In CKCSs, a congenital malformation resembling Chiari type 1 malformation in humans has been described and referred to as CLM.1,2 Chiari-like malformation refers to a disproportion in the volume of the cerebellum and medulla oblongata in relation to that of the caudal skull compartment (fossa caudalis cerebri or caudal fossa) that is associated with displacement or herniation of the most caudal aspects of the cerebellum (pyramis and uvula of the cerebellar vermis) into or through the foramen magnum.3–8 Results of studies9–12,a have suggested that this morphologic alteration is attributable to an underdeveloped occipital bone in CKCSs. As a consequence, the caudal fossa is too small to accommodate the cerebellum. A possible sequela of the overcrowding is syringohydromyelia (ie, fluid-filled cavities in the cervical, thoracic, and lumbar spinal cord).6,7,12–15,a
To our knowledge, the role of the volume of the caudal fossa in the pathogenesis of the malformation has not been clearly elucidated. Several investigators have estimated the intracranial volume in humans and dogs by use of linear measurements9,11,16,17 or the caudal fossa triangle.17,b However, linear measurements do not represent the 3-dimensional shape of the cranial compartments, and therefore the linear dimensions measured in those studies may not have accurately represented the actual volume of the caudal fossa.18 The purpose of the study reported here was to determine the volumes of cranial cavities in CKCSs with and without syringohydromyelia and compare the measurements with those in other brachycephalic dogs to clarify the association between reduced caudal fossa volume and the morphologic abnormalities characteristic of CLM in CKCSs.
Materials and Methods
Animals—All CKCSs that were scheduled to undergo MRI of the head and cervical spinal cord at the Small Animal Clinic at Justus-Liebig University between March 2005 and August 2007 were included in the study. Six of the CKCSs that had a clinical history of cervical pain or persistent flank scratching were scanned as part of a neurologic evaluation. The other CKCSs were evaluated for breeding selection at the request of the owners. Additional CT examination was performed upon approval by the owners. None of the brachycephalic dogs had signs of neurologic impairment, scratching, or pain, and all were scheduled to undergo MRI for diseases unrelated to the skull or the brain. Immature dogs (< 1 year of age) were not included because of possible incomplete skull growth. Dogs weighing < 5 kg or > 15 kg were excluded from the study to provide weight-matched groups.
Imaging procedures—All dogs underwent CT imaging of the head, followed by MRI of the head and spinal cord. Before imaging, all dogs were sedated via IV administration of diazepamc (0.1 mL/kg) and propofold (0.3 mL/kg). During imaging, general anesthesia was maintained after endotracheal intubation by inhalation of isofloranee in oxygen.
Computed tomographic images for determination of the volumes of the caudal fossa and the RMF (fossa rostralis et medialis cerebri) were acquired with a multislice CT scannerf (settings, 120 kV and 350 mA; matrix, 512 × 512; and slice thickness, 0.8 mm). Magnetic resonance images were acquired by use of a 1.0-T scanner,g and T1- and T2-weighted sagittal images of the head were obtained. In addition, T2-weighted and fluid-attenuated inversion recovery sagittal images of the spinal cord up to the level of T5 were acquired. The detection of a hyperintense signal within the spinal cord parenchyma that was hypointense in fluid-attenuated inversion recovery images was consistent with the existence of syringohydromyelia. Two of the authors used T2-weighted sagittal images of the cervical spinal cord to independently evaluate the dogs for the existence of syringohydromyelia.
Image processing for volume rendering was achieved with graphic softwareh that provides tools for manual and semiautomated image segmentation on a slice-by-slice basis. Image segmentation in the context of the present study involved manual creation of an image mask. All voxels corresponding to an anatomic structure in the images (eg, the caudal fossa and RMF) were selected and assigned the same value in the mask. The final mask thus contained information about all selected anatomic structures and, in combination with the original data and polygonal surface reconstruction algorithms, allowed visualization of various structures in the images (Figure 1). The morphologic characteristics of the caudal fossa were compiled in sagittal, dorsal, and transversal CT images. Internal boundaries of the caudal fossa were defined (rostral: dorsum sellae and caudal clinoid process; dorso-lateral: osseous tentorium and petrosal crest; and caudal: caudal end of the foramen magnum).19–21 The comparison of absolute volumes is typically biased because of the correlation of body weight and sex with brain volume.22–25 Therefore, the relative volume of the caudal fossa to that of the RMF was calculated as the volume index.26 In addition to the volume index, absolute volumes were compared to identify nonproportional growth of a cranial compartment that could influence volume index.
Multiplanar reconstruction of the caudal fossa volume (red region) based on a CT data set of the head of a CKCS. Outlines of the bony boundaries of the cranial cavities were manually segmented in all 3 planes and assigned to tissue label fields. Volumes of voxels assigned to the respective label field were visually displayed as endocasts of the skull.
