Info about EIC

  • A syndrome of exercise intolerance and collapse (EIC) has been recognized in young adult Labrador Retrievers. 

    A comprehensive investigation of EIC in Labrador Retrievers has been ongoing for nearly a decade, involving investigators from the University of Minnesota (EE Patterson, JR Mickelson, KM Minor), the University of Saskatchewan (SM Taylor, CL Shmon), and the Comparative Neuromuscular Unit at the University of California (GD Shelton). The objectives of this research have been to (1) describe the syndrome so that it can be recognized by dog owners, veterinarians and trainers, (2) to thoroughly evaluate affected dogs to try to establish an efficient means of diagnosis and to gain some insight into the cause of collapse, (3) to determine the mode of inheritance and the genetic basis for EIC and (4) to develop a DNA test for the condition. 

    This document will summarize some of what we have learned about the syndrome of Exercise Induced Collapse in Labrador Retrievers. 
    WHO GETS IT?  

    The syndrome of exercise intolerance and collapse (EIC) is being observed with increasing frequency in young adult Labrador Retrievers. Most, but not all, affected dogs have been from field-trial breedings. Black, yellow and chocolate Labradors of both sexes are affected, with the distribution of colors and sexes closely reflecting the typical distribution in field trials (black males most common). Signs first become apparent in young dogs - usually between 5 months and 3 years of age (average 14 months). In dogs used for field trials, this usually coincides with the age at which they enter heavy training. Littermates and other related dogs are commonly affected but depending on their temperament and lifestyle they may or may not manifest symptoms. Affected dogs exhibiting symptoms of collapse are usually described as being extremely fit, muscular, prime athletic specimens of their breed with an excitable temperament and lots of drive. 

    Affected Chesapeake Bay Retrievers and Curly-Coated Retrievers have also been identified. 

    Affected dogs can tolerate mild to moderate exercise, but 5 to 20 minutes of strenuous exercise with extreme excitement induces weakness and then collapse. Severely affected dogs may collapse whenever they are exercised to this extent - other dogs only exhibit collapse sporadically. 

    The first thing noted is usually a rocking or forced gait. The rear limbs then become weak and unable to support weight. Many affected dogs will continue to run while dragging their back legs. Some of the dogs appear to be incoordinated, especially in the rear limbs, with a wide-based, long, loose stride rather than the short, stiff strides typically associated with muscle weakness. In some dogs the rear limb collapse progresses to forelimb weakness and occasionally to a total inability to move. Some dogs appear to have a loss of balance and may fall over, particularly as they recover from complete collapse. Most collapsed dogs are totally conscious and alert, still trying to run and retrieve but as many as 25% of affected dogs will appear stunned or disoriented during the episode. 

    It is common for the symptoms to worsen for 3 to 5 minutes even after exercise has been terminated.  
    NOTE: A few affected dogs have died during exercise or while resting immediately after an episode of exercise-induced collapse so an affected dog's exercise should ALWAYS be stopped at the first hint of incoordination or wobbliness. 
    Click here for a video of an EIC episode. 

    Most dogs recover quickly and are normal within 5 to 25 minutes with no residual weakness or stiffness. Dogs are not painful during the collapse or after recovery. Massage of the muscles or palpation of the joints or spine does not cause discomfort. Affected dogs are not stiff or sore or limping upon recovery. 
    Body Temperature  

    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). We have shown experimentally, however, that clinically normal Labrador Retrievers doing this type of exercise for 10 minutes routinely had similar dramatic elevations in body temperature yet exhibited no signs of weakness , collapse or disorientation. (American Journal of Veterinary Research 60(1):88-92, 1999). 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 Labrador Retrievers. Although temperature may play some role in EIC, and may even contribute to the death of some affected dogs, inability to properly regulate temperature is not the underlying problem in dogs with EIC. 
    Ambient 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. Excessive panting (hyperventilation) in hot weather may be a contributing factor. Affected dogs are less likely to collapse in cold weather or while swimming, but some dogs have exhibited collapse while breaking ice retrieving waterfowl in frigid temperatures and some dogs have drowned when experiencing EIC -related collapse in the water. 
    Excitement. Dogs that exhibit the symptoms of EIC are most likely to have intense, excitable personalities, and it is very apparent that their level of excitement plays a role in inducing the collapse. There are some severely affected dogs who, if they are extremely excited, do not even require much exercise to induce the collapse. Dogs with EIC are most likely to collapse when engaging in activities that they find very exciting or stressful. This can include retrieving of live birds, participation in field trials, training drills with electric collar pressure and quartering for upland game. 
    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 grouse or pheasant hunting, repetitive "happy retrieves", retrieving drills or repetition of difficult marks or blinds where the dog is being repeatedly corrected or is anticipating electric collar correction, and excitedly running alongside an ATV. 

