Biology and Medicine of the Ferret

Exotic Pet Medicine

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Biology and Medicine of the Ferret

Cynthia L. Besch-Williford, D.V.M., Ph.D .*

The ferret, Mustela putorius furo, is the domesticated cousin, and perhaps a descendant, of the European fitch or polecat, Mustela putorius. The ferret has been in man's custody for centuries, which proves the assertion that the ferret is a wild animal to be erroneous. European pictorial records dating back to 400 B.C. show a weasel-like ferret that was used as a vermin exterminator. Ferrets became popular in sport hunting, and they were such efficient rabbit hunters that they were imported to New Zealand to help control the expanding rabbit population. The ferret was transported to the United States around the end of the 19th century and found a niche here, as in Europe, as a hunting companion. The commercial production of ferrets on a large scale in the 1930s resulted from a demand by the scientific community to provide a model for vaccine testing and biomedical research in the fields of reproductive physiology, virology, toxicology, and cardiovascular pharmacology. Over the last 5 years, however, the ferret has experienced increasing popularity as a household pet, with an estimated 6000 ferrets sold annually. 2 The current ferret fad has faced mixed reactions from the pet-owning community and the veterinary profession. There is a faction of enthusiastic owners who believe they have found a pet that seems to have the desirable characteristics ofboth cats and dogs and that weighs less than 6lb. Individuals who enjoy raising exotic pets discover that ferrets are unusual and relatively low-maintenance animals. On the other hand, a mid-1986 Ann Landers column highlighted the negative aspects of keeping ferrets as pets when readers responded to the report of the infant child whose face was chewed by the family's ferret. The Council on Public Health and Regulatory Veterinary Medicine, a reporting arm of the American Veterinary Medical Association (AVMA), noted that five children have been attacked and severely injured by pet ferrets since 1981. The AVMA has issued a cautionary statement that ferrets may not make suitable pets because they may injure small children. 2 The state of California does not allow ferrets as well as other exotic animals as house pets. In the midst of the controversy over including ferrets in the companion animal kingdom, veterinarians are vaccinating and med*Assistant Professor of Veterinary Pathology, Research Animal Diagnostic and Investigative Laboratory, University of Missouri College of Veterinary Medicine, Columbia, Missouri

Veterinary Clinics of North America: Small Animal Practice-Vol..l1, No.5, September 1987

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icating increasing numbers of ferrets, detailing their behavior, recognizing the symptoms of infectious and noninfectious diseases, and instituting therapy, often with reservation because the efficacy of many chemotherapeutic agents in ferrets is not known or published. Knowledge of the biology and medicine of ferrets will increase over time as ferret owners, practicing veterinarians, and researchers share their observations. Time will determine whether ferrets will be accepted as adequate pets. This article was compiled from the contributions of ferret fanciers and many practitioners. It is intended to be a guide for those unfamiliar with the husbandry and diseases of ferrets and a foundation on which one can base decisions on behavioral and medical therapies. BIOLOGY A ferret is a small carnivore that has a long, supple body, short legs, a long neck, a small triangular head, little cup-shaped ears, and a lengthy tail. The color of the thick fur is used to identify the variety of ferret. A fitch or sable color is the wild-type tan body with black guard hairs, black mask, and points on the feet, body, and tail. The recessive coat colors of albino (or English), Siamese (brown guard hairs and points), silver mitt (sable with white feet and chest patch), and Siamese-silver mitt (Siamese with white feet and chest patch) represent variations in the absence or dilution of the fitch coat genes. Seasonal pelt cycling with summer shedding and production of a winter coat occurs in ferrets as it does in mink. There is sexual dimorphism in body weight and size, with the male ferret averaging between 2 to 6 lb (1000 to 2700 gm), which is about twice the size of a female ferret (1 to 3 lb, or 450 to 900 gm). 98 The seasonal fluctuation in body mass that can account for up to 40 per cent of the body weight is due to the accumulation of subcutaneous fat in the winter and its subsequent depletion in the spring. 87 Anatomy Ferrets have a few anatomic features that are unique when compared with other domestic carnivores. The permanent dental formula is 2 (I 3/3, C 111, P 3/4, M 112). Deciduous teeth begin to erupt at 14 days of age, and the permanent canines begin to show at 47 to 52 days of age. 87 Supernumerary incisors are commonly found in the permanent dentition. 8 Flattening of cheek teeth and deposition of calculus occur with age. 7 Ferrets lack a cecum, appendix, and teniae coli. There is no gross morphologic distinction between the ileum and the colon. The large intestine appears .as a dilated tube that begins at the flexure of the small intestine at the lower end of the spleen and continues for about 10 em to the rectum. 75 The ileocolic valve consists of a band of connective tissue in the tunica muscularis that appears to disrupt the contractile activity of the ileum at the level of the colon. 14 Paired anal sacs open via ducts at the 4 and 8 o'clock positions at the anus. The neck of the sac and 3 to 4 mm of the duct are surrounded by well-developed glandular tissue comprised of sebaceous glands covered by apocrine glands. Fibrous tissue and muscle of the external anal sphincter penetrate the glandular

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complex, and dissection along the wall of the sac during routine surgical removal often results in destruction or inadequate removal of the apocrine glands. 26 The carotid arteries of ferrets arise from a single ascending artery that branches from the descending aorta at the level where the left carotid artery branches in dogs and other species. This singular artery is referred to as inominate artery I. The left carotid artery and inominate artery II (from which the right carotid artery arises) branch from inominate artery I at the level of the thoracic inlet. It has been postulated that this midline artery may have functional importance in allowing the ferret to retain cerebral blood flow when its head, neck, and thorax are extremely flexed. 100 The heart is separated from the diaphragm by about 10 mm, which on a lateral radiograph provides a cardiac silhouette similar to that of a cat. 3 In healthy ferrets, the left ventricle appears to be enlarged on the dorsoventral radiographic view of the chest. Like other carnivores, ferrets do not have well-developed sweat glands in the skin and regulate their body heat through panting. They do not tolerate heat well and may overheat if shade and breezes are not provided on days with ambient temperatures approaching 90°F. 87 Male ferrets, or hobs, lack a prostate gland, seminal vesicles, and a bulbourethral gland. They have a glans penis with curved, horn-like spines like that of a cat. Female ferrets, or jills, have a bicornate uterus with a single vaginal and uterine os. Reproductive Physiology Ferrets reach puberty at about 9 to 12 months of age. The breeding season for hobs begins in December and ends in July. Their readiness for breeding is evidenced by the descent of the testes from the subcutis into the scrotum. The jills are seasonally polyestrous, and the breeding season usually runs from March to August. The breeding season can be hastened and lengthened by the use of artificial light. 84 For example, immature ferrets will display puberty at 7 to 8 months if the photoperiod is gradually lengthened from 6-hour to 16-hour days. The breeding season can be extended if they are maintained on a photoperiodic cycle of 16 hours of light and 8 hours of darkness. With the increasing photoperiod, jills display the onset of estrus by vulvar enlargement, which reaches peak size after 30 days. The female should be bred 2 weeks after the first observation of vulvar swelling. 83 The mating behavior in ferrets may resemble fighting, but the male's dragging of the female by the scruff of the neck is part of the mating ritual. Intromission may be prolonged, lasting up to 30 minutes. Like other mustelids, ferrets are induced ovulators. Intromission, and not the prolonged courtship behavior, is responsible for the luteinizing hormone (LH) peak that triggers ovulation. 19 Some breeders practice double breeding, in which the jill is mated to two hobs in the same day or in consecutive days in order to maximize conception. 87 After mating, the vulva will regress to its normal size in 2 to 3 weeks. If the vulva remains turgid, then the jill should be rebred. If the jill is not bred at the onset of estrus, she will remain in estrus throughout the entire breeding season.

