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Papers Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach A. D. Short, A. Dunne, H. Lohi, S. Boulton, S. D. Carter, D. Timofte, W. E. R. Ollier In this study, previously unreported cohort characteristics and seizure patterns for canine epilepsy were identified from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbreed dogs. CANINE epilepsy is not a single disease entity, but represents a group of heterogeneous conditions that present as chronic, recurring seizures. Epilepsy in dogs can be broadly divided into idiopathic (primary) and acquired (secondary) forms, with the latter commonly having an identifiable cause such as a tumour or trauma to the brain. Idiopathic epilepsy has no identifiable cause and is the most common form of epilepsy in dogs. Studies have demonstrated that idiopathic epilepsy has a hereditary basis in many dog breeds (van der Velden 1968, Hall and Wallace 1996, Famula and others 1997, Famula and Oberbauer 1998, Jaggy and others 1998, Berendt and others 2002, Morita and others 2002, Oberbauer and others 2003, Lohi and others 2005, Jokinen and others 2007) and that males are more commonly affected than females in some breeds (Kathmann and others 1999, Casal and others 2006). Studies investigating the aetiopathogenesis of canine epilepsy generally focus on a single breed or pedigree and have concentrated on the identification of breed-specific, genetic risk factors. Epidemiological analyses of epilepsy can be subject to bias due to the difficulties involved with the correct classification of seizures; this is further complicated in dogs, as seizure characteristics are subject to the owners’ definition and neurological parameters are likely to be normal between seizures. Furthermore, owners may not be aware of seizures, and night-time seizures may not be noticed and therefore not reported. This paper describes the sex ratio, neuter status, age, and the number of seizures in a cluster from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbred dogs, identifying previously unreported cohort characteristics and seizure patterns for canine epilepsy in multiple breeds.

Veterinary Record A. D. Short, BSc, MPhil, PhD, A. Dunne, BSc, W. E. R. Ollier, PhD, FRCPath, FIBMS, Centre for Integrated Genomic Medical Research, School of Cancer and Enabling Sciences, University of Manchester, Stopford Building, Manchester M13 9PT H. Lohi, PhD, Department of Veterinary Biosciences, Program in Molecular Medicine, Folkhälsan Institute of Genetics, University of Helsinki, PO Box 63, 00014 Helsinki, Finland

doi: 10.1136/vr.d1901 S. Boulton, BVetMed, MRCVS, Vétoquinol UK, Vétoquinol House, Great Slade, Buckingham Industrial Park, Buckingham MK18 1PA S. D. Carter, BSc, PhD, FRCPath, D. Timofte, DVM, PhD, School of Veterinary Science, University of Liverpool, Liverpool L69 7ZJ E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed

Materials and methods

Details of sex, neuter status and age (as determined at the time of sampling) for the epileptic dogs were received from a UK-based diagnostic company providing routine screening of phenobarbitone levels in epileptic dogs undergoing treatment. Phenotype was established as a cross-sectional assessment at the time of phenobarbitone measurement; additional clinical data were not available. All samples had been collected with informed owner consent, and the diagnosis of idiopathic epilepsy was based on three or more generalised/focal or myoclonic seizures more than 24 hours apart. Dogs were excluded from the study if they suffered from acquired epilepsy (seizures secondary to brain disease such as tumours, arachnoid cysts or trauma) or reactive epilepsy (seizures secondary to metabolic disease, eg, exogenous or endogenous toxins due to liver disease), if they had had fewer than three seizures, and if less than 12 months had passed since the start of seizures and a brain MRI had not been performed; 1260 dogs satisfied the inclusion criteria (Table 1). It was difficult to assess the relatedness of affected dogs, as UK Kennel Club registration numbers were not available for the majority of the dogs. Cases were collected over a three-year period, with duplicate samples being identified and excluded using owner and referring practice information in addition to the dog’s name, breed, sex and date of birth or age at sampling. Seizure frequency and the number of seizures in a cluster were obtained for 260 cases by follow-up telephone calls to the referring veterinary surgeon. Analysis was performed in a breed-by-breed fashion for breeds where there were nine or more cases. To compare epileptic dogs with non-epileptic dogs, details of sex, neuter status and age were retrieved from a large sample (n=2040) of dogs that were resident in the UK (UK DNA Archive for Companion Animals, University of Manchester). Phenotype data (and DNA samples) had been collected with owner consent from a wide range of dogs with a variety of clinical conditions, for example, diabetes, cancer, cardiomyopathy, infections and injuries (traffic accidents, lameness, lacerations, minor traumas). Data on dogs with a diagnosis of epilepsy or suspected epilepsy were excluded. A wide range of breeds was present in the comparative dataset. Statistical significance was determined using the Monte Carlo method via CLUMP (Sham and Curtis 1995), which generates chisquared and P values in a 2 x n contingency table. Repeated simulations of the data were carried out (1000 for this analysis), and the frequency of chi-squared values in the simulated data associated with the observed data was counted, giving unbiased significance levels. CLUMP generates four chi-squared statistics (T1-T4); for the purpose of this study, the normal chi-squared statistic (T1) was used. Odds ratios were calculated using a web-based tool (www.hutchon.net/ConfidOR.htm).

