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The pathogenesis of Chiari malformations is incompletely understood. We tested the hypothesis that different etiologies have different mechanisms of cerebellar tonsil herniation (CTH), as revealed by posterior cranial fossa (PCF) morphology.
In 741 patients with Chiari malformation type I (CM-I) and 11 patients with Chiari malformation type II (CM-II), the size of the occipital enchondrium and volume of the PCF (PCFV) were measured on reconstructed 2D-CT and MR images of the skull. Measurements were compared with those in 80 age- and sex-matched healthy control individuals, and the results were correlated with clinical findings.
Significant reductions of PCF size and volume were present in 388 patients with classical CM-I, 11 patients with CM-II, and five patients with CM-I and craniosynostosis. Occipital bone size and PCFV were normal in 225 patients with CM-I and occipitoatlantoaxial joint instability, 55 patients with CM-I and tethered cord syndrome (TCS), 30 patients with CM-I and intracranial mass lesions, and 28 patients with CM-I and lumboperitoneal shunts. Ten patients had miscellaneous etiologies. The size and area of the foramen magnum were significantly smaller in patients with classical CM-I and CM-I occurring with craniosynostosis and significantly larger in patients with CM-II and CM-I occurring with TCS.
Important clues concerning the pathogenesis of CTH were provided by morphometric measurements of the PCF. When these assessments were correlated with etiological factors, the following causal mechanisms were suggested: (1) cranial constriction; (2) cranial settling; (3) spinal cord tethering; (4) intracranial hypertension; and (5) intraspinal hypotension.
Cerebellar ectopia is a relatively common magnetic resonance imaging (MRI) finding. Chiari malformation type I (CM-I) is defined radiographically as a simple displacement of the cerebellar tonsils 5 mm or greater below the foramen magnum (FM)  and is distinguished from the less common Chiari malformation type II (CM-II) occurring with myelodysplasia and the rare Chiari malformation type III (CM-III) occurring with cervical encephalocele . Whereas CM-II and CM-III are gross defects of neuroectodermal origin, there is accumulating evidence that CM-I is a disorder of the paraaxial mesoderm that results in underdevelopment of the posterior cranial fossa (PCF) and overcrowding of the hindbrain [19, 25, 30]. However, CM-I can also occur in association with disorders that appear to be unrelated to skull base hypoplasia such as hydrocephalus , intracranial mass lesions [12, 22], cerebrospinal fluid (CSF) leaks , prolonged lumboperitoneal shunting , hereditary disorders of connective tissue (HDCT) associated with occipitoatlantoaxial joint instability (OAAJI) and cranial settling , tethered cord syndrome , and miscellaneous conditions such as craniosynostosis , acromegaly , and Paget’s disease . This raises the possibility that generically defined CM-I may have more than one causal mechanism.
In the current study, morphometric assessments of the PCF were correlated with clinical findings in 752 patients with Chiari malformations. When the data were stratified according etiological factors, five distinct mechanisms of cerebellar tonsil herniation (CTH) were identified that appear to have diagnostic and therapeutic implications.
The study population was selected from a database of 3,318 patients with Chiari malformations who were evaluated consecutively between January 2002 and December 2008. Inclusion criteria were limited to clinically symptomatic patients between the ages of 15–69 years who had one or more disabling symptoms, complete neuroimaging of the head and spine, and no prior Chiari-related surgery. For clarity and focus, all patients met the unambiguous and widely accepted radiographic criteria of tonsillar descent (≥5 mm) below the FM. Patients younger than 15 years and older than 69 years were excluded to minimize age-related changes of the skull and brain . There were 545 females and 207 males with a mean age of 32.7 years (±11.0 SD).
We used the database (Microsoft Access 2007) of a clinical research repository that included detailed information about the medical history, family history, symptoms and signs, and genetic associations of patients with Chiari malformations and related disorders. All patients had undergone a physical examination, complete neurological examination, measurement of articular mobility, whole neuraxis MRI, and 3D-CT scans of the head and upper cervical spine with two-dimensional computerized tomography (2D-CT) reconstructions. Additional information was provided in some patients by Cine-MRI, upright MRI, flexion and extension X-rays of the cervical spine, cervical traction tests , and CT scans of the lumbosacral spine.
