An Update on EPM: The Latest in Diagnostics and Treatment

Jean-Yin Tan, DVM, DACVIM Large Animal Internal Medicine

Diagnostics

“My horse has been just a little off, Doc. I don’t really want to pay for a full-blown lameness or neuro exam or anything. Would you mind just taking a blood test for EPM while you’re here?”

If you’re a general equine practitioner, you’ve likely been asked a question like this in the middle of a routine vaccine visit, by a horse owner who’s been dabbling in reading a few of the latest horse publications and learning some catch phrases from her friends. Since you were hoping to just quickly knock off a few vaccines while on your way to 5 more lengthy calls that you have to cram into your afternoon, chances are you’ve been tempted to just pull the blood sample. After all, a full neurologic exam would take a lot of time and money, and that’s not what the owner wants to do, right?

It might be time to educate your client. The first rule of interpreting any diagnostic tests for EPM is that a clinical diagnosis of EPM must be made. In the absence of detectable neurologic deficits and elimination of other differential diagnoses, confirmation of exposure to Sarcocystis neurona via any number of diagnostic tests can mean very little.

Western Blot. Sensitivity is 80% and specificity 38% for testing of the serum of neurologic horses. That means it can be used to rule out EPM, but the low specificity means a large number of false positives, making the test inappropriate for diagnosing EPM. Cross-reaction may also occur with nonpathogenic Sarcocystis fayeri, which uses the horse as a natural intermediate host.

IFAT. The indirect immunofluorescent antibody test is a quantitative serologic test for EPM which provides actual titers and a likelihood ratio of the disease. Although sensitivity (83% for serum) is similar to that of the Western blot, specificity (97% for serum) is higher using the IFAT. Serum and CSF results have a moderately strong correlation. Furthermore, blood contamination of up to 104 RBCs/l does not affect CSF test results. The IFAT can also be used to detect EPM attributed to Neospora hughesii. There is however, cross-reaction with S. fayeri.

SAG-1 ELISA. The latest test is an ELISA that detects a specific surface antigen SAG-1 found on S. neurona merozoites. Although the low sensitivity and specificity (68% and 71% respectively) and geographical variation in presence of the surface antigen inhibits the commercially available SAG-1 ELISA from being a reliable diagnostic test, there is some potential for a more reliable SAG-2 ELISA in the future, especially given the lack of cross-reactivity with S. fayeri and N. hughesi.

So, what should I do? The Western Blot, IFAT, and SAG-1 ELISA are all different ways of detecting anti-S. neurona antibodies in serum or CSF. Currently, the IFAT offers the highest sensitivity and specificity. It is important, however, to take into consideration that cross-reaction with S. fayeri and vaccination can affect results.

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Treatment
“Doc, I read in a horse magazine about a medication called toltrazuril? Do you think we should try that on my horse? I think it’s supposed to work real well on EPM.”

It’s busy season and you haven’t had much of a chance to sit down, let alone read the latest in journals on equine neurologic disease. If you’ve never heard of toltrazuril, don’t panic. I’ve put together a brief synopsis of drugs used for EPM below.

Antiprotozoals. FDA approved options are: sulfadiazine/pyrimethamine, ponazuril, nitazoxanide, and diclazuril. In the studies cited, successful treatment is defined as improvement in neurological grade by at least 1 level or CSF testing becoming negative on Western blot.

Sulfadiazine/pyrimethamine (ReBalance). At 20mg/kg sulfadiazine and 1mg/kg pyrimethamine orally daily for 90 days, 62% of affected horses have successful outcomes. However, adverse effects from folic acid deficiency include bone marrow suppression (12%), GI disturbance, decreased spermatogenesis in stallions, and congenital defects in foals when used in pregnant mares.


Ponazuril (Marquis). At 5mg/kg orally daily for 28 days, this antiprotozoal drug is responsible for the successful treatment of 60% of horses and at double-dose, 65% of affected horses. There were no adverse effects in a study of 101 horses. However, possible side effects listed by the manufacturer include blisters, hives, diarrhea, colic, and a seizure.

Nitazoxanide (Navigator). Although no longer commercially available, this antiparasitic drug used at 50mg/kg orally daily for 28 days has been found to successfully treat 57% of horses. However, fatal enterocolitis, fever, anorexia, lethargy are noted side effects and affect up to 31% of horses.

