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Exotic Geriatrics Peter G. Fisher, DVM, DABVP (Exotic Companion Mammal) Care Veterinary Hospital, Virginia Beach, VA, USA

TAKING CARE OF THE OLDER EXOTIC MAMMAL The average life span for the domestic ferret is six to eight years, the domestic seven to ten years, the three to four years and for the rat two to three years. consider the ferret and rabbit to be middle-aged at three years and geriatric at five or more years of age, while a two year old rat is already entering its senior years. Ferrets as old as 10 years, as old as 13 years and guinea pigs as old as 6–7 years of age are no longer considered unusual. With aging comes the need for more hands on care and observation. As in any geriatric species, the exotic mammal will spend a good amount of its time resting and sleeping. As a result, geriatric pet owners should be encouraged to take time to observe their older pet and make note of changes in behavior, appetite or body functions. They should periodically run their hands over their pet to assure that they aren’t missing subtle changes in muscle mass, and body condition. that lose control of urination or defecation need to be housed on substrate that allows urine to soak away from the body thus avoiding scald. As well, perineal areas may need to be clipped/shaved periodically to discourage soiling. For those seniors with neurologic or orthopedic problems; rolled towels or stuffed animals can be placed around the pet to allow them to remain sternal and comfortable. All exotic should have a yearly physical examination. Starting at the age of three, annual blood work may help the detect changes in function of the liver, pancreas, kidneys and other organs. After the age of five, a veterinary examination, including blood profile and urine exam, should be scheduled every 6 months along with annual radiographs to monitor changes in size and shape of the heart and other organs. The focus of the wellness exams is to ensure the pet’s health, develop a plan for preventing future health problems and follow up on any previous health issues

NUTRITION In general, specific geriatric diets are lacking for the exotic mammal and those available are based on modifications made for senior dogs and . Many senior diets advocate lower levels of protein, sodium, phosphorus to help diminish the side effects of nutritional intake on renal and cardiac health in particular. For herbivores both senior diets and supplements designed with the aging patient in mind are now available. Ferrets require a diet high in protein and fat. As a guideline, look for foods with no less than 20% fat and 40% protein. When checking the ingredient list, the first three contents listed should be proteins such as chicken, eggs or poultry by-products. The future of ferret nutrition will be towards even higher levels of protein as diets try to mimic what a non-domesticated ferret would eat in the wild. Some veterinarians and ferret owners advocate whole prey foods such as mice, rats or chicks.

SPECIMEN COLLECTION For blood collection the author prefers the vena cava or other large veins accessed at the sternal notch in ferrets, guinea pigs and hedgehogs, the lateral saphenous vein in rabbits and rats. Alternatively a 25 ga needle placed in the lateral saphenous vein followed by capillary tube collection works well in smaller species. Depending on species and animal temperament sedation or is often preferred to avoid potential accidental trauma. Newer chemistry analyzers or outside laboratories specializing in exotic species allow for serum chemistry and CBC results on minimal (100 uL) volumes of blood. It is estimated that 10% of blood volume (55–70 ml/kg bw) can be safely taken for blood sampling every 3 to 4 weeks. Cystocentesis via a ventral midline approach is the preferred method of urine collection. Due to the thin bladder wall of exotic mammals, patient sedation and use of a 23- gauge, 1-inch needle in rabbits and ferrets and a 25-gauge needle in smaller species is preferred for cystocentesis urine collection in order to avoid inadvertent bladder wall laceration and subsequent urine leakage. Three to six ml of urine provides enough volume for a thorough urinalysis. Manual expression and free-catch samples can be used but are less than ideal due to vaginal, preputial or environmental contamination.

MODIFICATION OF THERAPEUTICS In small animal medicine drug dosages may be modified in the geriatric patient based on body and muscle condition scores as well as assessed renal and hepatic function. Although specific recommendations for geriatric exotic mammals are unavailable, drug dosage modification should be considered, especially when organ disease has been positively identified.

