NEUROMUSCULAR CASE OF THE MONTH - JULY 2001

SPECIAL FEATURE: Update! Exercise induced collapse in
Labrador Retrievers- What do we know now?
Contributed by Susan M. Taylor, DVM, Diplomate ACVIM (Internal Medicine)
Western College of Veterinary Medicine
Department of Small Animal Clinical Sciences
University of Saskatchewan
Saskatoon, Saskatchewan, Canada

Last year we began a study of the syndrome of EIC in Labrador Retrievers by putting out a call for affected dogs in a couple of Field Trial Publications (Retriever Field Trial News and Retrievers ONLINE). We have been overwhelmed by the response, receiving letters, emails and telephone calls from greater than 150 owners of affected dogs. This condition is much more common within the breed than we had anticipated when we started the study.

Phase I of our study is designed to intensively evaluate severely affected dogs at rest and then to exercise them for 10 minutes (retrieving bumpers) and evaluate physical, cardiac, neurologic and biochemical parameters during an episode of collapse. We also collect muscle biopsies for microscopic and biochemical evaluation. We are working in collaboration with Dr. Diane Shelton at the Comparative Neuromuscular Laboratory (University of California, San Diego), an authority on neuromuscular and muscle diseases of dogs . Phase I of the study is designed to (1) Determine whether or not the results of routinely available physical, hematologic or biochemical tests could aid veterinarians in establishing the diagnosis of EIC in affected dogs, and (2) Determine whether we could find evidence that EIC is indeed a metabolic myopathy (a problem with energy production within the muscle), and if it is, to attempt to determine the affected biochemical pathway and potential treatment options. This portion of our study is now nearly completed, and although we do not have the test results back from all of the laboratories involved, we have learned quite a bit about what is NOT wrong with these dogs. Dogs with EIC are normal at rest . They are usually extremely fit, muscular, prime athletic specimens of their breed. Orthopedic and cardiovascular examinations are unremarkable before and after exercise. These dogs are not lame and they do not have sore joints, muscles or bones at the time of collapse. They are not developing heart failure or heart rhythm disturbances at the time of collapse. Routine blood analysis is normal at rest and following exercise when compared with normal exercising (but not collapsing) Labradors. These dogs do not therefore have hypoglycemia (low blood sugar) or electrolyte disturbances as has been hypothesized by some veterinarians. They also do not have a respiratory problem, as lung radiographs, ventilation, oxygenation of the blood and acid-base status are normal when compared with unaffected dogs exercised in the same manner. Muscle biopsies from dogs with EIC are structurally normal . This helps to establish the diagnosis by eliminating other muscle diseases causing weakness such as Hereditary Labrador Retriever Myopathy, polymyositis (an immune mediated condition) and infectious myositis (such as Neosporosis). Preliminary laboratory testing of muscle has not supported a diagnosis of exercise-induced malignant hyperthermia or of exertional rhabdomyolysis in dogs with EIC. Serum testing has eliminated acquired myasthenia gravis as a possibility. Biochemical analysis of muscle and some specialized blood and urine tests are still pending. We will need those test results to determine whether or not there is evidence that EIC is a metabolic myopathy and to help identify the affected biochemical pathway.

While the results from Phase I are still pending, we have already been very involved in Phase II of the study. We are examining medical histories (obtained by questionnaire), pedigrees and DNA samples (simple blood test) from as many affected dogs as possible. We are also happy to evaluate videotapes of episodes of collapse in dogs with EIC. We are working in collaboration with scientists at the Canine Neuromuscular Diseases Laboratory in the Department of Veterinary PathoBiology at the University of Minnesota. Phase II of the study is designed to help us to: (1)describe the condition so that it can be more easily recognized and diagnosed by practicing veterinarians and so that the long-term prognosis for affected dogs can be predicted, (2)determine the heritable basis (dominant, recessive, etc)of the condition, and (3)develop a simple DNA test that could be used on adult dogs or puppies to determine if they have the disorder. Participation in Phase II of the study simply involves having owners of affected dogs fill out a questionnaire (Exercise Induced Collapse Questionnaire) and send us a pedigree and permission to access results from blood tests already done by their local veterinarians. We then request that a simple blood sample be sent to our collaborators in Minnesota for DNA analysis (our research grant pays the courier costs). All information provided is kept strictly confidential.

Description of Collapse
Affected dogs can tolerate mild to moderate exercise, but 5 to 15 minutes of strenuous exercise induces weakness , apparent incoordination, and then collapse. Severely affected dogs may collapse whenever they are exercised to this extent - other dogs only exhibit collapse sporadically and the factors important in inducing an episode have not yet been well established. Weakness usually starts in the rear limbs, but if the dog continues to exercise, it will usually progress to the forelimbs, resulting in a generally weak, wobbly gait. Continued exercise will result in collapse and an inability to walk. Even if exercise is terminated before actual collapse is seen, some dogs will continue to deteriorate for 4-5 minutes, exhibiting progressive worsening of their weakness and an inability to rise. The dogs are not in pain during the collapse. They are conscious and usually wanting to continue exercising. After 10 to 20 minutes of rest, the dogs return to normal. NOTE: A few affected dogs have died during exercise or while resting immediately after an episode of exercise-induced collapse so the dog's exercise should ALWAYS be stopped at the first hint of incoordination or wobbliness.

