Etiology and natural history of adolescent idiopathic scoliosis: A review

Rajasekaran Shanmuganathan; Karuppanan Sukumaran Sri Vijay Anand; Ajoy P Shetty

doi:10.4103/isj.isj_62_19

SYMPOSIUM: ADOLESCENT IDIOPATHIC SCOLIOSIS

Year : 2020 | Volume : 3 | Issue : 2 | Page : 131-142

Etiology and natural history of adolescent idiopathic scoliosis: A review

Rajasekaran Shanmuganathan, Karuppanan Sukumaran Sri Vijay Anand, Ajoy P Shetty
Department of Spine Surgery, Ganga Medical Centre & Hospitals Pvt Ltd, Coimbatore, Tamil Nadu, India

Date of Submission	13-Sep-2019
Date of Decision	04-Nov-2019
Date of Acceptance	21-Jan-2020
Date of Web Publication	13-Jul-2020

Correspondence Address:
Dr. Rajasekaran Shanmuganathan
Department of Spine Surgery, Ganga Medical Centre & Hospitals Pvt Ltd, Mettupalayam Road, Coimbatore, Tamil Nadu.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/isj.isj_62_19

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity with a prevalence of 1.34%, although the percentage of population requiring treatment is substantially less. Understanding the etiopathogenesis and natural history of a disorder is most important to formulate effective treatment strategies. For the past few decades, researchers have probed the etiopathogenesis of AIS from various angles of genetic, neurological dysfunction, biomechanical, hormonal, and developmental disturbances. Various theories have been put forward based on association studies that found no correlation. However, direct cause–effect relationship has not been established for any individual factor till now. Also whether these findings are either primarily the cause for scoliosis or secondary to AIS remains unknown. From the existing literature, AIS appears to be a multifactorial disorder with a strong genetic predisposition, hormonal and environmental disturbances. Literature on the natural history of AIS is limited with only few studies that have long-term follow-ups on untreated scoliosis. On the basis of the available literature, it can be safely said that AIS has a benign course with very minimal or no functional disability in the long-term follow-up. The minimal risk of mortality is present only in curves of more than 100° with severe pulmonary dysfunction and cor pulmonale. Here we review the important theories, hypothesis, and recent trends in research on etiopathogenesis of AIS and also summarize on the natural history of the disorder.

Keywords: Adolescent idiopathic scoliosis, etiology of scoliosis, natural history

How to cite this article:
Shanmuganathan R, Sri Vijay Anand KS, Shetty AP. Etiology and natural history of adolescent idiopathic scoliosis: A review. Indian Spine J 2020;3:131-42

How to cite this URL:
Shanmuganathan R, Sri Vijay Anand KS, Shetty AP. Etiology and natural history of adolescent idiopathic scoliosis: A review. Indian Spine J [serial online] 2020 [cited 2021 Jan 17];3:131-42. Available from: https://www.isjonline.com/text.asp?2020/3/2/131/289656

Introduction

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of spine with a prevalence of around 1.34%.^[1] The etiology of AIS has been probed from various angles, which includes genetic, neuromuscular, growth and hormonal disturbances, bone mineral density, biomechanical alteration, and calmodulin levels. To date, there is no accepted theory on etiopathogenesis of AIS and most of the existing studies have reported mere associations to support their hypothesis but have failed to provide conclusive evidence. It appears that scoliosis is a multifactorial disorder with genetic heterogeneity where complex interplay of genetic and environmental factors exists. The natural history of AIS is rather benign with only 0.23% requiring treatment.^[2] This is a narrative review attempting to give an overview of the various proposed etiopathogenesis of AIS along with the natural history.

Materials and Methods

We conducted a comprehensive search in PubMed and Google Scholar database in August 2019 using keywords “Adolescent idiopathic scoliosis,” “etiopathogenesis,” and “natural history” combined with Boolean operators. We included full-text articles with no language or date restrictions. The PubMed examination showed 1614 abstracts pertaining to the subject selected. We excluded studies that dealt on secondary, early onset, or adult scoliosis. Also studies on surgery, management strategies, and duplicates were excluded resulting in 432 studies. The authors reviewed full-text articles when inclusion in review was unclear from title and abstract. All original articles discussing etiopathogenesis of AIS and natural history were included. Additional articles from the recent reviews and literature were handpicked and included in this review resulting in a total of 142 studies. The schema of search and exclusion is given below.