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Ovulation occurs 30 to 40 hours after copulation, and if the ova are fertilized, a 42-day pregnancy ensues (with a range of 39 to 46 days). 60 Abdominal palpation will confirm pregnancy at 14 days. If fertilization did not occur, pseudopregnancy will also last about 42 days. 87 The length of gestation decreases with increasing photoperiod and with large fetal loads, but increases with maternal age, averaging an increase of 5 hours with each successive pregnancy. 60 The jill looks gravid after 30 days and will begin nesting behavior with fur pulling at about this time. Irritability hallmarks the last week of gestation. }ills should be alone 2 weeks prior to the delivery of their young. Kits are born hairless, blind, and deaf. The average litter size is 8 (range of 2 to 17), with a survival weight of lO gm. Litter size declines as the breeding pair passes 3 to 4 years of age. Fuzzy hair can be seen on the kits at 2 days of age and forms a complete coat at 2 weeks. Deciduous teeth start to erupt at 2 weeks. Eyes and ear canals begin to open at 28 days and are complete by 37 days. 64 ·91 Kits show interest in food at about 2 weeks, but will not eat food exclusively until weaned. The jill will stimulate urination and defecation by licking the perineal area until the kits are about weaning age. The kits are weaned at 6 to 8 weeks of age and will weigh around 300 to 450 gm. Their adult weight will be reached at 16 weeks of age. The ability of the jill to feed more kits than she has teats depends on the demand from the kits and the genetic predisposition of the jill to produce large quantities of milk. }ills have four pairs of teats, and the composition of their milk approximates that of cats, with an average of 7.8 per cent protein, 10.4 per cent fat, and 2. 9 per cent lactose. 98 Neonatal mortality or the delivery of small litters of less than six kits may result in a postpartum or lactational estrus. 82 }ills with kits should be bred in this estrus in order to maintain lactation. Early neonatal mortality, ranging from 8 per cent to 10 per cent of the litter, is greatest within the first 4 days after birth. 60 Cannibalism, stillbirths, and congenital defects are common causes of early kit deaths. Spontaneous congenital abnormalities in kits have been reported to include agenesis of limbs and tails, anencephaly, corneal dermoids, hemivertebrae, scoliosis, gastroschisis and cranioschisis, cl~ft lip and palate, open eye, and kinked or short tails. 60·87 •91 •100 The mortality rate decreases drastically after the kits reach 5 days of age. Causes of mortality in kits of this age group and older may include lactational failure, maternal neglect, dirty or overheated nest boxes, and infectious disease. Two weeks after weaning; the jill may return to estrus if she is maintained on an artificial light period of 16 hours, or if the 'natural photoperiod remains long (midseason). It is possible to produce two litters per jill per season under natural lighting, given that the interval from onset of estrus to kit weaning is about 3.5 months (14 weeks). With manipulation of artificial light, a jill may produce 3 or 4 litters (average 3. 7 litters). The incidence of fertile matings decreases somewhat after the first litter in a breeding season. The overall breeding efficiency of both jills and. hobs declines after three breeding seasons. 60 •87

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Table I.

Hematologic Parameters of Healthy Adult Ferrets

PROFILE

FITCH55.IOI

ALBIN095

PCV(%) Hemoglobin (gm/dl) RBC (106 cells/mm 3) Platelets (103 cells/mm 3) WBC (106 cells/mm 3) Band neutrophils (%) Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils

43.4-48.4 14.3-15.9 6.5-8.7

49.2-55.4 16.2-17.8 8.11-10.23 453-545 9.7-10.5 l.l-1.4 57.0-59.5 33.4-35.6 4.4-4.6 2.4-2.6 0.1-0.2

650 5.9-11.3 0.9-1.7 31.1-40.1 49.7-58.0 4.5-6.6 2.3-3.6 0.7-0.8

RANGE

36-61 12-18.2 6.77-12.18 245-910 2.5-19.1 0.0-4.2 11-84 12-95 0-9.1 1-9 0-3

Physiology Physiologic parameters frequently assessed during routine physical examinations include temperature (38 to 40°C) and respiratory rate (33 to 36 breaths per minute). The ferret's heart rate averages 250 beats a minute. The configuration of the electrocardiogram in leads I, II, and III has all the recognizable components: P wave, QRS complex, and Twave. The amplitude of the QRS complex in lead II approaches 2.0 mV; otherwise the electrocardiographic measurements are similar to those in a lead II feline electrocardiogram. Mean systolic blood pressure ranges from 133 mm Hg in females to 160 mm Hg in male ferrets. 3 ·95 The hematologic parameters for ferrets are listed in Table 1. The values are again similar to those of cats except that the hematocrit, total erythrocyte count, and percentage of reticulocytes are higher. The microhematocrit tubes require longer spinning times due to a reduced erythrocyte sedimentation rate. 95 Variations in the packed cell percentage and leukocyte and platelet numbers occur in estrous females. Early in estrus, a leukocytosis and thrombocytosis occur, followed by leukopenia and thrombocytopenia after 8 weeks. The anemia observed in estrous jills is usually a mild normochromic, normocytic anemia. A drastic decrease in the hematocrit and the appearance of hypochromic, macrocytic red cells often are an indication of hemorrhage. 90 Total blood volume is estimated to be between 5 per cent and 7 per cent of the body weight, such that 8 to 10 ml of blood from an adult represents roughly 20 per cent total blood volume. 55 Serum chemical analyses of the ferret are not significantly different from the values derived from the dog or cat. There are no effects of blood collection site, coloration, or sex on the parameters, but an age-related decrease in the alkaline phosphatase has been noted. 55 Serum chemical data are provided in Table 2. Ferret urine should be neutral to slightly acidic, with a pH range of 6.4 to 7.5. Alterations of values derived on the chemical test strips may include proteinuria and, occasionally, blood (from estrous jills). The urine from bobs may give false-positive values for ketones because the dark urine is similar in color to that of the test strip. 86 Struvite ccystals are occasionally seen in urine sediments.

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Table 2.

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Serum Chemistry Values of Healthy Adult Ferrets

PARAMETER

Glucose (mg/dl) BUN (mg/dl) Total protein (gm/dl) Albumin (gm/dl) Total bilirubin (mg/dl) Cholesterol (mg/dl) SAP (IU/L) ALT (IU/L) AST (IU/L) Creatinine (mg/dl) Sodium (mmoi!L) Potassium (mmoi!L) Chloride (mmoi!L) Phosphorus (mmoi!L) Calcium (mg/dl)

FITCH 55

ALBIN095

MEAN

62.5-134 12-43 5.3-7.2 3.3-4.1

94-207 10-45 5.1-7.4 2.6-3.8 < 1.0 64-296 9-84

ll8.5 25 6.0 3.5 < 1.0 165 38 170 65 0.5 150 5.4 liS 6.2 9.2

30-120 82-289 0.2-0.6 146-160 4.3-5.3 102-121 5.6-8.7 8.6-10.5

28-12 0.4-0.9 137-162 4.5-7.7 106-125 4.0-9.1 8.0-ll.8

HUSBANDRY Housing The types of enclosures preferred by ferret owners vary in size and configuration depending on the needs of the owners and the number of ferrets . Indoor cages such as dog or cat transport cages or specifically constructed wire-mesh cages with wire mesh or solid-bottomed floors provide a place for a plastic box, the ferret's "den," where the ferret can retreat to sleep. These dens can be suspended from the side or top of the cage. 87 Outdoor pens should include provisions for shade and protection from the weather. In parts of the country that experience hot and humid temperatures, the pens may be covered with a metal roof that can be wetted with sprinklers to reduce the heat and cooled with fans to circulate the air. As the ambient temperature begins to fall to near freezing, bedding material should be provided in the boxes for the ferrets to burrow for warmth. Ferrets will pick an area of the cage, usually a corner, for elimination, and a litter box can be placed in that spot in cages with solid floors. 100 A tray placed under the wire floor aids in easy cleaning for suspended cages. Nest boxes for gravid jills need not be large, but just big enough (16 inches long by 8 inches wide by 13 inches high) for the jill to curl up comfortably. 60 The floors may be solid so that bedding material, such as wood shavings, sugarcane pulp, or straw, can be introduced. Wooden boxes tend to cause less of a sweating problem compared with metal boxes when temperatures are warm. Some nest boxes have a wire floor covered with a piece of wood, plastic, or metal. This floor allows the use of bedding materials for new litters, and after the kits are fair sized, the false floor can be removed for efficient cooling. 98 • Ferrets can be housed singly or grouped by sex in the nonbreeding

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season. Male ferrets are less tolerant of one another during the breeding season. Estrous jills are reported to have greater incidence of pseudopregnancy when group housed. 87 However, studies on the activities of the male ferret that contribute to the LH surge and ovulation in estrous jills revealed that none of the neck-grappling or mounting activities induced ovulation; intromission alone caused the LH surge and ovulation, as confirmed by laparoscopy. 19 Perhaps the playful activities of group-housed jills may have a contributing effect rather than a direct hormonal effect on the induction of ovulation. Housing or allowing shared activities of a spayed jill with an intact hob should be carefully monitored because attempted breeding behavior by the hob may result in neck wounds and vulvar trauma in the jill. Containers for food should be washable, especially if moist food is provided. Plates and bowls may be tipped over, so they should be bottom heavy or mounted to the wall. Open-topped food hoppers that are mounted to the outside of the cage are not recommended because the ferrets can empty them and escape through the open top. Ferrets are wasteful with their food and prefer to eat small quantities over time rather than one large meal. When allowed free access to food, the ferret will eat 9 to 10 meals a day. 49 Large quantities of moist food should not be allowed to sit for prolonged periods of time in the cage because it may be dropped around on the cage floor and may spoil. Fresh water can be provided in a small bowl, trough, or water bottle. Ferrets enjoy exercise to satisfy their curiosity and innate playfulness. Activity seems to coincide with eating of meals and is followed by periods of rest. Estrous jills usually extend their activity past the daylight hours, unlike their behavior out of season. 3 ° Ferrets may not need exercise pens if the cages are large or if they have regular, supervised exercise periods. Nutrition