EUTHANASIA Determining the appropriate time for euthanasia is difficult in many circumstances. The author usually discusses quality of life issues with pet owners and lays down some criteria for the client to look for in their aged pet. Lack of appetite, inability to move well, and a lack of response to owner interaction may all be used. When it is time for euthanasia many owners want to be present. The author prefers to administer injectable anesthetics such as a combination of midazolam (0.3–0.5 mg/kg IM) and butorphanol (0.2–0.5 mg/kg IM) and encourages owners to hold their until sedated. Inhalant gas anesthesia is added as needed and euthanasia solution administered intravenously. The following will summarize some common clinical conditions seen in the older exotic mammal patient

THE FERRET Adrenal Disease Adrenal-associated endocrinopathy (hyperadrenocorticism) can be caused either by adrenal hyperplasia or neoplasia (most commonly cortical adenoma or adenocarcinoma) and is most commonly seen in neutered ferrets older than 3 years of age. The diagnosis of adrenal disease in ferrets is frequently straightforward and can often be made on history and clinical signs alone. Clinical signs include symmetrical bilateral alopecia, recurrence of sexual behavior after , and pruritus. In male ferrets dysuria and/or anuria may be seen due to development of peri-prostatic cysts or abscesses causing urethral obstruction, whereas the female (neutered) may show vulvar swelling and occasional mammary gland development. Recurrent bacterial cystitis may be seen in any ferret with hyperadrenocorticism. Ultrasonography is extremely useful in establishing the size and morphology of the adrenal glands and offers the benefit of determining if right, left or both adrenals are affected.1 In the ferret hyperadrenocorticism primarily results in elevations in sex steroids.2 The University of Tennessee provides an assay that measures plasma concentrations of androstenedione, 17 α-hydroxyprogesterone and estradiol. Complete blood counts and serum chemistries are generally within normal limits, with the exception of long standing cases in which anemia and thrombocytopenia may be seen. Treatment Options Surgery. May result in definitive treatment for adrenal disease in ferrets if the affected adrenal tissue can be removed in its entirety. This is more easily accomplished when the left adrenal gland alone is affected. Due to intimate association of the right adrenal gland with the posterior vena cava it may be impossible to remove the right adrenal gland in its entirety without vena caval resection. Medical. The most effective drugs currently used for the hormonal treatment of hyperadrenocorticism are the GnRH-agonists leuprolide acetate and deslorelin. Depot GnRH-agonists interrupt the normal pulsatile stimulation of, and thus desensitize, the GnRH receptors. This indirectly down-regulates the secretion of gonadotropins LH and FSH and disrupts the stimulation of adrenal cortex LH-receptors subsequently blocking adrenal sex steroidogenesis. Note that these drugs do not suppress adrenal growth, but rather block the clinical signs. Insulinoma - Ferret Insulin-secreting pancreatic islet cell tumors are among the most common neoplastic diseases affecting ferrets. The disease affects both male and female ferrets between the ages of 2 and 8 years, but is most commonly diagnosed in ferrets 4 to 5 years of age. On histopathologic examination beta cell carcinoma is most often found, sometimes in combination with beta cell adenoma or hyperplasia. Metastasis is uncommon. Neuroglucopenic signs result from the effect of low blood glucose on the central nervous system and include mental dullness confusion, seizures and coma. Adrenergic manifestations occur when blood glucose levels drop rapidly, resulting in catecholamine release and increased sympathetic tone and include tachycardia, hypothermia, tremors, nervousness and irritability. The definitive diagnosis of insulinoma depends on the histopathologic examination of pancreatic tissue. However, in most ferrets a tentative diagnosis of insulinoma is made by demonstration of hypoglycemia in association with history and clinical signs. The serum glucose concentration required for diagnosis of hypoglycemia in the ferret is a matter of some debate. However, most clinicians agree that a 4-hour fasting glucose concentration of less than 60 mg/dl is very suggestive of insulinoma.3 The reference range for normal fasting blood glucose concentrations in ferrets is 90 to 125 mg/dl.4 Long term treatment options include dietary, medical and/or surgical management, and many ferrets require a combination of all three to successfully control the clinical signs of hypoglycemia associated with insulinoma. Prednisone and diazoxide (Proglycem, Baker Norton Pharmaceuticals, Inc. Miami, FL), a benzotriadizine diuretic, are used singly or in combination depending on the severity of clinical signs. Diazoxide at an initial dose of 10 mg/kg divided two times daily is instituted and can gradually be increased to a maximum of 60 mg/kg divided two times daily. If clinical signs are not controlled with diazoxide alone prednisolone may be added to the regimen with doses ranging from 0.5 to 2 mg/kg every 12 hours. Begin at the lowest dose and increase as needed, to control clinical signs and maintain appropriate blood glucose levels. Regardless of which treatment option is instituted, owners need to be aware that the disease is controlled, not cured, and that blood glucose concentrations need to be evaluated on a regular basis. Malignant Lymphoma Malignant lymphoma is a common diagnosis in pet ferrets. In a retrospective study of 574 ferrets with neoplastic disease, Li, et al found that 15.2% were hemolymphatic in origin and of these 78% were malignant lymphomas.5 Clinical signs of malignant lymphoma vary with the location of the disease as well as the age of the animal. Lymphoma can affect numerous tissues with the visceral and peripheral lymph nodes, spleen, liver, mediastinum, bone marrow, lung, intestine, and kidney being most commonly affected. Less frequently involved are the , pancreas, nervous system and orbit. Clinical features of lymphomas in ferrets have been linked with animal age and tumor location, both of which are useful for evaluating diagnostic and therapeutic options. Diagnosis of lymphoma involves biopsy of affected lymph nodes or visceral organs with direct visualization of neoplastic cells and evaluation of cellular morphology. Treatment choices for ferret lymphoma include surgery, chemotherapy, radiation, alternative or combination therapy involving these modalities. Surgery may be considered as an alternative or an adjunct to chemotherapy in those ferrets affected with a solitary abdominal mass or cutaneous lesion. In ferrets with splenomegaly in which the spleen occupies more than 50% of the abdominal cavity, performing a splenectomy may augment treatment and patient comfort.