[INLINE 1]

Search on natural history yielded 164 studies, of which articles on surgery and bracing were excluded resulting in 34 studies. After full-text review, a total of 12 handpicked studies were used for this review. Although a thorough search was carried out, the authors acknowledge the possibility of missing some relevant literature in this subject.

Etiopathogenesis of scoliosis

We would be broadly discussing multiple theories and hypothesis under the following categories: genetic theory, neurological dysfunction, hormonal and biomechanical factors.

Genetic theories

AIS has strong genetic basis as evidenced by increased incidence of AIS among first-degree relatives (6%–11%).^[3] A meta-analysis of twin studies documented a higher AIS concordance rates in monozygotic twins (73%) in comparison with dizygotic twins (36%).^[4] Segregation analysis to determine whether the familial occurrence of AIS fits a particular type of inheritance has not shown a clear mode of inheritance of AIS. Family linkage studies have identified many gene loci associated with AIS. Miller et al.^[5] in their study on 202 families with 1198 individuals reported gene loci in the primary regions in chromosome 6, 9, 16, and 17 and the secondary regions in 1, 3, 5, 7, 8, 11, 12, and 19 indicating the genetic heterogeneity.

Genetic association studies have identified numerous genes including melatonin 1B receptor gene,^[6]chromodomain helicase deoxyribonucleic acid (DNA)-binding protein 7,^[7]collagen type 1 a 2 gene,^[8]COL11A2 (collagen type XI alpha 2 chain),^[9] matrillin-1 gene,^[10]ESR1 (estrogen receptor alpha), ESR2 (estrogen receptor beta),^[11]CALM1 (calmodulin 1),^[12]VDR (Vitamin D receptor),^[13]TNFRS11B (tumor necrosis factor receptor superfamily member 11b), GPER (G protein-coupled estrogen receptor 1),^[14]IGF-1 (insulin-like growth factor 1),^[15]HSPG2 (heparin sulfate proteoglycan 2),^[16]FBN1 (fibrillin-1), FBN2 (fibrillin-2),^[17]LBX1 (ladybird homeobox 1),^[18]GPR126 (G-protein-coupled receptor 126),^[19]TGFB1 (transforming growth factorβ1),^[20]IL-17RC (interleukin-17 receptor C), POC5 (POC5 centriolar protein),^[21],[22] and homeobox genes (HOXB8, HOXB7, HOXA13, and HOXA10). These genes are related to connective tissue structure integrity, involved in bone metabolism, melatonin signaling pathways, puberty, growth, axon guidance pathways, and genes that encode melatonin and estrogen receptors.

The LBX1 gene located on chromosome 10q24.31 is a homeobox transcription factor and supposedly takes part in spinal cord differentiation, patterning, and somatosensory signal transduction. Recent meta-analysis of the published case-control studies on the association between LBX1 gene polymorphisms and AIS in Asian and Caucasian populations revealed that T allele of rs11190870, G alleles of rs625039, and rs11598564 represent risk factors for AIS, whereas G allele of rs678741 may in fact have a protective role in the occurrence of AIS.^[23],[18]

Many of the aforementioned genes have been found to be associated with progression of curve but not with initiation of scoliosis.^[24] Another major problem has been the replication of the results in different population. Moreover, they have not been found to be significant in genome wide association studies (GWAS). In Cheng et al.’s^[25] genetic model of AIS, they proposed that the “initiation phase” and “progression phase” genes act independently or are in concordance and lay emphasis on role of epigenetic factors. Future studies should incorporate large cohorts with phenotypic subgroups to derive at a clinically useful inference of identifying susceptible individuals and who are at risk of progression in AIS.

Genetic factors: Key points

AIS has a strong genetic basis.

Family linkage studies have identified many gene loci associated with AIS.

Genetic association studies have identified multiple genes involved in bone metabolism, melatonin signaling pathways, puberty, growth, axon guidance pathways, and genes that encode melatonin and estrogen receptors.

However, the results have been inconsistent in different ethnic populations and in GWAS.

Neurological dysfunction

In scoliosis patients, neurological dysfunctions such as postural imbalance, vestibular, and locomotor deficits are known to occur indicating a possible defect in central nervous system contributing to etiopathogenesis of AIS.

