurrent research and the need for
concepts
Once a scoliotic curve is established, attempts to
determine the biological and biomechanical mechanisms [6] that led to its formation are dicult to decipher [7] and have been likened to the reconstruction of
a railroad accident (Lovett) and to archaeology [8].
However, as Urban [9] pointed out, as scoliosis occurs
during the growth spurt, it is likely that the growth
plate is a major factor in the development of a scoliotic
deformity.
Current aetiologic research on AIS is focusing on
biological and biomechanical factors. The research is
Pediatric Rehabilitation ISSN 13638491 print/ISSN 14645270 online # 2003 Taylor & Francis Ltd
http://www.tandf.co.uk/journals
DOI: 10.1080/13638490310001642757

R. G. Burwell
multi-disciplinary and relates mainly to growth, the central nervous system (CNS), melatonin, muscles, platelet
calmodulin, bone density, elastic bres, the skeletal
framework including vertebral disproportionate growth
and genetics [6, 1018]. Growth saltations and stasis
during puberty [19] have not been evaluated in AIS
subjects.
There is no generally accepted theory for the aetiology of AIS [13, 14]. Many concepts have arisen in the
struggle to understand the causation of AIS, but they
have not been published collectively. Their aim is to
clarify thought and help to plan new researches with
the ultimate aim of improving prognosis and attaining
prevention.
Spinal concepts
an overall concept for the aetiology of AIS
the scoliotic spine as a columntheory and

buckling
Emerging as an overall concept for the aetiology of

progressive AIS in girls is the timing of the adolescent
growth spurt in relation to maturational changes that
occur during puberty in the spine, thorax and nervous
system. This concept is in accordance with current
knowledge that:
1.
2.
Growth is more than an increase in size and

includes the maturation of the child [20, 21]. A
recent paper [18] has shown that AIS girls have
anomalous vertebral proportions involving disproportionate endochondral-membranous growth
and spine slenderness. Subject to conrmation, the
ndings suggest new concepts of aetiology and
prognosis for progressive AIS and with it the
potential for selective early preventive surgery.
In embryogenesis spatio-temporal control involves
internal clocks, the temporal aspects of which are
termed chronomics [22, 23].
Knowledge from developmental biology has been used

to create three multi-factorial spatio-temporal concepts
for the aetiology of AIS, but none is fully integrated
with existing knowledge about the causation of AIS.
a neurodevelopmental concept as part of an

holistic concept of aetiology
A neurodevelopmental concept is outlined for the
aetiology of progressive AIS in girls. The concept
involving lipid peroxidation, if substantiated, has initial
therapeutic potential by dietary anti-oxidants.
138
the scoliotic spine as an helixtorsions and

counter-torsions
Perdriolle and Vidal [24] proposed that the scoliotic
spine, when observed from above, progresses with the
apical vertebrae moving in an arc, anterior to posterior,
around the upper end vertebra; this explained the three
successive stages of lordosis, at back and paradoxical
kyphosis when viewed from the side. Asher and Burton
[25] conrmed this view and maintained that thoracic,
thoracolumbar and lumbar scoliosis deformities evolve
as imperfect torsions and counter-torsions similar to an
elongated helical line and not as mechanical torsions
in which two objects immediately adjacent are rotated
on each other.
Column theory and biology

Millner and Dickson [6] stated that the deformity of
IS is three-dimensional, resulting from viscoelastic
buckling of the spine in both the coronal plane (producing a lateral bend) and the transverse plane (axial
rotation or torsional buckling) as a lordoscoliosis in
an approximation of Eulers Laws. For a progressive
deformity to ensue, the buckling process must occur
during spinal growth. Biological factors bring the spinal
column to and beyond its buckling threshold so that
a taller and slender spine is more liable to bend and,
being stier in the sagittal plane, favours movement
in other planes. The opposite they stated occurs in
Scheuermanns disease, where the deformity is rotationally stable and remains in the sagittal plane.
spine and vertebral slendernessgender
difference linked to curve progression and
expressed in the body build of AIS subjects?
In the technical theory of column buckling, slenderness is dened as the ratio of the square of the columns
length to the moment of inertia of its cross-sectional
area [26]. Spine slenderness has been suggested as one
factor in the predisposition of girls spines to buckle
under load and develop progressive AIS [6, 26, 27].
Normal vertebraegenetic and epigenetic
factorsdierential growth and spinal deformity
In normal spines, sexual dimorphism in vertebral
body shape has been found, with female vertebral bodies

Aetiology of idiopathic scoliosis

being more slender than male vertebral bodies from 8
years onwards [28], as well as in spine slenderness
where spinal length is taken into the equation [26].
Sexual dimorphism implies a genetic control in the
relative contribution of endochondral ossication and
periosteal bone formation to vertebral body shape [29].
According to Ganey and Ogden [30], vertebral growth
not only relies on genetic factors but also responds
to epigenetic factors including paravertebral muscle
tone, upright posture, physical activity, intermittent
hydrostatic compression emanating from the discs
and the check-rein eect of the periosteum [27, 30].
While vertebral body height in the mid-sagittal plane
may be primarily genetically determined and relatively
unaected by mechanical factors, peripheral vertebral
growth (anteroposterior and latitudinal) is more
dependent on the upright posture [30, 31]. The concept
has been suggested [30] that the dierential growth
response of the peripheral (membranous as well as
endochondral ossication) vs central portions (endochondral ossication) may be a factor in the eccentric
growth patterns that lead to the development and
progression of scoliosis and kyphosis.
Idiopathic scolotic vertebraegender dierence

conrmed
In the thoracolumbar spine of children with IS,
Skoglund and Miller [32] reported higher vertebral
height/width indices, suggesting an increased slenderness compared with non-scoliotic children. This nding
was questioned by Veldhuizen et al. [33], but they
conrmed a gender dierence in vertebrae from AIS
subjects. The latter nding supports a role for spinal
slenderness in progressive AIS curves [18] where females
predominate and less so in curve initiation (or induction)
where the female-to-male prevalence is similar.
The external phenotype of AIS subjects

Spine slenderness may reect the somatotype of AIS
girls who are more ectomorphic and less mesomorphic
than healthy girls; and ectomorphy may be associated
with a susceptibility to curve progression [3436].
These concepts need testing, including an evaluation
of the relation of vertebral and spine slenderness to
disproportionate (uncoupled) anterior/posterior vertebral growth [18]. The body composition prole in AIS
girls (weight, body mass index, percentage of body fat
and somatotype) was found to be anomalous [37].
Possible implications of a more ectomorphic

phenotype
Coillard and Rivard [38] suggested that being ectomorphic means mesodermal derivatives are in some
respects underdeveloped, with their skeleton and
muscles being longer and frailer than they are strong
or stocky. In the event of disturbance, the neuromusculoskeletal stability is diminished, making greater the
risk of deterioration.
relative lengthening of the anterior spinal

columndisproportionate endochondralmembranous bone growthdo these findings
represent vertebral slenderness linked to
ectomorphy? concepts for AIS aetiology and
prognosis
Relative lengthening of the anterior spinal column
The long-held view [27, 39] that scoliosis is an isolated
growth lengthening of the anterior spinal column with
torsion has been conrmed by more recent anatomical
studies of structural scoliosis [18, 4044]. This relative
anterior spinal overgrowth, the result of vertebral body
growth plate activity, is generally considered to explain
the apical vertebral translation and both the geometric
and mechanical torsion of the scoliotic spine. Roaf [40]
pointed out that while it is possible to have a lordosis
without rotation and lateral curvature, the sternum and
abdominal muscles prevent this.
Disproportionate endochondral-membranous bone

growthaetiologic and prognostic?
In a recent whole spine MRI study of 83 girls with
AIS and 22 age-matched controls, Guo et al. [18] found
longer vertebral bodies between T1 and T12 in the anterior column and shorter pedicle heights with longer
inter-pedicular distances in the posterior column.
Scoliosis curve severity correlated signicantly with
the ratio of vertebral body length to pedicle height at
all thoracic levels. It was concluded that uncoupled
endochondral-membranous bone formation causes the
relative anterior spinal overgrowth in AIS that may
allow the potential for progression of the deformity.
The mechanism is considered to be an intrinsic
abnormality of skeletal growth that may be genetic.
Importantly, the morphological vertebral patterns
may be prognostic for curve progression in AIS
girls [18] and with it the potential for selective early
preventive surgery.
139
R. G. Burwell
An additional hypothesisvertebral slenderness
predisposes to curve progression in AIS

There is an additional hypothesis to explain their

ndings; namely that spine slenderness predisposes
to AIS progression involving both membranous and
endochondral ossication [30]. The vertebral features
described by Guo et al. [18] may be those of individuals
more ectomorphic than the controls. More research
is needed, including vertebral shape in relation to
somatotyping in scoliotic and normal subjects.
Concepts for AIS aetiology

Three concepts or schools of thought that may
account for the relative anterior spinal overgrowth
(RASO) in AIS girls are:
1.
2.
3.
Primary morphological feature [18]. The RASO

results from an intrinsic abnormality of skeletal
growth involving vertebral disproportionate vertebral body height (signicant sequentially from T612)
that may be genetic. An additional morphological
feature was vertebral body anteroposterior and
latitudinal size (recorded only at T6) that was not
signicantly dierent from the controls implying
vertebral body slenderness of width relative to
height.
Secondary morphological feature [44]. Before the
publication of the paper of Gou et al. [18], the
RASO was thought to be localized to the scoliosis
curve and result from extrinsic mechanical factors
including gravity, tonic muscle action [45, 46], a
short spinal cord [44, 47] or failure of growth of
the posterior elements of a segment of the spine
[48]. This concept does not explain the nding
that scoliosis curve severity correlated signicantly
with the ratio of vertebral body height to pedicle
height at all thoracic levels [18]. A third concept is
needed.
Third and holistic concept. The ndings of Guo et al.
[18] can be used to show that the RASO is maximum at T9 and T10 (respective increase of 12% and
10% relative to the controls against an average of
6% increase from T112). This suggests that about
the curve apex there are superimposed biomechanical
and biological features to cause the increased periapical RASO (with or without other planes being
involved). Theoretical requirements for this concept
to explain progressive AIS include:
(a) Putative primary ligamentous or neuromuscular
mechanisms acting directly on the spine and
140
possibly indirectly through the ribcage in

susceptible girls with primary vertebral morphological features [19] including hypokyphosis
to initiate a 3D thoracic scoliotic deformity
with a short segment lordosis.
(b) The scoliotic deformity may then provoke a
secondary apical RASO as part of an increasing
3D deformity through growth-induced torsion
during the adolescent growth spurt that is
enabled and potentiated by obligatory hormonal
activity and possibly platelet activation,
perhaps in relation to postural maturation.
Other factors that may contribute to curve
progression include less torsional rigidity of
younger intervertebral discs, more mobile spines,
a growth force when some vertebral bodies
and discs outgrow their surrounding tissues
and a large extrathoracic skeleton relative to
chest size in a putative mechanism aecting
spinal biomechanics in gait and other activities.
neurocentral synchondroses (NCSs)pedicle

length asymmetry at 6 years
The relationship of NCSs to the aetiology of IS is
unknown. The concept that greater growth of the apical
concave NCS is aetiologic for AIS is controversial
because of lack of agreement on the exact age at
which closure occurs [30, 4951]. The pedicle length
asymmetries of mid-thoracic vertebrae generally
observed by 6 years of age [52] were conrmed by
Taylor [53], who suggested that longer left pedicles
about 8 years by rotating the vertebral body to the
right may predispose a girl to the development of IS
at a later age. Farkas [52] interprets the pedicle asymmetry as one of torsion and a delusion of rotation.
facet joints?growth asymmetry and

loop effect
According to Roaf [42], the earliest morphological
changes of slight scoliosis are hypoplasia and alteration
of the alignment of the articular processes on the concave side. Later, these changes become very marked
with degeneration, osteophytes and bony ankylosis [27].
Ganey and Ogden [30] suggest the concept that
alteration of rates of growth can aect the shape of
posterior elements and secondarily aect muscle function, which aects growth rates (loop eect).

osteopeniagender difference in healthan
AIS sub-group having low skeletal mass, or
are the vertebral findings due to spine
slenderness?