Results

The epilepsy cohort contained 1260 dogs in total, comprising 79 pedigree breeds and a group of crossbred dogs. Four breeds and crossbred 10.1136/vr.d1901 | Veterinary Record | 1 of 4


Papers S e i z u re f re q u e n c y a n d number of seizures in a cluster Breed Number (%) Breed Number (%) Breed Number (%) were analysed in a breed-specific manner for 260 epileptic dogs Alaskan malamute 8 (0.6) Keeshond 3 (0.2) Sheepdog (old English) 2 (0.2) where these data were available. 139 (11.0) Shih tzu 5 (0.4) Australian shepherd dog 1 (0.1) Labrador (retriever)*† Basset griffon vendéen 5 (0.4) Lhasa apso 7 (0.6) Spaniel (Cavalier King Charles)* 21 (1.7) No pattern was identified for Basset hound 3 (0.2) Lurcher 10 (0.8) Spaniel (cocker)* 26 (2.1) the seizure frequency (data not Beagle 12 (1.0) Munsterlander 1 (0.1) Spaniel (Irish water) 1 (0.1) shown) but two distinct patterns Belgian shepherd dog 5 (0.4) Newfoundland 1 (0.1) Spaniel (springer)* 29 (2.3) were identified for the number Bernese mountain dog 1 (0.1) Northern Inuit 5 (0.4) Spinone (Italian) 6 (0.5) of seizures in a cluster (Fig 2). Bichon frise 5 (0.4) Pinscher (miniature) 1 (0.1) Terrier (Airedale) 1 (0.1) Bouvier des Flandres 1 (0.1) Pointer (English) 6 (0.5) Terrier (border)* 27 (2.1) Overall, 62 per cent of epileptic Boxer* 29 (2.3) Pointer (German) 7 (0.6) Terrier (Cairn) 4 (0.3) dogs experienced no clustering, Bulldog 8 (0.6) Pomeranian 1 (0.1) Terrier (English bull) 1 (0.1) while 30 per cent experienced Bullmastiff 1 (0.1) Poodle (miniature/toy) 5 (0.4) Terrier (fox) 2 (0.2) three to five seizures, 5 per cent Chihuahua 8 (0.6) Poodle (standard) 9 (0.7) Terrier (Jack Russell)* 63 (5.0) experienced five to 10 seizures, Chinese crested dog 5 (0.4) Pug 3 (0.2) Terrier (Lakeland) 1 (0.1) 1.6 per cent experienced 10 to 20 Collie (bearded) 2 (0.2) Retriever (curly coat) 1 (0.1) Terrier (miniature bull) 1 (0.1) 132 (10.5) Retriever (flat coat) 1 (0.1) Terrier (Norfolk) 1 (0.1) Collie (border)*† seizures and 1.4 per cent experiCollie (rough) 2 (0.2) Retriever (golden)* 58 (4.6) Terrier (Norwich) 1 (0.1) enced more than 20 seizures per 259 (20.5) Rhodesian Ridgeback 6 (0.5) Terrier (Patterdale) 5 (0.4) Crossbreed*† cluster. However, in the springer Dachshund 18 (1.4) Rottweiler 8 (0.6) Terrier (Scottish) 4 (0.3) spaniel, Jack Russell terrier and † 66 (5.2) Dalmatian* 19 (1.5) Saint Bernard 3 (0.2) Terrier (Staffordshire bull)* collie cross, only 20 to 35 per Doberman 2 (0.2) Saluki 1 (0.1) Terrier (Tibetan) 3 (0.2) Dogue de Bordeaux 1 (0.1) Schnauzer (giant) 1 (0.1) Terrier (West Highland white) 14 (1.1) cent of dogs did not experience 82 (6.5) Schnauzer (miniature) 3 (0.2) Terrier (Yorkshire)* 39 (3.1) German shepherd dog*† clustering, and it was common German spitz 1 (0.1) Setter (English) 2 (0.2) Viszla (Hungarian) 8 (0.6) for these breeds to experience Great dane 2 (0.2) Setter (Irish) 8 (0.6) Weimaraner 7 (0.6) three to five seizures in a cluster Greyhound 10 (0.8) Setter (red) 1 (0.1) Whippet 5 (0.4) (more than 50 per cent of dogs). Husky (Siberian) 1 (0.1) Setter (red and white) 1 (0.1) The proportion of these breeds * Top 14 breeds accounting for more than 75 per cent of the epileptic cohort experiencing five to 10 and 10 to † Top five breeds accounting for more than 50 per cent of the epileptic cohort 20 seizures in a cluster is comparable to that of the other breeds examined (5 to 15 per cent), but dogs together contributed more than 50 per cent of the total epilepsy there were some dogs that experienced more than 20 seizures in a cohort: crossbreeds (20.5 per cent), labrador retriever (11 per cent), cluster (10 per cent), which was not found in the other breeds of dog border collie (10.5 per cent), German shepherd dog (6.5 per cent) and used in this study. Staffordshire bull terrier (5.2 per