Body temperature is normal at rest in dogs with EIC but is almost always dramatically increased at the time of collapse (temperature >41.5 C, >107.6F). Recently, however, a study performed at the Western College of Veterinary Medicine showed that clinically normal Labrador Retrievers had similar dramatic elevations in body temperature after 10 minutes of strenuous retrieving exercise while exhibiting no signs of weakness or collapse. Dogs with EIC will pant hard during the time of collapse, in an attempt to cool off, but this is similar to normal dogs exercised in the same manner. The time it takes for dogs with EIC to return to their resting temperature after exercise is not different from normal dogs. Although temperature may play some role in EIC, and may contribute to the death of some affected dogs, inability to properly regulate temperature does not appear to be the underlying problem in dogs with EIC.

Factors Contributing to Collapse in Dogs with EIC
Temperature. Actual ambient temperature does not seem to be a critical factor contributing to collapse, but if the temperature is much warmer or the humidity is much higher than what the dog is accustomed to, collapse may be more likely. Affected dogs are less likely to collapse while swimming than when being exercised on land. There are dogs, however, who have exhibited collapse while breaking ice retrieving waterfowl in frigid temperatures.

Excitement. Dogs that exhibit the symptoms of EIC are most likely to have intense, excitable personalities, and it is apparent that their level of excitement plays a role in inducing the collapse. There are severely affected dogs who, if they are very excited, do not require much exercise to induce the collapse. Activities that have been associated with excitement and collapse include quartering for upland game, retrieving birds, balls or frisbees and excited play with other dogs.

Type of Exercise. Routine exercise like jogging, hiking, swimming , most waterfowl hunting and even agility or flyball training are not very likely to induce an episode in dogs with EIC. Activities with continuous intense exercise , particularly if accompanied by a high level of excitement or anxiety most commonly cause collapse. Activities commonly implicated include upland hunting, repetitive "happy retrieves", retrieving drills, and repetition of difficult marks where the dog is being corrected or anticipating correction.

Long Term Outlook
Dogs with EIC do not appear to have progressive disease. Symptomatic dogs are, however, rarely able to continue training or competition. It seems that if affected dogs are removed from training and not exercised excessively the condition will not progress and they will be fine as pets. They are able to continue to live pretty normal lives, if they learn to limit their intense exercise and excitement. Many dogs will seem to "get better" as they age and slow down their activity and their excitement level. It is important that owners of dogs with EIC be made aware that the dog's exercise should be stopped at the first hint of incoordination or wobbliness as some affected dogs have died during collapse when their owners allowed or encouraged continuing exercise.

Veterinary Evaluation of Affected Dogs/Diagnosis
The EIC syndrome can only be diagnosed by ruling out all other muscle disorders and by observing characteristic clinical features, history and laboratory test results in affected dogs. Any dog with exercise intolerance should always have a complete veterinary evaluation to rule-out joint diseases, heart failure, anemia, heart rhythm disturbances, respiratory problems, low blood sugar , myasthenia gravis, myopathies and other systemic disorders. If the syndrome of Labrador Retriever Exercise-Induced Collapse is suspected, then further metabolic and muscle testing should be performed by a veterinarian in collaboration with a laboratory possessing expertise in metabolic disorders of canine muscle.

Treatment
Unfortunately, there is no effective treatment for EIC at this time. Owners of some affected dogs have reported that if they feed their dogs a higher fat diet and/or keep more weight on their dog, that the episodes may be more difficult to induce. Some dogs with EIC have had lower than normal levels of muscle carnitine. This low carnitine is most likely secondary to a metabolic defect in the muscle, rather than indicating a primary deficiency of carnitine, but some affected dogs have had a positive response to oral supplementation with carnitine (50mg/kg 2X/day), CoEnzyme Q10 (100mg/day) and Riboflavin (100 mg/day) - a standard cocktail for metabolic myopathies. The best treatment in most dogs consists of avoiding intensive exercise in conjunction with extreme excitement and ending exercise at the first sign of weakness/wobbliness. Other treatment: There is anecdotal evidence that a few dogs have responded to a nutraceutical (a drug-like substance available through health food stores) called 7-KETO. This is a breakdown product of a steroid hormone dehydroepiandrosterone (DHEA). The dosage used has been 100 mg 2X/day. The precise mechanism of action is unknown, and may be related to insulin and glucose uptake in muscle. It is important that if you try your dog on a treatment and it seems to work (or if it does not) that you let us know. This may hold an important clue in terms of determining the mechanism of collapse in these dogs.

Heredity
Dogs that are clearly affected by the Exercise-Induced Collapse syndrome should not be bred. Littermates and other related dogs are often affected, suggesting that the condition is hereditary, but the genetics of the condition have not been well established. A major problem currently exists in classifying a dog as affected or unaffected by EIC. We believe that there may be many dogs who have the genetic makeup and metabolic abnormalities underlying EIC, yet who never collapse because they do not exercise to the necessary degree. They may not be asked to do the exercise or they may pace themselves or perform the exercise without the mix of enthusiasm and excitement necessary to induce collapse. We will not be able to identify these dogs as being affected by EIC until we have a simple, specific test for the condition. Researchers at the Western College of Veterinary Medicine, in collaboration with researchers at the University of Minnesota are currently involved in a study trying to identify the genetic mutation causing EIC. Once that is accomplished, a simple DNA test will be developed to test any adult dog or puppy for the condition. This will also allow us to establish the heritability of the condition (dominant, recessive, dominant with incomplete penetrance, etc), providing very useful information for breeders trying to prevent or eliminate the condition in their lines.

If you have an affected dog and would like to participate in this study, please contact:
Dr. Susan Taylor, DVM
Diplomate, ACVIM (Internal Medicine)
Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine
University of Saskatchewan, Saskatoon, Saskatchewan, Canada, S7N5B4
Phone:306-966-7093
FAX: 306-966-7174
e-mail: sue.taylor@usask.ca

**All participants in the study will receive periodic updates of our progress in this research**

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