Ferrets are carnivores that, like mink, have a very short digestive tract and a limited ability to digest fiber. The rate of food passage averages 3 hours and is short compared with most monogastric species. 13 The shortened interval that food remains in the digestive tract suggests that there is less time for enzymatic and bacterial digestion or bacterial synthesis and absorption of dietary elements. Diets high in protein and fat but low in fiber are suited to this type of digestive pattern. Frequent, small meals keep food in the intestinal tract, which decreases irritability associated with hunger. Diets commercially available and suitable for adequate maintenance of ferrets include moist and dry dog, cat, and mink food. Because ferrets consume as much food as necessary to meet their caloric requirements, supplementation of a primary cat food diet with canned meat (~uch as infant meat products or commercial canned pet food) or a limited amount of milk (powdered or regular) is often needed to ensure adequate consumption of protein, especially in pregnant and lactating jills.86 Subtle hair loss, dry hair coats, and poor reproductive performance may be attributable to cat food diets, and these conditions improve with the feeding of milk solids or liver. 87 ·99 A great variety of foodstuffs used to formulate adequate diets for raising ferrets has been described. However, if the diet contain~ substantial portions of fish (mackeral, tuna) or freezer-burned (oxidized) horsemeat containing

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Table 3. DRUG

Tranquilizers Acepromazine Xylazine Ketamine Preanesthetic drugs Atropine Acepromazine Injectable anesthetics Ketamine alone Ketamine plus* Ketamine and diazepam Xylazine and ketamine Pentobarbital Inhalant anesthetics Halothane Methoxyflurane Enflurane

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Drugs Used for Chemical Restraint DOSAGE

ROUTE

0.2-0.5 mg!kg 1.0 mg/kg 10-20 mg/kg

IM , SQ IM, SQ

IM

0.5 mg!kg 0.1-0.25 mg/kg

IM, SQ IM, SQ

20-30 mg/kg 20-30 mglkg 25 mg/kg ketamine 2 mg/kg diazepam 1-4 mg!kg xylazine 20-30 mg/kg ketamine 30 mg/kg

IM IM IM IM IM , SQ IM, SQ IP

To effect To effect To effect

Mask, intubation Mask, intubation Mask, intubation

high levels of polyunsaturated fatty acids, daily supplmentation with 10 mg (IU) of vitamin E may be required to prevent steatitis. 15 Table scraps containing bones should be avoided to prevent wounds or entrapment of the bones in the mouth or gastrointestinal tract. Foodstuffs high in fiber will not provide much in the way of nutritive value to ferrets. Although the minimum dietary requirements for growth, pregnancy, and lactation have not yet been published for ferrets, the similarities in the dietary habits and the gastrointestinal physiology to mink suggest that diets adequate for mink are also adequate for ferrets. 87 Restraint Ferrets presented for examination can usually be handled without the use of a protective glove. Lactating or preparturient jills or newly acquired ferrets may resist casual attempts to be restrained, and the use of a light leather glove will afford some protection in the event that biting ensues. Ferrets hiss when annoyed and will scream iffrightened, so these behaviorial traits ought to let the handler anticipate resistance from the ferret. 98 Ferrets can be removed from transport cages by slowly and deliberately grasping the nape of the neck or by pulling them by the tail. 35 Further restraint can be accomplished by grabbing them around the shoulders and pushing the forelimbs together with the thumb and forefingers. Restricting the forelimbs prevents any scratching. The hindquarters can be supported by the other hand. Ferrets do not tolerate holding or stretching of the hindlimbs. While on the examination table, ferrets can be allowed to roam the top because they will refrain from jumping. 98 Immobilization on the examination table can be accomplished by first pulling the ferret's tail, which will elicit forward motion with the front legs. The other hand can-wrap around the shoulders or the nape of the neck so that the ferret can be stretched out on the table.

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Chemical restraint offers a range of sedation from tranquilization to general anesthesia. Anesthetics delivered via intramuscular injection or by inhalation are preferred because there is limited or no access to peripheral veins for intravenous injections. An alternative route to intravenous drug administration is the intraperitoneal injection, and sodium pentobarbital and other relatively neutral drugs can be delivered by this route. Table 3 lists the most commonly used tranquilizers and anesthetics. Sites for subcutaneous and intramuscular injection are the same as for dogs and cats and can include epaxial lumbar muscle groups. Care should be taken to avoid deep injections in the lumbar muscle to prevent kidney trauma. Ketamine alone may not provide adequate muscle relaxation or analgesia and is most often combined with acepromazine, xylazine, or other analgesics. 41 ROUTINE PREVENTATIVE CARE

Sample Collection Collection of feces for endoparasite examination is facilitated by the ferret's toiletry habits of defecating in one particular place. A fresh sample can be obtained from the litter pan or from the drop pan under the cage. Urine samples should be removed from an empty litter pan or from a clean drop pan as soon as it is voided to prevent contamination with food or feces. Occasionally, ferrets will eliminate urine and/or feces when physically restrained. Blood in small volumes can be obtained from unanesthetized ferrets by a variety of techniques. Cutting the vascular bed of the toenail with toenail clippers will provide about 0.5 ml of blood that can be recovered with a microhematocrit or Unipet capillary tube. Peripheral veins are difficult to locate in the small limbs. Venipuncture of the jugular and caudal tail veins and the caudal tail artery using syringes fitted with 25-gauge needles will allow collection of several milliliters of blood. 12·86 The collection of blood from the caudal tail artery is performed after the ferret has been "warmed" in a box placed on a heating pad or exposed to incandescent bulbs (75 watt). The animal is placed in dorsal recumbency, and the 25-gauge needle is directed toward the body and inserted into the groove on the ventral side of the midsection of the tail at a shallow angle. The artery lies about 2 to 3 mm beneath the surface, so care must be taken not to push the needle through the vessel. After the sample has been taken, pressure placed on the puncture site will prevent seepage of blood. 12 Blood can be collected from an anesthetized ferret by retro-orbital puncture techniques that are often used for rodents . 37 Once th~ ferret is anesthetized and in dorsal recumbency, the globe is partially protruded by manual retraction of the eyelids. A microhematocrit capillary tube is broken in two pieces, and the sharp end is inserted into the medial canthus at a 45° angle to the long axis of the head. Gentle pressure and rotation of the tube will aid in advancement of the tube toward the retrobulbar venous plexus. Once blood flow begins, the end of the capillary tube can be placed at the mouth of the collecting receptacle. Blood flow is stogped by removing the tube and applying gentle pressure with a gauze sponge on the medial can-

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thus. Anesthesia is also required for collection of blood via cardiac puncture, but there is substantial risk associated with this technique, which limits its use to emergency procedures. Vaccine and Vaccination Schedules Routine vaccine administration should include modified live canine distemper vaccine that has been propagated on chick embryo tissue-culture systems. The egg-propagated live canine distemper virus has been proved safe and quite effective in ferrets during years dedicated to vaccine production and testing for use in dogs. 6 ·65 ·71 Ferrets dosed with killed canine distemper vaccines slowly develop temporary immunity or none at all. 72 Canine distemper vaccines from canine cell lines may not induce as effective an immune response, and they have been implicated in clinical distemper diseases following administration. 72 •81 The symptoms of vaccine-induced distemper range from a mild upper respiratory infection with accompanying skin manifestations to fulminating, fatal disease. Postvaccination distemper is suspected to comprise a significant number of the postmortem distemper diagnoses in ferrets submitted to our diagnostic laboratory. Historically, some of the ferrets had been vaccinated with multiantigenic products containing leptospiral bacterin with canine parvovirus, canine hepatitis, and parainfluenza viruses and canine distemper virus produced in canine cell systems. Because ferrets are not susceptible to disease from Leptospira spp., canine adenoviruses, parainfluenza virus, and canine parvovirus, vaccination with these attenuated live viruses and bacterin is unnecessary. 40 •44 •87 The extra antigenic burden from use of the multiple antigen vaccine may preoccupy or suppress the ferret's immune system, providing less efficient virus processing and increasing the risk of overt disease induction from the canine distemper vaccine. The first dose of canine distemper vaccine should be administered to kits 6 to 10 weeks of age; a second booster 2 weeks later has also been recommended. Kits from unvaccinated jills should receive a vaccine at 4 weeks of age, with a second booster given 3 weeks later. Because the immunity elicited by egg-propagated vaccines is prolonged in ferrets, booster vaccines can be administered every other year or every 3 years after the first annual booster. 86 •87 Pregnant jills can be safely vaccinated. 43 Vaccinating a colony of susceptible ferrets in the face of an epizootic of distemper will provide protection within 72 hours; however, simultaneous infection with the vaccine and the wild-type canine distemper virus strains results in no protection. 34 No other immunizations for ferrets are required because ferrets are not susceptible to disease produced by feline panleukopenia vjrus, mink enteritis virus, feline rhinotracheitis virus, or feline calicivirus. 40 •86 Ferrets may briefly shed panleukopenia virus if exposed but do not exhibit disease symptoms. 40 Rabies vaccination is not recommended because there is no supporting experimental evidence that any of the licensed vaccine products afford protection when used in the ferret . There have been four cases of rabies diagnosed in ferrets since 1958. In one of these cases, the ferret was suspected of receiving a modified live rabies virus vaccine. 8? Ferrets are susceptible to rabies, and the latency or incubation period cannot be well documented