Diclazuril. This FDA-approved but unmarketed antiprotozoal drug has been used as pellets at 1mg/kg orally daily for 28 days with a 67% success rate. Adverse reactions that may not necessarily be correlated with the drug include laminitis or decline in neurologic status.

Toltrazuril (Baycox 5%). An anti-coccidial drug used in other species, this drug is being reviewed by the FDA for use in horses for EPM. At 5mg/kg orally daily for 10 days, it has been found in limited studies to achieve excellent absorption into CSF with no adverse effects.

Antiinflammatories. Nonsteroidal antiinflammatory drugs can help decrease initial worsening of signs during treatment associated with inflammatory response to the parasite. Corticosteroids are not recommended but single doses may help curb inflammation and allow antiprotozoal drugs to work. Many veterinarians use DMSO as well. There have been no clinical trials to support or refute the use of Vitamin E and thiamine supplementation.

Immunostimulants. Some veterinarians have advocated the use of immunomodulation with drugs such as Prioponibacterium acnes, mycobacterial cell wall extracts, levamisole, and alpha-interferon. These could potentially affect T cell-mediated immunity and stimulate macrophages. However, without further investigation, theoretical immunopathologic effects on the CNS should also be considered.

What do I do if the horse relapses? It is theorized that 10% of horses relapse within 3 years of discontinuation of therapy. Treatment options include longer duration of therapy (off-label doubling of the standard period of treatment), using higher doses of ponazuril, combining ponazuril with sulfadiazine/pyrimethamine, using twice-weekly continuous therapy with sulfadiazine/pyrimethamine, and possibly using anthelmintic levamisole as an immunostimulant.

So…What should I treat with? Currently the only commercially available antiprotozoal with the least reported adverse effects is ponazuril. However, look for other options such as diclazuril or toltrazuril appearing on the market in the future. Although conservative use of antiinflammatories is widely accepted, the efficacy of treatments such as DMSO, thiamine, Vitamin E, and immunostimulants has not been specifically investigated but can be used at your discretion.

UPDATE
The new SAG-2 and SAG-4,3 assays for EPM which are now available. These have possible advantages over the previous available assays because:

-These surface antigens are those most commonly expressed by S. neurona strains
-Quantitative test

-Provide serum/CSF ratios

The disadvantage is that both CSF and blood samples need to be submitted to provide accurate information.

References
1. Daft B, Barr, BC, Gardner, IA, et al. Sensitivity and specificity of western blot testing of cerebrospinal fluid and serum for diagnosis of equine protozoal myeloencephalitis in horses with and without neurologic abnormalities. J Am Vet Med Assoc 2002;221:1007-1013.

2. Duarte P, Daft, BM, Conrad, PA, Packham, AE, Gardner, AE. Comparison of a serum indirect fluorescent antibody test with two Western blot tests for the diagnosis of equine protozoal myeloencephalitis. J Vet Diagn Invest 2003;15:8-13.

3. Duarte P, Daft, BM, Conrad, PA, et al. Evaluation and comparison of an indirect fluorescent antibody test for detection of antibodies to Sarcocystis neurona, using serum and cerebrospinal fluid of naturally and experimentally infected, and vaccinated horses. J Parasitol 2004;90:379-386.

4. Dubey J, Lindsay, DS, Saville, WJA, et al. A review of Sarcocystis neurona and equine protozoal myeloencephalitis (EPM). Vet Parasit 2001;95:89-131.

5. Furr M, McKenzie, H, Saville, WJA, et al. Prophylactic administration of ponazuril reduces clinical signs and delays seroconversion in horses challenged with Sarcocystis neurona. J Paristol 2006;92:637-643.

6. Granstrom D, Howe, D, Bentz, B, et al. Current treatments for equine protozoal myeloencephalitis. Equine Disease Quarterly 2007;16.

7. Hoane J, Morrow, JK, Saville WJ, et al. Enzyme-linked immunosorbent assays for detection of equine antibodies specific to Sarcocystis neurona surface antigens. Clin Diagn Lab Immunol 2005;12:1050-1056.

8. Johnson A. Evidence-based review of diagnosis and treatment of Sarcocystis neurona infection (Equine Protozoal Myeloencephalitis). AAEP 2009.