    Cardiovascular and musculoskeletal examinations are unremarkable in dogs with EIC as is routine blood analysis at rest and during an episode of collapse; however, nervous system examination is normal at rest, but patellar reflexes are diminished or absent in dogs with EIC during collapse and these do not reappear until after the dog has completely recovered, which usually takes 10 to 30 minutes. These dogs do not experience heart rhythm abnormalities, low blood sugar, electrolyte disturbances or respiratory difficulty that could explain their collapse. Body temperature is remarkably elevated during collapse (average 107.1F [41.7C], many up to 108F [42.2C]), but this magnitude of body temperature elevation has been found in normal exercise-tolerant Labradors as well. Affected dogs hyperventilate and experience dramatic alterations in their blood carbon dioxide concentration (decreased) and their blood pH (increased) but these changes are also observed in the normal exercising dogs. Testing for myasthenia gravis (ACh-R ABy) is negative. 

    Thyroid gland function (T 4, TSH) and adrenal gland cortisol production (ACTH Stimulation test) appear to be normal. Affected dogs are negative for the genetic mutation known to cause malignant hyperthermia in dogs (mutation of the skeletal muscle ryanodine receptor RyR1). 
    EIC is the most common reason for exercise/excitement induced collapse in young, apparently healthy Labrador Retrievers. Until recently, EIC could only be diagnosed by systematically ruling out all other disorders causing exercise intolerance and collapse and by observing characteristic clinical features, history and laboratory test results in affected dogs. Any Labrador Retriever with exercise intolerance should always have a complete veterinary evaluation to rule-out treatable conditions such as orthopedic disorders, heart failure, anemia, heart rhythm disturbances, respiratory problems, low blood sugar, cauda equina syndrome, myasthenia gravis, hypoadrenocorticism, and muscle disease. Genetic (DNA) testing for EIC is necessary to confirm a suspected diagnosis of EIC. 
    Dogs symptomatic for EIC are 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 fairly normal lives if owners 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. Not all of the EIC deaths have occurred in dogs rated as severely affected based on their number of episodes of collapse or the amount of activity required to induce an episode. 
    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. A few dogs have, however, responded to medical treatment to the degree that they can re-enter training and competition at a high level. There are now numerous reports of severely affected dogs improving when they were treated with Phenobarbital (2 mg/kg every 12 hours or every 24 hours). The actual mechanism underlying its effectiveness in dogs with EIC is uncertain. It is possible that this drug just "takes the edge off" and decreases the dog's level of excitement, thus making it less likely that they will have an episode. This drug should only be administered with strict veterinary supervision and monitoring. 

    If a collapsing Labrador Retriever is confirmed to have EIC (i.e. blood test confirms two copies of the EIC mutation), it should be recommended that participation in trigger activities be limited and that the dog be monitored closely so that exercise can be ended at the first sign of weakness/wobbliness. If the dog does collapse, (1) make sure that it has unobstructed breathing so it can hyperventilate to blow off heat, (2) offer water and ice orally, and (3) cool the dog by immersing it in cool water or wetting it down. Enforce rest until the dog is fully recovered. 

    There have been a number of good veterinary reviews of heat stroke in dogs recently and the syndrome we are seeing with EIC is very different. With heat stroke - induced collapse in dogs you expect to see a very slow or prolonged recovery that can take hours to days, or else progression to death. Laboratory evaluation reveals a dramatic increase in muscle enzymes (CK usually 7-11X normal). Mentation changes that are severe, progressive and persistent (for hours to days) occur in 80% of affected dogs and significant endothelial injury leads to microvascular thrombosis, DIC, thrombocytopenia and bleeding as well as acute renal failure in most patients. In contrast, dogs with EIC collapse without showing laboratory abnormalities and they recover quickly - happy and running around within 5 to 25 minutes. 

    We have also learned enough about EIC to say with certainty that it is not the same as malignant hyperthermia (MH). The Minnesota collaborators in the EIC Project (Mickelson et al) recently confirmed that in dogs as in other species MH is caused by a mutation in the calcium release channel of the sarcoplasmic reticulum in skeletal muscle – the ryanodine receptor. All of the affected EIC dogs evaluated at the WCVM were genotyped and tested for the known ryanodine receptor mutation and for linkage to other sites on chromosome 1, eliminating this mutated gene as the cause of EIC. Dogs with collapse due to MH typically look very different from our dogs with EIC. Their muscles are rigid (not flaccid/floppy like EIC) and they have increased CK in their serum. Histologically their muscles show rhabdomyolysis (our dogs muscles are normal). Dogs with MH often hypoventilate due to persistent muscular contraction so they are hypercarbic (where dogs with EIC hyperventilate). 

