C. R. Palevol 18 (2019) 1011–1023 Contents lists available at ScienceDirect Comptes Rendus Palevol www.sciencedirect.com General Palaeontology, Systematics, and Evolution (Vertebrate Palaeontology) The most ancient evidence of a diseased lagomorph: Infectious paleopathology in a tibiofibular bone (Middle Miocene, Germany) L’évidence la plus ancienne d’un lagomorphe malade : paléopathologie infectieuse dans un os tibiofibulaire (Miocène moyen, Allemagne) Blanca Moncunill-Solé a,b,∗ , Albert Isidro c , Alejandro Blanco b,d , Chiara Angelone a,e,f , Gertrud E. Rössner d,g , Xavier Jordana h a Dipartimento di Scienze, Università degli Studi Roma Tre, Largo S. Leonardo Murialdo 1, 00146 Roma, Italy b Centro de Investigacións Científicas Avanzadas (CICA), As Carballeiras s/n, Campus de Elviña, Universidade da Coruña, 15071 A Coruña, Spain c Department of Orthopedics, Hospital Universitari Sagrat Cor, 08029 Barcelona, España d SNSB - Bayerische Staatssammlung für Paläontologie und Geologie (BSPG), Richard-Wagner-Str. 10, 80333 München, Germany e Institut Català de Paleontologia Miquel Crusafont (ICP), Edifici Z ICTA-ICP, Carrer de les Columnes s/n, Campus de la Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain f Key Laboratory of Vertebrate Evolution and Human Origins, Institute of Vertebrate Paleontology and Palaeoanthropology, Chinese Academy of Sciences, 142 Xi Zhi Men Wai Da Jie, 100044 Beijing, China g Department of Earth and Environmental Sciences, Paleontology & Geobiology, Ludwig-Maximilians-Universität München, Richard-Wagner-Str. 10, 80333 München, Germany h Unitat d’Antropologia, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Edifici C Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain a r t i c l e i n f o a b s t r a c t Article history: Few pathological cases have been identified in fossils of small mammals. Here we report the Received 9 August 2019 most ancient paleopathological evidence identified in a lagomorph (Ochotonidae, middle Accepted after revision 13 October 2019 Miocene). The tibiofibular bone was macro- and microscopically (␮CT) inspected to provide Available online 23 November 2019 a diagnosis, an etiology, and its possible relationship with the individual’s cause of death. Osteogenesis (reactive bone growth) and osteolysis, processes related with neoplasms and Handled by Lorenzo Rook infections, are identified in the abnormal bony region. Its location (juxta-articular) and morphology allow us to identify it as a joint infection (septic arthritis) consequential of a Keywords: violent mechanism, such as a bite. Both the origin of bone accumulation (avian pellets) and Goldberg site the poor vital state of the specimen (with a joint infection) point to predation as the most MN6 probable cause of death. Up to now, lagomorph paleopathologies had only been described Ochotonid Osteolysis in insular populations, and the present one is the first evidence in a mainland specimen. Septic arthritis © 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved. Small mammals ∗ Corresponding author at: Universidade da Coruña, Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Física e Ciencias da Terra, As Carballeiras s/n, Campus de Elviña, 15071 A Coruña, Spain. E-mail addresses: blanca.moncunill@udc.es, blanca.moncunill@gmail.com (B. Moncunill-Solé), aisidro.cot@gmail.com (A. Isidro), alejandro.blancoc@udc.es (A. Blanco), chiara.angelone@uniroma3.it (C. Angelone), roessner@snsb.de (G.E. Rössner), xavier.jordana@uab.cat (X. Jordana). https://doi.org/10.1016/j.crpv.2019.10.007 1631-0683/© 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved. 1012 B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 r é s u m é Mots clés : Peu de cas pathologiques ont été identifiés dans des fossiles de petits mammifères. Nous Gisement de Goldberg rapportons ici les preuves paléopathologiques les plus anciennes identifiées chez un lago- MN6 morphe (Ochotonidae, Miocène moyen). L’os tibiofibulaire a fait l’objet d’une inspection Ochotonidé macroscopique et microscopique (␮CT) afin de fournir un diagnostic, son étiologie et sa Ostéolyse relation possible avec la cause de décès de l’individu. L’ostéogenèse (croissance osseuse Arthrite septique réactive) et l’ostéolyse, processus liés aux néoplasmes et aux infections, sont identifiés Petits mammifères dans la région anormale de l’os. Sa localisation (juxta-articulaire) et sa morphologie per- mettent de l’identifier comme une infection articulaire (arthrite septique) consécutive à un mécanisme violent, tel qu’une morsure. L’origine de l’accumulation osseuse (granulés aviaires) et le mauvais état vital du spécimen (avec une infection articulaire) indiquent que la prédation est la cause de décès la plus probable. Jusqu’à présent, les paléopathologies lagomorphes n’avaient été décrites que dans des populations insulaires, et celle-ci est la première preuve sur un spécimen du continent. © 2019 Académie des sciences. Publié par Elsevier Masson SAS. Tous droits réservés. 1. Introduction middlePleistocene–Holocene endemic insular ochotonid from Sardinia (Italy). Paleopathologies reported in conti- Occasionally, biological remains of extinct species show nental lagomorphs are completely lacking, in spite of the pathological conditions (Rothschild and Martin, 2006). fact that the members of this order are extremely common, Developmental disorders, stress marks, tumors, infections widespread and abundant in the fossil record, especially or traumas are among the most common. Because these since the Neogene onwards. abnormalities are comparable to those observed in extant In the present research, we report on the most ancient living beings, paleontologists can provide an accurate diag- known paleopathology in the order Lagomorpha up to now nosis and can investigate their etiology (Rothschild and (middle Miocene, MN6), and the first ever documented on Martin, 2006; Shufeldt, 1893). Paleopathological inves- a mainland taxon. The aims of this study are: (1) to describe tigations can unveil many biological aspects of extinct and assess this bony abnormality macro- and microscopi- species, inter alia