Cerebral Xanthoma in a Long-nosed Snake (Rhinocheilus lecontei) Eric T. Anderson1, DVM, Brigid V. Troan2, DVM, DACVP, Elizabeth M. Stringer1,2, DVM, Sathya K. Chinnadurai1, MS, DVM, DACZM, Ryan S. DeVoe2, DVM, MspVM, DACZM, DABVP (Avian)

1. Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA

2. North Carolina Zoological Park, 4401 Zoo Parkway, Asheboro, NC 27205, USA

ABSTRACT: A case of cerebral xanthomatosis is described in a long-nosed snake (Rhinocheilus lecontei). Downloaded from http://meridian.allenpress.com/jhms/article-pdf/20/2-3/58/2210923/1529-9651-20_2_58.pdf by guest on 28 September 2021 A 13-year-old long-nosed snake presented for pronounced lethargy, anorexia, and diminished righting reflex. The snake failed to respond to medical therapy and was euthanized. On histology, a focal cerebral cholesterol granuloma (xanthoma) was found within the lateral ventricle causing mild hydrocephalus, marked compression atrophy of the overlying dorsal cortex, and mild compression and disorganization of the ventral nucleus sphericus. Xanthomatosis is believed to be the cause of the neurological signs and the ultimate lack of response to medical therapy in this case. This case demonstrates another differential for neurologic dysfunction in snakes.

KEY WORDS: long-nosed snake, Rhinocheilus lecontei, xanthoma, xanthomatosis, cholesterol granuloma.

Xanthomas are granulomatous lesions characterized by volume. Reptile ringers (equal parts 5% Dextrose, 0.9% cholesterol clefts surrounded by foamy macrophages and NaCl, and Lactated Ringer solution; Carpenter et al., 2001) multinucleated giant cells, and have been found in various were administered at 3 ml subcutaneously, and 2 ml dilute tissues of mammals (Fluehmann et al., 2006; Fliegner et al., a/d cat and dog food (Hill’s Pet Nutrition, Inc., Topeka, 2007; Romanucci et al., 2008; Balme et al., 2009), birds KS) was tube fed since the animal had not eaten in several (Hoekstra et al., 1998; Monks et al., 2006; Souza et al., weeks. 2009), reptiles (Ryan and Whitney, 1980; Garner et al., The following day the snake was slightly brighter but 1999; Kummrow et al., 2010), and amphibians (Russell developed bilateral swelling just lateral to the nares. Due to et al., 1990). Cerebral xanthomas are rare and are most the potential for abscessed nasal passages, the snake was commonly reported as incidental postmortem findings in anesthetized with isoflurane via induction box for surgical horses (Sullivan, 1985). Brain involvement has also been exploration of the swellings. The affected sites were surgi- observed in a cat (Fluehmann et al., 2006), geckos (Garner cally prepared with dilute betadine scrub and lanced using et al., 1999), and green water dragons (Physignathus cocincinus) a number 11 surgical blade. A small amount of purulent (Kummrow et al., 2010). This report describes a case of a material was expressed from the right nasal swelling, whereas cerebral xanthoma in a long-nosed snake (Rhinocheilus the left side produced a small amount of clear fluid. The lecontei). surgery sites were flushed with sterile saline, and 1% silver sulfadiazine cream (Watson Pharmaceuticals, Corona, CA) CASE REPORT was applied topically to the affected areas. The incisions were left open to facilitate topical therapy. A 13-year-old, female long-nosed snake, weighing 66.0 g Cytology of the purulent material showed degenerative and in moderately thin body condition, presented for evalu- white blood cells and low numbers of both Gram-positive ation of lethargy and inappetence of several weeks duration. and Gram-negative bacteria. A culture of the site failed to The snake had been at the current facility for 11 years and produce aerobic or anaerobic bacterial growth. Ceftazidime was housed in a 26 L painted concrete walled enclosure with (Fortaz®, GlaxoSmithKline, Research Triangle Park, NC) sand and gravel substrate. The only recent clinical history therapy was initiated at 20 mg/kg IM every 72 hours for was that the snake was treated for mild stomatitis 2 months five doses, and over the next week the snake was assist-fed earlier, which had fully resolved with supportive care that a half to a full pinkie mouse every few days. The animal included antibiotic and fluid therapy. On physical examina- began to regain body condition and became more alert tion the animal was thin, lethargic, and had a diminished and responsive, so no further treatment was administered righting reflex. Blood was drawn from the ventral tail vein and the snake was returned to the exhibit for continued for analysis. Reference values for this species are lacking, monitoring and supportive care. so observed values were compared to mean (PSD) values Three months after treatment was discontinued, the from the gopher snake (Pituophis catenifer) (Mader et al., keepers reported that despite increasing the variety of the 1985; Carpenter et al., 2001). The hemogram showed mild diet to include pinkies, crickets, and small frozen/thawed anemia (HCT=20%; 29P7%) and leukopenia (WBC= lizards, the snake remained anorexic. The snake was 1.7x103 cells/µl; 6.2P3.9x103/µl). A plasma chemistry pro- observed pushing the foodstuff around the cage, but would file was not performed at this time due to inadequate sample not consume them. On physical examination the animal

