Todd D.L. Woods, M.D.
Neurology with Added Qualifications in Clinical Neurophysiology
Epilepsy has become an increasingly expanding area of concern in many breeds. Perhaps because I am a human neurologist and perhaps because I am involved in a number of breeds that are really struggling with epilepsy as an inherited condition (Irish Setters, English Springer Spaniels, Siberian Huskies) , I have been asked more about epilepsy than any other health problem in purebred dogs.
Genetic inheritance varies by breed and more certainly within each line of each breed. In some cases inheritance is most likely simple recessive or simple dominance carried on an autosome.
If the genetics of epilepsy is fairly obviously inherited in one of these manners, the ethical choice of how to proceed in the breeding program is clear. Carriers of a clearly inherited form of epilepsy, in my opinion, must be removed from breeding. With autosomal recessively and autosomal dominantly inherited traits, it is often easy to identify those carriers or at least to predict the likelihood of an individual being a carrier.
More commonly the mode of inheritance either cannot be determined or is probably multifactorial and polygenic. In these cases, the ethical decision may not be clear and risks throwing the baby out with the bath water depending on the prevalence of the polygenic carrier state within the breed.
Epilepsy in its simplest description is an uncontrolled electrical state of the brain. It may be disorganized, a sort of electrical storm of the brain, or more commonly is a synchronous and rhythmic discharge of all or part of the brain, disturbing or distorting normal electrical activity, with wave after wave of electrical discharges that produce the behavior that is seen by the observer to represent a seizure.
Seizures can take a variety of outward appearances though within the same animal, the seizure is usually stereotyped (the same from spell to spell). Seizures may be a simple and brief period of confusion lasting 15-30 seconds, without actual loss of consciousness or even control of posture.
Seizures are broadly categorized into seizures affecting a focal area of the brain ( partial seizures ) and seizures affecting the entire brain ( generalized seizures ). Generalized seizures are most commonly experienced as repeated and rhythmic motor spasms of all extremities, preceded by a sudden tightening or stiffening of the whole body and the eyes rolling back into the head . These kinds of seizures are usually followed by a post-ictal phase, lasting a period correlating to the duration of the motor phase of the convulsion, during which the animal is difficult if not impossible to arouse.
Generalized seizures can be either inherited or caused by medical diseases such as diabetes, liver disease, etc... Partial seizures are variable in expression depending on the area of the brain involved. They may be seen as spells in which the animal may demonstrate repeated jerking of just one limb (contralateral motor cortex), may produce repeated behaviors (e.g. blinking, licking, pacing,...), or may produce one sided posturing (contralateral premotor areas), but are characterized by some maintenance of an awareness of the environment since only a portion of the animals brain is involved in the abnormal electrical discharges.
Partial seizures are not followed by the phase following the clinical seizure during which the animal is obtunded. Partial seizures may also be inherited but focal structural disease also must be considered as a possible etiology.
Generalized seizures may start as a partial seizure in which the abnormal brain discharge starts in one area of the brain, staying there for a short time, before spreading to involve the entire brain. While the discharges remain isolated to one area, the seizure appears clinically as a partial seizure. Once the discharges spread to involve the entire brain, the seizure is seen clinically as a generalized seizure.
Determining the type of seizure seen clinically aids the physician in diagnosing the most likely cause of the epilepsy. Of course a thorough knowledge of the family tree and the dog s individual medical history are also essential in making the correct diagnosis. Causes of epilepsy are legion. My own personal view is that unless it can be proven that epilepsy is acquired, it should be presumed inherited. Fundamental to the understanding of inheritance of epilepsy however is the knowledge that all animals, given the right (or perhaps I should say wrong) circumstances, can have a seizure. Sleep deprivation, hypoglycemia, dehydration and the corresponding electrolyte abnormalities among many other life situations can cause an animal to have a seizure and should not be taken to mean that animal is epileptic.
An animal that falls from a great height (compared to its own size) and breaks a leg is not necessarily thought to have an inherited bone condition predisposing it to fractures. Likewise, an animal placed in metabolically stressful conditions may have a seizure and not be epileptic. Repeated seizures are usually required to make the diagnosis of epilepsy. If epilepsy is known to exist in the line and to be a genetic risk of the breed, a single seizure may be sufficient to remove that animal from breeding, but a single seizure does not indicate that an animal will have a life long history of repeated convulsive events or that any anticonvulsant treatment is indicated. In my opinion, premature decisions to euthanize epileptic dogs are arrived at by people afraid of seeing their animal have a seizure or misperceiving that the animal is suffering horribly during and shortly after a spell. During a seizure, animals are not able to perceive or at least do not remember pain or fear. This is based on the knowledge of human epilepsy and while not fully provable, seems a reliable extrapolation from human research. The seizure is almost always far more traumatic for the observers than for the animal that is having the seizure.