THE RABBIT Perineal Soiling and Dermatitis Rabbits often present with matted and soiled perineal fur with secondary dermatitis. Causes include inappropriate diet and subsequent soft stools or diarrhea, urine leakage as the result of or excessive crystalluria (bladder sludge syndrome), environmental factors resulting in behavioral urine retention, and decreased ability to groom due to obesity or pain. A work up includes using case history, physical exam and imaging to determine underlying cause. Management includes ruling out underlying infectious cystitis via bacterial culture and sensitivity of an uncontaminated urine sample preferably obtained via cystocentesis. Rabbit Neurological Disease Signs of neurologic disease in rabbits include behavioral changes, head tilt (labyrinthine or wry neck), nystagmus, tremors, paresis, paralysis, and seizures. Head tilt, usually an indication of vestibular dysfunction, can be central (cerebellum, brain stem) or peripheral (inner ), and was the most common clinical sign noted in a retrospective study of rabbits with neurologic disease.6 Causes include bacterial otitis interna and infection with . A diagnostic and therapeutic plan for head tilt includes: Diagnosis of otitis media/interna is based on clinical signs, aural exam, and imaging, including skull radiography and CT or MRI scanning where available. Bacterial culture and sensitivity of deep aural or nasal swabs taken under anesthesia are indicated when physical exam supports infection. Endoscopic exam performed under general anesthesia aids in visualization of the distal ear canal and tympanic membrane. Antimicrobial therapy, preferably based on results of a bacterial culture and their ability to penetrate the CNS are recommended. In addition to antibiotic therapy, affected rabbits often benefit from nutritional supplementation, environmental support to minimize the rolling and severe ataxia associated with this disease Encephalitzoon cuniculi is a microsporidium, obligate intracellular protozoan parasite. The most commonly recognized neurological sign in rabbits infected with E cuniculi is vestibular disease. Clinical means of diagnosing definitive antemortem encephalitozoonosis are limited. However, since E cuniculi infection is persistent, continue to be produced and as a general rule the validity of assays for the detection of E. cuniculi compares favorably with histology in rabbits.7,8,9 In the absence of controlled studies it is difficult to assess the efficacy of therapeutic agents against E cuniculi as latent occur and some clinical cases may improve spontaneously without treatment, presumably as a result of the host's immune response.10 Several benzimidazole derivatives including albendazole (30 mg/kg POq24h for 30 days)11, oxibendazole (30 mg/kg PO q24h for 7–14 days, then 15 mg/kg PO q24h for 30–60 days)111, and fenbendazole (20 mg/kg PO daily for 30 days)12 have been used to treat presumptive E cuniculi infections in rabbits based on their anti-inflammatory actions and their in-vitro anti-protozoal activity including bioenergetic disruptions of membranes and microtubular (tubulin) inhibition of E cuniculi13,14. Spondylosis and Osteoarthritis Age-related osteoarthritis (degenerative joint disease) and spondylosis (degenerative spinal defects) are now more commonly encountered as improved husbandry and nutrition have extended the lives of pet rabbits. Owners of affected rabbits typically report an abnormal gait, lameness or inability to hop. The signs of musculoskeletal pain may be more subtle with the quiet and immobile nature of affected rabbits being attributed to age. Still other rabbits demonstrate lack of proper grooming due to a reluctance or inability to reach the caudal body and perineum resulting in an unkempt coat and/or perineal soiling and dermatitis. Radiographs of joints with degenerative disease may show capsular distension, osteophytosis, narrowing joint spaces or surrounding soft tissue thickening or mineralization. Spondylosis is identified radiographically by spinal exostoses, degenerative changes and spinal defects such as kyphosis, lordosis or scoliosis. Abduction or splaying of the front limbs may also be seen in sedentary senior rabbits. This may occur as the result of inactivity and resulting muscle wasting so that over time the front limbs are not adducted under the body and splay out. Obesity and osteoarthritis probably contribute to this condition and once started is hard to reverse. Rabbits with pain and due to degenerative musculoskeletal conditions often show remarkable improvement when treated with analgesics such as non-steroidal antiinflammatory drugs or a centrally acting opiate agonist such as tramadol. Perineal scald treatment involves long-term hygiene maintenance with cleansing of affected areas, as well as topical and systemic to control infection.

