**Abstract**

Despite the important achievements made with respect to our understanding of their clinical and image features, Chiari malformations are the result of etiopathogenetic mechanisms still sunk into mystery, while most of the efforts to dissipate it are isolated attempts that deal with rather late, secondary pathogenetic events, such as the reduction of the posterior fossa volume, the crowdedness of its contents or the disturbances of the cerebrospinal fluid flow at the level of the foramen magnum. Nevertheless, until new research will shed light onto many of these processes, the actual partial, fragmented knowledge can be structured in a much more reliable manner if one holds the theory of caudal traction as a guiding principle. We present a potential pathogenesis that could culminate into an abnormal axial tension throughout the spinal cord, as well as some image and therapeutic features found during our clinical practice, testifying in favor of this relentless caudal traction.

**Keywords:** Chiari malformation, tonsillar descent, hindbrain, spinal cord, caudal traction

### **1. Introduction**

The commonest variant of Chiari malformations, the one that has been labeled "type I," including some recently derived variants (type 0, type 1.5), is unique among the central nervous system abnormalities by its capacity to elicit just as much apprehension within the community of patients, as bewilderment among the clinicians. Its ominous relationship with sudden death, as well as its resemblance with the tonsillar herniation seen in terminal stages of brain tumors, intracranial hemorrhage, and other space-occupying lesions, would very well serve to explain many of these feelings. Nevertheless, their deeper reason seems rather to be the apparent mystery that clouds its pathogenesis, hindering many attempts at agreement among the authors involved in its investigation.

Notwithstanding, an attentive eye can discover interesting pathogenetic clues issued from recent research that one only has to pin up at the right spots on an older scaffold initiated long ago by some intuitive theories that started to explore into these matters even from the discovery of the hindbrain malformation: while Hans Chiari favored hydrocephalus as the cause of tonsillar descent, Julius Arnold proposed the concept that cord tethering at the level of the associated

myelomeningocele determines a caudal traction along the spinal cord that ends in the tonsillar descent of Chiari malformation type II [1].

This is why every effort to unveil the origin and the mechanisms of formation of Chiari malformation type I should be greatly welcomed. It is very likely that the same can be extrapolated to the less common Chiari malformation type II, which could be just a more severe form of the same deformity, caused by more intense but qualitatively similar pathogenetic alterations. The unifying theory that follows is merely the result of attentive, scrupulous efforts to acknowledge valuable data in the middle of puzzling research results and connect them orderly in a logical explanation of the mechanisms likely to be involved in the production of Chiari malformation type I.

The concept of caudal traction as we use it through the following lines should not be understood merely from a physical point of view, as a purely mechanical force, as it refers to a biological system with certain viscoelastic properties and an intrinsic capacity to develop a reaction to any force acting upon it. The development of the human body is a continuous interplay of genetic, molecular, biochemical, and mechanical changes that result in a more or less dynamic structure and function. Absolutely all human beings, as well as other vertebrate species, are subjected to this phenomenon of caudal traction, which is a necessary part of the development of the spinal cord and brainstem, as they grow by lengthening, distinctly from the forebrain and cerebellum, which do it by expansion. In fact, the notion of caudal traction points to a group of deformities of the nervous system and its surrounding tissues, identifiable on diagnostic images and likely to result from this longitudinal growth of its caudal segments during development; they may be discovered at various stages during this process or even later, during adulthood, which is by no means a cease of it, but merely a continuation, as an involution—apparently a reversed process, but in fact an ongoing, caudal traction at a deep structural level of the involved neural organs. After all, the definition and understanding of this dynamic concept will certainly improve in parallel with the abilities of the diagnostic tools that we shall be able to use in these patients.

After an initial presentation of this new pathogenetic theory, we will follow with a second part where we shall bring into view some conditions quite likely to be produced by means of a mechanism of caudal traction and which are frequently associated with Chiari malformation type I. The third part of this chapter will deal with the clinical arguments of our demonstration, presenting a range of suggestive, but often neglected proofs of this pathogenesis, which we meet during the diagnosis and treatment of these patients.

### **2. Embryology of asynchronism**

It is very likely that the events that eventually lead to Chiari malformations take place at a very early stage during embryogenesis; a plausible idea if one takes as an example the defects of neural tube closure, related in some way to our problem, as we know well enough that during their evolution, some of them can cause a Chiari malformation type II—and the future will probably show that the relationship between these conditions is not limited to this (and caudal traction could be the link). If some parallel, very early, processes, related but not identical to neurulation abnormalities, would finally result in a Chiari malformation type I, it means that actually all purported etiopathogenetic mechanisms of this condition are in fact late secondary features that simply result from the abnormal development of the cranio-cervical junction. Most importantly, both the small volume of the posterior fossa and the disturbances of cerebrospinal fluid circulation across the foramen magnum would be such *effects* wrongly converted in *causes* by the most prevalent theories that try to explain at present the genesis of Chiari malformations.