traits of their immunology, physiology, cally (␮CT); and (2) to provide a diagnosis and to determine life history, behavior, and of inter- and intraspecific inter- its etiology as well as the cause of death of the individual. actions (Anné et al., 2016; Böhmer and Rössner, 2018; Hone and Tanke, 2015; Rothschild and Martin, 2006; Waldron, 2009). In this regard, non-lethal pathologies 2. Material and methods that leave a trace in bones or teeth over time are of special significance (Foth et al., 2015). The big boom of 2.1. Geological setting paleopathological studies is relatively recent, coinciding with the improvement of non-invasive diagnostic tech- The examined pathological tibiofibular bone comes niques (Mariani-Costantini et al., 1996; Shaffer and Baker, from the Goldberg site, a fossiliferous locality of the 1997). Pathological abnormalities have been described in Nördlinger Ries, Bavaria, southern Germany (Fig. 1). a wide range of fossils, including plants, invertebrates Nördlinger Ries is a circular, shallow depression (22–24 km (mainly trilobites), and vertebrates (such as fishes, amphib- in diameter), formed by one of the cosmic impacts of ians, reptiles, carnivorans, several odd-toed and even-toed a binary stony meteorite, at approximately 14–15 Ma ungulates, and primates) (Anné et al., 2016; Böhmer and (Abdul Aziz et al., 2008; Arp, 1995, 2006; Buchner et al., Rössner, 2018; Dieguez et al., 1996; Flynn et al., 2013; 2013; Göhlich and Ballmann, 2013). The depression was Foth et al., 2015; Haridy et al., 2019; Lyras et al., 2016, filled with an enclosed evaporitic soda shallow-water lake, 2019; Pawłowska et al., 2014; Petit and Khalloufi, 2012; which probably existed for a time span of 0.3 to 2 Ma Rooney, 1997; Rothschild and Laub, 2013). Only a few (Jankowski, 1981). The Goldberg site (among other coeval, paleopathological conditions have been described in small neighboring sites as Steinberg-Spitzberg or Wallerstein) is mammals, mainly in rodents. Luna et al. (2017) noted the a spring mound of calcareous cool-water tufa (“travertine” presence of fractures, enthesial changes, osteoarthroses, hills) that rose at the level of a sublacustrine spring water and other abnormal conditions in several species of rodents source (Arp, 1995, 2006; Göhlich and Ballmann, 2013). It (Cueva Tixi, middle to late Holocene, Argentina). The pale- is assumed that, during certain periods, the spring mounds oparasitological analysis in rodent coprolites carried out emerged from the soda crater lake as little islands. Fissures by Sardella and Fugassa (2009) detected the presence of and pockets were formed in the sediments in the subaerial nematodes (Cerro Casa de Piedra, Holocene, Argentina). In medium, and birds of prey used their crevices for resting fossil lagomorphs, Zoboli (2003) and Zoboli et al. (2018) or nesting. Their regurgitated pellets were accumulated in described several abnormal conditions (arthrosis, perios- the late freshwater stages, forming the fossil vertebrate titis, osteomalacia, fractures, osteosarcoma, osteonecrosis, assemblages. Miotyto montispetrosi Göhlich and Ballmann, etc.) of remains in Prolagus sardus (Wagner, 1829), a 2013, the barn owl described from Steinberg, was the main B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 1013 Fig. 1. Schematic map of Germany and detail of the Nördlinger Ries (Bayern, southern Germany). The position of the meteorite crater and its limits is highlighted in light grey. The black dots indicate towns and cities, whereas the dark grey squares indicate fossil localities with middle Miocene faunas (Goldberg and Steinberg). The data is from the Bayerisches Geologisches Landesamt (2004). The scale bar represents 2 km. Fig. 1. Plan schématique de l’Allemagne et détail de la localité de Nördlinger Ries (Bavière, Sud de l’Allemagne). La position du cratère de météorite et de ses limites est surlignée en gris clair. Les points noirs indiquent les villes et les cités, tandis que les carrés gris foncé indiquent les localités fossilifères avec des faunes du Miocène moyen (Goldberg et Steinberg). Données : Bayerisches Geologisches Landesamt (2004). L’échelle représente 2 km. agent of accumulation (Göhlich and Ballmann, 2013). The latter fuses between the 16th and 28th weeks after birth vertebrate assemblages contain mostly small vertebrates, (Kaweblum et al., 1994; Masoud et al., 1986), whereas including fishes, amphibians, reptiles, birds, and small no data is available for ochotonids. The examined speci- mammals (Arp, 2006; Heizmann and Fahlbusch, 1983; men is attributed to the family Ochotonidae. Its geological Rachl, 1983; Ziegler, 1983). The state of preservation of age (middle Miocene, MN6), body size and morphology these fossil remains is excellent (Göhlich and Ballmann, exclude its classification as a leporid. Actually, leporids set- 2013; Heizmann and Fahlbusch, 1983). tled definitively in Europe only in the latest Miocene (7 Ma), The age of the Goldberg site dates back to the Early and their presence in European sites before 11 Ma is a mat- Astaracian (middle Miocene, MN6), younger than 14.7 Ma ter of debate (Flynn et al., 2014; López Martínez, 2008). (Bolten, 1977; Lindsay et al., 1989). The paleoclimate of this Moreover, the tibiofibula from Goldberg has a total length region at that moment has been interpreted as semi-arid of 35 mm, and a weight of 126 g based on the transver- with a mean annual rainfall of 584 ± 252 mm (Böhme et al., sal diameter of the distal epiphysis (allometric models in 2006; Heizmann and Fahlbusch, 1983). Moncunill-Solé et al., 2015). Both dimensions fit with its taxonomic placement among ochotonids (Moncunill-Solé 2.2. Specimen et al., 2016a, fig. 3; Smith et al., 2018). Indeed, in the coeval, neighboring site of Steinberg (Fig. 1), Heizmann and A lagomorph right tibiofibular bone is described and Fahlbusch (1983) reported the presence of two ochotonids: examined (Figs. 2A–B, 3A; Appendix S1). It is curated Prolagus oeningensis König, 1825 and Lagopsis verus Hensel, at the fossil mammal collection of the Staatliche Natur- 1856, the latter in larger quantities (Prieto et al., 2009). It is wissenschaftliche Sammlungen Bayerns–Bayerische very likely that the pathological specimen from Goldberg Staatssammlung für Paläontologie und Geologie pertains to one of these two species. However, as detailed (SNSB–BSPG) in Munich (Germany) under number studies and statistics about the postcranial bones of fos- 1966XXXIV 3340. The specimen, as the other fossil sil ochotonids are lacking, we refrain to assess a generic remains from Goldberg, was gained from subjecting the taxonomic attribution of the tibiofibula. blocks of calcareous tufa to dilute acetic acid (Göhlich and Ballmann, 2013). 