**3. Illustrative associations**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

spinal cord and thus determine a progressive caudal traction on the cerebellum and the tonsillar descent through the occipital foramen. The concept of "tethering" involves both a pathological lesion that fixes the spinal cord to the vertebral column at some point and an uncompensated load, either in the form of continuous growth, repetitive forward flexion movements, or a fracture-dislocation with sudden cord traction. In fact, there is also a third, mandatory component, the lack of an adequate adaptive reaction of the body, which may be due to the overwhelming intensity, suddenness, or persistence of the pull. Now, all these features can yet be expressed in another way if we view tethering more generally, as a relative shortness of the spinal cord, underlying both Chiari malformation types I and II, with the mention

*The interplay of molecular and growth influences that grant a special importance to the cranio-cervical* 

that in the former, there is absolutely nothing of spinal cord tethering.

tion type I, but we shall develop more of these aspects later.

Therefore, patients with Chiari malformation type I would tend to have relatively shorter spinal cords because the neural territory assigned to the formation of the future spinal cord is reduced with respect to the nearby somitic mesoderm, a disproportion that will result in a continuous spinal cord tension during growth, as the neural tissue will always be "one step behind" its mesodermal counterpart

Interestingly, similar arguments in favor of these pathogenetic mechanisms have come from the other side of the problem, that is, from attempts to explain a supposedly defective development of the mesodermal tissue composing the prospective vertebral column, resulting in idiopathic scoliosis: the so-called "Roth-Porter theory" invokes exactly the same "asynchronism" between the spinal cord and spine during growth [7–9], reflected in the tridimensional deformity of idiopathic scoliosis in a much more visible manner [10] than in the case of Chiari malforma-

Just as a collateral observation, here we should mention that retinoic acid was

also suspected as a pathogenetic factor in adolescent idiopathic scoliosis [11]. By the way, given its role of mechanical support, the development of osseous tissue has always been regarded as being associated to the creation and maintenance of tensile or compressive forces in the neighboring tissues. Thus, the development of the cranial vault by intramembranous ossification seems to proceed by means of tensile forces created in the sutures by the growth of the underlying brain [12]. Just in the same way, it should not be surprising that the growing vertebral column could exert a barely perceptible but relentless, tensile force that by some yet unknown mechanism stimulates the growth of the contained spinal cord accordingly.

**248**

(**Figure 1**).

**Figure 1.**

*junction.*

Without pretending to be exhaustive, Chiari malformation type I is associated with a few pathological conditions that could be explained by similar mechanisms involving genetic and molecular abnormalities followed by an axial traction throughout the spinal cord and the brainstem. But before all, in order to have a crystal clear vision of these associations, we have to rule out any tonsillar descent that is obviously secondary to compressive forces from above, as in benign intracranial hypertension, hydrocephalus of any etiology, craniosynostosis, or Paget disease of the bone and other conditions with calvarial thickening, as these are not real instances of Chiari malformation [1] and only compound the problem unnecessarily: one should better consider them as merely secondary tonsillar descents in specific clinical contexts that require only the treatment of the primary pathology and nothing more, just as is always done in the posterior fossa tumors, the deadliest cause of downward displacement of the cerebellar tonsils, where nobody disputes the foremost therapeutic objective. Nevertheless, if really and honestly open-minded, one has to acknowledge that perhaps every tonsillar descent is secondary to a pathological process, even though in most cases its nature is still unknown. But in the actual state of knowledge, we should better consider as "Chiari malformation type I" only the apparently *primary* and *congenital* cases of tonsillar displacement, just keeping in mind that both features can still be open to debate in any particular case.

Malformations of the occipito-cervical junction, representing a diverse and complex group of pathological conditions and related deformities, are often multiple in the same patient and many times occur in conjunction with Chiari malformation type I—with as many as 38–40% of hindbrain herniations in cases of atlas assimilation combined with Klippel-Feil syndrome [13]. In these patients, the abnormal fusions involving the occiput, atlas, and other cervical vertebrae would most probably be generated by defects in the functions of Hox and Pax-1 genes at different levels in the occipital and cervical somites [14] at a more delayed stage than those mentioned above. A possible explanation could be that the genetic and molecular alterations are more severe and thus extend their effects over segmentation and resegmentation of the somites and specification of the sclerotomes, not only affecting the hindbrain-spinal cord boundary as we have mentioned. A second possibility might be that the anomalous establishment of this boundary creates the conditions for a defective feedback from the neural counterpart to the mesoderm, disturbing these molecular pathways and secondarily the formation of cervical vertebrae. And we could add to these qualitative alterations the obvious quantitative one: if too much mesodermal tissue has been wrongly assigned to build the prospective spine, it goes without saying that the amount of tissue left for building the skull will be insufficient (**Figure 1**). The consequences of this relative lack of occipito-cervical mesodermal tissue will be distinct from those of the lack of spinal cord progenitor tissue, as the prospective growth of this segment of somitic mesoderm will be governed by the underlying hindbrain which, as far as we know, is very strictly divided in rhombomeres with distinct features, as opposed to the

monotony of the spinal cord organization in these early stages. Their feedback over their corresponding (and quantitatively defective) mesodermal counterpart will put quite stressful limits on the availability of compensatory mechanisms and thus determine an abnormal formation of the osseous and ligamentous elements of the occipito-cervical junction.