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because experimental infections resulted in a relative lack of centrifugal spread to organs other than brain. 33 Vaccine trials in which wild or exotic animals were given killed rabies vaccine prior to challenge with virulent Flury rabies virus strain resulted in incomplete protection to many species, including the ferret . 34 Routine Surgeries Surgical procedures commonly performed in ferrets include anal sac removal, which is often performed at the time of ovariohysterectomy or castration. The resection of the anal sacs will decrease the musky odor, but sexually active ferrets will still have a strong aroma from the hormonally sensitive sebaceous glands in the skin and the apocrine and sebaceous glands left after removal of the anal sac. Several descriptions of the descenting procedure have been published and include modifications of the approach or dissection procedures used in dogs. 9•23·66·83 In one technique, an incision around the duct openings located at the mucocutaneous junction of the anus is followed by careful dissection through significantly developed rectal sphincter muscles to remove the friable sac. Infrequent complications include fecal incontinence or rectal prolapse from anal sphincter damage. 9 Postoperative care may include antibiotic packing of the surgery site. 23 A second procedure incorporates the infusion of anal sac gel, which facilitates location of the sac(s) such that an incision can be made adjacent to the anus and over the body of the sac rather than at the mucocutaneous junction at the anus. The warm gel cauterizes the muscle contiguous with the body of the sac, which aids in dissection through the muscle fibers. The incision site can be closed in two layers with skin sutures made with either absorbable or nonabsorbable material. 83 Another technique utilizes a perianal incision to isolate and excise the neck of the sac adjacent to the ductal opening followed by careful, blunt dissection of the sac. No suturing is required, and the postoperative complications of slight bleeding or bruising are minimal. 66 Ovariohysterectomy is performed on 6- to 8-month-old ferrets that are not intended for breeding stock. The conventional surgical procedure for dogs and cats is used . Ideally, the jills should be spayed prior to estrus to prevent the depression of the bone marrow resulting from the high estrogen levels associated with prolonged estrus. Female ferrets in estrus can be spayed within the first month after the onset of vulvar swelling without serious operative complications of bleeding. Alternately, the pubertal jill can be chemically induced to ovulate after the second week of estrus by intramuscular administration of human or bovine chorionic gonadotropin (HCG) at a dose of 50 to 100 IU or gonadotropin releasing hormone (GnRH) at a dose of 20 ,_.,g. 9 · 20 •86 Vulvar swelling will regress in 2 to 3 weeks, and the ferret will be anestrus from pseudopregnancy for about 40 days. Hormone therapy may need to be repeated if vulvar regression does not occur. A packed cell volume and blood smear to evaluate red cell morphology and platelet numbers would be advised prior to surgery on any jill in estrus. If the jill has been in estrus for months and has a complete blood count (CBC) indicative of anemia and thrombocytopenia, surgery is not advised. Instead, hormonal induction of ovulation and supportive care a.r;e indicated (see the section on hyperestrogenism).

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Castration of a hob is done during the breeding season when the testes have descended into the scrotum. It is recommended that hobs be at least 7 to 8 months old, perhaps to prevent inadequate development of the urethra, as has been described to occur in prepubertal castrated cats. Open or closed feline castration techniques work well, with the ferret paying little to no attention to the incisions. Supportive care for the ferret prior to and during surgery should include fasting for 6 hours, physical examination including weight measurements and CBC, provision of a warmed surface to maintain body heat during anesthesia, and monitoring of cardiac function. Although injectable anesthetics are dosed by animal weight, adjustments in the anesthetic volume calculations may be necessary to account for the excess fat ferrets accumulate in the winter. Inhalation anesthetics should be delivered via nonbreathing systems to prevent inadequate ventilation associated with dead air spaces. The intravenous infusion of fluids during prolonged surgical procedures may be difficult because of the relative inaccessibility of peripheral veins. Occasionally, the cephalic or saphenous veins can be catheterized externally when the ferret is anesthetized. In cases in which fluids are demanded, a surgical exposure and catheterization of the jugular or peripheral veins or the intraperitoneal administration of fluids can be performed. 36 An intraperitoneal needle or catheter is inserted just off the midline in the lower quadrants of the abdomen while the ferret is in dorsal recumbency. The cranial left quadrant of the abdomen should be avoided to prevent puncturing the spleen. After needle placement, the veterinarian should aspirate with a syringe to ensure that the urinary bladder has not been centesed. Fluids need not be continuously infused into the abdominal cavity but can be given in increments to satisfy the physiologic demand.

INFECTIOUS DISEASES Parasites Routine examinations for internal parasite infections in ferrets incorporate the flotation, direct smear, concentration, and filtration techniques used in preventative medicine practices. Ferrets have been diagnosed with a number of intestinal parasites of dogs and cats, including Toxascaris leonina, Dipylidium caninum, Giardia spp., and coccidia.87 Ferrets are also susceptible to Toxoplasma infection. 53 Drugs and the dosages for treating parasitisms in ferrets are included in Table 4. Dirofilariasis occurs in ferrets and induces symptoms of respiratory distress, fluid accumulation in the chest and/or abdomen, pale mucous membranes, and muffled heart sounds followed by death. The burden of the adults in the heart obstructs cardiac outflow, resulting in congestive heart failure. It has been postulated that between 5 to 10 heartworms in the heart would acutely kill the host, but ferrets have died from heart failure with as few as one nematode coiled in the right side of the heart. 18•63 •74•87 Diagnosis of heartworm infection is frustrating because microfilaremia occurs in less than 2 per cent of naturally infected ferrets. 18 The antigen-detection kits available for diagnosing canine dirofilariasis have not successfully identified infected ferrets. Thoracic ra-

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Table 4. NAME OF DRUG

DOSE

List of Common Drug Doses COMMENTS

10 mglkg bid, PO Monitor BUN 0.2-0.4 mglkg 3 times/week Canine regimen 0.4-0.8 mglkg weekly Ferret regimen (total dose of 7-25 mg) Excitation lasts 4 hr Apomorphine HCI 5 mglkg, SQ Ampicillin 5 mglkg qid, PO 22-50 mglkg tid, PO Chloramphenicol 6 mglkg bid, IM 10 mglkg qid, PO, IV, IM Cloxicillin 10 mglkg every week, IV Cyclophosphamide 6.6 mglkg for 3 days, then 2.2 mglkg sid Diazoxide 5 mg bid Diethylcarbamazine 5.5-11 mglkg sid, PO Pivided bid, digitalization 0.007-0.008 mglkg, PO Digoxin Divided bid, maintenance 0.002-0.004 mglkg, PO 5-11 mglkg, IV Doxapram Erythromycin 10 mglkg qid, PO 2.2-4 mglkg bid or tid, PO Furosemide 4.4 mglkg bid, SQ for 2 days, Gentamicin then od thereafter Griseofulvin 25 mglkg od for several weeks Use with topical therapy Hydrocortisone sodium 25-40 mglkg, IV succinate Monitor blood/urine glucose 0.5-6 IU/kg or to effect, SQ Insulin, NPH Ivermectin 0.2 mglkg, SQ, IM, PO Ketaconazole 10-30 mglkg tid, PO Lincomycin 11 mglkg tid, PO Predisposes to pyometra 4.0 mglkg sid, PO Megestrol acetate Meperidine HCI 15 mglkg, SQ No adverse reactions, like cat Neomycin 20 mglkg qid, PO Oxytetracycline 17 mglkg tid, PO 5-10 IU, IM Oxytocin Penicillin G, procaine 44,000 IU/kg sid, IM Pepicillin G, Na, or K 40,000 IU/kg tid, PO 23 mg/<2.3 kg, PO 23 mg is one half tablet Prazequone 46 mg/2.3-5.0 kg 46 mg is one tablet Taper off dose as in dog or cat 0.6 mglkg sid, PO Prednisolone Propranolol 2 mglkg bid, SQ Pyrental 4.4 mglkg sid, PO Sulfadimethoxine 22 mglkg sid, PO 50 mglkg tid, PO Sulfasoxisole 0.025-0.5 mglkg, IV Vincristine Ammonium chloride Amphotericin B