Roth^[26] and Porter^[27] postulated that in idiopathic scoliosis, there is disproportional growth occurring between the skeletal and neural systems, due to the spinal cord being short or because of a rapid growth spurt of the spine. This was furthered by Chu et al.^[28] with magnetic resonance imaging (MRI) and they suggested that anterior spinal overgrowth stretches the spinal cord and cauda equina, leading to hypokyphosis and deformity of the growing thoracic spine - causing scoliosis.

Burwell et al.^[29] in their double neuro-osseous theory proposed that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous system. This is mediated by selectively increased sensitivity of the hypothalamus to circulating leptin (genetically determined upregulation) with asymmetry as an adverse response (hormesis); routed bilaterally via the sympathetic nervous system to the growing axial skeleton initiating the scoliosis deformity (leptin–hypothalamic–sympathetic nervous system concept = LHS concept). Low leptin levels initiate the asynchronous neuro-osseous growth with which, as the spine lengthens, tension is created in the tether. During the pubertal growth spurt, these issues translate into changes in spinal conformation, which initially occurs in the sagittal plane by the tethering of anterior vertebral growth. In the somatic nervous system, dysfunction of postural mechanisms fails to control, or may induce, the spinal deformity of girls with AIS (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. This developmental disharmony in spine and trunk is compounded by any relative osteopenia, biomechanical spinal growth modulation, intervertebral disc degeneration, and platelet calmodulin dysfunction.

Brain imaging in patients with AIS has shown larger regional brain volume difference in the brainstem and in the corpus callosum in comparison with controls^[30] and this difference has been confirmed by diffusion MRI as well.^[31] Also functional MRI showed greater interhemispheric asymmetry index^[32] and decreased structural connectivity between hemispheres when patients with AIS were compared with controls.^[33] Asymmetry between the vestibular system, and^[34] abnormal connections between lateral and posterior semicircular canals^[35] have also been reported to cause postural imbalance and abnormal somatosensory function.

Neurological dysfunction: Key Points

In patients with AIS, presence of postural imbalance, vestibular disturbances, and locomotor deficits suggest a possible neurological dysfunction in pathogenesis.

Disproportional growth between vertebral column and spinal cord has been postulated to stretch spinal cord,cause hypokyphosis and deformity in growing spine.

Double neuro-osseous theory postulates that increased sensitivity of hypothalamus to leptin initiates asynchronous neuro-osseous growth. This developmental disharmony is further accentuated by various biomechanical factors.

Radiological evidence for neurological dysfunction such as brain stem and corpus callosum volume differences, decreased structural connectivity between hemispheres, and vestibular asymmetry have been found in AIS subjects in comparison to controls.

Hormones

The progression of curves in AIS during puberty, the female preponderance of the disorder, and the prevalence of curves with higher Cobb’s angles in females in comparison with males have laid foundation for the hormonal theory in etiopathogenesis of AIS.^[36] Ahl et al.^[37] and Willner et al.^[38] have found higher endogenous secretion of growth hormone than normal girls, implying an earlier growth spurt in scoliotic girls. IGF-1 values in serum correlate well with peak growth velocity^[39] and it has been claimed to be a better indicator than growth hormone due to its lack of diurnal variation. However, genetic studies on SNPs (single-nucleotide polymorphisms) of IGF-1 have failed to show any significant correlation between IGF-1 and AIS.^{[40],[41],[42]}

Strong female preponderance (8:1) especially in curves >30°^[43] and strong correlation found between age at onset of menarche and progression of AIS implies a significant role for sex hormones in pathogenesis of AIS. FSH (follicle stimulating hormone) and LH (luetinizing hormone) were found to be lower and levels of progesterone and estradiol were found to higher in premenarcheal patients with AIS in comparison with normal premenarchal girls by Kulis et al.^[44] Pöllänen et al.^[45] suggested that serum levels of 17 beta estradiol measures underestimate the levels and do not correspond to muscle levels.

