1Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, United Kingdom

1 Morphological variation of the caudal fossa of domestic cat skulls assessed with computed2 tomography and geometric morphometrics analysis 34 Caroline R Gordon1, Thomas W Marchant2, Joanna Lodzinska1, Jeffery J Schoenebeck2, Tobias5 Schwarz167 1Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, United Kingdom8 2Roslin Institute, University of Edinburgh, Roslin, United Kingdom910 Corresponding author: Caroline R Gordon BVSc MRCVS 11 [email protected] 12 Hospital for Small Animals, Royal (Dick) School of Veterinary Studies, University of Edinburgh13 Midlothian EH25 9RG, United Kingdom14 Tel: +44 (0) 7729 2467061516 Keywords: caudal fossa, foramen magnum, computed tomography, geometric morphometrics17 analysis, feline, occipital1819 Author Note20 Preliminary results of this study were presented at the 2016 European Veterinary Diagnostic Imaging 21 Conference in Wroclaw, Poland. 222324 25 Abstract26 Objectives This study aimed to investigate differences and demonstrate a normal range of27 morphological variation of the caudal fossa of the cranium of domestic cats. 28 Methods Computed tomographic scans of thirty-two domestic cat heads of eleven breeds were29 included. Isosurfaces from skulls were characterised through three-dimensional geometric30 morphometrics using geographic landmarks placed on the internal surface of the caudal fossa and31 foramen magnum. Raw data was transformed with a Procrustes fit and coordinate covariance was32 analysed by principal components to establish breed- and sex-level differences. Skulls were also33 classified according to the number of concavities along the mid sagittal vermiform impression.34 Differences were investigated between breed groups and sex, and correlation was sought with age. 35 Results Analyses revealed size-independent differences in occipital bone morphology across breeds36 and sex, however no clustering was evident. Most variability was observed at the exoccipital bones,37 ventral portion of the supraoccipital bone, dorsum sellae of the basisphenoid, and the osseous38 tentorium cerebelli. No statistically significant differences were identified via 2-sample t-tests39 between breed groups or sexes. No statistically significant correlation using Spearman Rho40 correlation coefficient was identified with age. 41 Conclusions and relevance The feline caudal fossa displays a wide range of intra- and inter-breed 42 variation, not linked to age or sex. Concavities along the vermiform impression have not previously 43 been described. As advanced imaging modalities are becoming more frequently used for domestic 44 felids, an established range of normality is important for discriminating pathological changes from 45 anatomical variances.46474849 50 Introduction51 The caudal fossa has been the focus of extensive research in humans and canids, in part due to its role52 in the pathogenesis of various disorders such as Chiari and Chiari-like malformations as well as 53 occipital dysplasia.1-8 There is, however, a paucity of information regarding variability in skull 54 morphology amongst existing breeds of the domestic cat (Felis catus). With the increasing use of 55 advanced diagnostic imaging in this species, recognition of the breadth of normal anatomical 56 variation is crucial. In the authors’ experience, cats display a wide variability in caudal fossa shape in 57 the absence of associated clinical signs.5859 The caudal fossa of the cranial cavity encompasses the midbrain, pons, and medulla oblongata 60 ventrally and the cerebellum dorsally. Rostrally it extends to the dorsum sellae of the sphenoid bone 61 and the osseous tentorium cerebelli of the occipital bone. Caudally it is enclosed by the supraoccipital 62 bone, which forms the dorsal border of the foramen magnum.9 The internal surface of the 63 supraoccipital bone displays shallow depressions which conform to the surface of the cerebellum; the 64 vermiform impression.9 The basioccipital bone forms the ventral border of the foramen magnum and 65 joins the basisphenoid via a cartilaginous suture. The exoccipital bones form the lateral portions of the66 foramen magnum and bear the convex occipital condyles.9 6768 The objectives of this study were to investigate and describe differences in caudal fossa shape and 69 determine whether these differences are stereotyped by breed or sex. To detect shape trends of the 70 caudal fossa, the authors used computed tomography, an imaging modality that is amenable to 71 geometric morphometrics analysis. 7273 Materials and methods74 Sample population 75 Imaging records of the authors’ academic veterinary referral hospital were searched retrospectively 76 between January 2011 and December 2015 to identify adult cats (>12 months of age) that had 77 undergone a CT examination of the entire head to at least the level of the second cervical vertebra. 