Canine epilepsy is a common neurological diseases encountered in veterinary practice. The International Veterinary Epilepsy Task Force (IVETF) has defined epileptic seizures as manifestation(s) of excessive synchronous, usually self-limiting epileptic activity of neurons in the brain (1) and epilepsy as a disease of the brain characterized by an enduring predisposition to generate seizures. Epilepsy in dogs can be classified as structural, caused by an underlying intra- or extra-cranial pathology or idiopathic epilepsy (IE). The latter serves as an umbrella term encompassing genetic epilepsy (where a causative gene for epilepsy has been identified), suspected genetic epilepsy (where a genetic influence is suspected but not confirmed) and epilepsy of an unknown cause (EUC; age at seizure onset < 6 months old or >6 years old and where no known cause for epilepsy has been identified) (2).

Canine IE has a prevalence ranging between 0.5 and 5% in most canine populations (3, 4). Canine genetic epilepsy with an autosomal recessive inheritance pattern has been confirmed in the Lagotto Romagnolo and Rhodesian Ridgeback (5, 6). To the authors' knowledge, only a few studies have been published in which risk loci for IE have been described. A common risk haplotype in the ADAM 23 gene has been reported for the Belgian Shepherds, the Schipperke, Finnish Spitz, Beagle, Australian Shepherd, Kromfohrländer, Labrador Retriever, and Whippet (7, 8).

Two recent studies identified additional risk haplotypes in the Belgian Shepherd: a significant association between canine IE and a risk haplotype on chromosome 14 (9, 10).

If a genetic cause or risk factor of epileptic seizure (ES) is lacking, patterns and characteristics in specific canine breeds, such as the age of disease onset as well as prevalence of status epilepticus (SE) or cluster seizures (CS), may induce genetic research into more targeted treatment and clear breeding guidelines.

The Irish red and white Setters are a native Irish breed considered highly vulnerable due to its limited population (11). The Dutch Irish Setter Club was registered in 1915. The breed became increasingly popular in the Netherlands in 1930s and experienced a boom in the 1970s with a high demand for pups, leading to as many as 1,700 new pups being born per year. That number decreased in the 1980s to 300–400 new pups per year and a steady decline in the litter numbers has been observed until today (with an average annual birth rate at 150–200 puppies). Many of the dogs were not bred according to the recommendations of the Dutch Irish Setter Club.

To date, IE has been reported to occur in the IS (8, 12–14) but its phenotypic characteristics have not been previously described. Therefore, the aim of this study was to characterize IE in this breed and to determine the mode of inheritance.

A cross-sectional analysis of idiopathic epilepsy in the Dutch population of IS was performed, including analysis of the occurrence of seizures, clinical outcome, and family relations. Cases were collected via the Dutch Irish Setter Club, who were asked to send out a questionnaire to owners of living and deceased IS dogs with a history of epileptic seizures.

This is the first study providing a phenotypic analysis of IE and EUC and its inheritance in the ISs. In the reported group of IS dogs, the mean age of seizure onset was 41 months, which is higher than reported in most reported breeds, including the Border collie (median age of onset 27 months), Vizsla (median age of onset 36 months) and Great Swiss Mountain dog (mean age of onset 28.8 months) but lower than that reported in the Standard Poodle (median age of onset 43 months) (16–19). Early-onset seizures, occurring at < 1 year, were observed in four dogs. Seven dogs with late-onset seizures occurring at or above 6 years of age, were also included in the study. Seizure onset occurring at the higher end of the range for IE (≥60 months) has been reported in other breeds of dog, including the poodle, English Springer Spaniel, Labrador Retriever, Italian Spinone, Finnish Spitz and Border Terrier (20). In a study assessing the cause of seizures in dogs above 5 years of age, primary epilepsy was diagnosed in 35% of the population (21). In another study assessing aged dogs with seizures, 29% of the dogs between 7 and 10 years old were diagnosed with cryptogenic epilepsy (22). According to the consensus of the IVETF, epilepsy in dogs with a seizure onset above 6 years of age cannot be termed IE. However, the consensus also states that IE is chiefly a diagnosis of exclusion, where other causes of seizures have been excluded. We believe IE needs to be considered in dogs with a later onset of seizures (above 6 years of age) where a genetic background is suspected. This type of epilepsy complicates selection for breeding as many cases are used for mating before the occurrence of their first epileptic seizure.

We reported a higher occurrence of IE in males than females (56 vs. 44%), which is consistent with observations in other breeds (61.6 vs. 38.4% in the Irish Wolfhound, a ratio of 1.4:1 for all epilepsy-related insurance claims in Sweden, 57–43% in the Border Collie, 1.69:1 for dogs with epilepsy of unknown origin in the UK) (3, 4, 18, 23). The occurrence of ES in IE males was not statistically significant. The majority of the dogs in this study were intact. Previous studies have suggested that neutering may positively affect seizure frequency and severity (24, 25), although one study found this not to be true for females (26). The effect of neutering on seizure frequency was not analyzed in this study.