9. MacKay R. Equine essentials - equine protozoal myeloencephalitis: Managing relapses. Veterinary Technician 2008;29.

10. Reed S, Saville, WJ, Schneider, RK. Neurologic disease: Current topics in-depth. AAEP 2003.

11. Saville W, Dubey, JP, Oglesbee, MJ, et al. Experimental infection of ponies with Sarcocystis fayeri and differentiation from Sarcocystis neurona infections in horses. J Parasitol 2004;90:1487-1491.

Blue Buffalo Dog Food Recall

The endocrine lab at Michigan State recently made the association between dogs with hypercalcemia and ingestion of Blue Buffalo dog food.

There is now an official recall of certain lot numbers. Here is the FDA announcement.

Meet Dr. Jean-Yin Tan

Dr. Tan graduated from Cornell University in 2005. She went on to complete an internship at Mid-Atlantic Equine Medical Center in NJ and a large animal internal medicine residency at the University of Minnesota. She spent a year at UC Davis completing an Equine Primary Care fellowship and is now working in New Jersey. Dr. Tan has publications in journals including the American Journal of Veterinary Research and the Canadian Veterinary Journal and has spoken at various local conferences as well as ACVIM Forum. Her interests include neonatology, respiratory disease, and gastroenterology. She has experience with all large animals as well as horses!

Case Spotlight - Young Anemic Cat

“Teddy” – 1 and ½ year old MN DSH -
Cindy Stubbs, DVM, DACVIM (Small Animal Internal Medicine)

History
Owner reports lethargic, not as playful as normal, appetite decreased. PCR panel pending.
Cat one of three from a litter raised by owner. Littermates still in same household and are clinically normal with normal blood work. This pet reported to be quieter than the rest.

Never tested for FeLV/FIV. Was exposed to a FeLV positive cat in same house but separated.
No fever.
Inside only cat.
On Revolution for flea control. No history of exposure to fleas and ticks.

Pet looks fine on exam - normal weight and appearance. No overt abnormalities.

Blood work shows significant anemia with little to no regeneration. Path review still pending.

Assessment
Anemia - suspect infectious disease as underlying cause (Feline Leukemia virus most likely), immune-disease also a consideration. Could have had an infectious disease that sparked an immune component to anemia.

Recommendations
(1) Check FeLV/FIV status on peripheral blood of this cat and other cats in the household.

(2) If negative, consider bone marrow aspirate or core biopsy. Perform CBC at time of bone marrow sampling so lab can compare. Perform Feline Leukemia IFA or PCR on the bone marrow sample (National Veterinary Labs recommended).

(3) Consider empirical treatment with doxycycline 5 mg/kg every 12 hours or 10 mg/kg once daily (follow with food or water to prevent esophageal issues) and/or prednisolone 5-10 mg/cat daily. Prednisolone preferred in feline patients as it is the active form of prednisone. Cats can make the conversion of prednisone to prednisolone in their liver but it is not reliable.

(4) Based on exam, pet has been anemic for some time and has adjusted to the anemia. A blood transfusion is not indicated at this time.

Follow Up
Follow-up telephone discussion: "Teddy" tested positive for both FeLV and FIV. The littermates were negative. Since the owner wishes to keep all the cats together, it will be important to stress the need for continued vaccination for FeLV and advise owner of the efficacy of the vaccines.

I recommend treatment for "Teddy" consist of doxycycline 10 mg/kg once daily for 3 weeks and possibly prednisolone 5 mg daily for 3 weeks. Reassess the PCV after that period of time to determine if there is a response to therapy. If the red blood cell count improves, the medications may have to be continued long term to maintain the PCV.

Pet should be handled as an immunosuppressed patient, with every cough or sneeze treated in a more aggressive manner. His long-term prognosis is quite guarded especially with the development of the apparent non-regenerative anemia. However, if the anemia does improve there is a chance he might do well for a longer period of time.

Anti-viral therapy has been met with questionable efficacy and I do not routinely recommend their use.