78 Studies were excluded if there were any pathological cranial or neural abnormalities identified on the 79 imaging study or clinical records. All CT examinations were acquired with the same 4-slice CT unit 80 (Siemens Somatom) using a 1mm slice width, 1.5 pitch, 130mAs, 120kV, 0.75s tube rotation time, and 81 high resolution image kernels (proprietary term U90).8283 Three-dimensional landmarking84 Skull isosurfaces were generated from DICOM images using Stratovan Checkpoint 85 (v2016.11.21.0711). Twelve geographical landmarks were placed on the internal surface of the caudal 86 fossa and foramen magnum of each skull (Figure 1a,b) to represent the overall shape and dimensions.87 Specifically, landmarks were placed at the osseous tentorium cerebelli, along the internal sagittal 88 curvature of the caudal fossa, opisthion, basion, the basioccipital bone, dorsum sellae, and the lateral-89 most points of the internal surface of the foramen magnum.9091 Geometric morphometric analysis92 Landmark coordinates and classifier data were imported into MorphoJ (v1.06d)10 for geometric 93 morphometric analysis. Superimposition, translation, rotation, and scaling of landmark 94 configurations were performed via a generalised Procrustes fit prior to generating a covariance 95 matrix. A one-way analysis of variance (ANOVA) was used to evaluate differences in centroid size 96 (the square root of the sum of squared distances of landmarks from the central point) amongst breed 97 groups. A multivariate regression of the symmetrical component of shape versus log centroid size 98 was performed to remove the influence of allometry, the shape changes correlating to changes in size.99 Principal components analysis (PCA) is a mathematical algorithm which reduces and expresses a 100 dataset in terms of vectors along which variation is maximal. A PCA of the resulting regression 101 residuals11 was used to explore patterns of covariance amongst landmarks. 102103 Classification104 A midline sagittal CT image was created for each cat using multi-planar reconstruction on freely 105 available DICOM viewing software (Horos v2.0). The skulls were classified into groups based on the 106 number of concavities along the vermiform impression of the caudal fossa. One reader, a second year 107 radiology resident, categorised each image, blinded to the signalment of each case. A two-sample t-108 test was used to evaluate differences in concavity number between sexes, and between breed groups. 109 A Spearman rank correlation coefficient (rs) sought correlations between the number of concavities 110 and age, PC1, PC2, and centroid size of the caudal fossa. A p-value of < 0.05 was considered 111 significant. 112113 Results114 The study population comprised of thirty-two CT scans of domestic cat heads. There were two entire 115 females, one entire male, eleven neutered females, and eighteen neutered males. Entire and neutered 116 cats were grouped together for statistical purposes; thus the overall study numbers were thirteen 117 (41%) female and nineteen (59%) male. Eleven breeds were represented including Abyssinian (n=1), 118 British shorthair (n=1), Bengal (n=1), Burmese (n=2), Chinchilla (1) domestic long hair (DLH) (n=3), 119 domestic short hair (DSH) (n=15), Maine Coon (n=4), Ragdoll (n=1), Siamese (n=2), and Tonkinese 120 (n=1). For statistical purposes, cats were grouped according to phylogenetic origin into Asian cats 121 (Burmese, Siamese, Ragdoll, Tonkinese; n=6), Western European cats (Abyssinian, Maine Coon, 122 British shorthair, Chinchilla; n=7), and mixed breeds (DLH, DSH, Bengal; n=19)12. CT images of all 123 cats were sufficiently detailed to allow consistent placement of all landmarks on stereotyped locations124 of the caudal fossa and foramen magnum. 125 126 Geometric morphometrics127 For the symmetric component of shape with allometry, principal component (PC) 1 accounted for 128 21.6% of the variation amongst all cats. PC2 accounted for 15.4% of variation. PC1 and PC2 thus 129 cumulatively accounted for 37.0% of the observed variation. Most variability explained by PC1 was 130 observed at the exoccipital bones and dorsum sellae. As the exoccipital markers shifted caudally, the 131 dorsum sellae shifted dorsally, whilst the roof of the cranial fossa shifted, less markedly, in an overall 132 rostral direction. Neighbouring landmarks along the roof of the caudal fossa varied between 133 rostroventral and rostrodorsal trends. Variability explained by PC2 was observed at the osseous 134 tentorium cerebelli and foramen magnum. As the tentorium shifted ventrally, the basion and ventral 135 portion of the supraoccipital bone shifted dorsally and caudally, respectively. None of the PCs 136 discriminated subpopulations based on sex (Figure 2a) or breed groups (Figure 2b). Western 137 European cat breeds demonstrated the largest mean caudal fossa size and Asian cats the smallest, 138 however centroid sizes were not significantly different between breed groups (p = 0.432) (Figure 3). 