2.3. Analytical tools The specimen was assigned to an adult individual based on the fusion state of its epiphyses. Although the proxi- The most common methodology for studying pale- mal ones are impossible to evaluate due to the abnormal opathological conditions is the histological analysis condition, the distal one is completely fused. In Orycto- (D’Anastasio, 2004; Lyras et al., 2016, 2019). Due to its lagus cuniculus Linnaeus, 1758, the growth plate of this destructive base, however, it is not recommended when 1014 B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 Fig. 2. Paleopathological tibiofibular bone of ochotonid from the Goldberg site (middle Miocene, MN6). A. Complete bone. B. 3D Reconstruction of the complete bone. C. Anterior view. D. Lateral view. E. Medial view of the proximal end of the bone. The scale bar represents 10 mm. Fig. 2. Os tibiofibulaire paléopathologique du gisement de Goldberg (Miocène moyen, MN6). A. Os complet. B. Reconstruction 3D de l’os complet. C. Vue antérieure. D. Vue latérale. E. Vue médiale de l’extrémité proximale de l’os. L’échelle représente 10 mm. Fig. 3. Detailed drawings of the paleopathological region of the tibiofibular bone of the ochotonid (Goldberg site, MN6). A. Scheme of the complete bone. B. Anterior view. C. Antero-Medial view. D. Antero-Lateral view. E. Proximal view. A: anterior; L: lateral; P: proximal. The scale bar represents 10 mm. Fig. 3. Dessins détaillés de la région paléopathologique de l’os tibiofibulaire de l’ochotonidé (gisement de Goldberg, MN6). A. Schéma de l’os complet. B. Vue antérieure. C. Vue antéromédiale. D. Vue antérolatérale. E. Vue proximale. A : antérieure ; L : latérale ; P : proximale. L’échelle représente 10 mm. B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 1015 the sample size is very small (Anné et al., 2016). Recently, pathologies (Quesenberry and Carpenter, 2004; Varga, other non-destructive analytical tools (␮CT or electron 2014). microscopes) allow one to explore paleopathologies with- Lagomorphs have a very fragile skeleton, which rep- out damaging the remains (Anné et al., 2016; Böhmer resents only 7–8% of their total weight (Raftery, 2014; and Rössner, 2018; Flynn et al., 2013; Foth et al., 2015; Richardson, 2000). Even though this offers advantages Rothschild and Martin, 2006). Because of the small size for a rapid escape, the lagomorphs also become more of our sample, we decided to evaluate the paleopathology prone to skeletal problems. The most common affec- macroscopically and via X-ray microtomography (␮CT). tions of their musculoskeletal system are dysplastic and The first methodology allows us to identify broadly the degenerative diseases, neoplasia, trauma (leg and verte- main important abnormalities of the bone, whereas the bral fractures), infection, and pathologies with a nutritional latter provides valuable data about the inner structure base (Quesenberry and Carpenter, 2004; Richardson, 2000; of the bone and the microstructural changes. The pale- Turner et al., 2018). In addition, this mammalian group opathological bone was scanned using a phoenix|x-ray is distinguished by two immunological conditions: lym- nanotom® m (GE Sensing & Inspection Techonologies phopenia and low production of neutrophils (Varga, 2014). GmbH, Wunstorf/Hannover, Germany) at the Staatliche This makes them more susceptible to developing infectious Naturwissenschaftliche Sammlungen Bayerns, in Munich. diseases and to a high probability of hematogenous spread The complete bone was scanned at a voxel size of (Langley-Hobbs and Harcourt-Brown, 2014). 0.0164 ␮m with a voltage of 120 kV and current of 70 ␮A Particularly, wild lagomorphs have fewer dental dis- and a 0.2-mm copper filter (dimensions 566 × 547 × 2326 eases (feeding on buds and young leaves of bushes), skin bytes). A high-resolution ␮CT of the proximal part of the diseases (benefits of grooming), and weight problems (not bone was also conducted (voxel size 0.0053 ␮m, voltage of overweight) (Quesenberry and Carpenter, 2004; Varga, 120 kV, current of 60 ␮A, 0.2 mm copper filter, dimensions 2014). On the other hand, their natural habitat fosters a 1548 × 2001 × 2364 bytes). Visualization, processing, and range of pathologies that are not common (or have a lower analysis of data were performed with software Amira 5.2.0 incidence) in domestic individuals (e.g., paratuberculosis, (Build 531) (Property of 1995–2008 Konrad-Zuse-Zentrum intestinal worms, myxomatosis, or other viral diseases) Berlin [ZIB] and 1999–2008 Visage Imaging, Inc.) and Avizo (Smith et al., 2018; Varga, 2014). Disabled wild lagomorphs Standard Edition 7.1.0 (Property of 1995–2012 Konrad- (e.g., as consequence of a chronic diseases or a trauma) Zuse-Zentrum Berlin [ZIB] and 1999–2012 Visualization have higher probabilities to be caught by a predator (Varga, Sciences Group [VSG], SAS). 