    Although our initial study of dogs with EIC was designed to detect a mitochondrial myopathy (a defect in the oxidative metabolism leading to energy production in muscle), we now know that EIC is not a metabolic myopathy. Most dogs with mitochondrial myopathies have severe exercise intolerance that can be consistently demonstrated with even mild exercise. Most develop extreme lactic acidemia with even mild exercise and an elevated lactate to pyruvate ratio. Many have “ragged red fibers” demonstrated on histopathology which are really just subsarcolemmal mitochondria as well as ultrastructural changes to the mitochondria - none of this is evident in dogs with EIC and it has become apparent that dogs with EIC suffer more from neurologic dysfunction than from muscular weakness. 

    Some Labrador Retrievers that we have evaluated because of collapse episodes do not have EIC but instead have an unusual form of epilepsy. The "collapse" episodes that these dogs experience typically have a very sudden onset and very sudden resolution and are sometimes very brief (less than 2 minutes) - unlike EIC where there seems to be a more gradual progression of weakness, incoordination or collapse and a gradual recovery taking from 5 to 30 minutes. In this unusual form of epilepsy (almost exclusively seen in Labrador Retrievers) the dog maintains consciousness but exhibits a problem with gait, balance, or muscle tone. Excitement and exercise are common triggers for these seizures in affected dogs (perhaps because of hyperventilation), leading to confusion between this seizure disorder and EIC. In some dogs with this form of epilepsy the episodes do not progress further, but other dogs will develop more typical generalized seizures later in life with loss of consciousness, muscle twitches, paddling of the limbs, etc 

    EIC is a hereditary condition, with littermates and other related dogs commonly affected. Clinically unaffected dams and sires commonly produce litters with more than one affected dog and pedigree analysis strongly supports an autosomal recessive mode of inheritance. 

    DNA harvested from the blood of affected dogs and their relatives was used to perform a full genome scan at the University of Minnesota in order to identify a genetic marker for EIC, and to find the genetic mutation causing EIC. In 2007 the chromosomal locus (site) of the mutation was found on chromosome 9, and the genetic mutation responsible for susceptibility to EIC was identified. This is a mutation in the gene for dynamin-1, a protein expressed only in the brain and spinal cord where it plays a key role in forming synaptic vesicles containing neurotransmitters. DNM1 is not required during low level neurological stimulation, but when a heightened stimulus creates a heavy load on release of CNS neurotransmitters (as with intense exercise, a high level of excitement and perhaps increased body temperature) DNM1 is essential for sustained synaptic transmission in the brain and spinal cord. 
    - Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, Ekenstedt KJ, Mickelson JR. A canine dynamin 1 mutation is highly associated with the syndrome of exercise-induced collapse. Nature Genetics 2008; 40(10): 1235-1239 
    - Taylor SM, Shmon CL, Adams VJ, Mickelson JR, Patterson EE, Shelton GD. Evaluations of Labrador Retrievers with Exercise Induced Collapse, including response to a standardized strenuous exercise protocol. Journal of the American Animal Hospital Association, January 2009. 
    - Taylor SM, Shmon CL, Shelton GD, Patterson EE, Minor K, Mickelson JR. Exercise Induced Collapse of Labrador Retrievers: Survey results and preliminary investigation of heritability. Journal of the American Animal Hospital Association, November 2008; 44: 295-301. 
    - Taylor SM. Exercise-induced Weakness/Collapse in Labrador Retrievers In LP Tilley and FW Smith (eds), 2008, Blackwell's Five Minute Veterinary Consult: Canine and Feline (4 th edition). 458-459. 

    Canine Neuromuscular Testing 
    VDL is currently offering new tests for neuromuscular diseases. For dogs, this includes genetic testing for Exercise-Induced Collapse (EIC). Click here to visit the VDL site. 
    EDTA blood samples will be required, and must be submitted by a veterinarian who will verify identity (tattoo, microchip) for the dog being tested and will be able to help owners interpret their test results. Certification will be managed through the Orthopedic Foundation for Animals (OFA), similar to thyroid and hip screening.  
    The test will determine whether a dog is: 
    *Affected by EIC (has 2 copies of the causative mutation: homozygous for EIC) 
    *A carrier of EIC (has 1 copy of the causative mutation: heterozygous for EIC) 
    *Clear of EIC (no copies of the causative mutation: normal)

    Veterinary Diagnostic Laboratory of the University of Minnesota