Melatonin, a hormone produced by pineal gland, is involved in signaling day or night and sleep regulation. Machida et al. reported lower 24-h melatonin levels in AIS and postulated that it has a role in progression of curve by its influence on nervous system.^[46] Melatonin or 5-Hydroxytryptamine receptors are believed to play a role in the modulation of the tone of skeletal muscles as well and may be very important in the pathogenesis of AIS.^[47],[48] Experiments on pinealectomized animal models of chicken and bipedal rats but not quadruped rats showed development of spinal deformity. Furthermore, these investigators also showed that development of scoliosis could be prevented by the reimplantation of the pineal gland in skeletal muscle or by the administration of melatonin as a replacement therapy.^[49] This led to hypotheses that inherited melatonin deficiency, bipedal posture, and horizontal localized neuromuscular imbalance resulting in generation of abnormal torsional force resulted in scoliosis.^[50] However, Cheung et al.^[51] in their experiments on pinealectomized chickens did not notice any development of scoliosis. These conflicting results led to the proposal that AIS instead is caused by a melatonin-signaling pathway dysfunction that only affects certain cell types, namely osteoblasts rather than mere deficiency.^[52] Moreau et al.^[53],[54] reported impaired melatonin-signaling transduction in osteoblasts, myoblasts, and lymphocytes linked to the inactivation of inhibitory guanine nucleotide-binding proteins. He reported that three different functional subgroups of AIS exist according to their cyclic adenosine monophosphate response to melatonin.

Calmodulin is a ubiquitous eukaryotic calcium-binding receptor protein that regulates contractile properties of platelets and muscles by actin–myosin interaction and regulation of calcium influx from sarcoplasmic reticulum in muscle fibers. Calmodulin is a secondary messenger in melatonin pathway and is believed to play a role in the regulation of spinal alignment by its muscle contractile properties. Cantaro was the first to note a 2.5–3-fold increase in platelet calmodulin levels in patients with AIS.^[55] Similar results were also reported by Kindsfater et al.^[56] and Cohen,^[57] who found correlation between severity and platelet calmodulin levels. Lowe et al.^[58] furthered it by correlating platelet calmodulin levels with curve progression and brace treatment. In another report, Lowe et al.^[59] added evidence by finding asymmetric distribution of calmodulin in paraspinal muscles, higher at convex and lower at concave side which was confirmed by Acaroglu et al.^[60] Burwell et al. in their platelet–skeletal hypothesis by linking several fields postulated that in a small scoliotic curve due to asymmetric loading, microtrauma occurs in end plates resulting in opening of juxtaepiphyseal vessels, platelet activation and release of growth factors. This hormone-driven growth on compromised vertebral physes promotes relative anterior spinal growth and curve progression.^[61] Studies have shown significantly lower leptin level and higher ghrelin level in patients with AIS. A recent publication by Hong-Gui et al.^[62] has concluded that high ghrelin may be a quantitative indicator for predicting curve progression.

Hormones: Key points

Strong female preponderance of curves and progression of curves during adolescent growth spurt indicate a hormonal influence in pathogenesis of AIS.

Few authors have documented increased growth hormone and IGF-1 levels in patients with AIS.

Also FSH, LH, and progesterone levels were found to vary in patients with AIS in comparison with controls.

Melatonin, a hormone involved in sleep regulation, is believed to play a role in pathogenesis of AIS by modulation of skeletal muscle tone, supported by animal experiments. Recently, melatonin signaling pathway dysfunction rather than mere deficiency is implicated in pathogenesis.

Calmodulin, leptin, and ghrelin are also reported to play a possible role in etiopathogenesis of AIS.

Vitamin D

Vitamin D (Vit D) is secosteroid hormone synthesized in the body. Of the many etiological theories in AIS, one with moderate evidence is its association with decreased bone mineral density. Favaro in his study on genes affected in AIS found Vit D to be involved in distinct pathways such as spinal cord injury pathway, the lung fibrosis pathway, the endochondral ossification pathway, and the endocrine resistance pathway.^[63] Vit D and its analogs are known to inhibit fibrosis mediated by TGFB1 and the plasminogen activator inhibitor, leading to reduced collagen deposition. Thus, Vit D deficiency could be a mediator in progression of paraspinal muscle fibrosis leading to curve progression. Vit D via its receptors in brain may modulate brain development and function and its deficiency is reported to cause postural imbalance by otolith dysfunction.