THE GUINEA PIG Hyperthyroidism Hyperthyroidism is the result of an overactive thyroid gland that is producing excessive hormone which increases the metabolic rate and calorie burning in the affected animal’s body. Affected pigs show an increased appetite, many times a voracious one, and a concurrent in spite of increased food intake.15 Other signs noted in hyperthyroid pigs include hyperactivity, increased thirst and urination, soft stools and a rapid heart rate. Nuclear scintigraphy of the thyroid glands has been performed in order to give a reliable idea of organ function and make a definitive diagnosis.15 Treatment involves daily oral anti-thyroid medication or radioactive treatment with I-131, both similar options used in cats with the same disease.15 In one study of 19 pigs pathologic aspects of thyroid tumors were discussed with 8 guinea pigs showing benign thyroid hyperplasia (increased cell growth) and 11 pigs demonstrating malignant thyroid adenocarcinoma.16 Of note, is that many of these thyroid pathologic findings were incidental; these pigs were being necropsied for other reasons and the thyroid disease was found as a secondary finding. The authors theorized that perhaps this disease is more common than we realize. Mammary Gland Tumors in Guinea pigs A retrospective study of pigs with mammary tumors found that males and females were equally represented, but that those tumors found in males were more likely to be malignant vs. benign.17 Benign hyperplasia was the more likely diagnosis in those female pigs with mammary gland enlargement.17 Ovarian cysts in the Guinea Pig Ovarian cysts in guinea pigs are frequently but not always derived from the rete ovarii. Other possible sources of ovarian cysts are periovarian structures, overgrown Graafian follicles, neoplasia, and infection.18 Clinical signs classically associated with ovarian cysts (including bilateral, non-pruritic alopecia of the flanks) are likely the result of excess steroid production by follicular cysts. Rete cysts are not believed to be steroidogenic.18 The most sensitive diagnostic test is abdominal ultrasonography, while the most specific is histopathologic analysis of the cysts. Hematology, serum biochemistry, serum hormone levels, radiography, and fluid cytology are neither sensitive nor specific. Ovariohysterectomy is the definitive treatment for all ovarian cysts. Ovariectomy without hysterectomy is not recommended, as ovarian cysts have been associated with several uterine diseases.18