An effort to protect the animal from harm during the seizure (falling in the water, running into something, etc... ) is all that bystanders need to be concerned with--not that the animal is suffering during the seizure. In regards to the quality of life issue of epileptic animals, another myth to be dispelled is that epileptic animals are unhappy and unable to lead a content life. While certainly this is at times the case, with many owners reporting a permanent change in temperament after the first seizure, and some owners reporting changes in perceived happiness of the animal while on anticonvulsant medication, it is quite common that animals live long and productive lives, interspersed by occasional or rare seizures, and it would seem unethical to conclude prematurely that such animals should not be lovingly cared for and allowed to live out their lives peacefully in the company of their human families.
Neither of these facts indicate in any way an endorsement of approaching epilepsy as anything less than a serious disease to be avoided as much as possible by the conscientious breeder, but they should come as welcome information to humans caring for epileptic loved ones.
Epilepsy is not just another problem to be avoided like a bad tail set or carriage. It is a devastating illness on many levels. But it is not necessarily a terminal diagnosis nor does it invariably reduce the dog s value as a companion or functional worker one bit. There are many wonderful companion dogs and hunting/working/etc... dogs who live out long and useful lives despite their epilepsy.
Acquired causes of epilepsy need to be exhaustively evaluated. If your veterinarian or the veterinarian of a puppy buyer immediately assumes it is inherited epilepsy--get another vet. For the animal s sake and for the breed s, a full evaluation is mandatory. Determining the cause is essential to make intelligent treatment choices (or to decide that no treatment is indicated) for the animal and to make the right decisions regarding littermates, parents, relatives in the breeding program.
Hypoglycemia is a common acquired cause of seizures. It is not uncommon for puppies in toy breeds to have seizures for this reason. Some sporting or hound dogs have been seen to have hypoglycemic seizures related to prolonged exercise felt to be related to failure of glycogen stores in the liver. Neoplasms in the pancreas may cause hypoglycemia and commonly occur prior to regular meals when sugar levels are at their lowest. Pre- and post partum hypoglycemia may produce seizures in isolation and not represent the onset of epilepsy.
Electrolyte abnormalities may provoke seizures. Hyponatremia can produce seizures and may be associated with dehydration, water intoxication and syndromes of inappropriate hormonal secretion (SIADH) associated with intracranial or intrathoracic disease. Dehydration and other electrolyte abnormalities secondary to intestinal disorders are obvious clinically but should not be overlooked as a cause of seizures.
Hypocalcemia associated with parturition, chronic renal disease or parathyroid disorders may arise and produce seizures.
Hypomagnesemia should be considered.
Hyperkalemia occurs in Addison s disease (adrenocortical insufficiency) and may also be precipitated by a too rapid withdrawal of chronic steroid use.
Hyperlipoproteinemias have been reported in a number of breeds and has been associated with seizures.
Intestinal parasitism, especially in young puppies, may produce seizures, perhaps by a variety of metabolic mechanisms including hypoglycemia, hypocalcemia and toxic effect. Food allergies have been identified in some dogs to be responsible with the elimination of certain foods resulting in clinical cure. Toxic etiologies are legion including but not limited to carbon compounds, organic phosphates, heavy metals like lead and mercury, flea dip preparations, overdosed food supplements .
Intracranial pathologies such as meningoencephalitis, malignancies, developmental central nervous system anomalies and traumatic brain lesions need to be ruled out.
Clearly an exhaustive list cannot be given in the context of this article. A competent veterinarian or veterinary neurologist relies on the history, age of the dog, type of seizure seen, individual health history of the dog, dog s neurologic and general medical exam, breed of the dog, family history of the dog, etc.... to determine the appropriate work up. Depending on the etiology of the seizure, treatment options are discussed and decisions about breeding the individual animal and the relatives can be made intelligently.
A premature decision to allay a dog s seizures to inheritance may result in mistreatment of the individual (i.e. anticonvulsant therapy when metabolic alterations need to be made) and may lead to bad decisions for the breeding program.
As previously stated, in my opinion, if a proven acquired cause of epilepsy cannot be found, it should be assumed that the epilepsy is inherited.
Less harm is done by assuming an acquired epilepsy is genetic and removing animals from breeding than assuming a genetic epilepsy is acquired and proceeding with the breeding of a line affected with inherited epilepsy.
Assuming that the proper work up has been performed, sparing no expense for the sake of the animal and the breed, and no identified acquired cause was demonstrated, we are left with the likelihood that the dog has inherited epilepsy. We are now faced with decision making regarding breeding related animals. This is of course a personal decision and many factors besides genetics do and should play a role in making that decision but an analysis of the genetics of the identified or presumed inherited epilepsy is the next logical step in making the final decision, to breed or not to, and which animals are to be excluded from breeding?