Literature reports that 29.5%–38% of patients with AIS have osteopenia. Although the presence of osteopenia has been credited as a significant predictor of curve progression by few authors, others have attributed the osteopenia observed in AIS to Vit D deficiency. Vit D deficiency leads to reduced estrogen production and thus may play a role in etiopathogenesis of AIS. Estrogen stimulates 1a hydroxylase activity in kidney resulting in increased production of bioactive Vit D. Although early menarche is associated with high circulating estrogen levels and peak bone mass, the deficiency of Vit D could lead to late onset of menarche and thus decreased bone mineral density predisposing to AIS. There is also an inverse relationship between leptin levels and 25-hydroxy vitamin D levels. In obese individuals, more Vit D is absorbed into adipose tissues resulting in reduced available Vit D resulting in osteopenia. Thus, low bone mineral density could cause vertebral wedging most likely in thoracic spine due to low cross-sectional area of vertebral body contributing to pathogenesis of AIS.

Vitamin D: Key points

Incidence of osteopenia is higher in patients with AIS and has been attributed to Vit D deficiency.

Vit D plays a role in inhibiting fibrosis and its deficiency could increase paraspinal muscle fibrosis and contribute to curve progression.

Vit D deficiency causes decreased estrogen production, delayed onset of menarche, and osteopenia.

Inverse relationship between Vit D levels and leptin exists and has been reported.

Biomechanical factors and influence of growth

Idiopathic scoliosis is a three-dimensional deformity with a combination of lateral flexion, thoracic lordosis/hypokyphosis, and axial rotation. Roaf^[64] hypothesized that basic lesion in scoliosis is relative lengthening of the anterior components of the spine compared with the posterior elements (relative anterior spinal overgrowth [RASO]). Animal experiments by Lawton and Dickson^[65] on rabbit models provided evidence for Roaf’s hypothesis. They also noted correlation of anterior-to-posterior length with Cobb’s angle and suggested that RASO is associated with curve progression. As an extension of RASO concept, Roth^[26] hypothesized that scoliosis results from disproportion of vertebroneural growth either because of a short spinal cord or a too rapid growth spurt of the spine.^[66] Porter^{[27],[67],[68]} verified this in anatomical specimens and concluded that overall length of vertebral canal was indeed short in comparison with summated vertebral bodies. This asymmetry could cause relative tethering and increased tension along the longitudinal axis of spinal cord and could result in subclinical neurological dysfunction such as abnormal somatosensory evoked potential in paraspinal muscles.^[28]

Another major theory that has been used to explain the initiation of scoliosis is Hueter–Volkmann’s principle, which suggests that increased pressure on concave vertebral epiphyseal growth plate retards its rate of growth, whereas decreased pressure across the plate on convex side accelerates growth^[69] [Figure 1]. As an extension of Heuter–Volkmann’s principle, Stokes et al.^[70] proposed their “vicious cycle” theory in which they postulated that irrespective of the initiating factor, the mechanical factors play a predominant role in rapid adolescent growth phase when risk of curve progression is higher [Figure 2]. They also suggested that the neuromuscular activation is different among individuals and may be the cause why some curves progress much faster than others. These neuromuscular activation strategies can be used to arrest curve progression and have been the principle behind scoliosis -specific exercise programs like Schroth’s method.^[71]

Figure 1: Hueter–Volkmann’s law. Growth depends on loading of growth plate. Concave side with increased load on epiphyseal plate shows retarded growth in comparison with convex side with decreased loading

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Figure 2: Vicious cycle. Spinal curvature increases during growth because it leads to asymmetric loading of vertebrae, which in turn causes asymmetric growth and additional wedging of vertebrae.

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Normal spine is not symmetrical and has been shown to show certain degree of vertebral rotation in transverse plane.^[72],[73] Castelein et al.^[74] hypothesized that these existing asymmetries coupled with a posteriorly directed shear forces increase the rotational instability by asymmetric loading in accordance with the Hueter–Volkmann principle. However, many authors have claimed that Hueter–Volkmann is oversimplification and is not explanative of multitude of growth modulation changes observed in children.^{[75],[76],[77],[78]} The earlier work by us using finite element method (FEM) models suggested that vertebral growth follows chondral growth force response curve rather than Hueter–Volkmann law.^[79]

Impaired forward flexion (IFF) is an area in the lower thoracic region where the arch of the thoracic spine is interrupted by a short vertebral segment that appears straight and cannot actively or passively be flexed forward. Tomaschewski^[80] in his study on 686 healthy children aged 9–10 years noted an IFF rate of 16.5% and of that 27% developed idiopathic scoliosis within a year. Weiss and Rauf reported the prevalence of IFF in 4- and 5-year olds to be 78.9% and 70.8%, respectively.^[81],[82] However, IFF resolves in most children as they adapt to walking upright. Persistence of IFF could be a factor creating instability in the spine––leading to rotational and lateral deviation during periods of rapid growth.