Meet Dr. Cindy Stubbs

Cynthia Stubbs, DVM, DACVIM - Small Animal Internal Medicine

Dr. Cindy Stubbs received her DVM from North Carolina State University in 1995. She then went on to complete a one-year rotating Internship in Small Animal Medicine and Surgery at Texas A&M University, followed by a Residency in Small Animal Medicine at Colorado State University (CSU). Her research interest was feline infectious diseases. In 1999, she received a Master's Degree in Clinical Sciences based on this research at CSU. Dr. Stubbs then worked for 2 years in a large, multi-doctor specialty hospital in Marietta, GA. From 2001-2008, Dr. Stubbs was the owner and internist for North Georgia Veterinary Specialty Care in Suwanee, GA. She currently provides internal medicine services at Triangle Veterinary Emergency Clinic in Durham, NC.

Her special interests in internal medicine include all things feline, especially infectious diseases. She speaks at local, state and national conferences about topics in feline medicine (systemic hypertension, diabetes mellitus, respiratory disease, renal disease, and geriatric care to name a few). She also enjoys working with canine patients, especially with their interesting endocrine concerns.

She currently lives in North Carilona with her husband, Paul Frank, their two young human children Jack and Lily, and their animal children (5 cats and 2 dogs). She enjoys reading and gardening in her "spare" time.

Meet Dr. Lisa Cellio

Lisa Cellio, DVM, Diplomate, ACVIM

Dr. Lisa Cellio is a Diplomate of the American College of Veterinary Internal Medicine. She completed her undergraduate education at the University of Notre Dame with a Bachelor’s Degree in biology in 1994. She then attended veterinary school at the Ohio State University College of Veterinary Medicine. She was awarded a Doctorate of Veterinary Medicine in 1998.

Dr. Cellio went on to further her veterinary education with a small animal rotating internship at Michigan Veterinary Specialists from 1998 to 1999. She spent the next three years as an emergency veterinarian in a busy emergency and referral institution. Dr. Cellio completed a three year residency program at Veterinary Specialty and Emergency Center in Overland Park, Kansas. In 2005, she became board-certified as a Diplomate to the American College of Veterinary Internal Medicine.

Dr. Cellio is married and has two young children. The family also includes two Cavalier King Charles Spaniels and one cat. Her hobbies include running, yoga and traveling.

HISTOPLASMOSIS

By Lisa Cellio, DVM, Diplomate AVCIM (Small Animal Internal Medicine)

Histoplasmosis is a soil-borne dimorphic fungus that lives in warm moist and humid conditions. The causative agent is Histoplasma capsulatum and grows best in soil rich in nitrogen organic matter (such as areas with bird or bat excrement.) Histoplasmosis is endemic in temperate and subtropical regions and, in the United States. is most commonly found around the Ohio, Missouri, and Mississippi river valleys.

Infections occur after inhalation of the microconidia. In the body, the microconidia convert to the yeast phase in the lungs and reproduce by budding. The yeast are phagocytized by mononuclear cells. The incubation period is 12-16 days. Infections usually start in the lungs and spread to the lymph nodes and then other organs, including the gastrointestinal system, liver, spleen, bone marrow, adrenal glands, eyes, and, occasionally, the skin or CNS. Occasionally there is an occurrence of the gastrointestinal histoplasmosis without respiratory involvement suggesting the gastrointestinal tract may also be a primary source of infection.

Clinical signs vary with species. Cats have nonspecific signs because of disseminated disease. Dyspnea, tachypnea and abnormal respiratory sounds are common findings. Dogs more commonly have signs of inappetance, fever and weight loss. Signs may be limited to the respiratory tract but most have gastrointestinal involvement. Pointers, Weimaraners, and Brittany spaniels seem to be overrepresented.

Diagnosis is best made by the identification of small (2-4 um) organisms with halos seen on aspirates or impression smears. Occasionally these can also be found in circulating white blood cells or even in CSF. Organisms are most commonly found in the lung, lymph node or bone marrow aspirates in cats. In dogs, rectal scrapes, imprints of colonic biopsies or aspirates of the liver, lung, spleen or bone marrow are best. Histoplasmosis can be difficult to detect in biopsy specimens with hematoxylin and eosin stain. Special fungal stains should be used on biopsy specimens. Fungal isolation is not recommended because the organism is pathogenic. Serology is unreliable. The Histoplasmosis antigen test (Mira Vista) is gaining popularity. It can be used to support disease and is useful in monitoring for resolution with treatment.