Inherited epilepsy can and does follow all known modes of inheritance. Sex linked inheritance is only seen in metabolic conditions such as some of the neurodegenerative disorders that produce epilepsy as one of many inherited abnormalities, not epilepsy in isolation. Thus normally one is faced with attempting to determine whether the epilepsy is inherited as a dominant trait (coming from one parent alone), a simple recessive trait (carried on one gene of both parents) or a polygenic recessive trait (carried by multiple genes, the combination of many genes producing the condition). A further complication is to determine whether the condition is inherited as a dominant trait with incomplete penetrance such that some individuals while genetically affected, do not demonstrate the gene (are not epileptic).
For a further discussion of genetics, reference to many basic texts on genetics should be done. An article posted on my home page under articles on basic genetics (http://www.teleport.com/~aatuk/aatuk.htm) is available for review and Internet searches are likely to result in equal or better didactic sessions on modes of inheritance that all breeders should be well versed in anyway.
It is not a valid assumption that within any breed, epilepsy is inherited in one mode. Epilepsy is an outward symptom of an inner abnormality. One member of a breed may have an acquired epilepsy, while another may have an inherited epilepsy related to glucose metabolism that is inherited by simple autosomal recessives, and another may have an inherited epilepsy related to abnormal central nervous system development inherited as a dominant trait with incomplete penetrance such that it s sire has the same condition, but doesn t have outward signs of epilepsy.
In conditions of simple recessive, at least in purebred dogs, it is most likely to arise in line bred or inbred litters. Line breeding and inbreeding are designed to maximize the combination of genes such that animals hopefully become homozygous for positive attributes. Unfortunately, these same animals may become homozygous for negative attributes such as inborn errors of metabolism that produce epilepsy.
In theory, simple recessive traits appear as a homozygous pair in 25% of a litter in which each parent carries one copy of the abnormal gene. Therefore in a litter of 8, one would suppose 2 affected littermates; of 16 (e.g. Irish Setters), one would suppose 4 affected littermates.. Investigation of the pedigree might well turn up affected uncles or aunts (whose littermates were thus carriers but not affected) but outcrosses of the same parents would probably not produce affected animals as the recessive gene (unless dispersed early in the genetic history of the breed) would not be expected to be present in other lines.
In terms of breeding decision making, one can determine the likelihood of each relative carrying the gene and thus make an appropriate decision. In a litter felt to have epilepsy inherited by a simple recessive mode, 25% of the individuals will be homozygous for the disorder and have epilepsy, 50% will be heterozygous for the disorder and will be carriers, 25% of the individuals will be non carriers and both parents can be identified as definite carriers. If carrier status is assumed to indicate a decision to eliminate from the breeding program, then both parents should be removed from breeding and 2/3rds of the unaffected littermates should be removed.
The problem arises in determining which of the unaffected littermates are carriers and should be removed from further breeding. There is no outward difference between carrier littermates and non carriers. The decision to consider a test breeding (littermates to known carriers--such as affected littermates which since homozygous for the gene would be expected to produce 50% affected if the test littermate is a carrier) is a personal one but would be viable.
An assumption that littermates not having epilepsy are probably not affected is a poor one since 2/3rds of the littermates that do not have epilepsy are carriers and only 1/3rd are not. My own decision in this case would be to eliminate all littermates and both parents from the breeding program. I could understand a different decision. Perhaps the epilepsy produced is a mild non debilitating form and this line is one of few that do not carry a more devastating genetic problem like PRA. Blindness is certainly worse than a chance of an occasional seizure. Then test breeding certainly becomes an attractive consideration.
If the mode of inheritance is considered to be polygenic recessive, the prevalence of the disorder within the breed is probably the most important consideration. In polygenic inheritance, it is the combination of multiple genes that produces the condition. In terms of epilepsy, this is the most likely cause of lowered seizure thresholds in which animals seem to have a predisposition to have seizures for seemingly minimal perturbations of normal metabolic states.
In other words, where one animal tolerates moderate dehydration on a hot summer day, another with a lower seizure threshold has a seizure in response to that stress. On the next occasion it may be in response to missing a couple meals with relative hypoglycemia or to an overload of parasites.
In polygenic recessive inheritance (a common inherited canine condition most likely polygenetically inherited is hip dysplasia), the genes again come from both parents and are most likely present with both parents carrying one or several genes contributing to the condition. One parent may carry multiple abnormal genes while another carries only one. It s the combination that produces the clinical manifestation of the disease, in this case epilepsy. The condition, unless the genetic dispersal occurred early in course of the disease, is common in both outcrosses and line breedings.
In the case of outcrosses, it is thought that particular combinations of genes deleterious in combination but not in isolation, produce the disorder because while each line may carry some genes that can contribute to the disease, each line lacks the particular genes that the other line carries, which when combined are particularly deleterious to the individual.