The same could happen also at more cranial levels, corresponding to the first occipital rhombomeres, where the same disproportion between the neural tissue contained within and the nearby mesoderm that receives its developmental induction would produce the deformities of basilar impression, platybasia, brainstem kinking, and retroflexed odontoid, found in 7.7% of our patients with Chiari malformation type I (Royo-Salvador et al., unpublished data). All these osseous anomalies could probably be explained by the interplay of discrete but persistent compressive and tensile forces developed among occipito-vertebral mesodermal segments during their development, secondarily to the mentioned genetic and molecular defects, recording somehow to the tenets of the Hueter-Volkmann law as applied to the spine [15].

At the same time, the disproportion between the contained, apparently hypertrophic hindbrain and the corresponding scarcely available mesodermal tissue will create the conditions for what Roth described in 1986 with such a brilliant intuition as "cranio-cervical growth collision" [16]: the impaction of the developing hindbrain against the growing vertebral column, which surpasses and deforms the insufficient occipito-cervical junction mesodermal primordium (the former from the inside, the latter from below (**Figure 1**)), accentuating the tonsillar descent, enlarging the occipital foramen, and leaving too little room for the formation of the occipital bone. It is amazing how the actual general opinion is able to conceive only this last developmental step [1, 17], but yes, finally, there is a para-axial mesodermal insufficiency associated with the Chiari malformations, but it is an associated phenomenon, somehow delayed and of secondary importance.

Among cranio-cervical junction malformations, a special mention deserves odontoid retroflexion, as it is a bony deformity that although it is less known and more imprecisely defined, it was found to be more marked and more common in children and adults with Chiari malformation type I than in normal controls [18, 19]. Moreover, in children with Chiari malformation type I, a study found it was correlated with the presence of syringomyelia and with a lower position of the *obex* [18]—that is, with a more intense cranio-caudal distortion of the brainstem*.* The pathogenesis of odontoid retroflexion seems more clearly related to an abnormal caudal traction exerted by the growing cervical spine than that of other occipito-cervical junction malformations, its mechanism of action being also more prolonged, as the dental central synchondrosis that connects the odontoid to the body of the axis can persist until the age of 8 years [13], being thus exposed to this axial strain, transmitted through the occipito-cervical dura mater and neighboring ligaments and membranes. But the most important detail that these studies on odontoid retroflexion provide is that they prove indirectly that the cerebellar tonsils were *pulled* and not *pushed* into the cervical funnel—in other words, that traction overrides compression at least in these cases—because if the opposite were true, the odontoid had been displaced anteriorly in patients with Chiari malformation type I, as a result of the "overcrowding" of the posterior fossa [18].

Since long ago, observations were published on the frequent association between Chiari malformation type I and idiopathic scoliosis [20], even though no coherent explanation of this fact has ever been provided. As a specific point, we have to insist that the presence of syringomyelia is not really necessary, as many have thought so far. Among our patients, Chiari malformation type I was associated with idiopathic scoliosis in 78.8% of cases, out of which only 52.1% also had idiopathic

**251**

fourth ventricle distortion [22].

adolescence.

*Caudal Traction as a Pathogenetic Mechanism of Chiari Malformation Type I*

syringomyelia (Royo-Salvador et al., unpublished data). Instead, a common pathogenesis, based on an abnormal caudal traction, seems more likely to be involved: in fact, as we mentioned before, the concept of "neuro-vertebral growth asynchrony" was coined in the realm of idiopathic scoliosis and constitutes the mainstay of the Roth-Porter pathogenetic theory [7–9], which uses various mechanical experimental models to demonstrate that an uncoupling of the growth velocity between the spine and spinal cord makes the latter to lag behind, putting tension on the posterior elements which will grow at a slower pace (here we come once again in close contact to the Hueter-Volkmann law), so that the anterior elements will grow too much and the vertebral bodies, "tethered" posteriorly, will start to rotate around an axis represented by the spinal cord itself and will deviate to one side as they grow restrained in this way, thus creating the scoliotic curve [21]. It is not difficult to imagine how a similar mechanism of caudal traction would produce both a Chiari malformation type I and an idiopathic scoliosis if this intrinsic "tether" acted continuously over the vertebral column and spinal cord throughout their development and associated longitudinal growth, a fact especially conceivable if, following the mentioned alterations in the definition of the hindbrain-spinal cord boundary, there is a relative excess of mesenchymal tissue composing the sclerotomes of the future thoracic spine, even though it would be much later that this unbalanced tissue distribution would become manifested, during the growth spurt of the