Other abnormalities noted include a normocytic, normochromic, nonregenative anemia. Hypoalbuminemia occurs more commonly in cats. Occasionally, clotting times can be abnormal suggestive of microangiopathic hemolysis. Chest radiographs may reveal a linear or diffuse pulmonary interstitial pattern. Hilar lymphadenopathy is more common in dogs than in cats.

Itraconazole is the treatment of choice in both dogs and cats. Side effects include anorexia, vomiting and diarrhea, increased liver enzymes and a dose-dependent cutaneous vasculitis or dermatitis. Itraconazole should be continued 30 days past resolution of clinical signs and usually is a 4-6 month course. Histoplasma antigen can also be monitored. Pulmonary histoplasmosis in dogs can be self-limiting and may resolve without treatment. Itraconazole has poor penetration to the eyes and CNS but has led to resolution. Fluconazole has better penetration to the eye and CNS but is not as effective overall as itraconazole in the treatment of Histoplasmosis. It may also antagonize amphotercin B. Lipid complexed amphotercin B can be used alone or in combination with itraconazole for severe disease. It is helpful in animals that are anorexic or having gastrointestinal signs which may worsen on oral antifungal medications.

Corticosteriods often need to be used early in the course of treatment, although their use is controversial. They may help to decrease the inflammation associated with destruction of the fungus. They can also help to increase the appetite of cats or dogs with histoplasmosis. Initial response to therapy with itraconazole may take 7-14 days. Some animals may experience worsening in their respiratory signs in the first week of therapy. Bloodwork should be monitored approximately every month for changes in the liver enzymes while animals are on itraconazole. Increasing liver enzymes or persistent anorexia in animals undergoing treatment may lead to dosage adjustment or changing of the medication to a different antifungal agent. The prognosis for animals with Histoplasmosis is guarded to fair.


References:
1. Greene, CE. Histoplasmosis, In: Greene, CE.ed. Infectious Disease of the Dog and Cat, 2nd ed. Philadelphia: WB Saunders; 1998, pp.577-583.
2. Sellon, RK, Legendre, AM. Systemic Fungal Infections, In: Bonagura, JD ed. Current Veterinary Therapy XIV. St. Louis: Saunders; 2009, pp.1265-1267

Understanding Normal Rabbit Behavior

Christal Pollock DVM, Dipl. ABVP-Avian

House rabbits can make wonderful pets, and more American households report owning rabbits than any other exotic mammal. Small animal veterinarians are being called upon to care for rabbits with increasing frequency, however approach to the pet rabbit often requires a significant shift in perspective for those used to dealing solely with cats and dogs. Normal rabbit behavior may be unfamiliar and rabbits possess few muscles of facial expression making them difficult to “read” when compared to cats and dogs.

Natural History

The first step in understanding rabbits is to understand the behavior of their wild predecessors. Free-ranging rabbits are communal, territorial animals that live in groups or warrens numbering anywhere from six to eight individuals up to several hundred animals. Rabbits live in burrows that make up a complex network of underground tunnels measuring up to 3 meters in depth and 45 meters in length. Rabbits spend most of the day in their burrows, coming out during early evening and morning hours.

Prey species behavior

Rabbits are prey species. Their survival in the wild depends on the ability to be alert and respond quickly, and this instinct has survived in the house rabbit. Rabbits possess acute senses of smell and hearing. Their first defense when danger is near is to be very still to avoid detection. If that doesn’t work, then rabbits will run using quick bursts of speed and rapid changes in direction.

Prey species like the rabbit tend to mask pain and discomfort, especially when frightened. Recognition and management of pain is crucial since pain in the rabbit may lead to gastrointestinal stasis, or even shock and death.
• Signs of fear in the rabbit include the body flattened in a crouched, motionless position with the feet tucked underneath and the head extended. Ears are often tucked tightly against the head, and the eyes may bulge. The clinician should respond by speaking softly, moving slowly, and approaching the rabbit at eye level.
• Signs of pain may include: anorexia, lethargy (reluctance to move, decreased interest in the environment), teeth grinding in a slow, loud crunching fashion, bulging, often unfocused, eyes, and a hunched posture with the head in an elevated, extended position. Rabbits may lick excessively or even pluck hairs over a painful area or seek hiding places. Respirations may be rapid and shallow.