2014), whereas most of the domestic animals survive. That For creating the interactive 3D model (Appendix S1), explains why literature provides a smaller number of doc- the segmentation tool of AMIRA 5.2.0 was used to dif- umented medical cases of pathologies in wild lagomorphs, ferentiate the tibiofibular bone from the modelling clay and a large amount in those that are kept in laboratories or (used to mount the bone in the chamber of the ␮CT private homes. during scanning). The bone material selected from all We compiled and listed in Table 1 data (description, slices was converted into a surface component (polygon incidence and prognosis) of known pathologies of extant mesh). Using Avizo 7.1.0, the number of faces of the model lagomorphs related with osteogenesis and osteolysis. was reduced (polygon reduction tool). The surface was saved in Wavefront Format (OBJ). MeshLab v2016.12 (Prop- 3. Results erty 2005–2017 Paolo Cignoni, Visual Computing Lab, and ISTI–CNR) allowed the conversion of OBJ Format into U3D 3.1. Macroscopic description File Format (U3D). This latter file was embedded into a PDF using Adobe Acrobat XI tools (Property 1984–2012 In the studied specimen, the tibia head (from the tibial Adobe Systems Incorporated, 2003–2011 Solid Documents, plateaus to below the tibial crest, approximately 10 mm) LLC, and 1987–2012 IRIS SA). The protocols described by and the most proximal part of the fibula, including the Ruthensteiner and Heß (2008) and van de Kamp et al. tibiofibular syndesmosis (Figs. 2C–E, 3), are the regions (2014) were followed. affected by the pathology. A local disease affects the meta- physis (the narrow portion between the epiphysis and 2.4. Pathologies in extant lagomorphs diaphysis formed mainly by cancellous bone) of the proxi- mal epiphysis and it does not continue along the diaphysis In order to achieve an accurate diagnosis of the studied (cortical bone). pathology, comparison with pathologies of extant indi- A macroscopic examination allows us to identify two viduals is paramount. Extant lagomorphs are prone to differentiated structures in the abnormal region: (1) a a large spectrum of diseases and disorders caused by jagged-like contour of the metaphyseal border of the tibia multiple factors (Varga, 2014). They have been mainly (mainly); and (2) a complete rarefaction of the proximal described in domestic and farmed specimens of the Euro- third of tibia and fibula, with the presence of pit holes pean rabbit O. cuniculus (Quesenberry and Carpenter, of different sizes. The proximal margin of the tibia is 2004; Richardson, 2000; Varga, 2014). The most fre- brittle and discontinuous, full of notches (osteolysis) and quent are abscesses (e.g., mandibular abscesses, ulcerative projections (osteogenesis) (Fig. 3B–D). In addition to osteo- pododermatitis or hock joint infection), ophthalmic, skin, phytes and protuberances, an important suprafibular bony and dental diseases, digestive, neurological and locomo- projection is located in the most proximal and lateral area tor disorders, as well as cardiorespiratory and urogenital of the tibia (Fig. 3B). It ends in a more lateral position than 1016 B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 Table 1 Skeletal pathologies in extant lagomorphs related with lysis and formation of bone tissue. A brief description, incidence, and prognosis are provided. Information has been taken from Richardson (2000), Ishikawa et al. (2012), Oglesbee (2012), Suckow et al. (2012), Harcourt-Brown and Langley-Hobbs (2014), Varga (2014), Meuten (2017), Azadian et al. (2018), and Turner et al. (2018). Tableau 1 Pathologies squelettiques chez les lagomorphes actuels liés à la lyse et à la formation de tissu osseux. Une brève description, l’incidence et les pronostics sont fournis. Informations de Richardson (2000), Ishikawa et al. (2012), Oglesbee (2012), Suckow et al. (2012), Harcourt-Brown and Langley-Hobbs (2014), Varga (2014), Meuten (2017), Azadian et al. (2018), et Turner et al. (2018). Condition Description Incidence Prognosis Infectious disease Osteomyelitis: bacterial infection of the bone, characterized by an osteolysis (bone Common (chronic Fair–Poora porosity) and secondary new bone production adjacent to the infected area (periosteal in some cases) reaction, thicken of compact bone and cortex), resulting in osteitis, periostitis, and spongiosclerosis. Drainage tracts appear in severe cases. Primary or secondary (contamination of wounds, open fractures or ulcerative pododermatitis) Tuberculosis: macro and microscopical lesions, including granulomatous Rare No datab inflammation of bone, with caseous necrosis (osteolytic process, from cancellous to cortical bone, leading to osteoporosis) and little areas of osseous proliferation (absence or little periosteal reaction, sequestra are rare, and cloacae are not formed). Bacilli reach skeleton via the bloodstream. In long bones, it is localized in the metaphyseal or epiphyseal region Septic arthritis: infection (bacterial, viral or fungal) of the synovial fluid of the limb Rare Poorc joints. It is characterized by a rapidly destruction of bone, osteonecrosis, considerable proliferation of new bone, and (partial or complete) bony ankylosis. Primary (penetrating injury, wound) or secondary (hematogenous spread, contamination of traumatic injuries, or extension of a primary osteomyelitis [metaphyseal spread] or an infection of soft tissues) Neoplasia Osteosarcoma: bone lysis and hyperplasia (periosteal and endosteal new bone growth Rared Poore and production of tumor bone, “spicular” form). Generally, they are centered in the metaphysis and they rarely cross joints (adjacent bones are not involved). “Sunburst” appearance in X-ray images Osteochondroma: pedunculated lesions (globular “bath-sponge” form) located in the Rare Fairf cortical surface (metaphyseal and diaphysis region, not involving the epiphysis), generally in the direction of muscle traction. There is neither osteolysis nor periosteal reaction. The cortex of the bone and the overlying tumorous mass are continuous. Their projection is opaque on X-ray images Osteonecrosis Necrotic region (osteolysis) in bones as a result of the loss of blood supply. It could be No datag Fairh the consequence of a trauma, fracture or dislocation. Located mainly on the femoral head, the proximal humerus, the femoral condyles, and the carpal and tarsal bones a Extremely difficult to treat. Prolonged therapy of systemic antibiotics and surgical debridement or amputation of the infected region. b No information, few cases diagnosed. c Initial acute diagnoses and an aggressive treatment may lead to a fair prognosis. Long-term antibiotic therapy, surgical debridement, and in last instance amputation. Recurrences are