Bone mass accumulation in health

Bone mass accumulation in the spine during puberty
in girls is restricted to a 4-year period at 1115 years of
age. In boys, the acceleration in bone mass accumulation is delayed to that of girls and is particularly
pronounced from 1317 years [54] to reach a plateau
in the third decade of life. Peak bone mass is strongly
aected by genetic (7580%), nutritional (such as
calcium, vitamin D and dietary fats [55]), lifestyle
and environmental factors as well as hormones, especially oestrogen [56, 57]. Dietary calcium in girls during
puberty is believed by some to be below recommended
levels [58].
AIS
Cheng [18, 56] concluded that there is a clear association between AIS and generalized osteopenia and
opined that intra-skeletal mechanisms can contribute
to the pathogenesis of AIS. In contrast, Lowe et al.
[14] concluded that they were not aware of any evidence
that inferior bone quality was an important factor in
the aetiology of IS. Courtois et al. [59] found lower
bone mineral densities in the patients than the controls
in 33 young women with AIS and brace treated
and suggested a need for osteopenia screening and prevention in children with scoliosis. Most recently,
Guo et al. [18] suggested that the low bone mineral
density in AIS subjects previously reported by Cheng
[56] could represent a relatively small bone mass and
slower circumferential bone growth.
Previous to the paper of Guo et al. [18], Cheng [56]
suggested multi-centre studies on the prevalence of low
bone mineral density among AIS patients, including
anthropometric data, skeletal growth pattern, associated life style risk factors of osteopenia, biochemical
bone turnover prole and genetic studies. The therapeutic hope was that treatment to improve bone mineral
status would alter the natural history of the scoliotic
deformity. In this connection, a synthesized estrogenlike hormone, estren, may become the rst of a new
class of osteoporosis drugs termed ANGELS (activators
of nongenomic estrogen-like signalling) [60]. In the light
of the ndings of Guo et al. [18], bone mineral density
studies should include evaluation of vertebral morphology and somatotyping.
Goto et al. [61], in a nite element study, implicated

bone resorption in the aetiology of AIS.
inter-vertebral discs (IVDs)not a primary
factor but discs contribute to the deformity
While the inter-vertebral disc does not appear to be
the primary factor in the aetiology of IS, as it becomes
signicantly and irreversibly wedged [62] the disc
contributes to the development of the scoliosis curve
[63, 64]. Roberts et al. [65] concluded that it is very
likely that the changes in cartilage endplate (vertebral
body growth plate) and IVDs are key factors in the
progression of scoliosis and the manner in which the
curve will respond to dierent therapeutic regimens.
According to Taylor and Melrose [66], the response of
IVDs to abnormal stresses imposed on them in scoliosis is central to the long-term prognosis of untreated
lumbar and thoracolumbar curves.
The diurnal variation in the water content of lumbar
IVDs evident on MRI in two young adult subjects [67]
was suggested as a contributory factor to the scoliosis
deformity. Aulisa et al. [68] concluded that the torsional
rigidity of the inter-vertebral discs increased throughout
growth that favoured the progression of early scoliotic
curves.
spinal mobility in healthy and scoliotic
childrendo girls have stiffer spines and
if so most in which plane?
Dickson and Weinstein [69] stated that girls have
stier spines than boys and that is one of the mechanical reasons favouring buckling of the vertebral column.
Spinal exibility during deep inspiration
Lowden et al. [70] examined 442 healthy children
aged 815 years using a Kyphometer and conrmed
that girls but not boys kyphosis reduced to a minimum
at 11 years of age. They showed that sagittal spinal
exibility during a deep inspiration showed striking
changes with age: it increased at 11 years of age signicantly more so in boys and decreased signicantly from
1215 years of age, suggesting thoracic spinal stiening.
Lumbar spinal exibility increased signicantly in girls
but not boys at 10 years of age.
Spinal mobility in healthy children
Mellin and Poussa [71] examined 294 healthy children
aged 816 years in ve age groups and found that each
141
R. G. Burwell
of thoracic extension, lateral exion and rotation
decreased signicantly from 1213 years in boys and
girls. In the thoracic spine at 13 years of age girls,
compared with boys, had less kyphosis and were stier
in forward and lateral exion, with more rotation to the
right than to the left. Widhe [72] examined sagittal
spinal shape and mobility in 90 children at 56 and
1516 years of age and found that kyphosis and lordosis
increased and mobility decreased, especially thoracic
extension.

Spinal mobility in scoliotic children

Poussa and Mellin [73] examined 71 girls with progressive AIS in three grades of severity for spinal mobility in the sagittal, frontal and transverse planes.
Thoracic rotation was most clearly decreased with
increased curves and, together with straightening of
the spine, was thought to be an important pathomechanism of progressive AIS. Viola and Andrassy [74]
examined children with structural scoliosis longitudinally at the age of 5, 10 and 14 years and reported
non-physiological spinal mobility with forward exion
increased between 510 years and decreased between
1014 years.
Figure 1 Mechanism of axial rotation in a thoracic and a lumbar

vertebra. Note the centre of axial rotation, anterior in the thoracic
vertebra and posterior in the lumbar vertebra where it is associated
with shear (from Gregersen and Lucas [177]).
Implications for sagittal plane research

In assessing impaired movements in the thoracic
spine in early AIS, current attention is directed almost
exclusively to the sagittal plane where in health exionextension is maximal at T12/L1. The above reports
suggest that before primacy is attributed to the sagittal
plane in aetiopathogenesis any impaired rotation or
deformity in the other two planes should be established.
primary rotation deformity?
Primary rotation deformity? (gures 1 and 2)
Roaf [45] suggested that all the phenomena of severe
scoliosis were explained solely on the basis of a primary
rotation deformity.
Intra-spinal and intra-discal axial deformity
Intra-vertebral and discal axial rotation have been
found in the scoliotic spine [52, 75, 76]. Posterior spinal
instrumentation and fusion can only correct the rotational deformity of a scoliotic spine at the discs,
which is less than that within the vertebrae. The greatest
asymmetric intra-vertebral deformity has been found
142
Figure 2 Axial vertebral rotation in structural scoliosis. Note the

posterior centre of axial rotation according to Adams. It is similar
to that of Smith et al. [281], their gure 6, but dierent from that of
Porter [44] and Guo et al. [18], who place it in the vertebral canal
(modied from Adams [282]).

at the curve apex that diminished away from the
apex with symmetrical vertebrae at the neutral vertebrae [77].
vertebral body growth platesthe vicious
cycle concept or growth-induced torsion
concepttraction treatment, a sound
theoretical basis for brace treatment?

Anterior lateral shear forces and posterior torque

forces (gure 3).
Wever et al. [78] interpreted the vertebral deformities
of structural scoliosis to bone remodelling due to lateral
shear forces created in the anterior column driving the
apical vertebra out of the mid-line, whereas torque
forces created by posterior musculoligamentous structure attempt to minimize the deviations and rotations of
the vertebrae.
Vicious cycle concept or growth-induced torsion
concept (gure 4)
Roaf [45, 46] suggested that spinal imbalance (lateral
spinal curvature) through gravity and continuous muscle action leads to asymmetrical loading of the vertebral
growth plates and, hence, to asymmetrical growth
that is in accordance with the Hueter-Volkmann law
[27, 39, 79, 80] (vicious cycle concept circular causality).
Perdriolle et al. [81] found no inter-vertebral movements
Figure 3 The force pattern in the scoliotic spine (modied from

Wever et al. [78]).
in the major curve of anatomical scoliotic specimens

and hypothesized that scoliosis from its onset was determined by a mechanical process termed torsion. The
change in orientation in both the frontal and sagittal
planes encouraged the redistribution of inter-vertebral
forces that tended to be located on the concave side of
the curve and cause cuneal deformations of the vertebrae; this resulted in further redistribution of forces
so that, after its onset, the spine was mechanically
unstable. In essence, structural scoliosis is a 3D rotatory
complex movement occurring mostly in the apical
region.
The view that cyclical eccentric forces on the vertebral end-plates in both frontal and sagittal planes with
vertebral growth modulation is the mechanism for AIS
(vicious cycle concept) is supported by most workers
[6, 9, 38, 6365, 80, 8284]. It provides the theoretical
basis for brace treatment [8083]. While girls scoliosis
curves are more likely to progress than boys, when
>30 , progression may be similar in boys and girls [85].
Progression is not usually vicious, in that most
small curves stabilize and are benign. Moreover, since
its mechanical basis has been questioned [86], a better
description might be the growth-induced torsion concept.
While the factors that determine which curves progress
have been examined clinically in relation to prognosis
with some success [85, 8790], the underlying mechanisms that determine curve, progression or stabilization
are unknown. The work of Guo et al. [18] suggests that
thoracic vertebral body shape and size and vertebral
proportions for age may be of critical importance to
curve progression.
Figure 4 Diagram of the vicious cycle concept by which eccentric

loads act on immature vertebrae in a curved spine to cause a progressive torsional growth of vertebrae and discs. As most small curves do
not progress, it would be better termed the growth-induced torsion
concept (modied from Stokes [80]).
143
R. G. Burwell
Is there a mechanism of deformation in AIS girls
intrinsic to anomalous thoracic vertebrae?

The recent nding of Guo et al. [18] that scoliosis

curve severity in AIS in girls correlated signicantly
with the ratio of vertebral body height to pedicle height
at all thoracic levels is consistent with the view
that an intrinsic anomaly involving endochondral
and membranous bone formation in all thoracic vertebrae contributes to curve severity. This may involve
both relative anterior spinal overgrowth and spine
slenderness.
What is the biological mechanism in vertebrae

of the torsion?Chronic cumulative stress,
involving stress-activated protein kinases in
a calcium-dependent mechanotransduction
possible physiotherapy?
The mechanisms of growth modulation and the
eects of tethering on disc function and integrity
deserve further study [9, 82, 91, 92] and may involve
both the tonic action of muscles [45, 46] and the biomechanical stresses of everyday life [64]. In the latter connection, the mechanical mechanism has been likened to
that of the chronic cumulative eect of repetitive biomechanical stresses of daily living applied unremittingly
and eccentrically to the 3D spinal deformity with its
malaligned immature vertebrae and discs [64]. This
possibility suggests that:
1.
2.
144
The biological mechanism may involve stressactivated protein kinases (SAPKs) released in
vertebral growth plates. SAPKs are important
regulators of a variety of repetitive loadings including tendons and are evaluated by measuring c-Jun
N-terminal kinase (JNK) activation [93]a signalling event in oxidative-stress-mediated cell death
protected or modulated by the selenium-containing
anti-oxidant enzyme glutathione peroxidase [94].
Such stress-activation appears to be mediated
through a calcium-dependent mechanotransduction
pathway.
Traction needs evaluating further as a treatment.
Stehbens and Cooper [95], after reviewing traction
as a treatment for IS, treated a child with juvenile
IS on a jungle gym (monkey bars) several times per
day with the swinging motion applying the stresses
equally to both sides of the body, with the weight
of the lower body providing traction, as well as
carefully selected exercises, with rapid improvement
within 10 weeks.
Platelets activated in a calcium-dependent mechanism?