Normal sounds and actions

Although comparatively silent, rabbits do make a variety of sounds.
• “Purring” is a sound of contentment made when the rabbit is getting a good petting or very tired. The teeth click softly, the head trembles, and the whiskers quiver.
• “Honking” or “oinking” sounds are made in courtship or to gain food or attention.
• Whimpering or low squealing are fretful noises made by a rabbit that does not want to be picked up.
• Finally, but most importantly for veterinarians, some rabbits “talk” by making wheezing or sniffing sounds.
These sounds may be distinguished from congestion by being heard inconsistently and only in conjunction with social interaction.

Interaction with a house rabbit tends to make one more one adept in non-verbal communication.
• A sign of possessiveness is “chinning” when the rabbit rubs its chin on items or people.
• One of the least subtle behaviors is called the “happy hop” or “binky”. The rabbit will jump into the air with the head going in one direction and the rest of the body going in the other direction. “Binkies” appear to denote pure joy. A video clip demonstrating the “happy hop” may be found at: http://www.thebunnyshed.co.uk/TheFAQ.htm.

Age and Breed

Not surprisingly, juvenile rabbits tend to be energetic and extremely inquisitive. Owners are most likely to complain of chewing and other “problem behaviors” in this age group. After one year of age, most rabbits become more sedate and predictable. Rabbits are considered geriatric after 6 to 7 years. At this age they generally sleep more and move more slowly. There are also breed differences in behavior. Large rabbits such as the New Zealand white tend to be calmer than smaller rabbits like the Netherland Dwarf.

Husbandry

Proper house rabbit care is based on normal rabbit behavior:
1. Most rabbits tend to urinate and defecate in the same place each time. This habit of picking a latrine spot means that most rabbits are easily litter trained.
• Place the litter pan in one area of the cage or just outside the cage door, and place many boxes around the room. Initially, limit the rabbit to a small space and limit the amount of time for the rabbit to roam outside of its cage. Placing hay or treats in the litter box may also attract the rabbit to the pan.
• A trained rabbit may urinate outside of its pan if it needs to mark territory due to a stressful event, or with urinary tract disease.
• Rabbits will also mark territory by depositing hard fecal pellets. This behavior is most intensely practiced by adult intact males, however even castrated rabbits mark new areas in this manner.

2. To feel comfortable and safe, rabbits like to go on, under, beside, or beneath objects.
• Boxes are often a favored item, however few rabbits will use a box with only one hole in it. After all, a predator can trap you if your burrow has only one opening.
• Females often have a stronger urge to burrow than males.

3. Rabbits have an instinctive urge to chew.
• “Bunny proofing” prevents property destruction and protects rabbits from harm. Avoid rooms with wall to wall carpet, low shelves, high numbers of electrical cords, and/or books or plants within 2 feet of the floor. Protect exposed cords using polyethylene tubing or armoured cable.
• Provide safe and fun chewing and digging alternatives free of chemicals or varnishes such as rice matting and willow bark. Many rabbit toys focus on the need to chew. The House Rabbit Society [link to http://www.rabbit.org/faq/sections/toys.html] has an excellent recommended toy list.

4. Rabbits are crepuscular creatures that normally rest and sleep during most of the day, and are most active at dusk and dawn.

5. Many experts on house rabbit care agree that most rabbits are not meant to live in solitude away from members of their own kind.
• The need for companionship can only be met partially by a human, although rabbits may display affection and acceptance for their owners through grooming.
• Signs of loneliness in rabbits commonly include boredom, depression, and withdrawal. Destructiveness and hyperactivity are seen in some smaller breed rabbits.
• Despite their need for companionship, introductions can prove challenging, and some aggression should be expected. Introducing two intact rabbits of any gender is likely to result in fighting, breeding behavior, or both. Introductions may be least stressful when they involve neutered adults of opposite sexes. Strive to match ages, however mixing breeds often works well such as a dwarf rabbit placed with a large breed rabbit. Introduce rabbits for short 20-minute sessions in a neutral territory.