**247**

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

This concept of very early pathogenesis of Chiari malformation type I has also another important consequence in the way we should try to understand it: most, if not all of the morphological and mechanical changes involved in its generation take place in the diminute body of a human embryo, then fetus, and then child (probably of a comparatively decreasing magnitude throughout these stages), even though the diagnosis will eventually be secured only at an adult age. This invalidates many recent research results and actual misconceptions based on mature or adult

Perhaps Chiari malformation type I is the best example of the meaning of Lewis Wolpert's famous phrase "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life" [2], as indeed, the events that finally lead to its development seem to originate during gastrulation (third week postfertilization), that is, at a much earlier stage of embrionary development than that stated

Thus, the primordium of the central nervous system divides along its freshly defined anterior-posterior axis into four regions, corresponding to the future forebrain, midbrain, hindbrain, and spinal cord [3], well in advance of any significant differences in shape or length among them. Interestingly, while the first two limits are represented by discrete junctional areas that function as organizing centers for nearby neural territories—the so-called anterior neural ridge between the forebrain and midbrain and the isthmic organizer between the midbrain and anterior hindbrain [4]—there is no specific anatomical hint as to the precise location of the posterior hindbrain-spinal cord transition [3]; moreover, its final position depends on quite sophisticated but also delicate mechanisms involving a negative feedback loop between retinoic acid signaling, Cdx4 transcription factor, and the Cyp26 enzyme involved in the degradation of retinoic acid [3, 5]. Despite its importance for all future development of the nervous system, this hindbrain-spinal cord transition is exposed to be moved cranially or caudally by various alterations in these complex, interconnected signaling pathways [3, 5]. For example, experimental loss of Cdx4 function in zebrafish led to caudal displacement of the transition as far as that corresponding to two somites inside the spinal cord territory. As a consequence, the hindbrain-spinal cord transition along the developing neural tube will be matched to a different mesodermal counterpart, belonging to the first pairs of somites, either occipital or cervical. In this way, it becomes easy to figure out how an alteration of the Cdx4 gene or an equivalent disturbance of retinoic acid signaling could displace the transition caudally and place the junction between the developing brainstem and the spinal cord at the level of the future atlas, while the cerebellum might be expected to expand until the same area well below the occipital foramen. In fact, maternal administration of exogenous retinoic acid has been used to produce Chiari

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

human anatomy and physiology.

by all theories invoked nowadays.

malformations in an experimental model in hamsters [6].

significance that it still has in the eyes of many clinicians.

By and large, the tonsillar descent seen in Chiari malformation type I would thus be the result of delicate molecular abnormalities that occur early in a critical area of the future body plan, representing the precise border separating the head, with a neural-driven expansile growth in three directions, from the spine, with a somatic-driven tensile growth in one predominant direction (**Figure 1**). This is why its developmental importance and pathological associations and consequences are so complex and puzzling in their diversity, far outweighing the apparent trivial

Of course, it is difficult to apply such an ultra-early pathogenesis involving molecular and genetic signaling pathways to what we actually think and know about Chiari malformation type I, but here we have again a point where an analogy with Chiari malformation type II is quite welcome. Since Julius Arnold's days, it was already supposed that a myelomeningocele would "tether" the growing child's

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

This concept of very early pathogenesis of Chiari malformation type I has also another important consequence in the way we should try to understand it: most, if not all of the morphological and mechanical changes involved in its generation take place in the diminute body of a human embryo, then fetus, and then child (probably of a comparatively decreasing magnitude throughout these stages), even though the diagnosis will eventually be secured only at an adult age. This invalidates many recent research results and actual misconceptions based on mature or adult human anatomy and physiology.

Perhaps Chiari malformation type I is the best example of the meaning of Lewis Wolpert's famous phrase "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life" [2], as indeed, the events that finally lead to its development seem to originate during gastrulation (third week postfertilization), that is, at a much earlier stage of embrionary development than that stated by all theories invoked nowadays.

Thus, the primordium of the central nervous system divides along its freshly defined anterior-posterior axis into four regions, corresponding to the future forebrain, midbrain, hindbrain, and spinal cord [3], well in advance of any significant differences in shape or length among them. Interestingly, while the first two limits are represented by discrete junctional areas that function as organizing centers for nearby neural territories—the so-called anterior neural ridge between the forebrain and midbrain and the isthmic organizer between the midbrain and anterior hindbrain [4]—there is no specific anatomical hint as to the precise location of the posterior hindbrain-spinal cord transition [3]; moreover, its final position depends on quite sophisticated but also delicate mechanisms involving a negative feedback loop between retinoic acid signaling, Cdx4 transcription factor, and the Cyp26 enzyme involved in the degradation of retinoic acid [3, 5]. Despite its importance for all future development of the nervous system, this hindbrain-spinal cord transition is exposed to be moved cranially or caudally by various alterations in these complex, interconnected signaling pathways [3, 5]. For example, experimental loss of Cdx4 function in zebrafish led to caudal displacement of the transition as far as that corresponding to two somites inside the spinal cord territory. As a consequence, the hindbrain-spinal cord transition along the developing neural tube will be matched to a different mesodermal counterpart, belonging to the first pairs of somites, either occipital or cervical. In this way, it becomes easy to figure out how an alteration of the Cdx4 gene or an equivalent disturbance of retinoic acid signaling could displace the transition caudally and place the junction between the developing brainstem and the spinal cord at the level of the future atlas, while the cerebellum might be expected to expand until the same area well below the occipital foramen. In fact, maternal administration of exogenous retinoic acid has been used to produce Chiari malformations in an experimental model in hamsters [6].