cent). Fourteen breeds accounted for Discussion more than 75 per cent of the cohort (Table 1). Canine epilepsy is commonly documented as having a breed-related Data on age were available for 2040 non-epileptic dogs and 1188 disposition and a genetic mode of inheritance (van der Velden 1968, epileptic dogs (Fig 1), with the distributions showing a similar trend, Hall and Wallace 1996, Famula and others 1997, Famula and Oberbauer although the non-epileptic population had a greater proportion of 1998, Jaggy and others 1998, Kathmann and others 1999, Berendt and dogs aged two years (12 per cent v 8 per cent) and there was a greater others 2002, Morita and others 2002, Oberbauer and others 2003, Lohi proportion of epileptic dogs aged three to five years than among the and others 2005, Casal and others 2006, Jokinen and others 2007). non-epileptic dogs. There was a greater proportion of older epileptic Despite the well-documented breed-related risk, no epidemiological dogs (more than 10 years) compared with non-epileptic dogs of the studies, encompassing multiple breeds, have been published. The data same age. Age of onset of epilepsy was not available for these dogs. presented in this study do not give any indication of the incidence or The epileptic case series contained 63 per cent male dogs, comprevalence of epilepsy in individual breeds, as it was not possible to pared with 51 per cent of the non-epileptic population (P=0.001) determine the number of new cases over established cases in the series. (Table 2), and 57 per cent of the epileptic dogs were neutered, comFurthermore, sample collection was limited to a single diagnostic compared with 45 per cent of the non-epileptic population (P=0.001) pany, and the number of epileptic dogs in each breed population at the (Table 2). When considering sex and neuter status, 49 per cent of the time of sampling was unknown. However, excluding crossbred dogs, male epileptic cases were neutered compared with 30 per cent of the the labrador, border collie, German shepherd dog and Staffordshire non-epileptic dogs (P=0.001) and 69 per cent of the female epileptic bull terrier were the four most common pedigree breeds in this cohort. cases were neutered compared with 61 per cent of the non-epileptic The labrador and German shepherd dog are popular breeds in the UK, dogs (P=0.01) (Table 2). with an excess of 40,000 and 20,000 dogs being registered with the UK Kennel Club, respectively, on a yearly basis; hence, a larger proporControl tion of these breeds would be expected to have epilepsy due to their Epilepsy 14.0 overall popularity. The border collie and Staffordshire bull terrier, however, have lower annual registration figures, with 3000 and 10,000 dogs, 12.0 respectively, registered annually. The proportion of epileptic dogs in this 10.0 series was similar for the labrador (11 per cent) and the border collie (10.5 per cent), and for the German shepherd dog (6.5 per cent) and the 8.0 Staffordshire bull terrier (5.2 per cent), despite the difference in annual 6.0 registration figures, suggesting that the border collie and Staffordshire 4.0 bull terrier are at a greater risk of developing epilepsy. The Staffordshire bull terrier is known to suffer a metabolic con2.0 dition called L2-hydroxyglutaricaciduria (L2-HGA), which presents 0.0 with tremors and ataxia, in the same way as epilepsy (Penderis and 17 others 2007). This condition is an autosomal recessive trait, which Age (years) follows classical Mendelian inheritance; it is well documented in the breed, and a genetic test and breeding strategy are in place to reduce FIG 1: Age distribution of a population of 1188 epileptic dogs and a the frequency of carriers within the breed. The epileptic Staffordshire population of 2040 non-epileptic dogs at the time of sampling Percentage

