Canine idiopathic epilepsy: pathogenesis and clinical characteristics

Article

The high incidence of seizures in some breeds suggests a strong genetic component to the disease...

The cause of idiopathic epilepsy (IE) has been debated for centuries starting when people first became aware of the disorder. Modern molecular techniques are beginning to clarify the role of genetics in epilepsy as in many other diseases (O'Brien 2003).

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Neurons are excitable cells with the driving force being the electrical potentials. Sodium is constantly pumped out of the cell in an energy dependant process. This causes a -60 mVolt charge inside the cell (hyperpolarization). The balance of excitatory and inhibitory signals a neuron receives controls whether an axon potential is generated. The major excitatory neurotransmitters in the brain are acetylcholine and glutamate. These neurotransmitters receptors are linked to ion channels that are selectively permeable to positively charged sodium or calcium. When these channels open, cations flow into the cell causing depolarization of the cell. An accumulation of small depolarizations (excitatory post synaptic potentials) can cause the cell to reach threshold and thereby produce an action potential. Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter. GABA receptors are linked to an ion channel that is selectively permeable to chloride ions. Additionally, potassium currents are important in repolarizing the cell after an action potential and controlling the excitability of the cell.

In its simplest form, epilepsy refers to repeated seizures over time. Studies of the role of genetics in epilepsy are confounded by the occurrence of acquired disease, which can look identical clinically (phenocopy). The response of a normal brain to some outside influence, such as an electrolyte disturbance or hypoglycemia is referred to as reactive epilepsy. Seizures caused by a structural lesion of the brain, such as a brain tumor or vascular accident, are referred to as symptomatic epilepsy. In this case, the seizure originates at a focal site of damage but sometimes spread causing a secondary generalized seizure. Depending upon what area of the brain is affected, a focal onset might not be apparent. Appropriate imaging or tests identify reactive or symptomatic seizures. Idiopathic epilepsy can be defined as repeated epileptic seizures where no underlying cause is identified, and in dogs, it is likely to have an inherited basis in most instances.

By strict standards, an abnormal EEG is necessary to make a diagnosis of epilepsy. Obtaining a meaningful EEG in animals can be difficult. Movement often obscures recordings in awake animals, whereas sedative drugs can suppress epileptic discharges. In veterinary medicine we are, thus, dependant upon observation of the clinical signs to make a diagnosis of epilepsy. This is not a big issue when classic seizures are observed but can be important when atypical episodes are reported. Videotapes of the episodes sometimes can clarify what is actually occurring.

Epilepsy is a common condition affecting approximately 1 percent of the human population (McNamara 1998). While many epilepsies have an identifiable cause (secondary epilepsy), about 40 percent of all human epilepsies are idiopathic and presumed to have a hereditary basis (Steinlein 1998). Many of the idiopathic epilepsy syndromes in humans appear to have a complex mode of inheritance that has yet to be elucidated. Recent advances in gene mapping have resulted in the identification of the causative gene mutations in 13 uncommon human IE's (Scheffer 2003). In these isolated human populations, a strong founder effect and minimal mixing of populations allowed the mutation to be widely spread in a local area. One interesting aspect of these families is that in some cases the seizures have a focal onset. Since seizures secondary to localized damage typically have a focal onset, it has long been assumed in people and dogs that focal epilepsies were acquired.

Ion channel mutations compromise most of these idiopathic epilepsy genes (Mulley 2003). This is not surprising given the important role of ion channels in controlling neuronal excitability. Ion channel mutations have been found in other neurologic diseases such as hereditary ataxias and hyperkalemic periodic paralysis, and the term "channelopathies" is sometimes used to describe mutations in ion channels, which lead to disease (Terwindt 1998). Channels that have been found that cause idiopathic epilepsy in people include voltage gated potassium channels, voltage-gated sodium channels, voltage gated calcium channels, GABA receptors, and Acetylcholine receptors.

There are no epidemiologic studies of the general canine population to establish the true lifetime incidence of idiopathic epilepsy in dogs, but estimates range from 0.5 percent up to 5 percent (O'Brien 2003). There is now, however, considerable evidence that genetics plays a significant role. In a study of seizures in a non-referral base population, Podell (1995) found that 92 percent of the dogs with seizures were purebred dogs, and 65 percent of the dogs who began seizing between 1 year and 5 years of age were diagnosed with idiopathic epilepsy.

Early studies of Belgian Tervueren Shepherds, Keeshonds, Dachshunds, and British Alsatians all suggested a hereditary basis of the seizures in those breeds. Studies in Beagles, British Alsatians, Golden Retrievers, and Bernese Mountain dogs have shown an inherited basis with slight male predominance. Conversely, in one family of Shetland Sheepdogs with frontal lobe epilepsy, almost 80 percent of effected dogs were females. Other breeds, such as the Tervurens, Labrador Retrievers, and Vizslas, show no sex predilection. While most studies have suggested a polygenic mode of inheritance, the disease in Vizslas (Patterson 2003) and Keeshonds (Hall and Wallace 1996) fits with a simple autosomal recessive trait.

The past dogma has been that idiopathic epilepsy in dogs is associated with generalized seizures, and that focal onset seizures usually indicate symptomatic epilepsy caused by focal brain lesion. As in human medicine, veterinary studies now are providing evidence that focal onset seizures also might have a genetic basis. Berendt (1999) first suggested that focal onset seizures were more common in epileptic dogs than originally thought and subsequently reported that 70 percent of epileptic Labradors had focal onset. In the study of familial epilepsy in Vizslas, our group (Patterson 2003), found almost 80 percent of the dogs showed signs suggesting focal onset of the seizures. In humans, rodents and dogs, focal onset familial idiopathic epilepsy has now been documented. Thus, although focal onset seizures should still stimulate an extensive search for an acquired lesion, it does not rule out a potentially hereditary condition.

Studies in humans and rodents conclusively have demonstrated genetic causes of idiopathic epilepsy. The high incidence of seizures in some breeds suggests a strong genetic component to the disease, and in some, a high heritability has been demonstrated. In Keeshonds and Vizslas evidence suggests an autosomal recessive mode of inheritance, while other breeds fit a polygenic mode, some with a strong sex influence. The variability between breeds suggests that different genes might contribute to epilepsy in different breeds.

The Canine Epilepsy Research Consortium (www.canine-epilepsy.net, in research section) is collecting DNA samples and medical information from epileptic pedigrees of all breeds. Members of the consortium agree: to share DNA samples, phenotype data, and genetic data; to share credit for scientific collaborations; that discoveries will be put into the public domain

Until the precise mode of inheritance and DNA markers for idiopathic epilepsy in different breeds is identified, avoiding breeding dogs known to have had seizures is the best strategy for reducing the incidence of the disease. Identifying specific mutations will also allow better tailoring of therapy based upon the molecular deficit rather than just the clinical signs.

Dr. Edward (Ned) Patterson is currently an assistant professor at the University of Minnesota College of Veterinary Medicine. He received his DVM in 1996, completed a residency in small animal internal medicine with a special interest in medical neurology in 2001, and finished a PhD on the genetics of epilepsy in dogs in 2004. He has NIH funding to map and identify canine idiopathic epilepsy genes at the Canine Genomics Laboratory of the University of Minnesota. He sees internal medicine patients and also has a canine and feline seizure clinic at the University of Minnesota Veterinary Medical Center. He is a founding member of the Canine Epilepsy Research Consortium.

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