Last but not the least, among enlightening pathological associations of Chiari malformation type I is the tethered cord syndrome, maybe the most interesting of all, the most difficult to explain, and nevertheless, the most important, as it forms a bridge between Chiari malformation types I and II. In fact, this association should be better regarded as a separate third category of Chiari malformations, taking into account the different mechanism of relative spinal cord "shortening": if in Chiari malformation type I this originated in a caudal displacement of the hindbrainspinal cord boundary and in Chiari malformation type II, in the traction exerted by a caudal myelomeningocele on the growing spinal cord, here there is an abnormal *filum terminale*, short, thickened, and/or lipomatous that hampers the spinal cord longitudinal growth and that alters the coupling between vertebral and neural growth. Among our patients, the level of the *conus medullaris* was below the L1 L2 disk in as many as 20.9%, and most interestingly, it was statistically correlated with

the degree of tonsillar descent (Royo-Salvador et al., unpublished data).

Now of course, if one accepts that the pathogenesis of Chiari malformations includes a common pathway of relative shortening of the spinal cord with respect to the vertebral column, of various etiologies that can be grouped into these three large groups, an important question comes about: why not any patient with this relative spinal cord shortening has a tonsillar descent? Well, the answer is quite simple, because, as we have already pointed out, there is another decisive factor that will eventually determine the occurrence or not of a Chiari malformation: the adequacy of the neural tissue reaction to the tensile forces developed as a consequence of the growth asynchrony. In other words, the tonsils will descend only if this homeostatic mechanism doesn't function properly for one reason or another; moreover, any degree of tonsillar descent and of brainstem and fourth ventricle distortion should be possible in every one of the three main etiopathogenetic groups mentioned, so it should be time that we stop associating Chiari malformation type II only to myelomeningocele and instead, consider, for example, three degrees of tonsillar descent, perhaps labeled as Chiari malformation types 1, 1.5, and 2 (even four if a Chiari malformation type 0 were added) and defined with clear-cut morphological criteria, including measures of brainstem elongation and

*DOI: http://dx.doi.org/10.5772/intechopen.90044*

### *Caudal Traction as a Pathogenetic Mechanism of Chiari Malformation Type I DOI: http://dx.doi.org/10.5772/intechopen.90044*

syringomyelia (Royo-Salvador et al., unpublished data). Instead, a common pathogenesis, based on an abnormal caudal traction, seems more likely to be involved: in fact, as we mentioned before, the concept of "neuro-vertebral growth asynchrony" was coined in the realm of idiopathic scoliosis and constitutes the mainstay of the Roth-Porter pathogenetic theory [7–9], which uses various mechanical experimental models to demonstrate that an uncoupling of the growth velocity between the spine and spinal cord makes the latter to lag behind, putting tension on the posterior elements which will grow at a slower pace (here we come once again in close contact to the Hueter-Volkmann law), so that the anterior elements will grow too much and the vertebral bodies, "tethered" posteriorly, will start to rotate around an axis represented by the spinal cord itself and will deviate to one side as they grow restrained in this way, thus creating the scoliotic curve [21]. It is not difficult to imagine how a similar mechanism of caudal traction would produce both a Chiari malformation type I and an idiopathic scoliosis if this intrinsic "tether" acted continuously over the vertebral column and spinal cord throughout their development and associated longitudinal growth, a fact especially conceivable if, following the mentioned alterations in the definition of the hindbrain-spinal cord boundary, there is a relative excess of mesenchymal tissue composing the sclerotomes of the future thoracic spine, even though it would be much later that this unbalanced tissue distribution would become manifested, during the growth spurt of the adolescence.

Last but not the least, among enlightening pathological associations of Chiari malformation type I is the tethered cord syndrome, maybe the most interesting of all, the most difficult to explain, and nevertheless, the most important, as it forms a bridge between Chiari malformation types I and II. In fact, this association should be better regarded as a separate third category of Chiari malformations, taking into account the different mechanism of relative spinal cord "shortening": if in Chiari malformation type I this originated in a caudal displacement of the hindbrainspinal cord boundary and in Chiari malformation type II, in the traction exerted by a caudal myelomeningocele on the growing spinal cord, here there is an abnormal *filum terminale*, short, thickened, and/or lipomatous that hampers the spinal cord longitudinal growth and that alters the coupling between vertebral and neural growth. Among our patients, the level of the *conus medullaris* was below the L1 L2 disk in as many as 20.9%, and most interestingly, it was statistically correlated with the degree of tonsillar descent (Royo-Salvador et al., unpublished data).