TABLE 1: Breed distribution of a cohort of 1260 dogs with epilepsy

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Papers TABLE 2: Significance of sex, neuter status, and sex plus neuter status in a cohort of epileptic dogs compared with a non-epileptic population

Sex 1070 (51) Male Female 1029 (49) Neuter status Neutered 916 (45) Entire 1129 (55) Sex and neuter status Male neutered 321 (30) Male entire 749 (70) Female neutered 595 (61) Female entire 380 (39)

Epileptic (number [%])

90 P

2

χ

OR

CI

Springer spaniel (n=9) Jack Russell terrier (n=21)

German shepherd dog (n=22)

Staffordshire bull terrier (n=16)

Labrador (n=38)

Yorkshire terrier (n=11)

Golden retriever (n=19)

Crossbreed (n=64)

80 787 (63) 462 (37)

0.001

45.9 1.64

1.42-1.89

583 (57) 451 (43)

0.001

36.9 1.59

1.37-1.85

319 (49) 333 (51) 264 (69) 118 (31)

0.001

62.1 2.24

1.83-2.73

0.01

7.7 1.4

70

60

1.1-1.8

OR Odds ratio, CI 95 per cent confidence interval

Percentage

Non-epileptic (number [%])

Border collie (n=46) Collie cross (n=14)