58 Journal of Herpetological Medicine and Surgery Volume 20, No. 2-3, 2010 DISCUSSION

Cholesterol granulomas, also called xanthomas, have been identified in several species, including humans, dogs, cats, horses, birds, frogs, lizards, and snakes, and have been observed in many tissues including the oral cavity, conjunc- tiva, middle ear, trachea, fat pads, visceral surfaces, skin, and brain (Ryan and Whitney, 1980; Carpenter et al., 1986; Jackson et al., 1994; Hoekstra et al., 1998; Garner et al, 1999; Gyimesi et al, 2002; Monks et al , 2006; Balme et al., 2009; Souza et al, 2009; Kummrow et al., 2010). The nodules usually contain lipid and or cholesterol clefts surrounded by vacuolated macrophages and multinucleated giant cells (Sullivan, 1985; Garner et al., 1999; Kummrow

et al., 2010). The mass in this case was composed predomi- Downloaded from http://meridian.allenpress.com/jhms/article-pdf/20/2-3/58/2210923/1529-9651-20_2_58.pdf by guest on 28 September 2021 nately of cholesterol clefts with minimal inflammatory cell reaction and few multinucleated giant cells. In horses, cholesterol granulomas are often subclinical Figure 1. Within the lateral ventricle (LV) there is a large, and are found as incidental findings at necropsy. They are discrete expansile mass of cholesterol clefts and macrophages most commonly found associated with the fourth ventricle, (cholesterol granuloma, CG) that compresses severely attenu- but may also affect the lateral ventricles. When involving ated overlying dorsal cortex (DC). The lateral ventricle is mildly the lateral ventricles, these granulomas can grow quite large expanded and there is compression and disorganization of the and can cause secondary hydrocephalus and ventricular underlying ventral nucleus sphericus (NS). wall atrophy (Sullivan, 1985). These structural changes may lead to neurological dysfunction including depression, reluctance to move, and abnormal gait (Jackson et al., 1994). was moderately to severely underweight (56.9 g), and mild In a case of cerebral cholesterol granuloma in a meerkat stomatitis had developed on the upper right gingiva. Assisted (Suricata suricatta), there were significant neurological defi- feeding with Hill’s a/d, subcutaneous fluids, and ceftazidime cits observed including depression and bilateral forelimb were reinitiated at the previous doses, and a complete blood paralysis (Sladky et al., 2000). Neurological abnormalities count and plasma chemistry were performed. The animal in five geckos with cerebral xanthomas included various = P was moderately anemic (18%, reference range 29 7%) degrees of hydrocephalus, stargazing, torticollis, dorsal and mildly hyponatremic (134 mmol/L, 134 mEq/L; refer- = P recumbency, and inappetance (Garner et al., 1999). In the ence range 171 1.6), hypokalemic (2.2 mmol/L, 2.2 mEq/L; current case, the long-nosed snake showed inappetence and reference range=6.6P0.6), hypercalcemic (5.9 mmol/L, diminished righting reflex that were attributed to neurologi- 23.5 mg/dl; reference range=14.4P1.9), and hyperphos- cal dysfunction secondary to the cerebral xanthoma. The phatemic (2.8 mmol/L, 8.7 mg/dl; reference range=4.1P0.6) snake was also observed pushing food around its enclosure as compared with reported blood values for other snakes (Mader et al., 1985; Carpenter et al., 2001). The snake without ingesting it. This behavior may also have been due was also moderately to markedly hypoproteinemic (26 g/L, to a neurologic derangement in either targeting the food 2.6 g/dl, reference range=4.3P0.3) and hypoalbuminemic items or prehending them. Neurologic disease in snakes can (8.0 g/L, 0.8 g/dl, reference range=1.9P0.1). Because of the be characterized as bacterial, fungal, viral, parasitic, toxic, animal’s failure to respond to medical management and nutritional, traumatic, or neoplastic (Done, 2006). This case blood work supportive of renal compromise, euthanasia demonstrates that cerebral xanthomas are another potential was elected. The snake was anesthetized with isoflurane cause of neurological disease in snakes and should be in an anesthetic chamber, and 39 mg pentobarbital was included in the differentials. administered intracardiac. Xanthomatous lesions have been associated with On gross examination the snake was emaciated with hypercholesterolemia and hyperlipidemia in other species, almost nonexistent fat bodies. The kidneys appeared small suggesting a potential link to diet, genetics, or abnormal and contained urate accumulations on the serosal surface. lipid metabolism (Carpenter et al., 1986; Russell et al., 1990; The liver appeared reduced in size, and the gall bladder Hoekstra et al., 1998; Sladky et al., 2000; Gyimesi et al., was markedly distended. On histopathological evaluation 2002; Fluehmann et al., 2006). In an evaluation of five of transverse sections of the brain, a focal, nonencapsulated, geckos, hypercholesterolemia was noted in the one lizard well-demarcated mass composed of numerous large, acicu- that had a serum chemistry profile performed (Garner et al., lar (cholesterol) clefts surrounded by epithelioid and occa- 1999). However, similar to the previous cases that suggested sional multinucleated macrophages with a few scattered an association with hypercholesterolemia, all of the geckos heterophils was found within a mildly expanded lateral evaluated had systemic xanthomatosis and not an isolated ventricle (mild hydrocephalus) (Fig. 1). The overlying dorsal mass. In the current case, the snake was emaciated and had cortex was markedly compressed with almost full thickness limited fat stores at necropsy, and only a single xanthoma loss of neuropil, and the ventral nucleus sphericus was was found in the lateral ventricle of the brain. The snake did mildly compressed with distortion of the underlying neural have moderate hepatic lipidosis at necropsy, which could cell layer. Additional findings included mild, multifocal indicate a degree of metabolic derangement. The plasma renal visceral gout; diffuse, mild to moderate glomerular cholesterol and lipid levels were not determined as they were fibrosis; and diffuse, moderate hepatic lipidosis. not included in the routine plasma profile performed at this