A recent hypothesis [9698] relates to growth factors
liberated from platelets activatedalso a calciumdependent mechanismin deforming immature apical
vertebrae and which stimulate anterior spinal growth
in progressive AIS (skeletal hypothesis).
Does uncertainty about brace treatment question
its theoretical basis? Is the growth-induced torsion
a primary skeletal change?
In view of recent dubiety about the eectiveness of
brace treatment for AIS [86, 99, 100], Goldberg et al.
[86] asked if the vicious cycle hypothesis on which it is
based has no greater standing than any other hypothesis? Their question has re-awakened interest in an
earlier concept that the structural changes in the scoliotic vertebrae may be a primary skeletal change (intrinsic)
[18, 27, 101, 102] rather than secondary to mechanical
factors.
Goldberg et al.s question is consistent with their
concept that IS results from developmental instability.
Goldberg et al.s suggestion ignores clinical and experimental knowledge that immature bones are readily
deformed by sustained asymmetric mechanical forces.
Compensatory scolioses or counter-torsions
As adjustments to torsions of the major curve(s), compensatory curves presumably involve neuromuscular
mechanisms to balance the head above the natal cleft.
concept of a ligamentous check-rein, or tether,
to growth causing the spine to buckleloads,
neuromuscular response and treatment in
recumbency
Restraining ligaments
The possible role of the anterior longitudinal ligament as a check-rein (like the periosteum of limb
bones) in limiting or permitting curve progression is
rarely discussed, and in this connection its innervation
may be relevant. Ponseti [103] and others [64] stated
that IS entails weakening of the powerful ligaments of
the vertebral and costovertebral articulations; unless
these ligaments weaken, vertebral rotation and, thus,
true scoliosis cannot take place in humans. This aspect
was recognized as a deciency of a recent nite element
study that omitted ligamentous structures, articulations
and muscles [61].

Spinal growth creates a restraining growth
force in ligaments and dura

Kawabata et al. [104], in a mathematical study, tested

the hypothesis that when some vertebral bodies and
discs outgrow their surrounding soft tissues, such as
the ligaments and dura, a non-physiological growth
force is created acting to restrain with buckling most
easily when the growth force was localized from
T9L1. Suggested tethering of spinal growth by
posterior musculoskeletal structures is an example of
the action of a putative growth force altering spinal
geometry [6, 78] (gure 3).
Concept of the interaction of the initial spinal deformity
with the nervous systemtreatment in recumbency
Coillard and Rivard [38] suggested that minimal
deformity can alter intra-spinal loads and cause a
change in static and dynamic balance without a morphological change in the spinal column. An inadequate
neurological response, muscular dysfunction or limited
ligamentary constraint could result in a cascade of
events with chaotic functioning, resulting in a change
of balance and a progressive deterioration. They note
that A reclining position over an extended period of
time was and furthermore remains in some countries
the best treatment for scoliosis, which worsens little
or not at all under such conditions [39, 46].
Important issues are: (1) what initiates the scoliosis
curve? and (2) is it possible to prevent the deformity
surgically? To achieve prevention, some knowledge
about curve initiation may be helpful.
thoracic sagittal spinal shape changes in
health and AISin curve initiation are other
planes involved simultaneously?
Fixed lordotic area
Somerville [48] concluded that the scoliotic deformity
consisted of lordosis, rotation and lateral exion arising
from failure of growth of the posterior elements of a
segment of the spine and suggested the term rotational
lordosis. This 3D view of structural scoliosis was supported by Roaf [40, 42, 45, 46]. Dickson et al. [105]
maintained that the essential lesion of idiopathic thoracic scoliosis was a xed lordotic area which under the
inuence of a transverse or coronal plane asymmetry,
rotates to the side and gives rise to a lateral curvature
(biplanar asymmetry concept). Millner and Dickson [6]
stated that the lordotic area being present before the
spine becomes deformed is the prime aetiology of IS.
In addition to lateral wedging, sagittal vertebral

wedging is a feature of the established curve [42, 106].
Somervilles view [48] that structural scoliosis is a 3D
lordoscoliosis is now generally accepted. The involvement of the sagittal plane to permit the axial rotation
about a posterior axis is also generally accepted
(gure 2). The controversy [6, 18, 78] relates to the
suggested primacy of the sagittal plane in initial pathogenesis, i.e. curve initiation.
Simultaneous occurrence of the spinal deformity
in three planes
Xiong et al. [107] examined 96 AP and lateral radiographs of girls of average age 13.8 years with scoliosis
curves of Cobb angles 130 divided by severity into
four groups. The results indicated the simultaneous
occurrence of the deformity in three planes and not
in any single plane. More research is needed to resolve
this controversy.
Hypokyphosisconcept of timing of adolescent growth
in relation to sagittal spinal shape changes and the
eect on axial rotational stability
Millner and Dickson [6], noting that the normal thoracic kyphosis diminishes during the pre-adolescent
growth period [108], write: At this time the girls are
growing and developing quickly, thus magnifying
any trend towards attening of the normal thoracic
kyphosis. No evidence is provided to support this timing concept [14]. Dickson [109] explains: The thoracic
kyphosis is normally protected from buckling by being
behind the axis of spinal column rotation but when the
thoracic lordosis develops it brings the apical region
anterior to this axis and thus under compression with
resultant buckling of the spinal column ( rotationally
unstable) (gure 2).
Reviewing the eld, Raso [110] concluded that,
while there is little scientic evidence that IS was due
to buckling of a hypokyphotic spine, the most likely
biomechanical factor based on accumulated circumstantial evidence was the development of a hypokyphosis, causing buckling of the spine. Such children, he
opined, are normal, but subtle growth dierences
between the anterior and posterior aspects of the
vertebral body may lead to lateral buckling of the
spine (a possible contribution of the ribcage was not
considered in Rasos review). Stokes [111] stated that
the most likely biomechanical mechanism for the
aetiology of thoracic IS is hypokyphosis as a risk factor,
not a unique cause of IS. Grivas et al. [112] viewed the
145
R. G. Burwell
proclive segment, have less capacity to neutralize
the rotation-inducing forces than does the spine in
boys.

Impaired forward exion (IFF) in segments of the

lower thoracic spine
Figure 5 Radiological segmental sagittal spinal prole in a 14-year

old girl with a left thoracic (LT) scoliosis of 49 , apex T10. Note (1) the
lordotic segment (LS), (2) the kyphotic angulation below it and
(3) the backward tilt of T12 vertebra of 6 is much less than the controls at this vertebral level. The latter may make it more rotationally
unstable in the transverse plane (modied from Kiel et al. [114]).
hypokyphosis as being permissive, by facilitating axial

rotation, rather than aetiologic in the pathogenesis of
IS. Some surgeons still implicate axial vertebral rotation
and small lateral curves in curve initiation. Lowe et al.
[14] concluded that there was no strong scientic
evidence implicating any particular biomechanical
factor in the aetiology of IS.
Sagittal spinal prole and radiological declive and

proclive angles (gure 5)
Studies of the sagittal spinal prole [113] and the
radiological declive angle at T1112 in 37 school screening referrals mainly with small curves [114] are consistent with the concept that hypokyphosis in some way is
a feature of the early pathogenesis of AIS.
Declive and proclive segments

Uyttendaele and De Wilde [115], in a study of 483
normal girls and boys aged 916 years, used Moire
topography and concluded that girls are more prone
to develop AIS because their spines, with a relatively
longer declive segment and a shorter and less inclined
146
1. Tomaschewski [116], in 686 healthy schoolchildren

aged 910 years, used the forward bending test,
looked at the child from the side and reported
IFF in 16.5%. In the subsequent year, 27% were
reported to have developed a structural spinal deformity, as judged clinically and radiographically.
2. Weiss and Lauf [117] extended these observations
to 614 healthy children aged 2, 4 and 5 years and
found IFF mainly in the lower thoracic region
in 7.9, 78.9 and 70.8% respectively, where the harmonic arch of the trunk was interrupted by a
short vertebral segment which seemed straight
and could not actively or passively be bent or
exed forwards. These workers concluded that
IFF, occurring before any trunk hump in the transverse plane was the pre-selection condition for
development of IS. In particular, they suggested
that IFF in more than three motion segments
may destabilize the childs spine so that progressive
rotation and lateral deviation occur during periods
of rapid growth.
3. Schmitz et al. [118], in a 3D ultrasound topometric
study of 102 healthy children aged 79 years in
a maximally exed position, detected seven children
with clinical signs of scoliosis and reduced exion
in the middle to lower thoracic segments.
4. Nakakohji [119], in a radiological study, compared
93 children with IS with 40 controls and found
localized areas of a severely reduced range of
spinal exion that was thought to contribute to
the pathogenesis of the spinal curvature.
Frontback asymmetry concept

The above ndings are consistent with the view
that the idiopathic patient buckles on exion [109].
Millner and Dickson [6] emphasized that, while
structural scoliosis is a complex 3D deformity, . . . the
problem is one of front-back asymmetry and not right
left. Cheng [18, 56] supported a loss of coupling in the
longitudinal growth between the anterior column
and posterior column. The crankshaft phenomenon,
especially in immature children and its prevention by
anterior spinal resection and epiphyseodesis [120, 121]

is a graphic demonstration of the importance of relative anterior spinal overgrowth in curve progression.
However, rib hump reassertion in patients after posterior Universal Spine System for AIS was explained
by unwinding the ribcage tensioned by surgery rather
than through relative anterior spinal overgrowth, i.e.
the crankshaft eect [122].
leftright asymmetries in AIS subjects [101, 102, 131

141], (5) pelvic asymmetry [142] and (6) increased and
asymmetric femoral neck-shaft angles [143]. The front
back asymmetry concept invokes leftright asymmetry
(frontal plane and/or transverse plane) to cause scoliosis (biplanar asymmetry concept [105]). Leftright
asymmetry ndings have provided the basis for three
multi-factorial concepts of etiology.

Recent evaluation by models

Murray and Bulstrode [123] constructed a simple
model and showed that overgrowth of the anterior
column relative to the posterior column caused it to
take up the shape of an IS. Azegami et al. [124] showed
that a buckling phenomenon caused by relative anterior
spinal overgrowth could produce scoliosis, with the
predominance of right curves being attributed to the
heart being on the left. Examining buckling and bone
remodelling in a nite element model, Goto et al. [61]
suggested that, while scoliotic changes are triggered by
the buckling phenomenon, this is counteracted by bone
formation, but worsened by resorption of loaded bone.
Preventive surgery?
Like the way anterior spinal surgery supported the
frontback spinal asymmetry concept, preventive surgery to correct sagittal spinal shape may substantiate
the concept [125].
Comment on the frontback spinal asymmetry concept
The evidence is consistent with the obligatory involvement of the sagittal plane in the initiation of thoracic IS.
However, the primacy of the sagittal plane in curve
initiation is not established for children referred
after screening, the scolioses already have 3D deformities [107] so that longitudinal vertebral growth
becomes eccentric leading to a growth-induced torsion.
Moreover, there is no substantial radiological evidence
to show that the other two planes are not simultaneously involved before the development of the lateral
curve [6, 109]. There are other concepts to explain the
initiation of a thoracic curve involving (1) the spine, (2)
the ribs (concave rib overgrowth) and (3) muscles.
The frontback asymmetry concept for thoracic
scoliosis does not explain or adequately explain [126]
(1) non-standard vertebral rotation [127], (2) the predominant laterality of thoracic AIS and progressive IIS
curves, (3) the laterality of leftright shape of the normal
back that develops mainly during the pubertal growth
spurt at ages 1214 years [128130], (4) the widespread
thoracolumbar and lumbar sagittal spinal

shape changes in AIS?
Millner and Dickson [6] write: For the sagittal plane
to be blamed primarily for thoracolumbar or lumbar
curves implies lordosis where the spine should be
straight (thoracolumbar region) or more lordosis than
normal (lumbar region) and evidence exists for both.
Lupparelli et al. [83] stated that lumbar curves were
characterized by dysharmonic evolution due to rotatory
subluxation phenomena with stability provided by the
lumbar facet joints that restrict axial rotation (gure 1).
Raso [110] commented that little work has been done
on the aetiology of lumbar scoliosis. The lack of aetiologic knowledge about these curve types suggests that
the mechanism at work is not yet understood for any
of the curve types. The mechanism may be a primary
skeletal or ligamentous change or result from segmental
neuromuscular imbalance that will now be discussed.
primary skeletal change, ligamentous change

or segmental neuromuscular imbalance for the
initiation of AIS?JIS and other asymmetries
In thoracic AIS, the growth-induced torsion concept
requires a sustained alteration of normal spinal geometry in one or more segments about the future apex of
the curve, so that normal linear vertebral growth is
converted to that of torsion (growth-induced torsion
concept). The theoretical requirement is for the centre
of axial rotation of certain thoracic vertebrae to move
posteriorly in order to explain the pattern of axial
rotation in thoracic scoliosis [6] (gures 1 and 2).
Once this segmental change in the thoracic spine has
occurred, the mechanical process of torsion is generally
thought to predominate, but it may be inuenced by
neuromuscular mechanisms.
The basic biological process that initiates sagittal
spinal shape change is unknown. It is not apparently
discogenic and could be:
1. A primary skeletal change [27] involving uncoupling of growth between the anterior column and
147
R. G. Burwell
2.
3.