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diography coupled with a history of outdoor exposure and lack of administration of heartworm prophylaxis may aid in developing a tentative diagnosis. Successful treatment of spontaneous heartworm disease is difficult because the ferrets are often in advanced stages of heart failure when presented for examination. In experimental trials, ivermectin (0.2 mg per kg) was effective in treating and preventing heartworm disease. 10·u Daily dosing of diethylcarbamizine (5 to 11 mg per kg) will also prevent maturation of heartworms should the ferret be exposed to infective larvae. Ferrets are hosts to a variety of ectoparasites commonly found on dogs and cats. Ear mites, Otodectes cynotis, have been associated with inflammation of the external ear canal. 67 Topical preparations with or without a miticide used weekly for 3 weeks are effective. Fleas, Ctenocephalides spp. , commonly infest ferrets and can be eliminated with pyrethrin-based products. Sarcoptes scabei infections have two clinical manifestations. There may be focal to generalized alopecia with accompanying pruritis; the mites are easily demonstrated with deep skin scrapings. Occasionally, ferret scabies is characterized by involvement of the feet only. The paws become swollen and scabs form. The toenails may be deformed or fall off if the condition is chronic. The paws should be soaked to remove the scabs and the toenails cut back. Topical sulfur ointment or lime/sulfur washes and carbaryl shampoos (0.5 per cent) will kill the mites. 86 Treatment should be repeated every 3 days (ointment) or weekly (wash/shampoo) to ensure elimination of all stages of the mite. Because ivermectin administration has been used to control scabies successfully in a number of animals, it may be safely incorporated in the miticide regimen for ferrets . 97 Bacterial Diseases Perhaps the most common bacterial diseases encountered in pet ferrets are related to wounds that have become secondarily infected with oral or fecal bacterial flora. Trauma to the oral cavity from ingesting bones or biting cage wires, and bite wounds from fighting or mating activities may allow entry of staphylococcal, streptococcal, or corynebacterial species with development of dermatitis, cellulitis, or abscesses. 87 "Lumpy jaw" has been described in ferrets, and the mixed gram-negative bacterial population recovered from the encapsulated submandibular abscesses was similar, in this case, to the fecal flora of the rats in the diet, not the fecal fauna of the ferrets. 4 Abrasions and cellulitis of the vulva are frequently observed in estrous and postestrous jills. Mastitis, observed most often in jills in early lactation, affects the inguinal glands initially and spreads rapidly to adjacent glands. Staphylococcus aureus and hemolytic Escherichia coli are frequently isolated from mastitic ferrets. 58 ·87 During replication, both baliteria are capable of liberating hemolysins and/or toxins that enhance tissue invasion and account for clinical signs of depression, pyrexia, and even death. Septicemia often occurs later in the short clinical course of the infection. Treatment of the superficial infections and abscesses follows regimens of medicinal therapy used for dogs and cats. Mastitis may progress too rapidly for hot-packs and antibiotic therapy with ampicillin and gentamicin to be efficacious. Surgical resection of affected glands coupled with parenteral antibiotic therapy may be necessary to save the life of the ferret. 58 Kits suckling jills with E. coli

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mastitis often carry the organism in the oral flora and may be responsible for transmission of the organism to unaffected glands of the dam or foster mother. These kits also may develop conjunctivitis, panophthalmitis, and septicemia as sequelae to the nasopharyngeal colonization of coliforms. The eye infections in kits with sealed lids often drain at the medial canthus, which allows a port for installation of a cannula for saline rinses and infusion of broad-spectrum ophthalmic ointment; systemic antibiotic therapy must also accompany local therapy. Culture with antibiotic sensitivity testing is recommended prior to treatment of mastitis or when there is poor response to antimicrobial therapy with progression of the pyogenic processes in other tissues. Antibiotic toxicities in ferrets are uncommon except for streptomycin, which is toxic at levels greater than 50 mg when given at less than 12-hour intervals. 87 Bacteria known to be primary pathogens cause diseases less frequently. Streptococcus zooepidemicus has been cultured from pneumonic lungs, blood, and infected uterus. 87 This isolant and other group C streptococci may induce valvular endocarditis during septicemia. 86 The treatment regimen should be vigorous and include broad-spectrum antibiotics like ampicillin (pending culture and sensitivity results), parenteral fluids, and oxygen therapy. Ferrets are moderately susceptible to toxins A and B and highly sensitive to toxin C produced by Clostridium botulinum.81 Muscle incoordination leading to paralysis and ptylism occurs by 96 hours after the ferret has consumed the spoiled food. Offal that has been improperly stored for a period of time in a warm environment provides the anaerobic nutritive environment conducive for growth of the bacterium. Mink vaccines include a toxoid for type C toxin of C. botulinum. Treatment of the paralysis should include administration of the toxoid and oral gavage with absorbants , but success in therapy has not been reported. 87 Provision of commercially prepared, dry diets eliminates the risk of exposure. Ferrets are susceptible to human, bovine, and avian mycobacteria and develop alimentary tuberculosis. Clinically, chronically infected ferrets begin to waste and display loss of adduction in the hindlimbs and occasionally forelimbs. 87 Mesentric lymphadenopathy can be palpated and confirmed on abdominal radiographs. Intradermal administration of mammalian tuberculin (0.1 ml) and mesenteric lymph node biopsy with culture and histopathologic examination are diagnostic routes to pursue. 87 Hyperemia and induration to the tuberculin test within 24 hours and demonstration of lymph node granulomas containing foreign body giant cells with intracytoplasmic acid·.fast bacilli provide a tentative diagnosis of tuberculosis pending definitive culture results. Tuberculous ferrets should be euthanatized because they are often diagnosed in advanced stages of active disease and pose a zoouotic threat. Proliferative colitis is a disease of young ferrets characterized by chronic, intermittent green mucohemorrhagic diarrhea often accompanied by rectal prolapse, anorexia, and weight loss. 38 The diarrhea can last for more than 6 weeks. Ferrets eventually die, and gross necropsy lesions include marked thickening of the muscular wall and mucosa of the caudal portion of the colon. The mucosal epithelium may be up to three times thicker than normal. Histologic features include replacement of goblet cells -with poorly differentiated enterocytes along elongated tortuous crypts, adenomyosis, and in-

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flammatory cell infiltrates in the lamina propria. Campylobacter jejuni has been routinely isolated from the feces, and intracellular bacteria with the morphology consistent with that of Campylobacter have been demonstrated in the proliferative colonic mucosa by use of the Warthin-Starry silver stains and electron microscopy. Campylobacter jejuni and other Campylobacterlike organisms have also been recovered from apparently healthy ferrets. Current hypotheses about the ability of Campylobacter spp. to act as a primary pathogen in ferrets and other companion animals or livestock are clouded by the recovery of the organism from asymptomatic animals and the inability to reproduce . the proliferative disease experimentally with a pure inoculum of the organism in animals with normal gut flora. 45 •57 •79 Concurrent infections with viruses, parasites, and other bacterial pathogens are thought to play a role in predisposing the enterocyte to infection with the Campylobacter organism. The description of other histologic lesions suggestive of Aleutian disease in the ferrets with proliferative colitis may offer some insight into the epidemiology of this bacterial disease. 16•38 Antibiotic and supportive therapy is unrewarding, even though erythromycin or tetracycline may be drugs of choice as determined by in vitro antibiotic sensitivity tests. Fungal diseases are rarely encountered in ferrets. Dermatophytosis from Microsporum canis occurs as a seasonal and transient infection in kits. 86 Griseofulvin therapy at a dose of 25 mg per kg and/or the topical application of antifungal ointments or iodine solutions will aid in the remission of the ringworm lesions. Systemic fungal diseases described in ferrets resemble the clinical and diagnostic presentation of these diseases in dogs and cats. Cryptococcal meningitis was diagnosed at necropsy in a ferret that had died from complications of congestive heart failure after completing a regimen of dexamethasone for treatment of paresis from intervertebral disk disease. 42 Clinically, the ferret displayed sneezing and moderate to severe dyspnea. These symptoms may have been entirely related to the cardiovascular disturbance rather than the Cryptococcus neoformans infection. A ferret with pyrexia and a cough was diagnosed with chronic blastomycotic pneumonia with systemic spread by confirmation of the interstitial pneumonia on thoracic radiographs, identification of splenomegaly, and demonstration of the organism in the exudates from a draining tract of the forepaw. 56 Chemotherapy with weekly intravenous amphotericin B (0.4 to 0.8 mg per kg) and daily oral ketaconazole (10 mg per kg) for 5 weeks resulted in clinical improvement with resolution of the extremity lesion and decrease in lung consolidation. The dose and frequency of amphotericin B therapy were regulated to minimize the azotemia and dehydration that occurred after intravenous administration. After the fifth week, inflammation of accessible veins forced the subcutaneous administration of amphotericin B on an alternateday regimen, which resulted in relapse and eventual euthanasia of the ferret. Installation of an indwelling jugular venous catheter or intraperitoneal dosing may have allowed the completion of the total dose of 7 to 25 mg per kg of amphotericin B. Increasing the dose of ketaconazole to the upper range of 30 mg per kg also may have been efficacious in controlling the disease. 56 Histoplasma capstilatum was demonstrated on cytology of an aspirate from one of multiple subcutaneous nodules on a 5-year-old cachectic ferret. 47