common. d In dogs, large-sized breeds or individuals are at higher risk of developing an osteosarcoma (unclear relationship in rabbits). The lifespan of laboratory and domestic rabbits have been prolonged, entailing an increase of the neoplastic incidence in the last period. e Generally, it is associated with metastasis to thoracic organs, abdomen or subcutaneous tissue. Even with an early proper diagnosis and a small size of tumor, the prognosis is poor. f They stop growing once the individual has reached skeletal maturity. In some occasions, the lesion resorbed or was incorporated into the metaphysis later. g No information available. h Successful treatment. a Extrêmement difficile à traiter. Antibiothérapie systémique prolongée, chirurgie ou amputation de la région infectée. b Aucune information, peu de cas diagnostiqués. c Les diagnostics aigus initiaux et un traitement agressif peuvent conduire à un pronostic correct. Antibiothérapie à long terme, débridement chirurgical et amputation de dernière minute. Les récidives sont courantes. d Chez les chiens, les races ou les individus de grande taille présentent un risque plus élevé de développer un ostéosarcome (relation incertaine chez le lapin). La durée de vie des lapins de laboratoire et domestiques a été prolongée, entraînant une augmentation de l’incidence néoplasique au cours de la dernière période. e En général, il est associé à des métastases aux organes thoraciques, à l’abdomen ou aux tissus sous-cutanés. Même avec un diagnostic correct précoce et une petite taille de la tumeur, le pronostic est mauvais. f Ils cessent de croître une fois que l’individu a atteint la maturité squelettique. Dans certaines occasions, la lésion résorbée ou incorporée à la métaphyse plus tard. g Pas d’information disponible. h Traitement couronné de succès. tibia and fibula heads and, over its course from medial to lateral condyle of the femur. The complete absence of lateral region, it increases in size. In lateral view (Fig. 3D), tibial plateaus (osteolysis) exposes the medullary cavity the projection is oval (measuring approx. 3.5 × 1.75 mm) (Fig. 3E). Cancellous bone in the abnormal metaphysis is and very porous. The smooth surface of the proximal part almost destroyed. Medullary cavity houses an incipient of this projection and the curvature in anterior view point mesh of large bony fibers; one of them is crossing the cavity to a possible facet joint, which would accommodate the halfway (Fig. 3E). Externally, the compact bone has a fragile B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 1017 and very porous appearance, with the presence of rounded differences between the distribution of the abnormal con- holes of little to middle size (range: < 0.04 mm–0.4 mm), dition. principally located on the lateral and central region of the Finally, other microstructural changes have been tibial head (Fig. 3B–D). In contrast, those of the suprafibular noticed in the pathology. From transversal slices, in the bony projection display elliptic outlines (Fig. 2D). At first union of the first quarter proximal region of the tibia with glance, the surrounding areas of all these pit holes shows the rest, it is drawn a first step of a fistula (abnormal chan- an increase of periosteal bone (periostitis). nel that connects internal organs among them or one of Overall, the fibula does not present a major destruction them to the outside surface of the body) from in to out of bone. The proximal epiphysis and diaphysis are com- (Fig. 4B). Besides, the images allow us to observe several plete (Fig. 3B and D). Externally, it has a smooth surface lines related with traumas or fractures. The first one is a with the presence of a few pores at the posterior and lateral healed fracture oblique line in the upper fibula, which is side (Figs. 2C–D, 3D). Under normal conditions, tibia and observed in coronal and sagittal slices (Fig. 5D, F–G). The fibula are connected by a syndesmosis at the proximal end second one is located at the level of the fibula too, follow- (Grove and Whitehouse, 1941). The abnormal condition has ing a proximo-distal axis, but its outline and surrounding a strong ankylosis of the two bones, with a reactive bone tis- bone highlight that, with all likelihood, it occurred post- sue that covers the most proximal end of the fibula (Fig. 3D). mortem (Fig. 5F). The slices of the inner region of the tibial From the lateral view, fibula and tibia are arranged in par- diaphysis show the appearance of the cancellous bone with allel, and an uncommon curvature is present in the most porosity (Fig. 5A–C). However, it is much less specific than proximal region (Figs. 2D, 3D). The cause of this abnormal the injuries that are present in the cortical bone. morphology is impossible to identify at simple sight, but it could be consequence of the strong ankylosis (reactive 4. Discussion bone growth), a fracture, or both. 4.1. Diagnosis 3.2. CT examination In the studied specimen, osteogenesis and osteolysis are the two principal processes observed in the abnor- The examination of the slices of the ␮CT reveals the mal bony region. Infectious diseases (bacterial, viral or presence of periosteal growth (reactive bone growth, fungal) and neoplastic disorders (osteosarcoma or osteo- osteogenesis) throughout the pathological region chondroma) are the two main conditions that show both (Figs. 4 and 5). This growth of new bone is distributed processes, whereas osteonecrosis solely related to oste- irregularly, showing lacunar-like spots of different size olysis is excluded (Table 1). In vivo, the differentiation (Fig. 4A–C). These spots or foramina, located inside of new between the first two pathological groups is problematic bone formation, could either be a new vascular supply (Raftery, 2014). It is obtained combining histopathological inside the periosteal bone (what is very uncommon) or examinations and biopsies, assessment of growth patterns, a cystic-like structure in the cortical new bone layers consistency, exudations, and X-ray images (Harcourt- (what is the most probable, as a secondary phenomenon Brown and Chitty, 2014). In