4.
posterior column of the spine [18, 48, 56], where

vertebral growth creates the maturational sagittal
spinal shape changes.
A primary ligamentous change [27] aecting
posterior spinal structures [48].
A segmental neuromuscular imbalance creating a
biomechanical susceptibility to the growth-induced
spinal torsion of AIS.
A combination of two or more of the abovethis
would be consistent with the concept of developmental instability for AIS.
Option (1) suggests that an uncoupling within the

columns of the thoracic spine may initiate the hypokyphosis of health and the xed lordotic area of IS.
In AIS, of all curve types any primary skeletal change
could occur segmentally in one or more planes to create
the main (primary) curve without any extrinsic factors
being involved. The diculty is refuting the concept.
Option (3) for AIS will now be outlined.
A segmental neuromuscular imbalance causing

a maturity risk factor?
The observations of Guo et al. [18] did not show any
apical lordotic area in contrast to those of Deacon et al.
[43]; this may be due to Guo et al. not using true lateral
projections of the spine.
In the thoracic region there is an obligatory need
for the sagittal plane to be involved so as to overcome
the kyphosis control of axial rotation [6]. A prudent
speculation is that of a maturational change in the
form of a segmental neuromuscular mechanism (as a
scoliogenic lesion [129]); by causing sustained segmental
changes of geometry in a slender spine when combined
with the rapid growth spurt of adolescence makes
it biomechanically susceptible to deformation by torsion [6]. This mechanism by creating a maturity risk
factor could operate in each of the thoracic, thoracolumbar and lumbar regions of the spine, with curve
laterality being determined by developmental mechanisms in the CNS [144].
Dubousset and Machida [145] incorporated a neuromuscular imbalance in their neurohormonal concept of
AIS. The putative segmental neuromuscular imbalance
concept was consistent with conclusions about the
role of the nervous system in the aetiology of AIS.
Although, like the primary skeletal change concept,
the present diculty is refuting it, there are ways of
evaluating any neurodevelopmental disorder.
148
Other types of AIS

The concept of segmental neuromuscular imbalance
explains the dierent lordotic patterns associated with
each of the single structural curve, double curves
and triple curves [146] as a function of aberrant neuromuscular activity, as well as other curve types now
dened in the new classications of AIS.
Juvenile idiopathic scoliosis
The concept of segmental neuromuscular imbalance
explains JISdiagnosed during a period of slower
spinal growthas needing either:
(a) earlier and stronger neuromuscular imbalance to
initiate a curve than in the presence of the adolescent growth spurt, and/or
(b) greater primary vertebral morphological features.
Other asymmetries
Skeletal asymmetries detected at other sites may be
explained by neuromuscular imbalance involving CNS
control.
a short spinal cord inducing neurovertebral
growth disparity? However, in syringomyelia
cord tethering occurs without a predominant
scoliosis laterality
In the 1960s, Roth proposed the hypothesis [147],
rediscovered by Porter [44, 47], that when spurts of
elongation of the spine are too rapid for the slower
growth rate of the spinal cord and nerve roots, the
neurovertebral growth disproportion is compensated
for by adaptive scoliotic curvature of the otherwise normally growing spine. Porter [47] suggested that the
spinal cord may fail to stretch in response to vertebral
growth due to molecular mechanisms with melatonin as
a powerful anti-oxidant protecting against cellular
damage. These novel concepts involving biorhythms
need testing [147]. Machida and colleagues [145, 148,
149] implicate melatonin in the aetiology and treatment
of AIS. The neurodevelopmental concept for AIS
outlined below also suggests a trial melatonin and
other substances.
Cord tethering and Chiari malformation appear to be
major causes of syringomyelia and scoliosis. However,
the laterality of these curves was about equal, right
and left [150], so, if cord tethering in syringomyelia
does not cause a predominant laterality for the associated scoliosis, how can a short spinal cord explain the
laterality patterns of AIS?

small right thoracic curvespredisposing to
scoliosis curve formation?
White [151], noting the presence of a physiological,
slight right thoracic curve [52], suggested that if the
precarious balance of the normal thoracic motion is
disturbed, vertebrae in the slight curve might somehow
rotate too much into the convexity of the curve. The
concept has been rejected [152, 153].

left lateral thoracic curvesdisease or

developmental biology?
Disease and developmental biology
Goldberg et al. [154], in reviewing left thoracic curves
and their association with disease, concluded that
gender in males and age at diagnosis in females are
more important risk factors.
The gender and age eect was conrmed by Grivas
et al. [155] in a school screening sample who found that
girls before menarche had signicantly more left curves
(10 or more) and after menarche more right curves.
This nding supports the view that left curves result
from a natural mechanism which determines left/right
laterality [129] rather than being an aberration from
the right bias in development due to putative stressors
[137, 138].
concepts for curve laterality in
AIS & IIScontroversy
The problem of curve laterality, like that of cerebral
laterality with a strong bias towards right-handedness
[156, 157], is complex and controversial.
Neural-, visceral- and diaphragmatic-determined curve

laterality (directional asymmetry)
Several causes had been invoked to explain why AIS
curves are predominantly right-sided, including handedness (Sabatier), the heart (52), the aorta (Bihat, adopted
by Taylor [158] and Millner and Dickson [6]), a larger
right lung [159] and the diaphragm (Jansen).
Developmental biology
The pattern of the common right thoracic curve
and less common left thoracic curve of AIS has been
attributed to one of two developmental concepts:
1. Physiologic from nature. The pattern of spinal
asymmetry during normal development is explained
by the hypothesis of oscillating axial torsion [129],
with an early bias to the left and a later bias to the
right; in a minority of the population the opposite
occurs. Patterns of leftright asymmetry observed
in each of pedicle lengths [52, 53, 158, 161, 162],
spinal mobility in the transverse plane [71], small
thoracic spinal curves, back contour asymmetry
[128130] and skeletal limb asymmetries [101, 102,
126, 139141] are explained by this physiological
concept; it also explains the left laterality of
progressive IIS and the predominant right thoracic
AIS. Taylor [158] suggested that vascular asymmetries probably determine the direction of a scoliosis
but could not account for plagiocephaly and limb
length asymmetries.
2. Aberrant from nurture. Goldberg et al. [137, 138]
hold that right thoracic curves of AIS are due
to an increase of the normal bias to the right and
left convex curvesthat are not secondary to some
pathologyare stress-induced, causing reversed
asymmetry or low directional asymmetry but
high stress resulting in antisymmetry, or random
leftright distribution.
continuous spinal realignment and position

sensing in health
Spinal stability as a mechanical process involves continuous realignment of the spine based on position-sensing at the motion segment level and involving the head
and trunk as well as the spine [14]. Lowe et al. [14]
pointed out that this dynamic process might lead
to the development of scoliosis in the presence of an
initially normal biomechanical structure, and research
eorts to validate this dynamic concept have only
recently been initiated [163].
Thoracospinal concepts
Handedness
The relation of handedness, a behavioural marker of
early neurodevelopment, to curve laterality in AIS was
addressed in two recent studies [144, 160], but remains
unresolved.
thoracic cage functions in health

and after surgery
The outstanding function of the thorax is respiration
using various muscles. However, no less important is
the support of the spine [39, 164] in standing, sitting,
149
R. G. Burwell

gait and other activities, thereby controlling the movements of the thorax on the pelvis and providing origins
for the muscles which run from the thorax to the
scapulae and arms. The ribs restrict axial rotation in
the thoracic spine [48]. Gardner [165] emphasized the
importance of the whole body wall in the pathogenesis
of IS and particularly how (1) the mid and upper
ribs are a signicant barrier to the surgical vertebral
derotation and correction of the upper rib hump and
(2) the sternum acts as the fourth column in stabilizing
the spine.
rib deformity in AIS

The rib deformity in scoliosis is discussed by Erkula
et al. [166]. Many workers hold the view that the rib
deformities of progressive AIS are adaptations to forces
imposed by the scoliotic spine [78, 167] with the
sternum, held nearly stationary by abdominal ties and
providing the opposing forces needed to deform the ribs
[168]. In scoliosis, the ribs may act as a couple to
increase rotation [45].
Some workers have attributed the initial spinal
deformity of AIS to changes in ribs [39, 79, 112, 164,
169174], with subsequent deformity resulting from
growth-induced torsion.
Figure 6 Drawing to show the dynamics in gait of the skeletal

framework as a basis for the Nottingham thoracospinal concept of
aetiopathogenesis of AISalso known as the dinner plate-agpole
concept or better dinner plate-tentpole concept. The pelvis is likened
to a dinner plate and the spine to a agpole or tentpole. The
gap between the upper spine and lower spine represents the transitional point (displacement node) above which axial rotation is in
the direction opposite to that below [177]. In the thoracic spine
axial rotation is maximal about T7 and minimal at the lower three
levels. See text and Gregersen and Lucas (modied from Burwell
[178]).
ribcage in the frontal planethe Nottingham

(or dinner plate-flagpole) conceptscoliosis
initiation by combined rib and spinal mechanisms
The pioneering prognostic work on the rib-vertebra
angle dierence (RVAD) in infantile IS by Mehta,
in juvenile IS by Tolo and Gillespie and subsequent
publications will not be discussed here. In AIS,
RVADs are not prognostic.
The Nottingham (or dinner plate-agpole) concept
femoral anteversion, sagittal spinal prole, the ribcage,
gait and scoliosis (gures 6 and 7)
This concept [39, 79, 169, 170] proposes that thoracic
AIS results from a puberty-related developmental
abnormality in the central nervous system that creates
rib-vertebra angle asymmetry (in the frontal plane)
which, with spinal mechanisms, initiates the curve [39,
79, 169, 171, 172]. In association with a short segment
lordosis, this leads to a cyclical failure of mechanisms
of axial rotation control in the trunk that involves
(gure 6):
1.
150
A pelvi-spinal rotation-inducing system (lower limbs

and pelvis), and
Figure 7 Schematic drawing to show the gait-driven spinal rotation