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Chronic sneezing was noted several months before the subcutaneous nodules were found. The ferret lost weight rapidly during the 3 weeks after the nodules were first noticed. Thoracic and abdominal radiographs were unremarkable The ferret did not respond to ketoconazole therapy and died 2 days after admission. Macrophages containing intracytoplasmic Histoplasma bodies were found in granulomatous infiltrates in the subcutaneous nodules, the interstitium of the lung, and periportal areas of the liver. Viral Diseases

Canine Distemper. Infection with canine distemper virus is uniformly fatal in ferrets. Transmission is from direct contact with the virus-contaminated saliva or nasal secretions or by inhalation of infected aerosols. 7(}...72 Virus actively replicates in the lymph nodes of the upper respiratory tract, spreads to thoracic and abdominal lymphoid tissues, and, by the fifth day of infection, enters the peripheral circulation via monocytes. 73 Virus begins replication in the mucosa of viscera of the respiratory, gastrointestinal, and urinary tracts, in skin, and in ocular tissues at about 1 week postinfection, which correlates to the expression of clinical signs. Virus replication in the respiratory tract peaks at about 12 days, and central nervous system involvement is noted at about this time. The course of clinical disease in the ferret is predictable, unlike that in a dog. After a week-long incubation period, the catarrhal phase is manifested by pyrexia (body temperatures up to 40.5°C), anorexia, and a mucopurulent oculonasal discharge with corneal ulceration and conjunctival swelling. The cutaneous involvement follows the catarrhal phase after several days . An erythematous rash with vesicle formation and pruritis occurs on the chin and inguinal area. The rash may become secondarily infected. The footpads may swell and develop hyperkeratotic foci of the classic description of hard pad. Progression of the respiratory tract disease to include suppurative rhinitis, bronchitis, and bronchopneumonia occurs readily. Diarrhea that is dark and tarry in consistency is infrequently passed. If the ferret survives the acute phase of the infection (3 to 4 days of clinical disease), central nervous signs including muscle tremors, hyperexcitability, myoclonus, convulsions, and coma may ensue. 70•73 ·74 Ferrets usually die within a week after onset of clinical signs. Ferrets suspected of developing vaccine-induced distemper may display a range of clinical signs. Mild upper respiratory disease and pyrexia may be followed by complete remission, or classic catarrhal respiratory symptoms with systemic and nervous system involvement may occur. 36•37 Diagnosis of distemper is based on the history of lack of vaccination, vaccination in the face of a distemper epizootic (in a colon¥ situation) or vaccination with a canine cell-propagated vaccine, exposure to a source of virus (usually a pet or roaming dog), and the consistent and rapid progression of clinical signs. Because ferrets are susceptible to influenza virus that induces a similar albeit transient upper respiratory disease, supplemental diagnostic testing may be warranted. Indirect fluorescent antibody (IF A) techniques will highlight viral antigen in circulating leukocytes and in conjunctival scrapings within the first few days of the catarrhal phase. 73 These tissues will remain IF A positive throughout the course of the disease, al-

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though the leukopenia-associated advanced disease may provide false-negative results. A lymphopenia will be demonstrated by CBC of blood samples but is not a specific indicator of distemper infection. A postmortem diagnosis is based on the histologic findings of catarrhal to suppurative conjunctivitis and keratitis, rhinitis, bronchitis and/or bronchopneumonia, widespread necrosis of lymphoid tissues in multiple organs and nodes, hyperkeratosis of the epidermis and footpad, and the demonstration of the acidophilic inclusions in the cytoplasm and occasionally the nucleus of epithelial cells of the bronchi, urinary bladder, stomach, bile ducts , and conjunctiva. Inclusion bodies are less numerous in the skin, lymphoid organs, and glial cells and neurons of the brain. Supportive therapy of fluid systemic and ophthalmic antibiotic administration may be indicated early in the disease when the symptoms cannot be distinguished from influenza. Affected ferrets should be isolated if susceptible cohorts are in the same household or colony. Once the pneumonia and/or the central nervous system phase of the disease has developed, euthanasia is recommended. Influenza. Several strains of human influenza virus will cause clinical disease in ferrets. Virus replicates in the upper respiratory tract, including the trachea, and can induce fluctuating fever (4l C), anorexia, lethargy, and sneezing within 48 hours. A serous nasal discharge can change to a mucopurulent nature after onset of clinical signs. The course of the influenza infection lasts about 5 days , and the symptoms are limited to the upper respiratory tract. Influenza infection in neonatal ferrets born to a susceptible jill may result in significant mortality from bronchiolitis and pneumonitis .75 Diagnosis is determined by vaccination history and onset and localization of the symptoms; often the owner will be recovering from the flu when the pet ferret becomes sick. Palliative use of antihistamines to ameliorate the nasal congestion and supportive fluid and antibiotic therapy for the mucopurulent rhinitis may be indicated. Immunity to the homologous strain of influenza virus will last 5 weeks, but the virus mutates rapidly and multiple infections may occur within a flu season. 76 Influenza vaccines can be used in ferrets but are unnecessary because the disease is mild. Aleutian Disease. Aleutian disease (AD) is a parvovirus infection that was first described in mink (Mustela vison). In adult mink, the disease is of two distinct forms : an inapparent nonprogressive infection and a clinically progressive and fatal disease. Both forms of AD are characterized by persistent viremia. In the progressive AD, mink develop plasmacytosis with overproduction of non-neutralizing IgG antibody and formation of virusspecific immune complexes that are deposited in the glomeruli, liver, and vessel walls. 77 The mink usually die of renal failure from the immune complex-mediated glomerulonephrosis. Mink infected with the AD parvovirus as neonates develop a fulminating and often fatal acute interstitial pneumonia. 78 Mink that are homozygous for the recessive Aleutian coat color gene (grey color) have a genetic defect resembling Chediak-Higashi syndrome . The AD in these mink progresses quicker and is more severe than AD in mink heterozygous for the Aleutian gene or mink with wild-type coat colors. 79 Spontaneous hypergammaglobulinemia in ferrets was recognized as a disease syndrome in which the gamma globulin fraction was persistently 0

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elevated for more than 3 months. 80 The syndrome was referred to as AD of ferrets , and clinically the ferrets exhibited a chronic progressive wasting disease, although some that died were in good flesh. Subsequent reports of lesions in spontaneously hypergammaglobulinemic ferrets vary somewhat with the extent and severity of the histologic alterations. In spontaneous and experimentally induced AD in ferrets, the lesions are mild compared with those described in Aleutian mink and include mild periportal plasma cell infiltrates, splenomegaly (greater than the normal 0. 68 per cent of total body weight) with plasma cell infiltrates and lymphoid follicular hyperplasia, infiltration of plasma cells in bone marrow, thymus, and myocardium, lymphadenopathy with follicular hyperplasia and sinusoidal accumulations of plasma cells, and perivascular cuffs of plasma cells and lymphocytes in numerous viscera including kidney, lung, heart, and brain. 81 •82 One report of spontaneous AD in ferrets described lesions much more similar to those of mink AD, which included mild to marked periportal plasma and lymphoid cell infiltrates with biliary duct hyperplasia, severe glomerulonephritis with large plasmacytic cuffs around renal vessels, splenic follicular atrophy, follicular hyperplasia in lymph nodes with sinusoidal plasma and lymphoid cell accumulations, fibrinoid necrosis of muscular arteries, and plasma cell aggregates in pancreas, adrenal gland, and peribronchial areas in the lung. 80 •83 In all spontaneous cases of hypergammaglobulinemia in ferrets, there was cross-reacting antibody to AD as measured by counterimmunoelectrophoresis, and the syndrome has been referred to as ferret AD. Ferret AD has been attributed to infection with a parvovirus that is distinct from mink AD isolates. 82 When recovered from experimentally inoculated ferrets , ferret AD does not approach the high titer of mink AD in similarly manipulated mink. There is persistent virus replicatation and circulation, but the low virus numbers may account for the lack of immune complex-mediated lesions commonly described in mink. A serologic survey of ferrets revealed 42 per cent of 218 unmanipulated adult ferrets had antibody to AD. 82 A significant number but not all of these ferrets with AD antibody had hypergammaglobulinemia, which was determined by a globulin fraction in excess of 20 per cent of the total serum protein value.81 Antemortem diagnosis of ferret AD can only be made by counterimmunoelectrophoresis because elevated gamma globulin values are not consistent indicators of infection. This test is offered by several commercial and institutional laboratories.* Ferrets with AD antibody may be more susceptible to development of concurrent infectious diseases, especially with those opportunistic agents that require an immunocompromised host in order to replicate. Such may be the case with the proliferative colic di-sease associated with Campylobacter injections and perhaps the early lymphoproliferative neoplasms frequently diagnosed in ferrets less than 1 year of age. Another factor to consider is the possibility of familial distribution of AD in ferrets, which bears significance in the epidemiology of disease in multiple-ferret households .81 The AD in mink is transmitted both horizontally and vertically, but the mode of transmission of ferret AD has not been reported. *United Vaccine , Inc., Madison, Wisconsin.