Sexual Behavior

Puberty occurs just after the maximal rate of growth, with small breeds reaching puberty between 3.5 to 5 months of age and large breeds maturing at 5 to 8 months. Does mature earlier than bucks. Signs of sexual maturity may include aggression, territoriality, circling and spraying urine, and frenzied digging. Males show constant libido, attempting to mount cage mates, while females tend to behave quite aloof. Rabbits are induced ovulators, with potentially long periods of estrus. If mating does not occur, ovarian follicles regress and new follicles mature, therefore sexual behavior does not go away in the rabbit unless the animal is neutered or bred.

Spaying and neutering improves litter box habits and reduces territorial aggression, mounting, and spraying. The average time for negative sexual activity to lessen significantly after surgery is 2 weeks, and activity may be completely gone by this time in females. It generally takes 2 months until sexual activity is completely gone in males, and cessation of sexual activity may take 4 to 8 months in larger breeds.

Conclusion

The approach to a prey species like the rabbit often calls for a profound paradigm shift for clinicians used to dealing only with cats and dogs. The ability to truly understand rabbits will improve the clinician’s ability to not only diagnose and treat medical conditions, but also help owners love and care for their pets.

References

American Veterinary Medical Association. US Pet ownership and demographics sourcebook. Schaumburg, IL: AVMA 2002.

Bays TB, Lightfoot TL, Mayer J. Exotic Pet Behavior: Birds, Reptiles, and Small Mammals. WB Saunders, St. Louis, 2006.

Bradley T. Rabbits: Understanding Normal Behavior. Exotic DVM 2(1): 19-24, 2000.

Checchi MJ. Are You the Pet for Me?: Choosing the Right Pet for Your Family. St. Martin’s Press, New York, 1999.

Davis SE, Demello M. Stories Rabbits Tell: A Natural and Cultural History of a Misunderstood Creature. Lantern Books, New York, 2006.

Harriman M. House Rabbit Handbook: How to Live with an Urban Rabbit, 4th edition. Drollery Press, Alameda, 2005.

Lockley R. The Private Life of the Rabbit. Avon, 1975.

Mayer J. Natural history of the rabbit (Oryctolagus cuniculus). Exotic Mammal Medicine and Surgery. p.6

McBride A, Bondarenko N. Why Does My Rabbit…? Souvenir Press, London, 2003.

Isbell C, Pavia A. Rabbits for Dummies. For Dummies, 2009.

Quesenberry KE, Carpenter JW. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. WB Saunders. St. Louis, Missouri, 2005.

Thompson, Henry. The European Rabbit: The History and Biology of a Successful Colonizer. Oxford University Press, New York, 1994.

Keeping up on the Science about Neutering

By C. Scott Bailey, DVM, MS, DACT

Keeping up with the discussion surrounding ovariohystorectomy can be difficult. In veterinary school, most of us were taught, as dogma, that dogs and cats should be neutered. Once in practice, however, other points of view and experiences make this decision less straightforward. We are faced with questions such as, “Should all animals be neutered? At what age should they be neutered? Are there contraindications or risk-factors associated with neutering beside the obvious surgical complications?” Often owners come with preformed opinions about these questions, and as veterinarians it is our job to give them balanced and scientifically accurate information so that their decision is based on more than blogs on the internet.

In the last 2 years, three well-written reviews of the veterinary literature have become available detailing benefits and potential complications (Root Kustritz MV - JAVMA 2007, Sanborn MS - Internet Source 2007, Reichler IM – Reprod Dom Anim 2009). Each discusses the potential population benefits in reducing the number of unwanted animals, many of which end up in shelters. In fact, the overall benefits of neutering animals for population control go largely unquestioned in all three reviews, despite a relative lack of epidemiologic studies to support the concept.

Perhaps of greater importance to the practitioner are the benefits to the individual animal and owner. Castration of male cats is often performed to avoid unwanted male sexual behaviors such as spraying and to control territorial behaviors. These behaviors can be so severe that intact males are considered undesirable by many owners. This incentive to neuter is often not present for owners of dogs or female cats; consequently the discussion can be much more heated.