(Nottingham) concept for AIS. See text (modied from Burwell
et al. [175]).
2. A rotation-defending system (thoracic kyphosis,

discal, costal and neuromuscular mechanisms
acting on the spine and ribs) in gait and other
activities in which a mechanical breakdown of
axial rotation creates the initial deformity of IS
( failure of rotation control) (gure 7)

Figure 8 Segmental RVADs (rib-vertebra angle dierence RVA asymmetry in the frontal plane) for infancy, childhood and puberty age
groups. Statistical analyses are for sex ( p/sex) and asymmetry ( p/asymmetry) Probabilities of signicance * 0.01<p < 0.05, ** 0.001<p < 0.01,
*** p < 0.001. See text (modied from Grivas et al. [171]).
The concept was based on studies in each of femoral

anteversion (FAV) [169, 175, 176], the radiological
declive angle at T11/T12 [114] (gure 5), the normal
ribcage [170172] (gure 8) and the biomechanics
of gait [52, 177] (gure 6).
Growth-induced torsion concept

The growth, both abnormal (secondary to vertebral
hyperpressures) and normal (linear spinal growth) with
gravity and muscle forces adds to the initiating and
continuing neuromuscular mechanisms to augment
curve progression (gure 4), i.e. the growth-induced
torsion concept.
Subsequently [178, 179], Burwell and his colleagues
considered that scoliosis curve progression was determined by how much the immature vertebrae remodel
under eccentric loading created by putative neuromuscular imbalance in the trunk in the presence of gravitational and growth forces. The sagittal plane rib
asymmetry evidence reported by Grivas et al. [112] is
consistent with the Nottingham concept of pathogenesis. Most recently, it has been suggested that growth
factors liberated from platelets activated in deforming
vertebrae may induce relative anterior spinal overgrowth in progressive AIS [9698]. A comparison of
gait patterns in AIS girls with controls revealed balance
problems during the stance phase and asymmetry
in frequency characteristics that was thought may
be a primary eect contributing to the medio-lateral
deformity of the spine [180].
Do the patterns of RVADs in the normal thorax

reveal an aetiologic factor and a biomechanical
susceptibility to progressive IS?
Figure 8 shows that, in normal chest radiographs
from 412 children, the patterns of RVADs reect the
age, sex and side patterns of progressive IS. It is as
though a proportion of these children had progressive
scolioses, yet none had a scoliosis of 5 or more. In the
puberty group, the adolescent girls show signicantly
more rib drooping at levels 47 on the left than
on the right to produce the pattern of the RVADs.
In contrast, the boys in puberty show no detectable
RVA asymmetry that is consistent with the lower
male prevalence of progressive thoracic AIS. It was
suggested that RVA asymmetry provides a biomechanical susceptibility or maturity risk factor to AIS, JIS
and IIS.
ribcage in the transverse planeSevastiks

thoracospinal conceptscoliosis initiation by
concave periapical rib overgrowth
Sevastik and colleagues [173, 174] adduced experimental, anatomical and clinical evidence for his thoracospinal concept that applies only to adolescent girls
with right thoracic AIS. It involves dysfunction of
the autonomic nervous system [174, 181] that causes
increased vascularity of the left anterior hemithorax
resulting in overgrowth of the left ribs. This in turn
disturbs the equilibrium of the forces that determine
the normal alignment of the thoracic spine and triggers
the thoracospinal deformity simultaneously in the three
151
R. G. Burwell
cardinal planes [107] (linear causality concept). Colour
Doppler Ultrasonography did not nd any evidence for
side dierences in vascularity of the anterior thoracic
wall in right thoracic AIS girls, thereby not justifying
the vascular component of Sevastiks concept [182].
continuation of foetal growth. The childhood component

corresponds basically to the eect of growth hormone.
The puberty component most likely describes the part of
the adolescent linear growth stimulated by oestrogen in
both boys and girls [57, 199, 200].

Growth-induced torsion concept

Sevastiks concept does not deal with the factors
involved in the progression of the curve which he considers to be of a biomechanical nature [174], i.e. the
growth-induced torsion concept.
Sevastiks concept has been applied surgically with
early success in a 7-year old girl with a right thoracolumbar IS [183]. Finite element models support such
early intervention on the ribcage to prevent curve progression in small-to-moderate IS [184].
Skeletal growth maturity indicators, certain
hormones and the saltatory hypothesis of
normal growth and maturation
Risser [185], in a study of 296 patients, observed a
direct relationship between vertebral growth and increasing spinal deformity, a view previously supported by
Somerville [48] and subsequently discussed at the Third
Zorab Symposium in 1970 [27]. There are now many
facts to establish that spinal growth is associated with
the initiation and progression of AIS [9, 18, 21, 89, 120,
121, 125, 139, 186191]. An important nding is the
strong correlation of factors that predict the potential
residual skeletal growth and curve progression [191].
maturity indicators for age
The current maturity indicators for age include chronological age, menarcheal status, bone age (Risser sign,
triradiate cartilage, less commonly ischial apophysis
and hand and wrist bones) and Tanner stage of sexual
maturity [192196].
growth velocity patterns and importance
of oestrogen in boys and girls
Infancychildhood puberty growth model
A biological basis for the grouping of IS into infantile, juvenile and adolescent types is found in the
infancychildhoodpuberty (ICP) growth model of
Karlberg and colleagues [197, 198]. The infancy component starting in mid-gestation and continuing up to
34 years of age is believed to represent the post-natal
152
AIS
Duval-Beaupe`re [186] showed that the progression of
IS occurred at the time of the most rapid adolescent
growth spurt but curve progression continued after
peak height velocity. She concluded [186] that there
is no cause and eect relationship between growth of
the vertebral column and scoliosis, except as contemporaneous phenomena. This conclusion provided the
bedrock for the mechanical growth-induced torsion
concept [81]. In brace-treated patients, greater progression was related to periods of rapid-to-moderate growth
in the spine [191]. Curve progression decelerates after
the completion of skeletal maturity [186], but may
continue through adult life [89, 201].
Hagglund et al. [198] found that AIS girls had an
above average height 2 years before the onset of the
pubertal growth spurt that did not persist. Willner
[188] reported that the growth velocity was elevated in
the year before the onset of the curvature attributed to
higher growth hormone secretion than in normal girls
[189, 198]. Veldhuizen et al. [33] could not demonstrate
any dierence in growth increments of vertebral bodies
involved in the scoliotic curve compared with the rest of
the vertebral column. Goldberg [21] and Cole et al. [139]
reviewed the few longitudinal studies of skeletal growth
in AIS subjects and noted (1) an earlier age at peak
height velocity (PHV) and (2) a signicant increase in
PHV. Goldberg [21] concluded that it is now generally
agreed that skeletal growth was a signicant factor
contributing to the natural history and prognosis of
AIS. Although growth mechanisms are assumed to act
directly on the immature vertebrae in curve pathogenesis, an indirect biomechanical mechanism of curve pathogenesis has also been suggested [39, 139, 170]; this
concept involves a large extrathoracic skeleton and a
normal chest width.
Goldberg et al. [187] found that the mean age at
diagnosis for progressive curves is at the start of the
acceleration phase of the growth spurt (gure 9). In
contrast for stable (non-progressive) curves, the mean
age at diagnosis is after the peak height velocity and
Goldberg asked, Is rising growth rate the trigger
for curve progression? This begs the question, What
causes the rising growth rate of adolescence?

Figure 9 Height velocity (cm/year) plotted against age to show the relationship between diagnosis and growth rate for progressive and stable
(non-progressive) AIS shown years before menarche (1, 2, 3) and after menarche (1, 2, 3). Note that the earlier onset of the progressive curves
occurs in the acceleration phase of the adolescent growth spurt when there is more residual growth (modied from Goldberg et al. [187]).
puberty, growth hormone, sex steroids and

gonadarche
The eects of growth hormone in juveniles is supplemented by sex steroids in adolescence [57, 197200,
202]. Adolescence begins with puberty, or more technically with gonadarche, which is an event of the neurendocrine system. Normal puberty is a consequence of
resurgence of episodic gonadotropin-releasing hormone
(GnRH) from the hypothalamus to receptors in the
anterior lobe of the pituitary that release luteinizing
hormone (LH) and follicular stimulating hormone
(FSH) which, in turn, stimulate oestrogen and androgen
secretion. Puberty can be delayed or switched o by
down-regulating the receptors to GnRH in the anterior
pituitary by gonadorelin analogues [200]. How may this
relate to scoliosis treatment?
possible therapeutic delay of the adolescent
growth spurt in AIS subjects by gonadorelin
analogues
Two groups of workers have suggested the possibility
of using a gonadorelin analogue to delay the onset of
puberty in girls with AIS [203205].
NOTOM hypothesis and a gonadorelin analogue
(gure 10)
Burwell [203] gave the name neuro-osseous timing
of maturation (NOTOM) hypothesis to Nachemsons
Figure 10 Neuro-osseous timing of maturation (NOTOM) hypothesis for AIS pathogenesis. Height velocity (cm/year) plotted against age
in relation to putative postural maturation at 12 years. Note the earlier
adolescent growth spurt (AGS) in girls in a phase of postural immaturity and later in boys in postural maturity (modied from Burwell
[203]).
concept [206] that there are more girls than boys

with progressive AIS for the following reason. The
maturation of postural mechanisms in the central
nervous system is complete about the same time in
boys and girlsfor which there is some evidence,
but the age and sex eect of postural sway in
healthy children needs further evaluation [207212].
153

R. G. Burwell
Girlsperhaps due to natural selection in evolution
enter their adolescent growth spurt before their postural
mechanisms are mature, so that if they have a predisposition to develop a scoliosis curve, the spine deforms.
In contrast, boys do not enter their adolescent growth
spurt until their postural mechanisms are mature, so
that they are protected from developing a scoliosis
curve (gure 10). Burwell proposed administering a
gonadorelin analogue to delay menarche and slow
bone growth, as in boys and girls with idiopathic precocious puberty. Expert scrutiny and conditional support
for this proposal has been obtained (Dr D. I. Johnston,
personal communication; Dr P. C. Hindmarsh, personal communication; Professor M. A. Preece, personal
communication).
Most recently [213], the NOTOM hypothesis was
evaluated in relation to the delayed puberty of ballet
dancers with thoracic curves [214] and rhythmic gymnasts with thoracolumbar and lumbar curves [215]. It
was concluded that the NOTOM hypothesis is not nullied, as there are discernible constitutional factors
(physique and laxity) and environmental factors (life
style and nutrition) in these particular sports-associated
scolioses that may render them non-idiopathic [213].
More research is needed.
Timing of the adolescent growth spurt in puberty and
a gonadorelin analogue
King [205] suggested the use of Lupron (a gonadorelin analogue) to delay the onset of the adolescent
growth spurt. Lupron is used for the treatment of
precocious puberty and works by blocking the release
of FSH that in turn blocks the release of oestrogen.
The concept underlying this proposed treatment for
progressive AIS is that girls begin their adolescent
growth spurt at the onset of puberty, whereas boys
are in advanced puberty before entering their adolescent
growth spurt. Therefore, the adolescent growth spurt
in boys is superimposed on a more mature and presumably more stable spine. In girls, delaying the onset
of the adolescent growth spurt by 12 years in girls
could mean that the adolescent growth spurt would
be superimposed on a more mature and more stable
spine.
why do only a proportion of girls develop
progressive AIS?
Both of the above concepts explain why there
are more girls than boys with progressive AIS, but
neither explains why only a proportion of girls develop
154
progressive AIS. One explanation is outlined below,

namely: a neurodevelopmental mechanism developing
in susceptible girls with spine slenderness associated
with ectomorphy leads to the initiation of AIS with
progression determined by mechanical factors including
spine slenderness.
melatonin deficiency as a causative factor?