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NONINFECTIOUS DISEASES Hyperestrogenism Jills allowed to remain in estrus throughout the duration of their breeding season develop bone marrow hypoplasia due to the circulating levels of estrogen. The ferret is quite susceptible to the toxic effect of estrogens on hematopoietic tissue, which results in the reduction of the precursor cells for the erythroid, granulocytic, and megakaryocytic series in the bone marrow. 9•90 Megakaryocyte production is the earliest and most severely affected series of the trilineage marrow population. Significant reduction in platelet numbers can occur within 4 to 6 weeks after the onset of estrus. 90 Mild leukopenia and mild normochromic, normocytic anemia represent the peripheral blood picture in estrous jills unless hemorrhage from thrombocytopenia occurs. Clinically, jills in prolonged estrus display vulvar swelling with bilateral symmetric alopecia in the inguinal area and the tail. Weight loss, decreased activity, and loss of appetite are signs commonly noted by the owner. Pale mucous membranes, cutaneous and buccal mucous membrane petechia, and melena reflect the clinical manifestations of hemorrhage from thrombocytopenia. Secondary bacterial infections of the respiratory tract, vulva, and uterus may occur and have been attributed to the estrogen-induced leukopenia. 9 Assessment of the seriousness of the pancytopenia can be accomplished by examination of a stained peripheral blood smear and/or PCV and white blood cell (WBC) count from a small amount of blood collected by toenail clip or orbital sinus bleeding techniques. Platelet numbers should be determined before any surgical procedure is performed. Treatment or reversal of the bone marrow depression begins with the reduction of the endogenous estrogen levels, followed by intense and often prolonged supportive care. Ovariohysterectomy should not be performed on jills with severe anemia or with thrombocytopenia. Induction of ovulation from exogenous HCG (50 to 100 IU,IM) or GnRH (20 1-1-g,IM) administration will induce pseudopregnancy for around 42 days. Repeat hormone therapy at higher doses may be indicated if estrus recurs after pseudopregnancy or if involution of the vulva does not begin within 2 weeks of the initial therapy. Supportive care includes intravenous or intraperitoneal transfusions of fresh (cross-matched) blood in small volumes of lO ml per transfusion. Multiple transfusions have been performed and may be necessary before the bone marrow responds , which may take months. 85 Anabolic steroid, corticosteroid, and lithium administration have all been reported to aid in stimulation of hematopoiesis. 86 ·90 Antibiotic therapy may be necessa.ry to treat or prevent secondary pyogenic processes. Force feeding high-energy, vitamin-supplemented diets may maximize the ferret's response to the treatment regimen. Periodic monitoring of the PCV, red cell morphology, and platelet numbers every 4 to 6 weeks will aid in assessing response to therapy. If the jill survives to the end of the breeding season, ovariohysterectomy can be scheduled when platelet numbers are adequate or the hemogram is normal. Success in reversing the bone marrow depression declines dramatically after 8 weeks of estrus, and any approach other than vigorous therapy can prove to be unrewarding.

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Hypoglycemia Several cases of hypoglycemia in ferrets have been characterized by recurrent, intermittent, and often progressive episodes of abnormal behavior, weakness, ataxia, tremors, seizures, paraplegia (hindlimbs), and collapse.47·50·59 Dehydration and hypothermia are the common symptow~ that require fluid therapy, and rapid amelioration of clinical signs occurs if dextrose solutions are used . Plasma blood glucose levels from clinically affected or fasted (6 to 12 hours) ferrets range from 30 to 60 mg per dl. Insulin assays have been greater than 40 j.LU per ml (normal insulin values for dog and cat are 0.5 to 0. 7 j.LU per ml). Calculation of the amended insulin ratio should give a value of 30 or greater to be diagnostic for beta-cell tumors or insulinoma. Treatment should include stabilization of the ferret by frequent feeding of high carbohydrate meals. Exploratory laparotomy is indicated, but presurgical fasting should be minimal, with provision of dextrose for consumption. Parenteral dextrose with hydrocortisone succinate supplementation should be included in the surgical care. Examination and resection of abnormal pancreatic foci, the pancreatic lymph node, and biopsy of other viscera (liver) are indicated because beta-cell tumors frequently metastasize to regional lymph nodes and liver. Histologic examination should be employed to confirm the clinical diagnosis. If blood glucose levels remain depressed after surgery, active neoplastic or hyperplastic beta cells remain. Medical management of the ferret pre- or postsurgically may include provision offrequent meals or high-calorie snacks, prednisolone (0.2 mg per kg twice daily) to enhance gluconeogenesis and reduce insulin binding at receptor sites, and diazoxide (5 mg twice daily) to inhibit insulin release. 50 Diabetes Mellitus Diabetes mellitus (DM) has been diagnosed in aged ferrets that present with polyuria, polydipsia, and loss of body condition. Blood glucose values of greater than 160 mg per dl are accompanied by glucosuria and, in some cases, ketonuria. Approach to therapy is the same as in dogs, although the dose of NPH insulin may be more difficult to regulate because of the problems associated with frequent blood sampling. Treatment of DM in a blackfooted ferret (Mustela nigripes, the indigenous and endangered ferret of North America) included administration of 5 to 6 units of NPH (isophane) insulin to induce euglycemia. 86 Practitioners treating pet ferrets with D M have started with a standard 1 to 2 units NPH insulin per kilogram body weight, but found that 3 to 4 units per kilogram body weight (up to 6 units of NPH insulin) as determined by monitoring glucose levels was necessary to reduce blood glucose levels. Insulin doses can be divided for twice daily administration, with feeding of a meal around 2 hours postinj.ection. The use of protamine zinc insulin (PZI) in ferrets has not been reported. Urinary Calculi Renal and cystic calculi may cause urinary incontinence, lethargy, uremia, and death. Ferrets as well as mink are frequently affected with "wet belly"; however, in ferrets, both sexes are affected. Diagnosis and medical management of urolithiasis and cystitis in ferrets are simi!ar to that used for cats. Surgical intervention may be necessary for large cystic calculi. Urethral

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obstruction or urethrostomy has not been reported in ferrets . Long-term management would include feeding low-ash diets, encouraging adequate water consumption, and acidifying the urine. Heart Disease Congestive heart disease with pleural and/or abdominal effusions has been diagnosed in aged ferrets. 31 Clinically, ferrets with heart disease present with a history of decreased activity; weight loss; dyspnea, polypnea, or exercise intolerance; cyanotic or normal mucous membranes; and distention of the abdomen. Auscultation of systolic murmurs, muffled heart sounds or moist rales; demonstration of electrocardiographic abnormalities including tachycardia, supraventricular or ventricular contractions, increased P or QRS waves, or conduction defects; echocardiographic imaging of reduced wall movement or large end-diastolic or end-systolic dimensions; and radiographic evidence of cardiomegaly, enlarged pulmonary veins, and effusions have been noted on examination. Diagnosis and the approach to medical management similar to that used in other companion animals should be instituted based on the functional failure of the heart and physiologic integrity of the ferret. Moderation of exercise, feeding a low-salt diet, diuretic therapy, thoracocentesis/abdominocentesis, and provision of an oxygen-rich environment are therapeutic strategies that should precede antiarrhythmic or inotropic drug therapy because removal of the excessive fluid often allows more accurate evaluation of cardiac function . Digitalization with monitoring of cardiac output has been reported in the ferret, although cardiac decompensation and effusions recurred. 31 Digitalization using feline doses for digoxin (0.007 to 0.008 mg per kg divided twice daily) can be followed by a maintenance dose (0.002 to 0.004 mg per kg divided twice daily). However, success with long-term digitalis glycoside or with nonglycoside inotropic drugs such as amrinone has yet to be documented. Ferrets with cardiac arrhythmias have been stabilized with beta-adrenoreceptor blocking drug therapy using propranolol (2.0 to 5.0 mg per mg once a day or divided twice daily) in conjunction with diuretic and supportive care. Use of other antiarrhythmic drugs including calcium- or sodium-channel blocking or dopaminergic drugs has not been reported in ferrets, but a rule of thumb in choosing drugs and their doses would be to use regimens compatible for cats. Postmortem examination of a small number of ferrets that died of heart failure revealed a range of cardiac lesions including thickening of mitral valve leaflet with myocardial and endocardial fibrosis, aortic outflow constriction, myofibrillar necrosis and hypertrophy with coronary arterial medial hypertrophy, vegetative bacterial endocarditis, and papillary muscle atrophy. 31 •86 Not too surprising, however, are the causes of clinical congestive heart failure that result from dirofilariasis, a frequent postmortem diagnosis. Miscellaneous Disorders A variety of functional abnormalities reported as clinical syndromes or necropsy diagnoses include polycystic kidneys, central nervous system disorders, atrophic gastritis, idiopathic hypersplenism, intervertebral disc syndrome with and without hemivertebrae, accessory splenic tissue, and gastric foreign bodies. 4 ·32·39•68