Various other theories such as contracture syndrome theory by Karski,^[83] local internal lateral flexion theory by Drobyshevskiy.,^[84] and thoracospinal concept by Sevastik et al.^{[85],[86],[87],[88],[89]} have been proposed but have not gained wide acceptance. Alteration in spine biomechanics does play a role in curve progression; however, it cannot be considered as the sole factor in initiation of scoliosis.

Most recent study by Shen et al.^[90] has investigated the influence of alterations in gut microbiome in AIS, where they found positive correlation between the abundance of the fecal genera Prevotella and plasma protein Fibronectin (FN1).

Biomechanical factors and influence of growth: Key points

Relative anterior spinal growth as compared to posterior elements and disprortionate neuro-osseous growth has been postulated in etiopathogeneisis of AIS.

Hueter–Volkmann’s law states that increased loading on concave growth plates retards growth and decreased loading on convex side accelerates growth.

However, studies using FEM models have suggested that vertebral growth follows chondral growth force response curve rather than Hueter–Volkmann law.

Persistence of IFF could be a factor creating instability in spine that is accentuated during growth spurt.

Summary of etiopathogenesis

To summarizer, the exact etiology of AIS is still unknown but now it is well accepted that it is a polygenic disease influenced by genetic, epigenetic, hormonal, nervous system, environmental, and musculoskeletal factors. Scoliosis is seen only in human beings, thus implicating the role of upright bipedal posture in etiopathogenesis of scoliosis.

Natural history of adolescent idiopathic scoliosis

The decision on the optimal time to intervene by bracing or surgery or to continue observation can only be made by a thorough understanding of the natural history of AIS. With the advent of improved knowledge, surgical expertise, and instrumentation available, AIS curves are managed successfully now and in the current scenario studies on natural history have become difficult and have ethical concerns as well. Much of the limited knowledge on natural history of AIS has come from earlier studies when surgical options and expertise were limited. Earlier reports by Nachemson,^[91] Nilsonne and Lundgren^[92] (Stockholm series), Pehrsson et al.^[93] (Gothenberg series), and Fowles et al.^[94] are biased as their study population included a significant number of juvenile and infantile curves. Their claim of poor prognosis for untreated scoliosis with increased mortality rates related to cor pulmonale and back pain, increased disability, and socioeconomic effects on work and marital status cannot be applicable to AIS. Most of understanding of natural history of AIS comes from the Iowa series. In 1950, Ponsetti and Friedman initially reported on 358 patients with untreated idiopathic scoliosis during their growing years, with a short follow-up of 2–5 years. In four follow-up studies over 50 years, Winstein and Ponsetti studied the natural history of AIS and published their results in 2003. The study is limited by low follow-up rate and a small number of patients in different curve categories. However, the Iowa studies with their detailed follow-up are considered to be the best follow-up and set standards for natural history studies. The natural history of AIS will be discussed below in terms of (1) curve progression before skeletal maturity, (2) curve progression after skeletal maturity, (3) death, (4) pain and functional limitation, and (5) psychological issues and cosmetic appearance.

Curve progression before skeletal maturity

Age at presentation, magnitude of the curve, menarchal status, Risser sign, and skeletal maturity are some of the factors used to measure risk of progression of curve in AIS. However, to date an accurate predictive model is not available. Studies by Brooks et al.,^[95] Soucacos et al.,^[96] Rogala et al.,^[97] Lonstein and Carlson,^[98] and Tan et al.^[99] have analyzed the progression of scoliosis in school children. The factors that were associated with progression include gender (female), initial curve magnitude, curve pattern (Right thoracic), and maturity (premenarchal). However, these studies were heterogeneous in their definition of scoliosis and what constitutes progression. Surprisingly many authors have noted spontaneous curve correction rates of 20%-35%. (Brooks et al.^[95]), (Soucacos et al.^[96]), (Rogala et al.^[97]). Curves with left thoracic and thoracolumbar curves had higher chance of regression.^[93] In a recent study by Tan et al.,^[99] they found that an initial Cobb’s angle of 25° at presentation was the important predictive factor for curve progression and have a 68.4% probability of progressing to 30° or more at skeletal maturity. On the contrary, curves with a Cobb’s angle of <25° have a 91.9% probability of not progressing to 30° or more at skeletal maturity. [Table 1] summarizes the findings from studies on curve progression.