our case, we will try to have to of a septic process). Periosteal growth is conspicuous rely on evidences to exclude one of the two possible causes. in coronal slices of the tibia (Fig. 5A–C), which shows Neoplasias are uncommon in rabbits and hares (par- clearly the apposition of two different layers of periosteal ticularly in juveniles and young adults), especially those bone. The medial bone wall shows only a vertical line, that affect the limbs (Tinkey et al., 2012; Varga, 2014). but the lateral one has a different and more complex Osteochondromas are generally pedunculated injuries, not pattern, full of irregularities and cystic-like structures. associated with bone destruction, and with a very low Some isolated fragments (Fig. 5A–C) are considered bony incidence in lagomorphs (Meuten, 2017; Suckow et al., micro-sequestra, without the presence of fistulous tracts 2012). Osteosarcomas mainly affect maxilla and mandible and cloacae. The presence of periosteal reaction is also in lagomorphs (Manning et al., 1994). They have a distin- evidenced around the regions of the pit holes of the guishable morphology (spicular) and generally never cross cortical (at different levels) (Figs. 4 and 5), confirming joints (adjacent bones are not affected) (Meuten, 2017). the macroscopic examination (periostitis). The ankylosis These specific traits (morphology, location, etc.) and their (osteogenesis) of the proximal articulation between tibia low incidence (Table 1) allow us to rule out neoplastic and fibula show both bones in a continuum (Fig. 5E). This conditions as the cause of the examined tibiofibular abnor- abnormal adhesion is a common and unspecific reaction of mality. the joint, which is produced after different types of aggres- As for infectious diseases, epithelial and dermic sions, including post-traumatic, degenerative, rheumatic abscesses are frequent in lagomorphs. The diagnosis in vivo or infectious pathologies (Venes, 2001). of the affected limbs includes the observation of palpa- On the other hand, there are evidences of different radi- ble masses, lameness, hair loss, and cellulitis (Oglesbee, ological density (rarefaction) between several regions of 2012). When an infectious disease affects bones, osteolysis the metaphyseal pathology (but not present in the diaph- and periosteal reaction are observed (Richardson, 2000). ysis). Particularly in coronal slices, this effect is marked Osteomyelitis, tuberculosis, and septic arthritis are the comparing the medial and lateral cortical bones of the most common bony infections in lagomorphs (Table 1). metaphyseal area (Fig. 5A–C). These differences could be The first two entail an inflammation of the bone, whereas related with an overloading of the medial side or with the latter is an infection of the joint (Oglesbee, 2012; 1018 B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 Fig. 4. ␮CT images of paleopathological region of the tibiofibular bone (1966XXXIV 3340) in transverse views. A–E. Slices at different levels (see cutting line in each case), from distal to proximal. The red dashed lines split the cortical bone from the periosteal reaction. A: anterior; bp: bony projection; c: cortical bone; F: fibula; fi: fistula; L: lateral; ls: lacunar-like spot; mc: medullary cavity; o: osteophyte; T: tibia; pr: periosteal reaction. The scale bar represents 5 mm. Fig. 4. Images ␮CT de la région paléopathologique de l’os tibiofibulaire (1966XXXIV 3340) en vues transversales. A–E. Coupes à différents niveaux (voir les lignes de coupe dans chaque cas), de distal à proximal. Les lignes pointillées rouges séparent l’os cortical de la réaction périostée. A : antérieure ; bp : projection osseuse ; c : corticale ; F : fibule ; fi : fistule ; L : latérale ; ls : tache lacunaire ; mc : cavité médullaire ; o : ostéophyte ; T : tibia ; pr : réaction périostée. L’échelle représente 5 mm. Richardson, 2000). Tuberculosis can be excluded because examined specimen, the macroscopic and radiologic it has a low incidence and it is not associated with a analyses (periosteal reaction, ankylosis and lysis) and the periosteal reaction (Table 1), a process observed in the local affection of the juxta-articular region are consistent examined tibiofibula (Barthold et al., 2016; Rogers and with the diagnosis of a septic arthritis of the knee (Table 1). Waldron, 1989). In addition, the origin of the Mycobac- We cannot evaluate the kind of affection that would be terium tuberculosis complex (the group of bacteria that presented in the femoral condyles, but the radiological includes Mycobaterium bovis, the main agent of tubercu- patterns of the studied individual put aside the diagnosis losis in rabbits), is dated back to only 40,000 years ago of degenerative joint disease (progressive deterioration of (Manning et al., 1994; Wirth et al., 2008). the articular cartilage) and post-traumatic joint disease. Osteomyelitis and septic arthritis affect different bony regions, although they are often difficult to distinguish, 4.2. Etiology because one can trigger the other. Osteomyelitis, related with bone lysis and periosteal reaction, causes a heat, In septic arthritis, the bacterium reaches the syn- swollen, and painful limb. Septic arthritis is an inflam- ovium of the bone/joint using two possible ways: (1) matory disease characterized by ticked periarticular direct, primary (infection of the bone, joint or surround- tissues, synovial effusion, osteolysis, irregular joint space, ing soft tissues, e.g., an osteomyelitis in the metaphysis of erosions and periarticular osteophytes, and is associated a long bone), and (2) indirect, secondary (hematogenous with lameness, decreased range motion of the joint, soft spread, bacteremia or septicemia, from a primary focus of tissue swelling, heat, and pain (Oglesbee, 2012). In the infection). In the former case, several conditions can be B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 1019 Fig. 5. ␮CT images of paleopathological region of the tibiofibular bone (1966XXXIV 3340). A–D. Coronal views. E–G. Sagittal views. Cutting lines indicate the level of the slices. The red dashed