50

40

30

bull terriers in the present cohort had been screened previously for the L2-HGA mutations, ensuring that these data were not skewed by an unrelated condition (Short and others 2010). Among the epileptic Staffordshire bull terriers, two of 52 (4 per cent) were L2-HGA-positive and eight of 52 were carriers (15 per cent); in the control Staffordshire bull terriers, 14 of 130 (11 per cent) were carriers and no animals were L2-HGA-positive, confirming that the over-representation of Staffordshire bull terriers in the epileptic cohort was due to true epilepsy, not L2-HGA. All other breeds were screened for the L2-HGA mutations (Short and others 2010), and this mutation was found only in the Staffordshire bull terrier. Apart from L2-HGA, there are no reports of any other conditions producing epilepsy-like signs, hence, the authors are able to assume that the cohort consists of truly epileptic dogs and that the over-representation of the border collie and the Staffordshire bull terrier is due to a breed-related genetic influence of, as yet, unidentified genes. Epilepsy is most commonly diagnosed between the ages of three and five years, while the conditions suffered by the non-epileptic dogs (for example, diabetes, cancer) are generally diagnosed at an older age. The difference in the age of onset of epilepsy and of the non-epileptic conditions could account for the higher representation of epileptic dogs in the three to five-year-old age range. Epileptic dogs are checked routinely and weighed when monitoring the levels of phenobarbitone; such regular check-ups are likely to be less frequent in a healthy control population, which would account for the higher proportion of older dogs in the epileptic cohort. The authors appreciate that the data analysed in this series of dogs come from a laboratory-based recruitment method as opposed to a clinical study. Consequently, this could introduce subtle biases such as issues around disease severity; furthermore, it is possible that these data may not fully reflect the UK epileptic dog population, but only the UK population that undergo routine phenobarbitone screening. However, it is accepted that if dogs suffer from a history of repeated seizures, they are treated with phenobarbitone. The over-representation of males in the epileptic cohort is in agreement with other studies conducted on the Bernese mountain dog (Kathmann and others 1999) and the Irish wolfhound (Casal and others 2006), although the latter study only showed a male bias before the age of 30 months. The significance of neutering, however, is a new finding, which may be specific to the UK, where neutering of pet dogs is common. It is possible that these findings could be ambiguous, however, because neutering is believed to reduce seizure frequency in epileptic dogs. Given that the data on these dogs were collected at the time of phenobarbitone measurement and additional clinical data were not available, it cannot be verified whether the animals in question were neutered before or after suffering repeated seizures. The age of neutering and the age of onset of epilepsy were not available for the dogs in the present study; however, given that many dogs in the UK are neutered at a young age and that there was a higher representation of epileptic dogs aged between three and five years, further investigations into the age of epilepsy onset and the age of neutering would be of interest.

20

10

0 No clustering

3-5 5-10 10-20 Number of seizures in a cluster

>20

FIG 2: Clustering of seizures for 260 epileptic dogs

In human beings, epilepsy is classified into more than 40 different types based on a diverse range of criteria including age of onset, seizure characteristics, and electroencephalographic readings. Such information is not available for dogs, and most canine epilepsy is classified as ‘generalised idiopathic’. The two distinct patterns observed in the present study for the number of seizures in a cluster (Fig 2) could be indicative of two distinct types of epilepsy, which could be easily characterised in different dog breeds. The differences and similarities between the epilepsy observed in these distinct patterns warrant further investigation. It is interesting to note that the border collies in this study exhibited the common pattern, with most dogs experiencing no clustering, but the collie crosses exhibited the less common pattern, with the majority of dogs experiencing three to five seizures in a cluster. A comparison of border collies and collie cross dogs could provide significant insights into the different types of canine epilepsy and be especially useful for genetic studies, where some disease-related genes would be shared between the two groups. This study has described series of 1260 epileptic dogs from the UK comprising 79 known pedigree breeds and a group of crossbred dogs. While risk factors could not be determined for the onset of canine epilepsy, five breeds (including crossbreeds) represent more than 50 per cent of the epileptic population in the study, and the data show a higher representation of male neutered dogs compared with a none pileptic population from the same geographical location. Two distinct patterns in the number of seizures in a cluster were identified, with the springer spaniel, Jack Russell terrier and collie cross deviating from the common pattern. This is the first report of a series of epileptic dogs in the UK and the numbers of some breeds are under-represented; however, it provides support for a differential breed-related disposition towards canine epilepsy and indicates that neutered males may be at increased risk of developing the condition. The observed difference in the number of seizures in a cluster is indicative of different subtypes of canine epilepsy, as is seen with human epilepsy, and warrants further investigations into the genetic and physiological causes of this condition.

Acknowledgements

This work was funded by the Biotechnology and Biological Sciences Research Council. H. L. was supported by the Academy of Finland, 10.1136/vr.d1901 | Veterinary Record | 3 of 4


Papers Folkhälsan Research Institute, the Jane and Aatos Erkko Foundation and the Sigrid Juselius Foundation. The authors thank the referring clinicians and the owners of dogs with and without epilepsy, who gave permission for their dogs to participate in this study.

References

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Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach A. D. Short, A. Dunne, H. Lohi, et al. Veterinary Record published online June 27, 2011

doi: 10.1136/vr.d1901

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References

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