The diagnosis of CM-I was made using the narrow but widely accepted radiographic definition of descent of the cerebellar tonsils 5 mm or greater below the FM . CM-I with no etiological cofactors was defined as classical CM-I. The diagnosis of CM-II was based on radiographic evidence of cerebellar tonsillar herniation in association with spina bifida, myelodysplasia, and associated neuroectodermal defects. Diagnostic criteria for HDCT have been published previously [20, 27]. Radiographic criteria for OAAJI and cranial settling in patients with either HDCT or posttraumatic craniocervical instability included evidence of atlantoaxial and/or atlantooccipital joint hypermobility with posterior gliding of the occipital condyles and cranial settling (≥3 mm) upon assumption of the upright position . The diagnosis of TCS was limited to patients who met the following criteria: (1) low position of the conus medullaris (at or below the L2–3 interspace); (2) thickening (<2.0 mm diameter) and/or fatty infiltration of the filum terminale (FT); and (3) typical TCS symptomatology [14, 19, 28].
All morphometric and volumetric measurements were by a single experienced observer (MN) who was unaware of other study data. Linear measurements were made to accuracy of 0.1 mm as determined by calibrated computer software. The results were reviewed independently by two experienced observers who oversaw the process and verified the calculations. Normative data were obtained from randomly selected, standardized radiographic images in age- and sex-matched individuals who had no identifiable clinical or radiographic abnormalities.
Using reconstructed 2D-CT and MRI scans of the head, the size of the occipital bone was determined by measuring its enchondral parts (exocciput, basiocciput, and supraocciput), which enclose the PCF (Fig. 1) [21, 24, 25]. Measurements included the axial length of the clivus (basiocciput and basisphenoid) from the top of the dorsum sella to the basion; the axial length of the supraocciput from the center of the internal occipital protuberance to the opisthion; the axial length of the occipital condyle (exocciput) from the top of the jugular tubercle to the bottom of the occipital condyle [19, 25]; and the widths of the clivus (distance between the bilateral carotid canals), the supraocciput (distance between the inner surfaces of the asterions), and the occipital condyles (distance between the outer surfaces of the condyles) [19, 25]. The anterior–posterior diameter of the FM was measured as the distance between the inner surfaces of the basion and opisthion on midsaggital reconstructed 2D-CT images. The transverse diameter (width) of the FM was measured as the maximal interval between the inner surfaces of the occipital condyles on axial reconstructed 2D-CT images. Radiographic analysis software (Rasband, W.S., ImageJ, National Institutes of Health, Bethesda, MD, USA, 1997–2008) was used to calculate the area of the FM at 2 levels: (1) the inferior outlet between the basion and opisthion and (2) the superior outlet at the level of the jugular tubercles.
The PCF was defined as the almost circular space bounded by the tentorium cerebelli, occipital bone, clivus, petrous bone, and petrous ridges [21, 25]. The ridges of the petrous bones form the anterolateral border of the cavity, and their connection to the posterior clinoids (posterior petroclinoid ligament) forms the anterior border. The posterior fossa brain volume (PCBV) was defined as the neural contents of the PCF including the cerebellum, mesencephalon, pons, and medulla. Volumetric calculations were performed using radiographic analysis software (ImageJ) and the Cavalieri method [16, 21]. The PCFV was calculated on reconstructed 2D-CT images, and the PCBV were calculated on MRI axial and sagittal images, excluding the fourth ventricle and including the herniated cerebellar tonsils and medulla. PCFV was divided into the volume above Twining’s line (PCFV-ATL) and below Twining’s line (PCFV-BTL). The volume of the CSF spaces was calculated as the PCFV minus PFBV.
Statistical analyses were performed with SPSS for Windows (version 15.0, SPSS Inc., Chicago, IL). Mean values are presented as ±1 SD in groups having Gaussian distribution. Median values are presented with ranges in groups having non-Gaussian distribution. The distribution of data was analyzed using the F-test. Significance was indicated by a two-tailed P value of less than 0.01. Demographic differences between patients and healthy control individuals were tested with the nonparametric Mann-Whitney U-test and either the Student’s t test for unequal sample sizes and equal variance or Welch’s t test for individuals of unequal sample sizes and unequal variance by F-test. Data were divided into the following subgroups: (1) classical CM-I with no etiological cofactors; (2) CM-I associated with OAAJI and cranial settling; (3) CM-I associated with TCS; (4) CM-I associated with hydrocephalus and/or intracranial mass lesions; (5) CM-I associated with lumboperitoneal shunts; (6) CM-I associated with craniosynostosis; (7) CM-I associated with miscellaneous disorders; and (8) CM-II.