lines split the cortical bone from the periosteal reaction. A: anterior; ak: ankylosis; bms: bony micro-sequestra; bp: bony projection; c: cortical bone; D: distal; F: fibula; hfl: healed fracture line; L: lateral; ls: lacunar-like spot; mc: medullary cavity; pfl: postmortem fracture line; T: tibia; pr: periosteal reaction. The scale bar represents 5 mm. Fig. 5. Images ␮CT de la région paléopathologique de l’os tibiofibulaire (1966XXXIV 3340). A–D. Vues coronales. E–G. Vues sagittales. Les lignes de coupe indiquent le niveau des images. Les lignes pointillées rouges séparent l’os cortical de la réaction périostée. A : antérieure ; ak : ankylose ; bms : micro- séquestre de l’os ; bp : projection osseuse ; c : corticale ; D : distale ; F : fibule ; hfl : ligne de fracture guérie ; L : latérale ; ls : tache lacunaire ; mc : cavité médullaire ; pfl : ligne de fracture post-mortem ; T : tibia ; pr : réaction du périoste. L’échelle représente 5 mm. susceptible of bone infection: trauma (fracture or fissure), joint reaction to a violent mechanism as a bite. Thus, the puncture/penetrating wounds (seeds or pieces of hay that entrance of the bacterium was direct (primary focus of penetrate the skin), or bite wounds (fights with other rab- infection). Bite wounds in lagomorphs could be consequen- bits or predators) (Oglesbee, 2012; Varga, 2014). Moreover, tial of combats among different individuals (intraspecific skin infections (ulcerative pododermatitis, nail-bed infec- competition, especially among males) or could be inflicted tion, abrasions or furunculosis) can extend to underlying by predators when lagomorphs try to escape or avoid their soft tissues, bones or joints (Oglesbee, 2012; Richardson, attack (e.g., carnivoran such as canids) (Varga, 2014). For 2000). It is also known that primary infections could spread the moment, we cannot identify the potential causative via bloodstream or lymph causing secondary infections in species. any other organ system (especially on thoracic cavity or The bacteria related with septic arthritis in lago- abdomen) (Varga, 2014). morphs are pyogenic ones, including staphylococci (e.g., The assessment of the patterns of the injury, the micro- Staphylococcus aureus), Pasteurella multocida, Pseudomonas, scopical analysis of the abnormal area, as well as the Fusiformis, and anaerobic ones (Nade, 2003; Oglesbee, affected body region (hindleg) allow us to consider that, 2012). Varga (2014) described that the most common bac- with all likelihood, the septic arthritis was a peri-articular terium isolated from infected bite wounds in lagomorphs 1020 B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 is P. multocida, a Gram-negative coccobacillus of small paleopathological changes (e.g., fused fracture or chronic size. pathologies) highlights survival of the individual for a certain time period (Luna et al., 2017; Mariani-Costantini 4.3. Cause of death of the individual et al., 1996). Accordingly, Mariani-Costantini et al. (1996) proposed that paleopathologies will be more frequent in The strong necrotic and osteogenic changes observed large powerful species, with a complex social behavior and in the tibiofibular bone highlight that the pathology cer- remarkable defensive abilities (Adams, 1990), conditions tainly had a large impact on the life of the individual, quite contrary to the biology of lagomorphs (Smith et al., affecting locomotion, feeding or predator escaping, among 2018). other vital activities. Abscessed joints are swollen and Studies of paleopathological dental or maxilla/jaw very painful, and the individual limps and keeps immo- remains of lagomorphs are not available in the literature. bile, avoiding moving (Oglesbee, 2012; van Praag et al., Instead, there are citations of probable abnormal condi- 2010; Varga, 2014). The infection can lead to a permanent tions. Crusafont et al. (1955) erected the species Heterolagus disability of the articular movement, preventing feeding albaredae Crusafont et al., 1955 (Molí Calopa, Spain, MN3b) or safeguarding. Additionally, the locomotive reduction based on an unnoticed pathological specimen of Lagopsis entails a poor blood circulation, and consequently a penai Royo, 1928 with “wrongly” inclined lower molars decrease of the vital conditions (van Praag et al., 2010). (López Martínez, 1989). Berzi (1967) described an unusual Infections have a very poor prognosis in this mammalian possible pathological condition (a diastema between the group (Table 1), and a generalized spread of the infection third and fourth lower premolars) in Prolagus savagei (septicemia) can cause a rapid death (Richardson, 2000; Berzi, 1967 (Italy, late Pliocene, MN16a). López Martínez Suckow et al., 2012). and Thaler (1975) argued that this condition was con- In natural environments, the decreased mobility and sequence of anomalous fossilization. López Martínez and the poor vital conditions of individuals with septic arthritis Thaler (1975) noticed that, in the material of Prolagus crusa- make them easy targets for predators (Varga, 2014). Indeed, fonti López Martínez, 1975 (in López Martínez and Thaler, the vertebrate assemblages from Goldberg are mainly the 1975) from Can Poncic (Spain, early late Miocene, MN9), result of the piling of pellets regurgitated by birds of prey there is a high incidence of teeth with an irregular occlusal (Göhlich and Ballmann, 2013). In this regard, the cause of surface. They associated this condition on teeth with a death of the concerned ochotonid is probably related to necrotic process affecting the mandibular condyle. That predation, and not a direct consequence of the infection part of the jaw is not preserved in the mentioned mate- (e.g., septicemia). rial. López López Martínez (1989, p. 108), p. 108) refers to a high number of pathological teeth of Titanomys calmaensis 4.4. Paleopathology in lagomorphs Tobien, 1974 from La Chaux-de-Fonds (Switzerland, MN2a) (Tobien, 1974, figs. 81, 84, 85, 87) supposedly characterized The study of paleopathologies is indeed a quite new by divergent axes of the tooth shafts. However, the figures field of research. However, there