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A multitude of miscellaneous conditions believed to have underlying or predisposing metabolic abnormalities includes juvenile cataracts (without diabetes mellitus), eclampsia, pregnancy toxemia, and gastric ulcers. 4 •5 •86 •87 •96 Although eclampsia and pregnancy toxemia tend to be less common in ferrets that are fed an adequate plane of nutrition for mustelids, the disorders appear to be familial and are perhaps associated with such traits as abundant lactation and large litter production. Gastric ulceration is thought to be stress induced. Ulcers can occur acutely (within 1 hour) and hemorrhage from the eroded mucosa probably contributes to the black or tarry nature of the diarrhea that is so frequently eliminated by sick ferrets. In one study, neither excessive acid nor pepsin production was measured in ferrets with gastric ulcers. 5 The metabolic diseases in ferrets may be an indication of APUDomas, or neoplasia of the amine, precursor, uptake, and decarboxylation (APUD) system. Hypothetically, the APUD system describes the function of cells of neural crest origin that secrete hormones, and includes cells in the pituitary, thyroid, and adrenal glands, pancreatic islets, gastrointestinal tract, and sympathetic nervous system. The most common APUD neoplasms in dogs, and perhaps in ferrets, are beta-cell tumors or insulinoma. Gastrinomas, which result in gastric mucosal hypertrophy and ulceration, have also been diagnosed in conjunction with pancreatic tumors in dogs. Other manifestations of APUDomas may include hyperglycemic syndrome, malabsorption, secretory diarrhea, and other neoplastic syndromes associated with excessive hormone production. NEOPLASTIC DISEASES Cutaneous Neoplasms A common cutaneous cancer of ferrets is the benign mast cell tumors most commonly characterized as hairless, raised, discrete nodules up to 1 em in diameter that are found on the trunk of older animals. 94 Fine needle aspiration biopsy and cytologic examination will reveal mature mast cells. These tumors disappear and recur over a period of time. Anaplasia, aggressive invasion of subcutaneous tissues, and systemic disease have not been described in the ferret. Discrete and disseminated forms of squamous cell carcinoma have been diagnosed in ferrets following biopsy of the tumors. 21 •70 Either surgical resection of the tumor alone (for discrete masses) or in combination with chemotherapy with melphalan (7 mg per m2 body surface once a day for 5 days) for disseminated tumors has been attempted and met with mixed results. Surgical resection of discrete carcinomas was apparently curative, but the ferret with disseminated squamous cell carcinoma that was treated with melphalan developed bloody diarrhea and died shortly after the completion of chemotherapy. Adenocarcinoma of preputial or sweat gland origin was diagnosed and surgically removed from a 4.5-year-old castrated hob. 62 Recurrence of the primary tumor and subsequent metastasis to the inguinal lymph node prompted cobalt 60 teletherapy. The first regimen consisted of a dose of 5 Gy twice a week for eight treatments and a total dose of 40 Gy (4000 rad).

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Complete regression of the tumor as determined by palpation occurred by the end of the teletherapy. The primary tumor and the inguinal mass recurred, and irradiation with 5 Gy doses for a total of25 Gy (2500 rad) followed surgical resection of the masses. Again, rapid tumor regression was noted. Nodules were again palpated at the site of the primary tumor 60 days after the second radiotherapy, but the animal was not treated further. A side effect of the radiation therapy was dry scaling of the skin. Basal cell carcinoma, sebaceous and sweat gland adenocarcinomas, and papillary cystadenocarcinoma of the mammary gland have been diagnosed in aged, captive, black-footed ferrets (Mustela nigripes). Although neoplasms of the adnexal and mammary glands are relatively common in bitches and queens, the incidence of these cancers in domestic ferrets is thought to be low. Hemolymphatic Tumors Ferrets, like cats, may have a high incidence of neoplasms of the hemolymphatic system. Lymphosarcoma, especially with thymic involvement, has been documented frequently in young, often pubertal ferrets. 21 Clinically, ferrets with lymphosarcoma display nonspecific signs of lethargy, anorexia, occasionally dyspriea, or acute death. On thoracic and abdominal radiographs, large cranial mediastinal masses, dorsal displacement of the trachea or sternal displacement of the cardiac silhoJ.lette, splenomegaly, and lymphadenopathy have been visualized. Attempts to induce remission with chemotherapeutic regimens of vincristine (0.025 to 0.05 mg per kg, IV), cyclophosphamide (10 mg per kg, IV), and prednisolone (0.5 mg per kg divided twice a day, orally) have been discouraging, perhaps because the neoplasia is well advanced before the ferret diplays clinical signs. Feline leukemia virus does not appear to produce disease in ferrets, and any relation between ferret lymphosarcoma and feline leukemia virus is speculative. Sera from asymptomatic ferrets have been test-positive on commercial feline leukemia kits, but the significance and the specificity of the positive results are not known. 86 A few other neoplasms reported in ferrets include malignant megakaryocytic myelosis and plasma cell myeloma in middle-aged animals. Malignant megakaryocytic myelosis was diagnosed postmortem in a jill after a short and unresponsive treatment regimen for dehydration and lethargy. 22 Hepatosplenomegaly was the prominent gross lesion at necropsy, and the morphologic diagnosis was based on the proliferation and anaplasia of the megakaryocytic line in extramedullary tissues. The possibility of inappropriate extramedullary hematopoiesis from estrogen toxicity was ruled out because none of the other hematopoietic cell lines we~e neoplastic. Plasma cell myeloma was also diagnosed from histologic examination of tissues from a neutered hob that presented with clinical signs of paraparesis that progressed to hindlimb paralysis prior to death. A tan, lobulated mass of neoplastic plasma cells encompassed the sixth lumbar vertebra and invaded adjacent bone, marrow, muscle, and the vertebral canal. Plasma cells also infiltrated liver, spleen, lymph nodes, kidney, and thyroid glands. Serum proteins were not measured or electrophoretically separated to evaluate the paraproteinemia expected with plasma cell myeloma.

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Endocrine Neoplasms With the exception of insulinomas, neoplasia of endocrine glands is somewhat uncommon and does not impair the activities of the ferret. Pancreatic islet cell hyperplasia and adenocarcinoma have been diagnosed on surgical and necropsy biopsy from ferrets with a history of intermittent hypoglycemia (see the section on hypoglycemia). In a report of estrous behavior in a spayed ferret, an adenoma of the adrenal gland was diagnosed and thought to have been actively secreting estrogens that incited the unexpected behavior. 21 Ovarian smooth muscle hyperplasia and leiomyoma are recognized as incidental findings in a high proportion of jills; the cellular infiltration did not seem to impede ovulation or affect reproductive indexes. 25 Ovarian thecomas were found in a jill at necropsy, and the tumors were associated with endometrial hyperplasia. 21 Miscellaneous Neoplasms A variety of other tumors that have been diagnosed antemortem and postmortem include adenoma and adenocarcinoma of the glandular pancreas, hepatocellular carcinoma, and osteoma. 4 •21 •46

SUMMARY There is still much more to be learned about ferret behavior, nutrition, and physiologic responses associated with aging, disease, and environmental stimuli. The many similarities in the clinical disorders of ferrets and other small companion animals should emphasize the importance of using the same diagnostic methods developed for common companion animals in examinations of ferrets. There is still very little known of the efficacy of a wide spectrum of drugs in ferrets, and judicious use of pharmacodynamic agents that are safe for cats would be a reasonable approach to drug therapy.

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