Neurohormonal concept of Dubousset and Machida
Machida and colleagues [145, 148, 149], having found
lower plasma melatonin levels through 24 hours only in
progressive AIS curves (n 12) concluded that melatonin disturbance has more of a role in progression than
in the cause of IS. They postulated that, in the development of progressive AIS, melatonin acts through the
nervous system. Dubousset and Machida [145], after
experiments on pinealectomized bipedal rats, suggested
that IS may be:
. an inherited disorder of neurotransmitters from
neuro-hormonal origin aecting melatonin,
. associated with the bipedal condition,
. when a horizontal localized neuromuscular imbalance with torsion starts, and
. it produces a scoliotic deformity of the bro-elastic
and bony structures of the spine.
The hypothesis that melatonin deciency is a causative factor of AIS was not conrmed by several workers
but has by others. Reinker [216] concluded that it seems
unlikely that IS results from a simple absence of melatonin. Rather, scoliosis could result from alteration in
the control of melatonin production, with either direct
or indirect consequences upon growth mechanisms.
the saltatory hypothesis of normal growth

Normal growth and growth-maturation
saltation episodes
Lampl [19] reviews evidence that growth is not linear
but occurs in saltations and stasis, with the saltations
(Latin leap) being accompanied by changes in
behaviour. The saltation and stasis hypothesis was
generated on time-intensive longitudinal data of infant
recumbent length. The protocol of daily measurements
has been applied to height during childhood and
adolescence with similar results. Infants and adolescents
have more frequent growth saltations than occur in
childhood [19].

pubertysaltatory hypothesis, maturation in

the spine, thorax and nervous systemmaturity
risk factors, saltations and possible significance
for IS
The saltatory hypothesis led to the concept that
growth is more than an increase in size and should be
viewed also in terms of the maturation of the child during puberty. The maturation changes in health that
may be of relevance to AIS aetiology are in vertebrae,
intervertebral discs, the spine, ligaments, the thorax,
pelvis and nervous system. These changes are separate
from maturity indicators.
Maturation in the normal spine during puberty
includes:
1.
2.
3.
4.
5.
Vertebral body slenderness, disproportionate

anteriorposterior vertebral growth and thoracic
sagittal spinal shape changes [6, 18, 26, 32, 33, 70,
71, 108, 113119].
Ligament [14] and disc [68] changes.
Spinal mobility changes [7074].
Ossication asymmetry in neural arches [158, 161,
162].
The laterality of small normal spinal curves.
Maturation in the normal thorax during puberty

includes:
1.
2.
3.
4.
5.
Proportions of width/height [170, 172].

Rib-vertebra angle asymmetry in girls [171, 172].
RVADs in girls [171, 172] (gure 8).
Putative rib length asymmetry [173, 174] associated
with small thoracic curves.
Back contour asymmetry [128130].
Maturation in the nervous system during puberty

includes or may include:
1.
2.
3.
Postural maturation changes involving neuromuscular mechanisms [207212].

Putative neuromuscular imbalance creating the
thoracic hypokyphosis.
Putative neurodevelopmental changes aecting the
CNS in the rapidly growing adolescent girls spine
involving lipid peroxidation.
The salutatory hypothesis [19] needs testing in IS

subjects. Should saltations be detected then consideration should be given to whether the eect of each
saltation on the trunk depends on the maturational
state of the spine, ribcage and nervous system, each of
which may have changed since the previous saltation
favourably or unfavourably with respect to susceptibility to AIS. This concept could then be likened to a
machine gun (growth saltations) hitting a moving target
(maturation for example of the spine, ribcage and spinal
cord) (machine gun-moving target concept).
Tissue concepts
nervous system
Younger children with IS
MRI has revealed neuranatomical abnormalities in
20% of younger children with putative IS and curves
of 20 or more [217, 218].
Possible neuromuscular disorder in AIS?
The possibility that AIS aetiology involves undetected neuromuscular dysfunction is considered likely
by several workers [11, 12, 14, 15, 17, 39, 56, 79, 126,
145, 148, 149, 169, 174, 178, 179, 181, 217, 219222] but
denied by Goldberg [223].
Lowe et al. [14] concluded that:
The current thinking is that there is a defect of central
control or processing by the central nervous system that
aects a growing spine and that the spines susceptibility
to deformation varies from one individual to another.
Girls may be more vulnerable to this process because
of the short and rapid adolescent growth of the spine
compared with that in boys.
Lowe et al. [14] stated that the most consistent clinical

studies point to the pontine and hindbrain regions as
the likely sites of primary pathology that could lead
to IS.
Postural maturation and neurodevelopmental
trunk size adaptations in puberty
Postural sway in healthy children needs further evaluation [207212].
Maturity risk factors, saltations and possible

signicance for IS
A new neurodevelopmental concept for AIS
Some of these maturational changes in the spine and

thorax with age are thought by some workers to be
biomechanical susceptibilities, or maturity risk factors,
to AIS during the adolescent growth spurt.
The putative neurodevelopmental maturational

changes in the thoracic region of the healthy childs
trunk during puberty have been expanded into a new
neurodevelopmental concept for AIS.
155
R. G. Burwell
muscles
The role of muscles in the aetiology of ISdespite
much research using electromyography, histochemistry
as well as mechanical and more recently nite element
modelsis unclear [224]. Three areas of current study
are outlinedat the hip, paravertebral muscles and
platelets as minimuscles.

Hip abductor muscles

Professor T. Karski (personal communication) provides the following account of his concept: There are
three stages in the development of idiopathic scoliosis:
(1) an abduction contracture, in reality a limitation of
adduction, mostly of the right hip; (2) a disturbance in
growth of the pelvi-sacral-lumbar region with the development of a left lumbar scoliosis; and (3) the development of a right thoracic scoliosis. . . . Detection of the
hip contracture in children aged 610 years and treating
it eectively with stretching exercises, and in some
patients surgery, slows the development of severe
scoliosis in adolescents and cures small curves in small
children [225].
The rotational preconstraint
A model to clarify the role of paravertebral muscles
provides a novel view of some scolioses [226]. The
hypothesis tested is that paravertebral muscle imbalance with interference of the postural reexes and
the body-weight related vertical loading leads to the
formation of a scoliosis curve.
On an educational plastic human spine with the pelvis
constrained, multidus from T110 on the right is
simulated by elastic rings causing a rotation. The
induced rotation of the upper spine is returned to the
frontal plane by springs attached to horizontal rods
and constrained by exerting a torque against the action
of all elastic rings (simulating postural correction);
then vertical loading (simulating upper body weight)
deformed the prepared section of the spine into a right
thoracic scoliosis. It was concluded [226] that hyperfunction of all the paraspinal muscles on one side provides an explanation for the rotation, frontal and
sagittal exions of IS with subsequent remodelling
(vicious cycle concept).
Platelets as minimusclesplatelet calmodulin and
modulation by melatonin
Over the last 20 years, from studies of patients with
IS, the concept has emerged that platelets act as minimuscles, with calcium kinetics, intracellular structure
156
and contractile protein activity similar to those of skeletal muscle [1].

Research on platelet calmodulin levels in AIS led
Lowe et al. [227] to conclude that the platelet is a
mini skeletal muscle with a similar protein contractile
system (actin and myosin) and suggest that calmodulin
acts as a systemic mediator for tissues with a contractile
system (actin and myosin) [9698, 227a]. (Platelet
calmodulin has not been used hitherto in platelet
research, S. Heptinstall, personal communication.)
Melatonin binds to calmodulin with high anity and
has been shown to act as a calmodulin antagonist [216,
224, 227].
ligaments
Increased ligamentous laxity has been described in
AIS, but Lowe [224] concluded that there is little evidence that it is an important aetiologic factor. Taylor
and Melrose [66] commented that, at present, there
seems little point in pursuing the examination of connective tissues from patients with AIS, but that there
may be a place for these endeavours once the questions
of aetiology and diagnostic markers are settled. A low
selenium level in the blood of AIS subjects has been
linked to the synthesis and maturation of collagen
aecting axial skeletal stability [228].
Proprioception and therapy?
There is evidence that the spinal ligaments in subjects
with IS were less innervated than controls [229]. Bagnall
[230] stated that studies of spinal ligaments and their
association with scoliosis should be related to the
neuromuscular feedback mechanisms common to all
joints. He concluded that, by developing methods to
assess proprioceptive abilities . . .patients with AIS who
have abnormal proprioceptive abilities can be isolated
and treatment methods specic for this deciency can
be developed.
Skeletal proportions and bilateral asymmetries in hard
and soft tissuesdevelopmental stability and instability
possible aetiologic significance of skeletal
disproportionsanthropometry, allometry and
vertebral endochondral-membranous
disproportions
Three types of whole body skeletal disproportion in
AIS girlsallometry
Burwell and colleagues [34] discussed anthropometric
evidence of three types of skeletal disproportion in AIS


girlsleftright, cephalocaudal and frontback. They
proposed the hypothesis that, at the time of diagnosis
of AIS in girls, there was a complex and basic disorder
of skeletal proportions associated with a predisposition
to curve progression [34, 139]. These nding may be
related to spine slenderness [18, 26] and determined by
nature and possibly nurture, involving allometric skeletal growth [101, 102, 139], developmental instability
[137, 138] and unsynchronized bone growth [38] as an
asymmetric chronomic disorder.
The concept that girls with progressive AIS have
whole body skeletal disproportions is supported by
the nding of disproportionately longer legs relative
to arms in AIS girls having spinal fusion compared
with brace-treated AIS girls [231].
Large extrathoracic skeleton/normal chest width

A nding in pre-operative girls with AIS was a large
extra-thoracic skeleton relative to chest size [39, 139].
Interpretation by the Nottingham concept of aetiology
(gure 7) suggested a biomechanical susceptibility
with inadequate ribcage defence against axial rotation
leading to failure of rotation control [139, 170]. This
concept needs testing in a longitudinal study.
. Directional asymmetry occurs when there is

normally a greater development of a character on
one side of the plane or planes of symmetry than
on the other. There is directional asymmetry in (1)
thoracic AIS curves show directional asymmetry
to the right, (2) upper limb length asymmetry
(the upper limb being longer on the convexity of
thoracic and thoracolumbar but not lumbar curves
[101, 102, 139] and (3) back contour asymmetry
predominantly right [128130] with a signicantly
shorter upper arm ipsilateral to the hump [129].
Dichotic listening tests in 31 AIS patients showed
that the brain was more strongly lateralized than
in 20 healthy children without scoliosis [135].
. Antisymmetry occurs when most individuals in
a population are asymmetric, but it is unpredictable which side shows the greater development.
Handedness is a good example of antisymmetry.
. Fluctuating asymmetry (FA) is characterized by
randomly directed deviations from perfect symmetry, with most individuals having little or no asymmetry [238]. It has been widely used in humans,
especially about the hands and head, in the diagnosis of congenital defects. It is claimed that FA is
the most sensitive indicator of a child to cope with
stresses during development [235, 236]. Growth
velocity and uctuating asymmetry are negatively
correlated [237, 238].
Vertebral endochondral-membranous disproportions

The ndings relating to vertebral disproportionate
anterior/posterior growth and vertebral body slenderness have been outlined.
upper limb length asymmetries in IS
Distinct patterns of leftright upper limb length
asymmetry were found to be related to the side and
site of the curve and the age at diagnosis [101, 102,
139]. These leftright asymmetries may be determined
by nature and nurture, involving allometric skeletal
growth [101, 102, 139], developmental instability [137,
138], unsynchronized bone growth [38] and a neuromuscular imbalance. The pattern of this asymmetry suggests
order rather than disorder.
bilateral symmetry and asymmetrythree types
and terminology
Bilateral, or leftright, asymmetry has three forms;
directional, uctuating asymmetry and antisymmetry
in hard and soft tissues [232238].
developmental stability and instability