The results of morphometric analysis of the PCF in patients with Chiari malformations are given in Tables 1 and and2.2. Table 3 summarizes morphometric distinctions according to etiology. The ranges of PFCV and FM outlet area are given in Figs. 2 and and3,3, respectively. Figure 4 shows variations of FM morphology.
In 388 patients with classical CM-I, diagnostic findings were limited to those known to occur with this disorder. Morphometric analysis of the PCF revealed significant reductions of occipital bone size including decreased axial lengths of the supraocciput (P<0.001), clivus (P<0.001), and occipital condyles (P<0.001). The FM was characteristically small with reductions of the transverse diameter (P<0.001), inferior outlet area (P<0.001), and superior outlet area (P<0.001). Volumetric calculations revealed a significant reduction of PCFV-BTL (P<0.001), enlargement of PCFV-ATL (P<0.001), and an overall reduction of PCFV (P<0.001).
CM-I was associated with OAAJI and cranial settling in 52 patients with craniocervical trauma and 173 patients with the following HDCT: Ehlers–Danlos syndrome (130 patients); Marfan syndrome (nine patients); MASS (mitral valve prolapse, aortic anomalies, skeletal changes, and skin changes) phenotype (five patients); and overlap phenotype disorder (29 patients). The large number of patients with this concurrence was biased by referral patterns . Clinical distinctions included a predominance of lower brain stem symptomatology, odontoid pannus formation with basilar impression, and radiographic evidence of cranial settling . Morphometric analysis of the PCF in this cohort revealed normal occipital bone size, normal PCFV, normal size and area of the FM, and normal PFBV.
CM-I was associated with TCS and a low-lying conus medullaris in 55 patients. Morphometric analysis of the PCF revealed no differences in occipital bone size, PCFV, and PFBV as compared with healthy control individuals. The FM was characteristically large with increases of the transverse diameter (P<0.001), antero-posterior diameter (P<0.001), inferior outlet area (P<0.001), and superior outlet area (P<0.001).
In 30 patients, CM-I was associated with a space-occupying intracranial lesion that presented with symptoms and signs of raised intracranial pressure and/or radiographic evidence of cerebral or cerebellar displacement. The lesions included: hydrocephalus (21 patients); arachnoid cysts of the posterior fossa (five patients); chronic subdural hematoma (one patient); falx meningioma (one patient); clivus meningioma (one patient); and acoustic neuroma (one patient). Morphometric analysis of the PCF revealed no significant differences in occipital bone size, PCFV, size and area of the FM, and PFBV as compared with healthy control individuals.
CM-I was present in 28 patients with a lumboperitoneal shunt that had been implanted as treatment for pseudotumor cerebri or hydrocephalus 5 months to 16 years (mean=2.2 years, ±1.87 SD) prior to morphometric analysis. The functional status of the shunts and the position of the cerebellar tonsils prior to shunting were not investigated. Measurements of the PCF in this cohort revealed normal occipital bone size, normal PCFV, normal size and area of the FM, and normal PFBV.
An association of CM-I and premature stenosis of the cranial sutures was present in two patients with Crouzon’s syndrome, one patient with Apert’s syndrome, and two patients with nonsyndromic craniosynostosis. In this cohort, morphometric analysis of the PCF revealed significant reductions of occipital bone size including decreased axial lengths of the supraocciput (P<0.001), clivus (P<0.001), and occipital condyles (P<0.001). The FM was characteristically small with reductions of the anterior–posterior diameter (P<0.001), transverse diameter (P<0.001), inferior outlet area (P<0.001), and superior outlet area (P<0.001). Volumetric calculations revealed a reduction of PCFV below Twining’s line (P<0.001), normal PCFV above Twining’s line, and an overall reduction of PCFV (P<0.001) as compared with healthy control individuals. PFBV was normal.
Morphometric assessments of the PCF were made in ten patients with CM-I and miscellaneous disorders. Reductions of occipital bone size, PCFV, and FM size and area that exceeded 2 SD were present in four of four patients with achondroplasia, two of two patients with acromegaly, and one of one patient with Paget’s disease. In three of three patients with osteogenesis imperfecta, occipital bone size, PCFV, and FM size and area were within 1 SD of normal. These data were not statistically significant owing to small sample size.