By and large, the tonsillar descent seen in Chiari malformation type I would thus be the result of delicate molecular abnormalities that occur early in a critical area of the future body plan, representing the precise border separating the head, with a neural-driven expansile growth in three directions, from the spine, with a somatic-driven tensile growth in one predominant direction (**Figure 1**). This is why its developmental importance and pathological associations and consequences are so complex and puzzling in their diversity, far outweighing the apparent trivial significance that it still has in the eyes of many clinicians.

Of course, it is difficult to apply such an ultra-early pathogenesis involving molecular and genetic signaling pathways to what we actually think and know about Chiari malformation type I, but here we have again a point where an analogy with Chiari malformation type II is quite welcome. Since Julius Arnold's days, it was already supposed that a myelomeningocele would "tether" the growing child's

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

the tonsillar descent of Chiari malformation type II [1].

myelomeningocele determines a caudal traction along the spinal cord that ends in

This is why every effort to unveil the origin and the mechanisms of formation of Chiari malformation type I should be greatly welcomed. It is very likely that the same can be extrapolated to the less common Chiari malformation type II, which could be just a more severe form of the same deformity, caused by more intense but qualitatively similar pathogenetic alterations. The unifying theory that follows is merely the result of attentive, scrupulous efforts to acknowledge valuable data in the middle of puzzling research results and connect them orderly in a logical explanation of the mechanisms likely to be involved in the production of Chiari malformation type I. The concept of caudal traction as we use it through the following lines should not be understood merely from a physical point of view, as a purely mechanical force, as it refers to a biological system with certain viscoelastic properties and an intrinsic capacity to develop a reaction to any force acting upon it. The development of the human body is a continuous interplay of genetic, molecular, biochemical, and mechanical changes that result in a more or less dynamic structure and function. Absolutely all human beings, as well as other vertebrate species, are subjected to this phenomenon of caudal traction, which is a necessary part of the development of the spinal cord and brainstem, as they grow by lengthening, distinctly from the forebrain and cerebellum, which do it by expansion. In fact, the notion of caudal traction points to a group of deformities of the nervous system and its surrounding tissues, identifiable on diagnostic images and likely to result from this longitudinal growth of its caudal segments during development; they may be discovered at various stages during this process or even later, during adulthood, which is by no means a cease of it, but merely a continuation, as an involution—apparently a reversed process, but in fact an ongoing, caudal traction at a deep structural level of the involved neural organs. After all, the definition and understanding of this dynamic concept will certainly improve in parallel with the abilities of the diagnostic tools that we shall be able to use in these patients. After an initial presentation of this new pathogenetic theory, we will follow with a second part where we shall bring into view some conditions quite likely to be produced by means of a mechanism of caudal traction and which are frequently associated with Chiari malformation type I. The third part of this chapter will deal with the clinical arguments of our demonstration, presenting a range of suggestive, but often neglected proofs of this pathogenesis, which we meet during the diagnosis

It is very likely that the events that eventually lead to Chiari malformations take place at a very early stage during embryogenesis; a plausible idea if one takes as an example the defects of neural tube closure, related in some way to our problem, as we know well enough that during their evolution, some of them can cause a Chiari malformation type II—and the future will probably show that the relationship between these conditions is not limited to this (and caudal traction could be the link). If some parallel, very early, processes, related but not identical to neurulation abnormalities, would finally result in a Chiari malformation type I, it means that actually all purported etiopathogenetic mechanisms of this condition are in fact late secondary features that simply result from the abnormal development of the cranio-cervical junction. Most importantly, both the small volume of the posterior fossa and the disturbances of cerebrospinal fluid circulation across the foramen magnum would be such *effects* wrongly converted in *causes* by the most prevalent theories that try to explain at present the genesis of Chiari malformations.

**246**

and treatment of these patients.

**2. Embryology of asynchronism**

**Figure 1.**

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

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

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 (**Figure 1**).

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

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.

**249**

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

of descent that most authors use to define Chiari malformations.

Well, this would be exactly the Achilles' heel in individuals with Chiari malformation type I, as they are exposed more than normal people to a deficiency of the homeostatic mechanisms that maintain coupled the growth of the two structures. In selected cases, this uncoupling can occur also in the absence of a tonsillar descent or with a minimal one, so that its pathological consequences do not require the 5 mm

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

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

**3. Illustrative associations**

Well, this would be exactly the Achilles' heel in individuals with Chiari malformation type I, as they are exposed more than normal people to a deficiency of the homeostatic mechanisms that maintain coupled the growth of the two structures. In selected cases, this uncoupling can occur also in the absence of a tonsillar descent or with a minimal one, so that its pathological consequences do not require the 5 mm of descent that most authors use to define Chiari malformations.