Table 1: Major studies on curve progression in AIS before skeletal maturity

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Prediction models to assess risk of progression were proposed by Lonstein and Carlson^[98], Nachemson and Peterson.^[100] Although Lonstein and Carlson used curve magnitude and Risser grading, Nachemson and Peterson used age and curve magnitude for their prediction models. [Table 2] and [Table 3] summarize their models.

Table 2: Probabilities of curve progression based on Risser grade and curve magnitude

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Table 3: Probabilities of curve progression based on curve magnitude and age

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Recent studies have used other parameters such as Sanders skeletal maturity staging^[101] and Distal radius ulna classification systems^[102] to predict curve progression. Sanders system has eight stages based on the radiographic appearance of the epiphyses of the phalanges, metacarpals, and distal part of the radius. Stage 1 is where all digital epiphyses are not covered, Stage 8 is complete closure of distal radius epiphysis indicating skeletal maturity [Figure 3]. The stages have been correlated with peak skeletal growth velocity to predict curve progression. Those at greatest risk are children with curves of ≥20° at Stage 2 and of ≥30° at Stage 3, for whom bracing is unlikely to succeed considering 50° as minimum threshold for surgery.^[103] Sanders system has been found to be more useful and reliable than Risser staging system.^[104] Recently, novel methods such as random forest regression^[105] have been used to predict the shape of spine from first visit through time. The estimated shape differed from the real curvature only by 1.83°, 5.18°, and 4.79° of Cobb’s angles in the proximal thoracic, main thoracic, and thoracolumbar lumbar sections, respectively. In future, simulation models based on artificial intelligence can play a role in assessment of risk and decision making.

Figure 3: Sanders’s skeletal maturity staging system. (A) Stage 1 (juvenile slow stage): All of the digital epiphyses are not covered. The epiphysis is not as wide as the metaphysis, most noticeable on the fifth middle phalanx and metacarpal head. (B) Stage 2 (preadolescent slow stage): All of the digital epiphyses are covered. The epiphyses are now all as wide as their metaphyses (covered) and some capping of the second through fifth proximal phalanges is present. (C) Stage 3 (adolescent rapid stage—early): Most of the epiphyses cap (small bend over the metaphyseal edge) their metaphyses, but not all. In the metacarpals, the second through fifth heads are wider than the metaphyses. (D) Stage 4 (adolescent rapid stage—late): Beginning of distal phalangeal physeal closure. A portion but not the entire physis is clearly closed. Physeal closure starts in the center of the physis. (E) Stage 5 (adolescent steady progression stage—early): All distal phalangeal physes are closed, whereas the proximal phalangeal physes are open. (F) Stage 6 (adolescent steady progression stage late): Proximal and middle phalangeal physes are clearly closing. This stage lasts until the phalangeal and metacarpal epiphyses are closed. (G) Stage 7 (early mature stage): All of the digital physes are closed, only the distal radial physis is open. (H) Stage 8 (mature stage): The distal radial physis is completely closed. Redrawn from Sanders et al.^[100]

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Curve progression after skeletal maturity

Robust evidence exists for progression of AIS curves after skeletal maturity but at a slower rate. Changes in magnitude of deformity and clinical appearance are typically noticed over a period of decades rather than months or years. As the magnitude of curve increases, the influence of gravity and alteration in biomechanical loading leads to curve progression even in the absence of growth influence. Studies have shown that curves >30° progress at a rate of <1°/year.^{[106],[107],[108],[109]} The progression of the curves is influenced also by location of the curves, with thoracic curves more prone for progression.^{[107],[108],[109],[110]} From the Iowa series, it is evident that thoracic curves measuring between 50° and 80° increased an average of 11.3° in 10 years (1.3°/year) and thoracolumbar curves of same magnitude progressed at a rate of 0.49°/year. On the basis of these observations, recommendations were made to fuse curves that reach 50° at skeletal maturity. Ascani et al.^[111] and Edgar^[107] reported a progression rate of 0.47°/year in thoracic curves between 40° and 49°, and 0.55°/year in thoracic curves between 50° and 59°. Slow progression of curves after skeletal maturity occurs and as degenerative changes and osteoporosis ensues there is acceleration in progression of curve with or without clinical deterioration [Table 4].

