Morphogenesis of experimentally induced arnold-chiari malformation

Abstract

The administration of a single dose of vitamin A to pregnant hamsters, early during the morning of their 8th day of gestation, induces types I and II Arnold-Chiari malformation (ACM), as well as various types of axial skeletal-dysraphic disorders known to be associated with the human disease. This new model provides a means of carrying comparative studies between the axial skeletal defects and neurological anomalies of this complex developmental malformation with those which characterize the other induced disorders related to it. Study of this experimental model has demonstrated that the basichondrocranium of fetuses with ACM is shorter than normal and slightly elevated (lordotic) in relation to the axis of the vertebral column. The shortness of the basichondrocranium of these fetuses is caused by the underdevelopment of the occipital bone specially noticeable in its basal component (basioccipital). This basic defect has resulted in a short and small posterior cerebral fossa which is inadequate to contain the developing nervous structures of that region. The developing cerebellum is displaced downward to an anomalous position just above the foramen magnum; and, the developing medulla is compressed or crowded into the small posterior cerebral fossa of affected fetuses. The lordotic elevation of the basichondrocranium is also responsible for the reduction of the pontine flexure and the increased angle of the cervical flexure of the hindbrain found in these fetuses. All of these neurological anomalies, which are characteristic and diagnostic of clinical ACM as well, are considered here to be secondary to the axial skeletal defects rather than primary abnormalities, as is generally believed. The peculiar type of protrusion of the odontoid process into the cranial cavity found in fetuses with ACM, as well as in those with cranioschisis aperta and occulta, is also considered to be caused by the slight depression of the underdeveloped basioccipital and therefore, comparable to the so-called basilar impression often described in clinical ACM. This study has emphasized various developmental features which are closely related with the morphogenesis of ACM, including: the somitic origin of the occipital bone, and the late growth of the cerebellum which is predominantly postnatal in almost all experimental animals. It has been pointed out that some developmental defects involving the occipital bone and the caudal vertebral column, such as those which characterize ACM type II, may be more closely related than previously recognized. It has been also pointed out that the so-called cerebellar herniation into the cervical spinal canal described in the human disease represents a late addition to this disorder which is related to the relatively late growth of the cerebellum. A prerequisite for the development of this late anomaly is the presence of a small posterior cerebral fossa which is overfilled during the postnatal growth spurt of the cerebellum which is then forced to grow into the available space of the upper cervical spinal canal. A new hypothesis concerning the origin and morphogenesis of axial skeletaldysraphic disorders, including ACM, is introduced in this study. The hypothesis proposes that a primary para-axial mesodermal insufficiency (vitamin A-induced) could affect embryos prior to, during, and after the closure of the neural folds resulting in a variety of developmental malformations which share a common type of axial skeletal defect and different neurological anomalies which reflect the degree of the dysraphic disturbance. ACM, in spite of its lack of a distinct dysraphic defect, represents an example of this type of developmental disorder, and as such it has been classified. Finally, the study introduces the idea that an early surgical intervention (nuchalectomy) in possible candidates of this disorder may prevent the development of the devastating neurological complications which characterize human ACM.