This is not an uncommon phenomenon in breeding dogs where it is known that combining those 2 lines just doesn t work . Staying within the one line may eliminate the opportunity to have the particularly dangerous combination occur. Of course in some lines, all the particularly deleterious genes exist in some of the individuals of the line and line breeding is as likely as outcrossing to produce the condition. In the case of breeding in litters thought to inherit traits as polygenic recessive, the model of decision making in the face of Hip Dysplasia is well known. In breeds where the condition is highly prevalent, to discard all individuals related to litters or individuals affected would be to accept the extinction of the breed. Breeding in those breeds should probably be restricted to animals from litters that are minimally affected in comparison to the breed prevalence as a whole--the less affected the better. In my main breed, Siberian Huskies, where the presumed mode of inheritance for juvenile cataracts is polygenic recessive and the prevalence of cataracts is probably in the range of 30-40%, I take a position that members of litters that have affected members should not be kept in the breeding program. I have made exceptions in extreme cases where a particular quality of an individual was hard to find in the breed, where that individual came from a large litter that had only a rare affected member, and where that individual had been bred previously and not produced the condition. As a rule however, even with a 30-40% prevalence of the condition in the breed, the safest approach would be to remove both parents and all littermates from future breeding. In dominantly inherited conditions, one of the parents is not a carrier and the other is. He or she may be clinically affected later in life or may remain clinically without the condition and be categorized as incompletely penetrated. This means that the animal carries the dominant gene but does not express the condition. Half of its offspring will get the gene and be predisposed to have epilepsy (though some may also be incompletely penetrated and remain free of clinical disease). In dominantly inherited conditions, the disease is usually much more apparent in the litter and in the line. 50% of the litter is likely to be affected and multiple litters, if for instance passed on by the sire, out of different unrelated bitches, will have multiple affected littermates. I had a litter of 6 once that produced 3 puppies that developed epilepsy at around age 2. One had quite severe epilepsy, the other 2 were minimally affected. The year the sire of that litter was used by me, he was bred to a couple other bitches. Every litter had multiple epileptic puppies. That strongly suggested the presence of dominant inheritance with incomplete penetrance since the sire had never seized (and never did despite his dying at a late age). Since the dams were not contributors, they could be left in respective breeding programs but as even the clinically unaffected siblings had some chance of being affected (with incomplete penetrance), they were all neutered/spayed--at least of my breeding. It would have been defensible to do test breedings with those animals, as with dominant inheritance, some of the offspring of the non- seizuring siblings (from the original litter) with the defective dominant gene would have been expected to seize, but given the dominant nature of the disease and the severity of the epilepsy in some of the individuals affected, this was not my choice. Had a test breeding been performed and all the pups grew up to be clinically unaffected, that test bred member of the original litter, could then have been fully used in the breeding program without risk of producing further epilepsy (at least by the mechanism inherited in that litter). Epilepsy is a complicated and historically burdened condition. From the days that seizures were thought to represent demon possession to the current seeming approach by the breeder determined to produce a big winner that epilepsy is just one more fault to deal with, epilepsy has been misunderstood and the genetic principles ignored or not incorporated into the decision making process to breed or not to breed. Many factors besides genetic likelihood of producing a particular condition are and should be considered in making that decision, not the least of which is individual merit of the animal and prevalence of the condition or worse genetic conditions in the breed. I have offered some of my own opinions in making decisions in my breeding programs in the variety of breeds I have the privilege to be a part of. These are just my opinions. The intent of this article was to educate readers about canine epilepsy in terms of what it may mean for the individual beloved pet and breed, to acknowledge the multiple causes of seizures and why a full work up is indicated, and to discuss the ramifications of multiple variables, including the most likely mode of inheritance if the epilepsy is identified or felt to be most likely genetic, on decisions regarding breeding.
Database: http://en-epilepsybc.weebly.com/europe.html and http://www.pbhf-dog.com/databases.html
The results of the ABCA funded Genome Wide Association Study (104 epileptic dogs; 104 healthy dogs; 174,000 marker gene chip) found no region in the genome associated with epilepsy in Border Collies (no gentest is possible). The genetic component of epilepsy in Border Collies is complex (multiple genes) enough that Dr Mark Neff believes it cannot be selectively bred out of our gene pool. Based upon the study results, my personal recommendation is to not repeat a cross that produced epilepsy but there is no evidence to support removing the sire and dam from the breeding population.
Studie zu Genorten für Epilepsie
Dies sind die Ergebnisse einer
genomweiten Assoziationsstudie (Definition s.u.), wie sie auf einer
Sitzung der American Border Collie Association als finanzierender
Auftraggeberin der Studie vorgetragen wurden. Die Studie wurde von
Molekulargenetiker Dr. Neff durchgeführt. Die Zusammenfassung
ist von Mark Billadeau.