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Statistical analysis—Statistical analysis was performed with a commercial software package.i Data were assessed for normality of distribution with a Kolmogorov-Smirnov test and are summarized as mean ± SD. One-way ANOVA was used to evaluate differences between CKCSs and other brachycephalic dogs with respect to volumes of the RMF and caudal fossa and the VI, and a Bonferroni correction was applied to account for the multiple tests. A value of P < 0.05 was considered significant.
Results
The skulls of 69 dogs (44 CKCSs and 25 brachycephalic dogs) were scanned between 2005 and 2007. Of these, 40 CKCSs and 25 brachycephalic dogs (10 Pugs, 4 Shih Tzus, 4 Pekingese, 3 Yorkshire Terriers, 2 French Bulldogs, and 2 Maltese Terriers) met the criteria for inclusion in the study. Magnetic resonance imaging revealed that all CKCSs had characteristic neuromorphologic changes consistent with CLM (indentation of the occipital bone and descent of the cerebellum into the foramen magnum; Figure 2). Four CKCSs with signs of hydrocephalus were excluded from the study. Fourteen CKCSs had evidence of moderate to severe syringohydromyelia, and 26 had no evidence of syringohydromyelia. No brain or skull abnormalities were apparent during MRI examination of the brachycephalic dogs.
Sagittal (A) and transverse (B) views of the head and cervical spinal cord of a CKCS as obtained via MRI. Caudal descent of the cerebellum into the foramen magnum and indentation of the occipital bone are evident. The medulla oblongata is thick and appears kinked. Syringohydromyelia is apparent in both images as a hyperintense signal in the spinal cord.
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Volumes of the cranial vaults were precisely determined and visually displayed as cranial endocasts (Figure 3). The median volume index of CKCSs with syringohydromyelia was 0.1805, that of CKCSs without syringohydromyelia was 0.1842, and that of other brachycephalic dogs was 0.1864 (Figure 4). These values were not significantly different. Absolute volumes of the RMF and caudal fossa of CKCSs with and without syringohydromyelia and other brachycephalic dogs were also not significantly different (Figures 5 and 6).
Representative computer-generated image depicting the determination of intracranial volume in a CKCS based on manual segmentation of the internal boundaries of the caudal fossa (gray region) and the RMF (red region) as determined from CT data sets.
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Box-and-whisker plot indicating median (horizontal bar), 25th and 75th percentiles (box), and range (whiskers) of volume index in CKCSs with (n = 14) and without (26) syringohydromyelia (SM) and other brachycephalic (BC) dogs (25).
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Box-and-whisker plot indicating median, 25th and 75th percentiles, and range of absolute volume of the caudal cerebral fossa in CKCSs with (n = 14) and without (26) syringohydromyelia and other brachycephalic dogs (25). See Figure 4 for remainder of key.
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Box-and-whisker plot indicating median, 25th and 75th percentiles, andrangeofabsolutevolumeoftheRMFinCKCSswith (n = 14) and without (26) syringohydromyelia and other brachycephalic dogs (25). See Figure 4 for remainder of key.
Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.508
Discussion
Chiari-like malformation is a complex neurodevelopmental disease, the exact etiology of which remains undetermined.a Chiari type 1 malformation in humans has been attributed to a primary osseous malformation.10 Although CLM in dogs cannot be directly compared with the disease in humans, a similar hypothesis regarding pathogenesis of the malformation has been adopted in veterinary medicine.
In several studies, researchers have attempted to determine the morphologic differences between the intracranial vaults of humans with and without Chiari type 1 malformations. Results of a morphometric study11 of the caudal fossa suggested smaller volumes in humans with Chiari type 1 malformations, compared with volumes in healthy humans, whereas results of another study27 suggested unremarkable caudal fossa dimensions in the same population.
In 2 veterinary studies,a,j the morphologic differences between the intracranial vaults of dogs with and without CLM were also evaluated. In those studies, linear and angular measurements of the caudal fossa were compared and no significant differences among healthy dogs and CKCSs with or without syringohydromyelia were detected. Unlike neurocranial growth in mesocephalic breeds of dogs, neurocranial growth in toy and brachycephalic breeds is restricted in its anterior-posterior dimension. In toy and brachycephalic breeds, growth occurs laterally by expansion, which is reflected by the greater interparietal width in brachycephalic dogs, compared with that in mesocephalic dogs.19,28 The volumes of the cranial cavities are not necessarily altered by this growth pattern. Therefore, low values for linear measurements of cranial vaults do not necessarily result in disproportionate volumes of skull compartments in dogs. Volumetric studies of cranial fossas are therefore superior to linear measurements.29
Established stereologic procedures exist for determining volume in morphologic research. When the Cavalieri principle is used, the volume of an anatomic structure can be estimated with no systematic error or sampling bias and the accuracy of volume determination is correlated with slice thickness and the number of slices obtained via CT.29–31 The volume of the caudal fossa and RMF as derived from 170 to 200 CT images can therefore be assessed with high accuracy.32 In our study, the manual segmentation method was superior to automatic segmentation of the digital areas of interest.