139140 After controlling allometry by regressing out isometric size, PC1 accounted for 20.3%, and PC2 16.0% 141 of the shape variation, cumulatively 36.3%. Overall shape trends matched the raw data in terms of 142 direction, however varied slightly in increments. Size-corrected PCA revealed no segregation of PC 143 scores between males and females (Figure 4a), nor was there any clustering amongst breeds (Figure 144 4b). 145146 Occipital bone classification147 Three cats displayed zero internal concavities along the vermiform impression, fourteen displayed 148 one concavity, eight cats displayed two, and seven cats displayed three (Figure 5a,b,c,d and Tables 1 149 and 2). No statistically significant differences were identified between the number of concavities 150 along the mid sagittal vermiform impression of males compared to females (p = 0.917), nor was there 151 significant difference between the mixed breeds and purebreds (p = 0.634). No significant correlation 152 was identified between the number of concavities and age (p = 0.527), PC1 (p = 0.562), PC2 (p = 0.873), 153 and centroid size (p = 0.086). 154155 Table 1 Relationship between vermiform impression morphology and sexConcavities Male Female 1560 2 (11) 1 (8) 1 8 (42) 6 (46) 2 5 (26) 3 (23) 3 4 (21) 3 (23) Total 19 (100) 13 (100) 157 Data are n (%) unless otherwise specified158159 Table 2 Relationship between vermiform impression morphology and breed groupConcavities Purebred Mixed breed 1600 2 (15) 1 (5) 1 5 (38) 9 (47) 2 3 (23) 5 (26) 3 3 (23) 4 (21) Total 13 (99) 19 (99) 161 Data are n (%) unless otherwise specified162163 Discussion164 A wide range of morphometric variation of the caudal fossa and foramen magnum was observed in 165 this study population of neurologically normal cats, with no identified links to breed, sex, or age. 166 Because PC shape trends were similar between the raw data and the regression residuals, and there 167 were no significant differences in centroid sizes between breed groups, the authors conclude that 168 allometry had negligible influence on shape differences of the caudal fossa. 169170 Shape variability demonstrated by PC1 may be interpreted anatomically as a lengthening of the 171 exoccipital bones occurring alongside a relative dorsoventral flattening of the entrance to the caudal 172 fossa caused by dorsal shifting of the dorsum sellae. Rostral shifting of the roof of the caudal fossa 173 reflects an alteration in space distribution. A previous morphometric study categorised feline skulls 174 into three phenotypically different skull formations; rounded, triangular, and cuneiform.13 This study 175 identified a frequent variant of the round-shaped skulls where the foramen magnum extended more 176 distantly between the occipital condyles thereby acquiring a bilaterally narrowed oval shape, similar 177 to the findings of the current study. Variability of rostroventral versus rostrodorsal directions of this 178 shift amongst neighbouring landmarks of the caudal roof of the fossa demonstrates an irregular 179 contour of this internal bony surface. The vermiform impression is described in dogs as an irregular 180 excavation of the median portion on the cerebellar surface of the squamous part of the occipital 181 bone.14 This is, to the authors’ knowledge, the first description of this anatomical feature specifically 182 in the cat.183184 Shape variability demonstrated by PC2 may be interpreted anatomically as an overall dorsoventral 185 flattening of the entrance to the caudal fossa owing to ventral shifting of the osseous tentorium 186 cerebelli. Caudal extension of the foramen magnum coinciding with relative dorsoventral narrowing 187 of the foramen reflects an overall redistribution of space. The ventral portion of the supraoccipital 188 bone shifted caudally, independently of the more dorsal landmarks, demonstrating a variable caudal 189 angulation of this site relative to the internal contour of the caudal fossa. Similar findings have been 190 reported in a recent MRI study of cats which described variants of the ventral aspect of the 191 supraoccipital bone of cats being straight throughout, caudally angulated, blunt ended, and/or 192 ventrally thickened.15 The same study also found that cats could be divided into those with a thin and 193 those with a thick occipital bone. Compared with MRI, CT has a higher sensitivity for accurately 194 displaying osseous contours, and adds further validation to these findings.195196 Morphology of the external squamous part of the occipital bone and foramen magnum of cats has 197 been described in a study involving gross morphology of 50 European cat cadavers.16 Two 198 morphological patterns of the squamous part of the occipital bone were identified; a triangular shape 199 and a semi-oval shape, denoting normal variation of this external surface amongst European cats. 200 None of the specimens in this previously reported study displayed a dorsal notch, nor any other 201 defect at the foramen magnum. The authors concluded that, in the European cat, the foramen 202 magnum is free from pathology and its shape is conservative. In contrast, a morphometric study of 69203 purebred cat skulls identified two individuals with a keyhole shaped foramen.13 Dogs display a wide 204 diversity of shape of the foramen magnum, many of which are considered as physiological variations 205 of morphology.8,17 It is apparent that a degree of physiological variation is also present in the cat and 206 that the spectrum of morphologies observed in purebreds is also seen in mixed-breed cats. From a 207 clinical perspective, this variation is important to recognise so that pathological processes are not 208 falsely assigned. 