Table 4: Major studies on natural history of adolescent idiopathic scoliosis

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Death

The Gothenberg and Stockholm series reported a higher mortality rate; however, their study population had included paralytic scoliosis and children from 8 years of age which makes the validity questionable. In the Iowa series at follow-up of 24 years (range, 20–36), the mortality was not significantly greater than expected, 7% versus 5.4% expected. In subsequent follow-up at an average of 39.3 years (range, 31–51), 33 had died for a mortality rate of 15%, in comparison with 17% expected mortality in a matched population.^[108] At the last follow-up with and mean follow-up of 51 years and mean age of 66 years, an additional 36 patients had died.^[109] The probability of surviving to age 65 years calculated for the study group was 0.55 against 0.57 for a matched population. Only 3 of 36 deaths that occurred in their series were contributed by scoliosis. Their age, curve pattern, and curve size at death were 63 years, thoracic, 140°; 69 years, thoracic, 148°; and 53 years, double, 102°/70° with breast cancer. In a 20-year follow-up study by Pehrsson et al.^[114] to assess lung function, respiratory failure occurred only in patients who had a vital capacity below 45% predicted in 1968 and an angle >110°. Thus, respiratory failure develops in adults with scoliosis with a large angle and a low vital capacity when normal aging reduces the ventilatory capacity further. From these evidences, it is apparent that AIS does not result in an increased mortality rate in curves <100°. An increased risk of death occurs only in thoracic curves >100° and may be due to cor pulmonale and right ventricular failure.

Pain and functional limitation

Back pain is not a common feature of AIS in adolescents; however, in adult life thoracolumbar or lumbar curves might cause significant impairment when degeneration ensues. Back pain in adult life may be due to spinal imbalance, facet arthritis, foraminal narrowing, and muscle fatigue. Thoracolumbar curves have the highest propensity for developing translatory shifts (i.e., lateral listhesis) during adulthood and cause back pain.^[107] Asymmetric loading of facets results in facetal degeneration, listhesis, and stenosis that might become symptomatic. Radiculopathy usually presents on side of concavity due to foraminal stenosis. Cordever et al. in a 22-year follow-up of lumbar curves >20° noted that 65% had back pain compared with 32% age-matched control. In Iowa series at 50-year follow-up, patients with scoliosis reported more chronic back pain.^[109] However, it was comparable in terms of duration and intensity and the ability to work and perform daily activities with peers of same age. The long-term prognosis with regard to pain is benign and there is no evidence to recommend surgery for asymptomatic adolescent or young adults with a large curve that has not shown progression in the anticipation of increased risk for back pain in future.

Psychological issues and cosmetic appearance

The clinical appearance varies with the curve patterns and magnitude of the deformity. A double curve of equal magnitude in a well-built individual is not as unsightly as a single thoracic curve of lesser magnitude with rib hump in a thin individual. Also the issues of cosmesis declines as the age of patient increases.^[106],[115] Patients with large curves are more conscious of the image. Ascani et al.^[111] reported psychological disturbances in 19 % of females with curves greater than 40°. In Iowa series, self-image-based assessment scores were worse for scoliosis in comparison with controls 3.6–4.2, P = 0.001.^[109] However, validated depression questionnaire in the same series showed no increased depression rates in scoliosis patients and scoliosis was not detrimental to getting married or childbearing.

Conclusion

Most of hypotheses on AIS etiology have theoretical value and to date no single factor responsible for initiation of AIS has been identified. Although multiple factors have been identified to have strong associations, a direct cause–effect relationship has not been established. Moreover, it is also unclear whether the observations made are primary or secondary to scoliosis. With the existing knowledge, it is evident that AIS is a multifactorial disorder with strong genetic predisposition. The natural history of AIS is benign with minimal functional disability and productive life at long-term follow-up. Thoracic curves >100 ° may have increased mortality due to cardiopulmonary complications. Currently, it is recommended to advise surgery for curves >50° at skeletal maturity. However, patients and families should be counselled for the benign natural course.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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