is an important scarcity of in Tobien (1974, figs. 81, 87) show a minimally inclined evidences of paleopathological conditions in lagomorphs shaft that makes us refrain to define it as pathological. and other small mammals compared with large ones. This At any rate, the incidence of lagomorph paleopathologi- fact may be consequence of several reasons. The study cal teeth is minimal in Eurasian collections and they have of small mammals is based on dental remains, which are been limited mainly to fractures or growth out of axis prob- the most numerous and best preserved parts of small ably due to feeding accidents and wrong position during mammals as fossils (sometimes the only to be preserved). eruption respectively. The evidence for those conditions is a Skeletal elements are less likely to be preserved and are bizarre or unusual occlusal surface pattern. The individuals less studied, as taxonomy is based mainly on teeth. In in which those conditions were observed were adults and addition, dental diseases have a minor incidence in wild apparently lived with the pathological condition without animals (Varga, 2014). On the other hand, extinct and being seriously affected (CA, pers. obs.). extant lagomorphs are considered small/medium mammal The first attempt to diagnose pathological conditions species (70–300 g) (Smith, 2008). Their little dimensions in fossil lagomorphs was based on postcranial elements could be a factor that hampers the observation, assess- of P. sardus, the middle Pleistocene–Holocene endemic ment, and diagnosis of abnormal bony conditions (Luna ochotonid of Corsica and Sardinia. Zoboli (2003) and Zoboli et al., 2017). Moreover, lagomorphs show a fast life history et al. (2018) reported abnormal conditions in Sardinian (marked by an earlier reproduction maturity, large litter materials, mainly related to traumas and infections, but size, and short lifespan, some of them do not live more secondarily to tumors and malnutrition conditions. Con- than one or two years) (Promislow and Harvey, 1990; genital diseases, on the other hand, were completely Smith, 2008). Thus, their interaction period with the excluded. The authors also noticed that the incidence of environment is lesser than in large mammals, as well as diseased remains was less than 2%. Their results are in the probability of suffering some pathological disorders. line with the several studies focused on the description of In the wild, injured or sick individuals are at increased abnormal conditions in insular mammals (Adrover, 1972; risk of predation (Varga, 2014). Although they could Dermitzakis et al., 2006; Jordana et al., 2011; Lyras et al., survive, this will depend on their ability as individual (for 2016, 2019; Maempel, 1993; Palombo and Zedda, 2016). feeding and avoiding predators) and the biological traits of Also, in those cases, pathological conditions are mainly their species (social behavior). In general, the presence of related to nutritional (long-term malnutrition, deficiency B. Moncunill-Solé et al. / C. R. Palevol 18 (2019) 1011–1023 1021 of some elements or vitamins) or environmental (traumatic Acknowledgments or degenerative) causes. The prevalence of pathological specimens in those samples ranges from 0.2 to 10%. This research is supported by the Xunta de Galicia, Spain Insular environments are characterized by a lower pre- (ED481B 2018/046, B.M-S.; ED481B 2017/027, A.B.), the dation pressure than in mainland ones (Sondaar, 1977). Visiting Professor grant of the President’s International Fel- Specially in small mammals, this different selective pres- lowship Initiative of the Chinese Academy of Science, China sure entails a modification of the life history, such as a (C.A.), the Spanish Agencia Estatal de Investigación, and longer lifespan (Palkovacs, 2003). In this regard, Moncunill- the European Regional Development Fund of the European Solé et al. (2015, 2016a) noticed a longer lifespan in Union, Spain (CGL2016-76431-P, C.A.), the CERCA Program, Prolagus apricenicus Mazza, 1987 than in mainland extant Generalitat de Catalunya (C.A), and a Grant of Excellence ochotonids. As bigger animals live longer, it is possible that Departments to the Dipartimento di Scienze, Roma Tre Uni- also the insular endemic Sardinian chronospecies Prolagus versity (MIUR-Italy, Art. 1, C. 314-337 L. 232/2016, C.A). figaro López Martínez, 1975 (in López Martínez and Thaler, We are indebted to Dr. Estella Böhmer, Juan Pérez García, 1975) and P. sardus, which weighed almost double than and Dr. Alejandro Tarragó for their valuable and helpful coeval congeneric species (Moncunill-Solé et al., 2016b), comments in the diagnosis of the paleopathology. Special had a longer lifespan, in spite of the fact that it coexisted thanks are also due to Luis Blanco for the revision of the with the Sardinian dhole Cynotherium sardoum Studiati, French version. 1857, which was a small prey hunter (Lyras et al., 2006). Thus, due to the longer lifespan of insular lagomorphs, it is not surprising that most of the evidence of paleopathologi- Appendix A. Supplementary data cal conditions in lagomorphs have been recorded in insular forms (Zoboli, 2003; Zoboli et al., 2018). Supplementary data associated with this article can To sum up, the finding of an extinct mainland ochotonid be found, in the online version, at https://doi.org/10. showing a pathological condition is a rarity. Thus, the 1016/j.crpv.2019.10.007. abnormal tibiofibular bone from Goldberg site is excep- tional. The diagnosis, etiology, and cause of death of the References individual that are provided here give us clues about the paleobiological traits of mainland lagomorph species (e.g., Abdul Aziz, H., Böhme, M., Rocholl, A., Zwing, A., Prieto, J., Wijbrans, survival capacity or circumstances of death) and their role J.R., Heissig, K., Bachtadse, V., 2008. Integrated stratigraphy and 40 in the ecological habitats (e.g., interaction between species Ar/39 Ar chronology of the Early to Middle Miocene Upper Freshwa- ter Molasse in eastern Bavaria (Germany). Int. J. 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