RODENTS Rodent Respiratory Disease Complex Rodent Respiratory Disease Complex is seen commonly in rats, hamsters and guinea pigs. Affected rodents show signs of repeated sneezing, nasal discharge, brown to red eye discharge and diminished appetite. Affected rodents may also make a “chattering’ noise because of nasal congestion. Sometimes the infection goes to the inner ear, affecting the balance center and resulting in a head tilt. Rodent respiratory disease is called a “complex” because it may be caused by a variety of infectious agents with environmental and nutritional issues also playing a role. To confuse matters more, many of the infectious organisms involved in Rodent Respiratory Disease Complex can be subclinical. When a new carrier or subclinical pet is introduced to a household with preexisting pet rodents the carrier may shed infectious agents and spread disease among susceptible members of the pet colony. Subclinical cases can also become clinical as a result of secondary environmental stresses particularly poor cage design/ventilation and an inadequate diet. Rodent Respiratory Disease Complex may be caused by a combination of: Viral Diseases: Sendai , Coronavirus (Sialodacryoadenitis virus (SDAV), Adenovirus ( guinea pig). Bacterial: Murine Respiratory Mycoplasmosis (MRM) Mycoplasma pulmonis is the primary pathogen in this disease.19 and is very common in rats. Cilia- Associated Respiratory (CAR) Bacillus, Bordetella, Corynebacterium kutscheri, Streptoccocus pneumonia, and Streptoccocus zooepidemicus (common in guinea pig and causes lymph node abscesses). Environmental/ Nutritional: Rodents kept in a soiled, poorly ventilated cage and crowded conditions may result in elevated urine ammonia levels affecting cage air quality, will be more prone Rodent Respiratory Disease Complex. Treatment of Rodent Respiratory Disease Complex includes antibiotic therapy and improving diet and cage care. In spite of the best care and nutrition it is not uncommon for this disease to recur. It is a common disease entity in the geriatric rat and in spite of varying treatment regimens, including varying systemic antibiotics, (enrofloxacin, 10 mg/kg PO q12h, doxycycline, 5 mg/kg PO q12h, or azithromycin (20 mg/kg q24h, 7 days).20 Rat Mammary Tumors Anatomically, the mammary gland tissue in the rat extends on either side of the ventral midline from the axillary to the inguinal regions, and mammary gland tumors may occur anywhere in this area.21 Mammary gland neoplasms are probably the most common spontaneous tumors found in the rat. Adenomas and cystadenomas are uncommon, and carcinomas of varying types (adenocarcinomas, papillary carcinoma, comedocarcinomas, and squamous cell carcinoma) are said to comprise less than 10% of all spontaneous mammary gland tumors in the rat.22 Mammary fibroadenoma represents approximately 85–90% of all mammary tumors in the rat. These neoplasms are most common in older rats, though may also occur in young females and males. Overall, the biological behavior is benign; the neoplasms can become very large, ulcerate, and infiltrate locally, but they rarely metastasize. For this reason, surgical excision is generally curative, but additional fibroadenomas are likely to develop in remaining mammary tissue. Rat Pituitary Adenoma Pituitary adenomas are a common clinical and necropsy finding in geriatric rats.23-25 Clinically, affected rats show signs of central vestibular disease, characterized by a wide-based stance, head tilt, proprioceptive deficits with ataxia, knuckling and stumbling.23 Blindness, typical of optic nerve compression, hypodipsia, and an aggressive behavioral change have also been reported.26 Diagnosis is based on patient signalment and clinical signs and can be confirmed via MRI. Due to a reduction of hypothalamic activity in geriatric rats prolactin secretion is increased.26 Prolactin secretion is unique in lactotrophic pituitary adenomas as compared with secretion of other pituitary hormones in that there are no specific prolactin hypophysiotropic hormones or releasing factors, but rather, prolactin secretion is inhibited by dopamine.26 This escape from hypothalamic inhibitory control leads to lactotroph hyperplasia of the pituitary gland and a high rate of prolactin-producing pituitary adenomas in geriatric rats.26,27 Mayer, et al26 described a treatment protocol for a rat pituitary adenoma, confirmed by MRI, using cabergoline, a dopamine receptor agonist that increases hypothalamic dopamine activity. Cabergoline (0.6 mg/kg q 72 h PO indefinitely) resulted in resolution of clinical signs and a substantial decrease in size of the pituitary mass on a 2 month follow-up MRI.

REFERENCES 1. Besso JG, Tidwell AS, et al. Retrospective review of the ultrasonographic features of adrenal lesions in 21 ferrets. Vet Radiol Ultrasound. 2000;41(4):345–352.

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