More than half of the dogs in this study were reported to have CS (54%). This occurrence of CS was lower than that reported in the Border Collie [94% occurrence of CS in a population of 49 dogs (27), and 59% reported in another study of 114 Border Collies (18)] as well as the Dalmatian [63.6% CS (20)]. However, it was higher than in the Australian Shepherd (20% of CS) and Belgian Shepherd (33%) (28, 29). The high occurrence of CS and low occurrence of SE in the studied population is consistent with a similar IE analysis on a large population of dogs of various breeds (30). In that study of 407 dogs of five breeds, 41% of the population experienced CS and only 2.5% were reported with SE. It has been previously reported that a high occurrence of CS leads to poor outcome and euthanasia (30). Hence, the occurrence of CS warrants early treatment.

The majority of the dogs in this study were treated medically. Most of the reported seizures in the studied IS population occurred out of rest and at night, which is consistent with similar findings in other breeds (16, 20). No known triggers were reported and no association between feeding and ES were found. The latter have been reported in a group of dogs, nine of which were diagnosed with IE (31). Most (67%) of the dog owners thought their dogs were not conscious during the seizures. The assessment of consciousness during a seizure is often difficult for owners and thereby subjective. It has been suggested by the IVETF that the assessment of consciousness is not a meaningful factor in the classification of canine seizures (2).

Spontaneous seizure-freedom was reported in two dogs. One of those dogs had been reported to previously have had cluster seizures. Although uncommon, spontaneous seizure-freedom has been reported in other breeds of dogs, including the Border Collie (27). Seizure remission on treatment was reported in three dogs (6%) in that study.

Recent literature suggests that a majority of owners of epileptic dogs are able to predict an upcoming ES (32). Prodromal signs were observed by most owners in this study. The behavioral signs prior to or following a seizure are consistent with those previously reported in dogs and humans including disorientation, autonomic signs, restlessness and lethargy (33). According to the IVETF, some pre-ictal signs such as restlessness, “clinging” to the owner or anxiousness may, in truth, be behavioral focal epileptic seizures (2, 20). Advanced diagnostic techniques, such as electroencephalography, may assist in determining the nature of the behavioral changes preceding a generalized epileptic seizure, but exceeded the scope of the present study.

All dogs reported in this study had generalized seizures, which were either primary or a secondary generalization of focal seizures (in one dog). Recent analyses suggest focal seizures may pose a diagnostic challenge, as they may mimic other disorders (34). A higher occurrence of generalized seizures than focal seizures has been reported in other breeds of dog, such as the Golden Retriever, Labrador Retriever, Irish Wolfhounds and the Shetland Sheepdog (23, 35–37).

The pedigree analysis of one subpopulation of IS allowed us to trace the inheritance pattern of thirteen dogs. Most canine IE data is based on owner observations. This data provides crucial insights into epilepsy in predisposed breeds and facilitates seizure categorization. Hence, it is essential to promote owner-veterinarian collaboration to identify, treat and limit canine epilepsy and to improve the quality of life of epileptic patients. Large scale studies on canine breeds may facilitate the detection of the genetic background of IE, which may then be used to limit its occurrence in susceptible breeds.

The diagnosis of IE in young individuals remains primarily based on owner observations and/or film recordings. The latter are not always available. If it is not available, clinicians can show owners recorded film material of seizuring dogs. This was done in this study, hence the diagnosis, together with the additional physical and neurological examination and blood/urine examination reached a tier 1 confidence level for the diagnosis of IE, or EUC in the older dogs. Although tier II and III confidence levels provide greater accuracy of IE diagnosis, they are cost-intensive, often rendering them impossible.

One of the limitations of this study was the means and time of data collection. Considering that the data was extrapolated from questionnaires filled out subjectively, the reliability of the data provided must be assessed critically. Also, focal seizures or focal seizures preceding a generalized tonic-clonic seizure may have been missed or unrecognized by the owners. The questionnaires were collected at a single time point, at various stages of the dogs' disease process, which may have influenced the answers. Creating clear inclusion criteria was an attempt to objectify this data. Features such as response to treatment, quality of life or survivability were not assessed in this study. A follow-up study at a second time point assessing the long-term outcome of IE in this population of dogs may be useful.

We reported IE and EUC in a Dutch population of IS based on owner questionnaires. The ES in this breed were predominantly generalized tonic-clonic seizures with post-ictal signs in the majority of the dogs, more commonly occurring in males than females. They also featured a later-onset compared to ES in other reported breeds. A strong genetic component is suspected in the breed, and the high percentage of CS supports the implementation of early ASM. A further study of IE, coupled with a genetic study, needs to be performed on a larger population of IS to identify causative genetic variants.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the animal study because it is a retrospective study performed on cases presented for veterinary care. Written informed consent was obtained from the owners for the participation of their animals in this study.

PM was responsible for the study conception and data collection in cooperation with MP, MD-E, QS, KS, and PL. The cases were either seen by MP, PM, MD-E, QS, and KS. Statistical analysis, data analysis, and manuscript writing were performed by MP, KS, and PM. PM supervised data analysis and manuscript editing, in cooperation with MD-E, QS, and PL. All authors contributed to the article and approved the submitted version.