Volume 20, No. 2-3, 2010 Journal of Herpetological Medicine and Surgery 59 facility. In addition, no banked plasma was available for similar to human verruciform xanthoma. J Vet Diagn Invest, a retrospective determination of cholesterol levels due to 21(1):124–128. the small nature of this animal and the inability to collect Carpenter JL, Bachrach A Jr, Albert DM, Vainisi SJ, enough for banking. This animal was also the only long- Goldstein MA. 1986. Xanthomatous keratitis, disseminated nosed snake at the facility, so the plasma cholesterol and xanthomatosis, and atherosclerosis in Cuban tree frogs. Vet lipid levels could not be determined for other long-nosed Path, 23(3):337–339. snakes under similar husbandry parameters. Future studies Carpenter JW, Mashima TY, Rupiper DJ. 2001. Reptiles. are needed to evaluate lipid profiles and diet in long-nosed In Carpenter JW, Mashima TY, Rupiper DJ (eds): Exotic snakes and their potential associations with xanthoma Animal Formulary. 2nd ed. Saunders, St. Louis, MO:39– formation. 105. In horses, xanthomas tend to be single, isolated masses in Done L. 2006. Neurologic disorders. In Mader DR (ed): the third or fourth ventricles of the brain, with no known Reptile Medicine and Surgery. 2nd ed. Saunders/Elsevier, association with hypercholesterolemia (Sullivan, 1985). St. Louis, MO:852–857. These lesions are instead believed to be secondary to chronic, Fliegner RA, Jubb KVF, Lording PM. 2007. Cholesterol intermittent congestion, edema, and hemorrhage in the granuloma associated with otitis media and destruction of Downloaded from http://meridian.allenpress.com/jhms/article-pdf/20/2-3/58/2210923/1529-9651-20_2_58.pdf by guest on 28 September 2021 choroid plexus (Jackson et al., 1994; Sullivan, 1985). Cho- the tympanic bulla in a dog. Vet Path, 44(4):547–549. lesterol released from damaged cell membranes and lysed Fluehmann G, Konar M, Jaggy A, Nicolier A, Vandevelde M. red blood cells accumulate, causing additional inflamma- 2006. Cerebral cholesterol granuloma in a cat. J Vet Intern tion and the development of a granuloma (Sullivan, 1985). Med, 20(5):1241–1244. In the current case, there was no evidence of hemorrhage, Garner MM, Lung NP, Murray S. 1999. Xanthomatosis in and only low numbers of inflammatory cells were identified geckos: five cases. J Zoo Wildl Med, 30(3):443–447. on histopathology. Gyimesi ZS, Stedman NL, Crossett VR. 2002. Cholesterol The majority of xanthoma cases in nondomestic animals granulomas in a great plated lizard, Gerrhosaurus major. have been observed in females, which supports a sex predi- J Herp Med Surg, 12(3):36–39. lection and possible association with folliculogenesis for Hoekstra KA, Nichols CR, Garnett ME, Godin DV, Cheng this disease process (Russell et al., 1990; Garner et al., 1999; KM. 1998. Dietary cholesterol-induced xanthomatosis in et al et al et al Gyimesi ., 2002; Monks ., 2006; Souza ., 2009; atherosclerosis-susceptible Japanese quail (Cotunix japonica). Kummrow et al., 2010). In the current case, the snake was J Comp Pathol, 119(4):419–427. an adult female; however, a true relationship between sex Jackson CA, deLahunta