In male dogs, the benefit to population control is likely the greatest, but the scientific evidence pointing to health benefits is the weakest. Intact male dogs have a low incidence of testicular neoplasms (0.9%), which rarely metastasize and have little impact on the dog’s wellbeing. Unlike men, the incidence of prostatic neoplasms is lower in intact animals (0.2-0.6%) than in castrated animals, which have roughly twice the risk of prostatic neoplasia and 2-5 x the risk of osteosarcoma and hemangiosarcoma (each 0.2% of animals, with significant breed variations). In addition, the risk of obesity is somewhat higher in neutered dogs of both gender, corresponding with a slightly increased risk of diabetes mellitus and rupture of the cranial cruciate ligament. That being said, the primary health benefit to a male dog is a dramatic decrease in the incidence of benign prostatic hyperplasia (BPH) and prostatitis, which can be seen in up to 80% of intact male dogs by 6 years of age. However, both these conditions are treatable (either medically or by castration) and BPH often is present in older intact animals without clinical signs and so only a small portion of those animals will be spared discomfort by preventive surgery.

With females, the situation is only slightly clearer. The primary benefit of neutering females lies solidly in the reduction of mammary gland tumors, which affect 2.5% (80% malignancy) of all queens and 3.4% (50% malignancy) of all bitches and which may cause significant morbidity and mortality. Furthermore, these neoplasms can be reduced by more than 90% if the animals are spayed before their first heat. In addition, the risk of pyometra is eliminated by ovariectomy or ovariohysterectomy. Pyometra affects up to 25% of dogs by the age of 10 years and may be associated with significant morbidity and mortality in some of these.
However, potential detriments of neutering include surgical complications (reported incidence of 2.6% in cats and 6.1% in dogs), obesity, and slightly increased risks of diabetes mellitus in both dogs and cats, as well as cranial cruciate rupture in dogs. With reported incidences of 5-20%, urinary incontinence is a common problem of spayed bitches. This has the potential to significantly impact the animal’s welfare, depending on the severity and the owner’s tolerance of this. In addition, spayed females are at increased risk of urinary tract infections, particularly those spayed at an early age and those animals spayed in the face of “puppy vaginitis”. These cases can result in chronic recurrent UTIs that may dramatically affect the animal’s welfare and result in large expenses to the owner.

As in males, neutered bitches also have a roughly 2-5x greater risk for osteosarcoma and hemangiosarcoma than intact animals. Overall the incidence of these neoplasms is low, affecting approximately 0.2% of all dogs. It should be noted, however, that significant breed variation is reported and that this may greatly influence the benefit-risk ratio of neutering a given animal. Dr. Root-Kustritz tabulated the relative risks for the population overall and also noted the breeds that were predisposed to a particular disease, but not the degree to which this would have an effect. Unfortunately, breeders/owners are often more aware of the diseases affecting their particular breed than their veterinarians. Consequently, they may question the traditional viewpoint presented to them. As an example, a study investigating 683 Rottweilers found an overall incidence of osteosarcoma of 12.6% (compared to 0.2% across all breeds), with the diagnosis twice as likely in neutered animals as in intact animals (Cooley DM - Cancer Epidemiology 2002). Furthermore, they demonstrated that Rottweilers neutered prior to one year of age had a significantly greater risk of osteosarcoma than other dogs, with diagnoses occurring in approximately 25% of animals. This example is one of several that highlights the need for breed- or animal-specific decision-making and owner consultation as opposed to a blanket approach to canine contraception.

A recent paper by the same group out of Purdue University further questions the policy of routine gonadectomy (Waters DJ – “accepted article”, Aging Cell 2009). An analysis of lifetime medical histories, age at death and cause of death for exceptionally long-lived Rottweiler dogs (>= 13 years, or >30% longer than the average life-expectancy) demonstrated that female dogs were more likely to achieve this age than male dogs and that gonadectomy before 4 years of age erased this advantage. “In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight and [genetics]”. This appears to fly the face of accepted tradition, which states that neutered animals live longer than their intact counterparts and may be interpreted as a reason to avoid gonadectomy by the larger community. However, the study focused only on exceptionally long-lived animals, not animals overall. In that larger population, it remains well-documented that neutered animals live longer than intact animals (Kraft W – Eur J Med Res 1998, Greer KA – Res Vet Sci 2007).

In conclusion, while many benefits of neutering the small animal patient remain important and valid, it is critical for veterinarians to remain aware of both benefits and contraindications to neutering in order to give owners a balanced, scientifically sound recommendation, individually tailored to the needs and benefits of our patients.