Now of course, if one accepts that the pathogenesis of Chiari malformations includes a common pathway of relative shortening of the spinal cord with respect to the vertebral column, of various etiologies that can be grouped into these three large groups, an important question comes about: why not any patient with this relative spinal cord shortening has a tonsillar descent? Well, the answer is quite simple, because, as we have already pointed out, there is another decisive factor that will eventually determine the occurrence or not of a Chiari malformation: the adequacy of the neural tissue reaction to the tensile forces developed as a consequence of the growth asynchrony. In other words, the tonsils will descend only if this homeostatic mechanism doesn't function properly for one reason or another; moreover, any degree of tonsillar descent and of brainstem and fourth ventricle distortion should be possible in every one of the three main etiopathogenetic groups mentioned, so it should be time that we stop associating Chiari malformation type II only to myelomeningocele and instead, consider, for example, three degrees of tonsillar descent, perhaps labeled as Chiari malformation types 1, 1.5, and 2 (even four if a Chiari malformation type 0 were added) and defined with clear-cut morphological criteria, including measures of brainstem elongation and fourth ventricle distortion [22].

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

occipito-cervical junction.

applied to the spine [15].

monotony of the spinal cord organization in these early stages. Their feedback over their corresponding (and quantitatively defective) mesodermal counterpart will put quite stressful limits on the availability of compensatory mechanisms and thus determine an abnormal formation of the osseous and ligamentous elements of the

The same could happen also at more cranial levels, corresponding to the first occipital rhombomeres, where the same disproportion between the neural tissue contained within and the nearby mesoderm that receives its developmental induction would produce the deformities of basilar impression, platybasia, brainstem kinking, and retroflexed odontoid, found in 7.7% of our patients with Chiari malformation type I (Royo-Salvador et al., unpublished data). All these osseous anomalies could probably be explained by the interplay of discrete but persistent compressive and tensile forces developed among occipito-vertebral mesodermal segments during their development, secondarily to the mentioned genetic and molecular defects, recording somehow to the tenets of the Hueter-Volkmann law as

At the same time, the disproportion between the contained, apparently hypertrophic hindbrain and the corresponding scarcely available mesodermal tissue will create the conditions for what Roth described in 1986 with such a brilliant intuition as "cranio-cervical growth collision" [16]: the impaction of the developing hindbrain against the growing vertebral column, which surpasses and deforms the insufficient occipito-cervical junction mesodermal primordium (the former from the inside, the latter from below (**Figure 1**)), accentuating the tonsillar descent, enlarging the occipital foramen, and leaving too little room for the formation of the occipital bone. It is amazing how the actual general opinion is able to conceive only this last developmental step [1, 17], but yes, finally, there is a para-axial mesodermal insufficiency associated with the Chiari malformations, but it is an associated

Among cranio-cervical junction malformations, a special mention deserves odontoid retroflexion, as it is a bony deformity that although it is less known and more imprecisely defined, it was found to be more marked and more common in children and adults with Chiari malformation type I than in normal controls [18, 19]. Moreover, in children with Chiari malformation type I, a study found it was correlated with the presence of syringomyelia and with a lower position of the *obex* [18]—that is, with a more intense cranio-caudal distortion of the brainstem*.* The pathogenesis of odontoid retroflexion seems more clearly related to an abnormal caudal traction exerted by the growing cervical spine than that of other occipito-cervical junction malformations, its mechanism of action being also more prolonged, as the dental central synchondrosis that connects the odontoid to the body of the axis can persist until the age of 8 years [13], being thus exposed to this axial strain, transmitted through the occipito-cervical dura mater and neighboring ligaments and membranes. But the most important detail that these studies on odontoid retroflexion provide is that they prove indirectly that the cerebellar tonsils were *pulled* and not *pushed* into the cervical funnel—in other words, that traction overrides compression at least in these cases—because if the opposite were true, the odontoid had been displaced anteriorly in patients with Chiari malformation type I,

Since long ago, observations were published on the frequent association between

Chiari malformation type I and idiopathic scoliosis [20], even though no coherent explanation of this fact has ever been provided. As a specific point, we have to insist that the presence of syringomyelia is not really necessary, as many have thought so far. Among our patients, Chiari malformation type I was associated with idiopathic scoliosis in 78.8% of cases, out of which only 52.1% also had idiopathic

phenomenon, somehow delayed and of secondary importance.

as a result of the "overcrowding" of the posterior fossa [18].

**250**