Developmental stability reects the ability of an individual to develop a regular phenotype under given
environmental and genetic conditions [238]. Perturbing
factors during development may disrupt developmental
processes and cause deviations from a regular phenotype, while regulatory processes such as feedback
may restore the growth trajectory towards the regular
phenotype [238]. Measures of developmental instability
include the degree of uctuating asymmetry and the
frequency of minor physical anomalies (phenodeviants).
Endocrine, neural and circulatory mechanisms that
control similar development of morphological characters on the two sides of the body are also involved
in controlling overall development.
relation of growth velocity to asymmetry and

to developmental instability
In reviewing studies of growth velocity and developmental instability, Mller and Swaddle [237] concluded
157

R. G. Burwell
that slow growth is generally associated with asymmetry
or that there may be a trade-o between growth velocity
and developmental instability. The signicance of this
conclusion for IS was not examined, but it seems likely
that it is in the slowly growing juvenile period that
the initial susceptibility to AIS develops in the spine,
possibly the ribcage, and/or CNS before the onset of
the adolescent growth spurt. The ndings of Schmitz
et al. [118] are consistent with this concept.
The possibility of a trade-o between growth velocity
and developmental instability [237, 238] implies that the
adolescent growth spurt should lead to less asymmetry
and modulate the biological response to cumulative
stress in the growth-induced torsion concept. This concept is dicult to refute.
Genetic concepts
According to Miller [239], while the role of genetic
factors in IS has been well documented, reports of
the specic mode of inheritance are inconclusive.
Moreover, the phenotype variability suggested that
the genetic expression of IS was dependent on multiple
factors and genetic interactions.
twin studies
In monzygous twins there was a high concordance of
73% and in dizygous twins 36% [240]. These values
were consistently higher than those reported for rst
degree relatives from more global population studies.
This was strong evidence for a genetic aetiology of AIS.
family studies of phenotype and spinal shape

Millner and Dickson [6] noted the familial trend
in growth and development in adolescence [242].
They also stated that normal spinal shape has a genetic
basis, as shown in a twin/sibling study.
the saltatory hypothesis of normal growth and

possible significance for IS
Lampl [19] writes:
A reasonable hypothesis . . . is that the temporal aspects
of the growth-maturation saltation episodes reect an
interaction between cell-intrinsic information (genes
uniquely expressed in individual cell lines) and central
neural signals mediated by endocrine, paracrine and
cytokine cascades. For example, it is known that growth
in the nervous system and bone occurs by cells that
express genes according to a pattern determined by
intrinsic programmes and external cues.
X chromosome inactivation in females

mosaicism
The X chromosome is unique among chromosomes
in that, early in an embryonic girls existence, each of
her cells commits to using just one X from the mother
or the father, as do the descendent cells [243]. Hence,
after such random X chromosome inactivation (evident
as the Barr body), girls are a patchwork of two dierent
cells, some using one X chromosome and some the
other, i.e. girls are a mosaic. Whether or not this mosaicism has relevance to the susceptibility of girls to progressive scoliosis is unknown. There is a need to search
in females for mosaicism in cells of tissues that may be
involved in AIS pathogenesis.
candidate gene approach

Miller [11] stated that the structural genes of collagen
types I and II, brillin 15 (FBN 1) and elastin were
excluded as potential causative factors of IS within
the studied populations.
polymorphisms, curve severity and the

oestrogen receptor gene
Polymorphisms in the oestrogen receptor (ER) gene
have recently been reported in association with
curve severity and progression in AIS [241]. Inoue
et al. [241] suggested there is a correlation between
ER gene polymorphisms and growth maturation, with
importance for bone metabolism.
158
microchimerism
There is growing evidence that microchimerism a
condition in which small numbers of another persons
cells persist in the body may not be so unusual in
humans [243a]. Any search for mosaicism in AIS subjects might include consideration of a search for microchimerism.
Multi-factorial spatio-temporal concepts
multi-factorial causation
Most, if not all, workers subscribe to the view that
AIS is multi-factorial resulting from several factors [6,
11, 12, 1417, 56, 126, 131137, 148, 149, 178, 179, 217,

219, 224, 230]. Three multi-factorial concepts for AIS
aetiology have been published since 1977. All are
spatio-temporal, but at present none is fully integrated
with existing knowledge about the causation of AIS.

embryogenesis
According to Duboule [22], animal development is,
in fact, nothing but time. For developmental biology,
the study of causal relationships implies the examination of two time points: inducing the cause and
looking at the eect. The animal clocks follow varied
temporal rules and often run in parallel without any
apparent interaction with each other. The developmental
asynchrony suggested for IS may have its roots in early
embryonic development.
altered developmental timingheterochrony

The three spatio-temporal concepts for IS all involve
altered developmental timing. Two involve skeletal
tissues and the other, developmental instability, any
number of tissues. The role of altered developmental
timing or the concept of heterochrony has recently
been extended from evolution to the earliest stages
of development [244] and used to interpret multiple
malformation syndromes [245]. There are close connections between heterochrony and allometry [244].
Heterochrony has not yet been extended to pubertal
development except for the three spatio-temporal concepts of IS.
cartesian axes and cardinal planes

Cartesian co-ordinates dominate animal and human
morphology: antero-posterior and dorso-ventral
axes are unidirectional, whereas the leftright axis is
bi-directional with two semi-axes, midline-to-left and
midline-to-right, giving rise to directional asymmetry
[246]. Minelli [246], writing in the new eld of evolutionary developmental biology (evo-devo), is critical of
their use and by implication the three cardinal planes
and regards them as gments of imagination rather
than biological reality.
an allometric skeletal growth disproportion

with genes acting in the fourth dimension
(foetal origins hypothesis)hypothesis of
oscillating axial torsion
After detecting various skeletal growth patterns in
infantile idiopathic scoliosis (IIS) and AIS patients,
Burwell et al. [101] concluded: If these growth disorders
are determined intrinsically in the growing bones, the
fundamental causes of IIS and AIS may be genetic
and/or environmental factors acting directly or indirectly on the developing skeletal primordial in early
embryonic life . . . Implicit in this hypothesis is that
the abnormalities may not become evident in the
growing skeleton until months or years after birth.
To explain the post-natal alternating leftright asymmetry of each of (1) neural arch asymmetry, (2) curve
laterality of IIS and AIS and the pattern of back
contour asymmetry, a developmental mechanism was
hypothesized, namely the hypothesis of oscillating axial
torsion [129].
Subsequently, discussing the sexual dimorphisms of
IS, it was suggested [129]: In early embryonic life,
developing skeletal primordia of the sexes may be
susceptible at dierent times to genetic and/or environmental factors which create aberrations expressed
morphologically later in life in a sex-related way.
Idiopathic scoliosis was interpreted as a disorder of
allometric (dierential) growth in the skeleton [101,
102, 139]. This disorder can now be viewed as one of
gene function, altered by environmental factors and
expressed in the fourth dimension of time [20, 22,
247]. Such environmental factors could be hormonal,
nutritional, alcohol, smoking, viruses, drugs, medicaments, radiation, maternal immunoreactivity to malespecic features of the foetus and hypoxia during birth.
The concept that environmental factors acting prenatally can be expressed later in post-natal life was
also suggested for Perthes disease [248, 249]. Barker
and colleagues [250, 251] and others have shown that
the origins of important chronic diseases of adult
life including coronary heart disease, stroke and type
2 diabetes, as well as rates of ageing, may lie in foetal
responses to the intrauterine environment. It is termed
the foetal origins hypothesis. It has led to the evaluation of pre-natal and early post-natal environmental
factors in relation to the development of some postnatal diseases.
159

R. G. Burwell
developmental instability
unsynchronized bone growth
Goldberg et al. [137] tested the hypothesis that symmetry is lost when the developmental programme coded
in the genome fails to run optimally. They used palmar
dermatoglyphics in groups of AIS girls and found an
increase in directional asymmetry, and all groups
showed uctuating asymmetry [137, 138]. Dangereld
et al. [136] reported an increase in FA about the head
and hand with increasing curve severity in IS.
Noting a close inter-relationship between age, Cobb
angle and apical vertebra, Goldberg et al. [138] invoked
the concept of developmental gradients in embryonic
life, namely of leftright and cephalo-caudal [233].
Dorso-ventral gradients were not studied, but are known
to be relevant in connection with the sagittal prole of
AIS subjects. Scoliosis was viewed as a whole body
phenomenon, as a nal common pathway of a variety
of destabilizing factors. The disruptive eects of any
stressors in IS may occur pre-natally and/or postnatally and aect various tissues including skeletal,
ligamentous, muscular and nervous tissues.
Goldberg [133] writes . . . scoliosis is not a disease
or group of diseases but a symptom or sign of
environmental stress, signicant enough to overwhelm
the intrinsic stability of the morphological genome.
As such, there is no specic aetiology but a large number of precipitating stressors . . . The natural history
is now viewed in a new way, simpler in that it is merely
an aberrant growth pattern, more complex in that
the molecular biology of growth and the morphological
genome is only beginning to be investigated.
Unsynchronized bone growth conceptor why a system

can turn chaotic
Some published comments on the developmental

instability concept
Swaddle [252], summarizing the developmental instability concept of AIS, writes The hypothesis proposed by the developmental stability theory is that
patients with large uctuating asymmetries in skeletal
characters will be more likely to develop a spinal
deformity. This hypothesis is eminently testable
through a detailed longitudinal analysis of morphological asymmetries.
Stokes [253], commenting on Goldbergs developmental theory for AIS, writes The report implies that
the original causes are beyond our control, perhaps
truly idiopathic and spontaneous. If so, we may soon
reach the point where research into the aetiology of
the original small curves can be put behind us, and
scoliosis researchers can focus on clinical problems.
160
Coillard and Rivard [38] thought it possible for

. . . unsynchronized bone growth, a temporal defect of
genetic origin, focused on a particular spinal section,
to trigger the formation of discordant vertebrae that
would alter the internal dynamic balance of the spine
and, under conditions of rapid maturation and growth,
result in dysfunction of the neuro-musculo-skeletal
system (NMSS). If major internal or external conditions
such as the cessation of growth, change in hormonal
environment or achievement of a new stable equilibrium
are not rapidly, spontaneously or articially altered
to break the vicious cycle that has been established,
the NMSS gets caught up in a dysfunction of highly
evolutive risksleading to the severe spinal column
deformities . . .
The unsynchronized bone growth concept is allied to the

allometric skeletal growth disorder concept [101, 102,
139], but lacks the nurture component.
left^right internal clocks in vertebraeis AIS
an asymmmetric chronomic disorder?putative
molecular basis for a primary skeletal change
in AIS
The challenge to developmental biologists is to
understand the temporal aspects of development,
termed chronomics, as well as the underlying genomics
[23]. In embryogenesis, the fourth dimension is found in
internal clocks that are in place to ensure a coordinated
developmental programme, and the spatial construction
can be understood only in the light of time [20, 22].
To scoliosis surgeons and scientists, how such mechanisms may create the deformity of AIS during puberty
is a daunting prospect. Fortunately, there are other
approaches at the macroscopic as well as microenvironmental level that currently have promise.
Concept of asymmetric internal clocks in vertebral
growth platesmelatonin in resynchronization?
primary vertebral cause of AIS?
Coillard and Rivard [38] suggested that, because
asymmetries exist in other structural pairs of the skeleton, why should they not exist in a vertebra? This could
concern two-to-ve consecutive vertebrae resulting in
a regional disturbance. Chondrocytes in growth plates
must be receptive to hormones in a synchronized manner for normal growth; if they are desynchronized this
can cause discordant vertebral growth. Coillard and