CM-II occurring in association with myelomeningocele and related neuroectodermal defects was present in 11 patients with no prior cranial surgery except for implantation and revision of ventriculoperitoneal shunts. None of the patients had ventriculomegaly at the time of morphometric analysis. Assessments of the PCF revealed significant reductions of occipital bone size including the axial length and width of the clivus (P<0.001 and P<0.004, respectively), the axial length of the supraocciput (P<0.001), and the axial length and width of the occipital condyles (P<0.001). The foramen magnum was characteristically large with increases of the anterior–posterior diameter (P<0.001), transverse diameter (P<0.001), inferior outlet area (P<0.001), and superior outlet area (P<0.001). Volumetric calculations revealed reductions of the PCFV (P<0.001) both above and below Twining’s line (P<0.001) as compared with healthy control individuals. PFBV was normal.
In 752 patients with Chiari malformations, morphometric assessments of the PCF were correlated with etiological factors as a means for examining causal mechanisms of CTH. We identified 388 patients with CM-I and no associated etiological cofactors in whom the PCF was characteristically small with increasing constriction inferior to Twining’s line. The FM was constricted transversely, and there was marked reduction of the inferior and superior outlet areas (see Fig. 4c, d). Above Twining’s line, the PCF was slightly enlarged. Taken together, these findings appear to be consistent with premature stenosis of the basi-exoccipital and exosupraoccipital synchondroses (see Fig. 4a), which permit lateral expansion of the FM with somatic growth . Focal stenosis of the basal sutures with compensatory expansion superiorly could explain the cone-like shape of the PCF. Reductions of PCF size and volume were also present in a small number of patients with Crouzon’s syndrome, Apert’s syndrome, nonsyndromic craniosynostosis, achondroplasia, acromegaly, and Paget’s disease. Although stenosis of the FM has been reported in association with achondroplasia , the reductions of PCFV reported here were more generalized than in classical CM-I, indicating different disease processes. Regardless, like classical CM-I, the presence of an abnormally small PCF suggests that cranial constriction was the most likely cause of CTH.
There were no significant abnormalities of occipital bone size, PCFV, or size and area of the FM in patients with hydrocephalus, intracranial mass lesions, OAAJI and cranial settling, and prolonged lumboperitoneal shunting. This excluded cranial constriction as the cause of CTH and directed attention to alternative mechanisms. In patients with hydrocephalus and intracranial mass lesions, there is presumptive evidence of raised intracranial pressure with attendant risk of compartmental shifts and rostral–caudal brain displacements . Interestingly, Chiari’s original description of CM-I was attributed by the author to “cerebellar coning” which he observed at autopsy in 14 patients dying of hydrocephalus . A similar mechanism of CTH can occur in patients with infratentorial cysts and tumors, cerebellar hemorrhage, and large supratentorial mass lesions [18, 26]. In patients with OAAJI, the primary mechanism of CTH appears to be cranial settling . Vivid evidence of gravitational descent of the cerebellar tonsils is sometimes provided by upright MRI . In patients undergoing prolonged lumboperitoneal shunting, overdrainage of CSF is thought to create a pressure differential between the cranial and spinal compartments that draws or “sucks” the cerebellar tonsils downward. Ligation or removal of the shunt may lead to resolution of CM-I . Intraspinal hypotension has also been implicated as a possible cause of CTH in patients with spinal CSF leaks, dural ectasias, and myelodysplasia [2, 18, 20].
Morphometric analysis of the PCF revealed pathological enlargement of the FM in two Chiari subgroups: (1) CM-II and (2) CM-I occurring with TCS (see Fig. 4e, f). This finding suggests that tonsillar impaction of the FM may have been present early in development before the foraminal sutures had closed. Given the complex pathology of CM-II, the cause or causes of CTH remain unknown. Proposed pathogenic mechanisms include: a lesion occurring with the primary neuroectodermal defect [3, 18], spinal cord tethering by the caudally fixed myelomeningocele [10, 15], hydrocephalus , or CSF leakage from the open neural tube . While there is evidence for and against each hypothesis, the possibility that spinal cord tethering may play a role is supported by the observation that early postnatal repair of myelomeningocele can result in significant ascent of the cerebellar tonsils . More recently, CTH has been linked to TCS in occasional patients with atypical CM-I in whom the size and volume of the PCF are normal . Supporting this hypothesis are reports of increasing descent of the cerebellar tonsils with somatic growth , cerebellar prolapse following Chiari decompression surgery , and anatomical improvements including ascent of the conus medullaris, ascent of the cerebellar tonsils, and resolution of brain stem elongation following section of the FT . The observation in the current study that enlargement of the FM is a pathological feature common to both CM-II and atypical cases of CM-I occurring with TCS provides additional evidence, but does not prove, that spinal cord tethering is a distinct mechanism of CTH. Table 4 classifies Chiari malformations according to presumed mechanisms of pathogenesis.