Brain size (and skull size) varies with body size in most species of animals,27 including dogs.20,33–35 Therefore, comparison of absolute volumes of the caudal fossa and RMF among various dog breeds is biased. To eliminate the size factor among the breeds of dogs in the study reported here, the volume index was used. Furthermore, the dogs were weight matched (5 to 15 kg).
In the present study, the volume index in CKCSs with and without syringohydromyelia was not significantly smaller than that of other brachycephalic dogs. This finding may have resulted from the calculation of the ratio from only 2 values. The volume index decreases when the numerator (ie, caudal fossa volume) decreases or when the denominator (ie, the RMF) increases. This phenomenon was evident in the volumes calculated for 4 CKCSs with hydrocephalus, which had a larger than typical RMF, leading to a low volume index (< 0.12). Consequently, those CKCSs were excluded from the study. Conversely, a nonproportional decrease in growth of the RMF could have led to a potentially false high volume index in the CKCS group. The lack of significant differences in absolute volumes of the RMF and caudal fossa of CKCSs versus those of other brachycephalic dogs does not support this hypothesis.
The common pathogenetic hypothesis for development of CLM in dogs appears to fit with the developmental principle of canine brachycephalic skulls in which a restricted growth of several cranial and facial bones (ie, the nasal bone and the ethmoid and basisphenoid bones) takes place.22,28,j Premature ankylosation of the skull-base bones is assumed to lead to an underdevelopment of the skull base and a truncation of the longitudinal axis of the skull in brachycephalic breeds. The process also involves constriction of the facial bones, which is a phenomenon that restricts the craniofacial angle, and this restriction is the basis for the assignment of dogs to dolichocephalic, mesocephalic, or brachycephalic breeds.36
It might be inferred that together with the genetic alterations leading to brachycephaly, additional gradual underdevelopment of bony structures can exist among other brachycephalic breeds and in CKCSs that were born of brachycephalic English Toy Spaniels.a The embryonic paraxial mesoderm, from which the occipital bone derives, is believed to play a major role in this underdevelopment.10,17 However, one must consider the ontogenetic rule that the expansion of the brain is a propulsive force for skull growth.36–38 The development of a dome-shaped skull in association with hydrocephalus in mammals supports this rule. However, it is possible that other bones of the skull (eg, temporal or parietal bone) grow in compensation for an underdeveloped occipital bone and that, although the volume of the cranial cavities is not reduced, the occipital bone is smaller than that in nonbrachycephalic dogs. Studies in which the structure and dimensions of the occipital bones are measured in relation to the same properties of other skull bones in CKCSs and other dogs are needed to identify whether nonproportionate growth develops. No hypothesis regarding the pathogenesis of CLM in CKCSs has been universally accepted, but the results of the study reported here suggested that a reduced caudal fossa volume is not prerequisite for the displacement or herniation of the cerebellum in the CKCSs.
Abbreviations
| CKCS | Cavalier King Charles Spaniel |
| CLM | Chiari-like malformation |
| CT | Computed tomography |
| MRI | Magnetic resonance imaging |
| RMF | Rostral and medial fossa |
Rusbridge C. Chiari-like malformation and syringomyelia in the Cavalier King Charles Spaniel. PhD thesis, Faculty of Veterinary Medicine, University Utrecht, Utrecht, The Netherlands, 2007.
Deutschland M. MRT-gestützte morphometrische und anatomisch histologische Untersuchung der Chiari Missbildung bei der brachyocephalen Rasse Cavalier King Charles Spaniel. PhD thesis, Veterinary Faculty, Free University of Berlin, Berlin, Germany, 2006.
Ratiopharm GmbH, Ulm, Germany.
Rapinovet, Essex, Tierarznei, Raduhn, Germany.
IsoFlo, Dr. E. Graeub AG, Bern, Switerland.
CT Brilliance, Phillips, Hamburg, Germany.
Gyroscan Intera, Phillips, Hamburg, Germany.
Amira Graphical Software, Mercury Computer Systems, Berlin, Germany.
GraphPad Prism, version 4.0, GrapPad Software Inc, San Diego, Calif.
Bali A. Rimanometrische Parameter bei gesunden Hunden in Abhängigkeit vom radiologisch erfassbaren Brachycephaliegrad. PhD thesis, Veterinary Faculty, University of Zürich, Zürich, Switzerland, 2004.
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