209210 The majority (69%) of the study population displayed one or two concavities along the vermiform 211 impression on median plane CT images. No sexual dimorphism was identified, nor did these 212 concavities differ between purebreds and mixed breeds, nor correlate with age. Concavities along the 213 vermiform impression have not previously been described. A certain degree of care must be taken 214 comparing the appearance of the caudal fossa on CT with the anatomy. Post mortem examinations to 215 confirm the shape of the caudal fossa were not performed because none of these clinical cases were 216 available for necropsy examination. The high spatial frequency allowed by CT, however, ensures a 217 detailed and accurate representation of the osseous surface.18 Although the current study did not 218 identify significant differences between breed groups or sexes, or correlate with age, it is evident that 219 the shape of this vermiform impression is not uniform amongst cats and these variants should be 220 clinically recognised. 221 222 A limitation of this study is the relatively small sample size. The lack of segregation in the PCA and, 223 likewise, the lack of differences amongst vermiform impression groups may reflect the small numbers224 of individuals representing each breed, age, and sex, and thus the inability to achieve statistical 225 significance. Categorisation of vermiform impression concavities was somewhat subjective and prone226 to bias due to the use of only one evaluator. Additional studies inclusive of larger groups of feline 227 breeds would be recommended to further investigate interbreed morphology differences. Breeds of 228 particular interest are those that are brachycephalic, as brachycephaly has been shown in dogs to be 229 associated with Chiari-like malformation19 and occipital dysplasia.17 Further studies could also 230 include lateralised landmarks along the caudal fossa, not included in the current study, which may 231 uncover further variants. 232233 Conclusions 234 A wide range of inter-breed morphometric variation of the feline caudal fossa was observed in this 235 population, which was not linked to age or sex, demonstrating that caudal fossa anatomy is not 236 homogeneous amongst cats. The findings support and expand on those previously reported13,15,16. An 237 established range of normality is important for accurate discrimination between pathological changes 238 and normal anatomical variants, and for the recognition of potential trends associated with disease in 239 this popular companion animal. 240241 Conflict of Interest242 The authors declared no potential conflicts of interest with respect to the research, authorship, and/or 243 publication of this article.244245 Funding246 The authors received no financial support for the research, authorship, and/or publication of this 247 article.248 249 Figure 1 Landmarks along the internal surface of the caudal fossa (a) and foramen magnum (b). 250 Images are not to scale. In (b), a portion of the occipital bone has been cropped out.251 Figure 2 PC1 vs PC2 of the symmetric component displaying PC scores classified by sex (a) and 252 breed (b)253 Figure 3 Box and whisker diagram of centroid size amongst breed groups. The horizontal line within 254 each box represents the median. 255 Figure 4 PC1 vs PC2 after controlling for allometry displaying PC scores classified by sex (a) and 256 breed (b)257 Figure 5 Concavities along the vermiform impression; (a) zero (b) one (c) two (d) three258259 References260 1. Noudel R, Jovenin N, Eap C, et al. Incidence of basioccipital hypoplasia in Chiari 261 malformation Type I: comparative morphometric study of the posterior cranial fossa. J 262 Neurosurg 2009; 111: 1046-1052.263264 2. Urbizu A, Poca MA, Vidal X, et al. MRI-based morphometric analysis of posterior cranial 265 fossa in the diagnosis of Chiari malformation type I J Neuroimaging 2013; 24: 250-256.266267 3. Yan H, Han X, Jin M, et al. Morphometric features of posterior cranial fossa are different 268 between Chiari I malformation with and without syringomyelia Eur Spine J 2016; 25: 2202-269 2209.270271 4. Shaw TA, McGonnell IM, Driver CJ, et al. 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1Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, United Kingdom

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