From a diagnostic standpoint, morphometric analysis of the PCF was found to be a useful supplement to the neuroradiological assessment of Chiari malformations. The analysis is easy to perform and can be made in a matter of minutes on standard MR and CT images using computer software. An important diagnostic distinction is whether the PCF is hypoplastic or normal in size. Evidence of an abnormally small PCF confirms the expected pathology and points to cranial constriction as the most likely cause of CM-I. If the size and volume of the PCF are normal, however, additional evidence is required to investigate alternative mechanisms of CTH such as cranial settling, spinal cord tethering, raised intracranial pressure, and intraspinal hypotension. Morphometric analysis of the FM was also found to be helpful in the differential diagnosis of CTH by demonstrating foraminal enlargement in patients with TCS and CM-II and foraminal stenosis in patients with classical CM-I, craniosynostosis, and miscellaneous disorders such as achondroplasia.
To date, the management of patients with Chiari malformations has not been standardized. It is generally assumed but rarely proven that patients undergoing decompressive surgery have a small PCF. This assumption seems questionable given the findings reported here and raises the possibility that some outcome failures may be the result of misdiagnosis. We recommend that future neuroradiological reports include a brief description of PCF morphology to assist clinicians in the differential diagnosis of CTH.
The term Chiari malformation, as currently defined, embraces a heterogeneous group of disorders with different pathogenetic origins. Morphometric analysis of the PCF is required to distinguish clinical cases occurring with a pathologically small PCF from those in which the size and volume of the PCF are normal. When correlated with clinical findings, morphometric assessments of the PCF provide useful clues about the following mechanisms of CTH: (1) cranial constriction; (2) spinal cord tethering; (3) cranial setting; (4) intracranial hypertension; and (5) intraspinal hypotension. The differential diagnosis of CTH is likely to inform management strategies.
We are grateful for the valuable comments by Marcus Stoodley, BMedSc, MB BS, PhD, FRACS (Professor of Neurosurgery, Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia), Victor M. Haughton, MD (Director of Neuroradiology, University of Wisconsin, WI, USA), and Yuichi Inoue, MD (Professor and Chairman of Radiology, Osaka City University Graduate School of Medicine, Osaka, Japan).
Competing interests None
Ethics approval Ethics approval was provided by the Institutional Review Board of the North Shore-Long Island Jewish Health System, NY, USA. The study analyzed a deidentified set of patients in the Repository for Clinical Research in Chiari Malformation and Related Disorders (IRB #09-065).
Support Funding for the study was provided by the Research Foundation of the North Shore-Long Island Jewish Health System, NY, USA, and a grant from the Column of Hope Chiari and Syringomyelia Research Foundation, NY, USA. The work was done at the Feinstein Institute for Medical Research, which received a proportion of its funding from the National Institute of Neurological Diseases and Stroke (NINDS), NIH, MD, USA.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
This article represents an enormous experience of the management of cerebellar tonsillar ectopia.The conclusion that tonsillar herniation is aetiologically heterogeneous is an important one and the recommendation to consider aetiology in the planning of management entirely valid.
It is in suggesting a potential aetiological association between tethered cord (in this publication the mildest form of tethering - fatty filum terminale) and tonsillar herniation that the article is perhaps most controversial particularly having used measurements from cases of Chiari II malformation as evidence to support this assertion. The Chiari II malformation, as pointed out by the authors is a pathologically distinct entity almost exclusively found in the context of neural tube defects. It is a primary defect of the CNS parenchyma, tonsillar herniation being only one component of a much more extensive hindbrain malformation. Inclusion of Chiari II patients in this study detracts from the hypothesis being tested.
Are we to assume that the traction generated through the whole spinal cord by a 2mm thick filum on a slightly low conus, is responsible for herniation of the cerebellar tonsils, particularly remembering that the spinal cord is of course not free floating in a spinal column of CSF but itself attached to its dural container for almost all its length via the dentate ligaments? If this were to be the case should not tonsillar herniation be an almost ubiquitous finding in the more severe dysraphic states such as lipomyelocele? Most neurosurgeons distinguish the modest 5mm descent of the cerebellar tonsils from cases where the tonsils extend to C2 or beyond. It would be helpful to know how the severity of the herniation varied between the subgroups in this study. Both fatty filum terminale and mild tonsillar descent are common incidental neuroradiological observations and their occasional coexistence may be little more than serendipidous. The hypothesis presented is provocative and the potential clinical implications significant....... all the more reason for the supporting evidence to be more robust.