A, Dykes NL, Divers TJ. 1994. and xanthoma formation cannot be established with only a Neurological manifestation of cholesterinic granulomas in single case. Further research is needed to establish any pos- three horses. Vet Rec, 135(10):228–230. sible link between xanthoma formation and the reproduc- tive cycle and follicular development. Kummrow MS, Berkvens CN, Paré JA, Smith DA. 2010. The cause of the bilateral facial swellings observed in Cerebral xanthomatosis in three green water dragons this snake shortly after initial presentation is uncertain. It (Physignathus cocincinus). J Zoo Wildl Med, 41(1):128–132. is possible that the swellings were due to an ascending Mader DR, Horvath CC, Paul-Murphy J. 1985. The hematocrit infection linked to the previous episode of stomatitis and and serum profile of the gopher snake (Pituophis melanoleucus the overall debilitated state of this animal; however, the catenifer). J Zoo Wildl Med, 16:139–140. stomatitis appeared to have fully resolved prior to the Monks DJ, Zsivanovits HP, Cooper JE, Forbes NA. 2006. development of the swellings. Even though the culture Successful treatment of tracheal xanthogranulomatosis in a was negative, the bacteria observed on cytology and the red-tailed hawk (Bueto jamaicensis) by tracheal resection and positive response to antibiotic treatment support a bacterial anastomosis. J Av Med Surg, 20(4):247–252. etiology. Romanucci M, Malatesta D, Guardiani P, Frescura P, Della Although xanthomas may be subclinical in horses, they Salda L. 2008. Xanthogranulomatous inflammation of the often cause significant neurological disease in other species. small bowel in a dog. Vet Pathol, 45(2):207–211. This report described a case of cerebral xanthomatosis in Russell WC, Edwards DL, Stair EL, Hubner DC. 1990. Corneal an adult female long-nosed snake that presented for inap- lipidosis, disseminated xanthomatosis, and hypercholesterol- petence and a diminished righting reflex. The findings give emia in Cuban tree frogs (Osteopilus septentrionalis). J Zoo another differential for neurological disease in snakes. It is Wildl Med, 21(1):99–104. therefore recommended to evaluate cholesterol and lipid Ryan MJ, Whitney GD. 1980. Xanthoma in a gopher snake. levels in snakes that present for neurological disease. Vet Med/Sm Anim Clinician, 75(3):503–507. Sladky K, Dalldorf FG, Steinberg H, Wright JF, Loomis MR. Acknowledgments: The authors thank the keepers at the 2000. Cholesterol granulomas in three meerkats (Suricata North Carolina Zoological Park for their hard work and suricatta). Vet Pathol, 37:684–686. dedication to this and every animal under their care. Souza MJ, Johnstone-McLean NS, Ward D, Newkirk K. 2009. Conjunctival xanthoma in a blue and gold maxaw LITERATURE CITED (Ara ararauna). Vet Opth, 12(1):53–55. Sullivan ND. 1985. The nervous system. In Jubb KVF, Kennedy Balme E, Thuilliez C, Lejeune T, Chatueau-Escoffier L, Bernex PC, Palmer N (eds): Pathology of Domestic Animals. 3rd ed. F. 2009. Multiple atypical mucosal xanthomas in a dog Academic Press, Inc., San Diego, CA:247–249.

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