Rivard proposed that, if the unsynchronized development is of genetic origin, the problem may be circumvented by delaying the eects of a drop in melatonin by
an articial cyclic rise in circulating melatonin levels
to cause a spontaneous resynchronization and thereby
eliminate or limit the impact of resulting discordant
growth.
The concept that AIS may result from an asymmetric
chronomic disorder provides a molecular basis for
primary scoliosis. It is an intrinsic mechanism, rather
than a mechanical mechanism, within the growthinduced torsion concept.
There is some evidence for a time control, or internal
clock, in growing bones [254, 255] that are globally
patterned in the axial and appendicular skeleton by
Hox genes [256, 257]. An internal clock may exist
in vertebral body growth plates [126] and function in
the blocks of mesoderm that are laid down in a
synchronous fashion on both sides of the body axis
under the inuence of a molecular oscillator underlying
vertebrate segmentation [258]. Internal clocks could
also be present bilaterally in ribs.
comment on the concept of left^right
vertebral internal clocksor segmental
neuromuscular imbalance?
The vertebral leftright internal clock concept neither
explains the sagittal spinal shape changes during puberty, nor does it relate skeletal growth to maturation.
Theoretically, there could be desynchronized front
back internal clocks for which there is no evidence,
although such clocks would explain Somervilles
concept of a posterior segmental growth failure [48].
To explain the sagittal spinal shape changes during
normal puberty, another suggestion is that of a segmental neuromuscular imbalance; this concept is consistent
rst with current thinking that AIS results from a CNS
defect [14] and, secondly, with speculations about
neural maturation in the childs trunk during puberty
viewed in the human perspective.
The human perspectivea neurodevelopmental disorder
related to the maturing trunk in puberty?
Until recently, idiopathic scoliosis has not been
described as occurring naturally in non-human primates
(Sevastik, personal communication). Moreover, the
failure of surgical techniques to induce experimental
scoliosis in non-human primates [259] and its development after injection of poliomyelitic vaccines into the
spinal cord of monkeys [260] are noteworthy. The low,
or nil, prevalence of naturally-occurring IS in nonhuman primates was examined in relation to the aetiology of human IS [39, 169]. It is evident that, during
evolution, humans, by acting against gravity and
through changes in the pelvis, have acquired a lumbar
lordosis to stand upright and developed a unique
posture [261] and bipedal gait, probably enabling IS
to develop in some subjects [39, 169].
Naique et al. [262] reported scoliosis in an Orangutan
and supported the view that in humans the lumbar
lordosis and the upright bipedal gait may in some
way be associated with the distinct morphology of
human IS.
human posture and gait
Human walking, unique among animals, involves
axial pelvi-spinal rotations and axial spinal counterrotations (gure 6). Body axial rotations start at the
feet and are eliminated by the upper cervical spine
so that the direction of vision is unaected and determined solely by head movements and saccades (voluntary eye movements). In addition, in humans axial
rotations of the trunk are carried out frequently and
forcibly in other activities that are not performed by
quadrupeds [263].
CNS rewiring in normal development
associated with acquiring the human unique
posture, bipedal gait and activities when
upright?
The adolescent growth spurt in the spine evidently
involves adjustments in the CNS to control movements
in the trunk as the child grows and especially in girls
with more immature postural mechanisms than boys
(gure 10).
The Red Queen concept in health and in aberration
A neurodevelopmental concept was proposed to
explain the putative CNS changes associated with the
rapid increase in trunk size during puberty [178, 264].
The concept postulates that, in gait, the motor output
from the upper trunk has to keep pace with the changing sensory input from the lower trunk (gures 6 and 7);
the two must run together like the Red Queen and
Alice with the forest (Alice Through the Looking
Glass [265]), or fail [178, 264]. This is in accordance
with the Red Queen concept [265]. It was proposed
that aberrations of such putative neural control,
particularly during the adolescent growth spurt, induce
161
R. G. Burwell

AIS [178, 264]. Factors that may lead to aberrations include the genome, stretch of the spinal cord
during the vertebral growth spurt due to disparate
rates of growth between the vertebral bodies and
the spinal cord [30] and a deciency of dietary antioxidants.
Other components of the concept relate to central
pattern generators [79, 126, 178, 179, 264], the CNS
internal body image [266] and the spinocerebellar loop
[178, 264, 267]. There is pruning of cortical synapses at
puberty [266] that may inuence postural mechanisms
within the spinal cord.
may have a specic impairment in the global processing

of spatial information [272]. In this connection, Herman
et al. [273] reported evidence of an association between
learning decits, altered processing of vestibular
information and IS and suggested an important role
of cortical structures in the aetiology of this disorder.
They suggested that that a visuo-spatial perceptual
impairment may be the common feature of IS.
future research and, if substantiated,
new safe dietary treatments?
Neurologic research and neuromorphic engineering
the basic neurodevelopmental disorder of

AISimmaturity of postural neural
pathwaysdevelopmental dyspraxia?
A new concept outlined here suggests that AIS is a
neurodevelopmental disorder [268] arising from the
interaction of genetic and environmental inuences
in the childs trunk and central nervous system
during puberty. The concept explains the short segment
lordosis and hypokyphosis in AIS and integrates with
six concepts outlined above, namely:
1.
2.
3.
4.
5.
6.
Vertebral
disproportionate
anterior/posterior
growth and vertebral body slenderness;
Thoracic spinal sagittal shape changes in health
and AIS (gure 5);
Vicious cycle concept or growth-induced torsion
concept;
Segmental neuromuscular imbalance;
The Nottingham (or dinner plate-agpole) concept (gures 6 and 7); and
NOTOM hypothesis (gure 10).
In addition to neurophysiologic and neuropsychologic research, further insight into the above neurodevelopmental concepts in health and deformity may
be gained by constructing a model of the human
trunk using the techniques of neuromorphic engineering
[266, 274].
Lipid peroxidation and possible prevention by
anti-oxidant diet
Certain neurodevelopmental disorders are associated
with abnormalities of fatty acid and phospholipid
metabolism, involving oxidative stress causing lipid
peroxidation [275277]. There are diagnostic tests on
red blood cell membranes, plasma, a skin test and
breath tests [278] for these disorders which suggest a
new line of research for IS and a possibly a new aetiologic paradigm for AIS. Fatty acid and phospholipid
metabolism can be inuenced by many factors both
constitutional and environmental [275, 277a, 277b].
Possible dietary treatment
Segmental neurogenic disorder and long-latency

reex activity
The neurodevelopmental concept is consistent rst,
with the ndings of Trontelj et al. [269], suggesting
that IS is a segmental neurogenic disorder and, secondly, with long-latency reex activity found in patients
with IS but not with non-idiopathic scoliosis [270].
If the neurodevelopmental paradigm be substantiated

for AIS, there is the possibility of new safe dietary
treatments, including anti-oxidants (a-tocopherol
(vitamin E), the selenium-containing enzyme glutathione peroxidase, melatonin) and fatty acids [276]
in the initial stages of deformation. Anti-oxidants may
also be benecial in controlling the growth-induced
torsion of AIS.
The basic CNS disorderdevelopmental dyspraxia?

The basic disorder of the neurodevelopmental concept is unknown, but it may reect immaturity of postural neural pathways, as suggested in the cerebral
cortex for developmental dyspraxia (insucient reinforced neural pathways) [271]. Developmental dyspraxia
162
Idiopathic scoliosis
Patients with idiopathic scoliosis showed a decrease
in blood plasma concentration of selenium in 51
patients compared with 20 controls ( p<0.01) and in
18 operative patients (curves > 45 ) compared with 33

conservatively-treated patients (curves<45 ) ( p<0.05)
[228]. It was suggested that the low selenium ndings
were linked to the synthesis and maturation of collagen
aecting axial skeletal stability [228]. The glutathione
peroxidase in erythrocytes was similar in the scoliotics
and controls. More research is needed.

Concept of initiating and progressive factors

There is a view that there are two types of pathogenetic factors for idiopathic scoliosis [279, 280]:
initiating (or inducing) factors and those that cause
curve progression.
The initiating factor(s) that triggers both small
normal and small idiopathic curves [112, 127] may lie
in the spine, ribs, muscles and/or nervous system.
Current concepts on the mechanisms of initiation of
such curves are discussed above. It seems likely that
mechanisms of initiation for thoracic, thoracolumbar and lumbar curvesbe they primary skeletal,
primary ligamentous, primary neuromuscular or a
combinationare associated with mechanisms that
determine the side (laterality) as well as site of the
scoliosis curves and possibly also constitutional back
asymmetry.
The vast majority of AIS curves of 20 or less do not
progress. As already outlined, progressive factor(s) are
generally thought to be a mechanical process (torsion),
involving eccentric loading of the spine, vertebral
growth modulation, spine slenderness and predicted
clinically by each of curve magnitude, pattern, apex,
laterality and exibility, and the growth potential indicated by maturity indicators including age at diagnosis,
menarche and bone age as determined by the Risser
sign. Morphological vertebral patterns may be prognostic for curve progression in AIS girls [18].
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PEDIATRIC REHABILITATION,

Aetiology of idiopathic scoliosis:

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Accepted for publication: October 2003

Author: R. G. Burwell, MD FRCS, Emeritus Professor,

difficulties in deciphering the aetiology of

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

an overall concept for the aetiology of AIS

the scoliotic spine as a columntheory and

Emerging as an overall concept for the aetiology of

Growth is more than an increase in size and

Knowledge from developmental biology has been used

a neurodevelopmental concept as part of an

the scoliotic spine as an helixtorsions and

Column theory and biology

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Aetiology of idiopathic scoliosis

Idiopathic scolotic vertebraegender dierence

The external phenotype of AIS subjects

Possible implications of a more ectomorphic

relative lengthening of the anterior spinal

Disproportionate endochondral-membranous bone

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

There is an additional hypothesis to explain their

Concepts for AIS aetiology

Primary morphological feature [18]. The RASO

possibly indirectly through the ribcage in

neurocentral synchondroses (NCSs)pedicle

facet joints?growth asymmetry and

Aetiology of idiopathic scoliosis

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Bone mass accumulation in health

Goto et al. [61], in a nite element study, implicated

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Spinal mobility in scoliotic children

Figure 1 Mechanism of axial rotation in a thoracic and a lumbar

Implications for sagittal plane research

Figure 2 Axial vertebral rotation in structural scoliosis. Note the

Aetiology of idiopathic scoliosis

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Anterior lateral shear forces and posterior torque

Figure 3 The force pattern in the scoliotic spine (modied from

in the major curve of anatomical scoliotic specimens

Figure 4 Diagram of the vicious cycle concept by which eccentric

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

The recent nding of Guo et al. [18] that scoliosis

What is the biological mechanism in vertebrae

Platelets activated in a calcium-dependent mechanism?

Aetiology of idiopathic scoliosis

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Kawabata et al. [104], in a mathematical study, tested

In addition to lateral wedging, sagittal vertebral

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14

Impaired forward exion (IFF) in segments of the

Figure 5 Radiological segmental sagittal spinal prole in a 14-year

hypokyphosis as being permissive, by facilitating axial

Sagittal spinal prole and radiological declive and

Declive and proclive segments

1. Tomaschewski [116], in 686 healthy schoolchildren

Frontback asymmetry concept

Aetiology of idiopathic scoliosis

leftright asymmetries in AIS subjects [101, 102, 131

Dev Neurorehabil Downloaded from informahealthcare.com by University of Newcastle on 08/21/14