The time has come for breeders, practicing veterinarians, and recognized veterinary neurology specialists to start working together with the aim of treating, controlling and curing this devastating canine disease. Only this joint effort will help to decrease the frequency of canine epilepsy.
A seizing dog can be a challenging case for any clinician: the diagnosis and management of such patients require the understanding of the most common causes of canine seizures. It is crucial to rule out the possible life-threatening underlying causes of seizures by a thorough diagnostic approach without wasting precious time. Not all epileptic dogs suffer from idiopathic epilepsy. There are many conditions that can trigger seizures, including brain tumors and strokes, meningitis, hyperlipidaemia, and liver disorder. Thus, for some of those, prompt treatment is crucial for a better quality and longer life. A consult with a veterinary-recognized specialist and the appropriate diagnostic work-up, including a full blood test, MRI, and lumbar puncture, is essential to reach a correct diagnosis.
Not a lot has changed regarding the fear and myths surrounding canine epilepsy since the first person observed seizing dogs when animal/human cohabitation started. Throughout history, thousands of people suffering from epilepsy have been killed because they were thought to be possessed by the devil. Sadly, despite all the scientific improvement and understanding of this medical condition, there is still a need to demystify one of the most common but devastating neurological diseases. Thus, even though enormous progress has been made in the last century in understanding the biological basis of canine epilepsy, and even more in developing effective antiepileptic drugs, our first reaction is not so different from that of our ancestors: the animal is often destroyed and the epileptic status not recognized.
This article first featured in the February Kennel Gazette. The official publication of the Kennel Club.
To start symptomatic antiepileptic treatment without ruling out the above possible causes will not achieve seizure control but, more importantly, it will allow a progression of a possibly life-threatening condition. Thus, exactly as in cases of seizures in people, it is important that an early diagnosis is made by a specialist neurologist because it is mandatory to start appropriate antiepileptic treatment in a seizing dog as soon as possible in order to achieve the best possible control and potential freedom from seizures.
What is epilepsy?
Epilepsy is a brain disorder characterized by recurrent seizures without a known cause or abnormal brain lesion (brain injury or disease). In other words, the brain appears to be normal but functions abnormally. A seizure is a sudden surge in the electrical activity of the brain causing signs such as twitching, shaking, tremors, convulsions, and/or spasms.
The exact cause of epilepsy is unknown, but a genetic basis is suspected in many breeds. Breeds that have a higher rate of epilepsy include Beagles, Bernese Mountain Dogs, Border Collies, Boxer Dogs, Cocker Spaniels, Collies, Dachshunds, Golden Retrievers, Irish Setters, Irish Wolfhounds, Keeshonds, Labrador Retrievers, Poodles, St. Bernards, Shepherds, Shetland Sheepdogs, Siberian Huskies, Springer Spaniels, Welsh Corgis, and Wire-Haired Fox Terriers. Epilepsy is somewhat common in dogs and rare in cats.
Belgian Shepherd (mainly Groenendal and Tervueren variants)
There are ten different studies available that focus specifically on idiopathic epilepsy in the Belgian Shepherd (mainly Groenendal and Tervueren variants) [23, 34–42]. This relatively high number of studies leaves the Belgian Shepherd as one of the most intensively studied dog breeds in the field of canine epilepsy. Interestingly, an inheritance of idiopathic epilepsy in this breed was first suggested in 1968 [42]. All of the available studies respectively focus on seizure semiology, prevalence, mode of inheritance and gene mutation identification; and have been conducted mainly in Denmark [23, 37, 41], the United States [35, 36, 38–40] and Finland [34]. The variability in results between individual studies may be attributed to the examination of geographically and genetically distinct populations and variable study designs and inclusion and exclusion criteria being applied. One Danish study published in 2008 was an epidemiological study of a larger population of Belgian Shepherds registered in the Danish Kennel Club in a 10-year period. Prevalence was estimated at 9.5 % based on interviews of 516 dog owners, which identified 49 dogs with idiopathic epilepsy [23]. Mean age at seizure onset was 3.3 years. However, 39 % of all affected dogs did not experience their first seizure until after four years of age. Of the investigated epileptic dogs, 63.3 % were females and 36.7 % were male; however, a significant gender predisposition was not detected. The seizure type was reported to be focal in 25 % of dogs, focal evolving into generalisation in 53 % of dogs and (primary) generalised in 18 % of dogs (in 4 % of dogs seizures could not be classified). The most commonly reported focal seizure phenomenology included ataxia, crawling, swaying, behaviour suggesting fear, salivation, excessive attention seeking and disorientation. The median survival time from seizure onset was 2.5 years among deceased dogs [23]. In 2009 the same authors investigated a selected large Danish Belgian Shepherd family including 199 individuals with 66 idiopathic epilepsy affected dogs [41]. The epilepsy prevalence in this selected family was estimated at 33 % [41], which showed that accumulation of epileptic individuals within certain breeding lines can result in substantially higher prevalence estimates than in the breed in general (as reflected by the two Danish studies) [23]. As found in the Danish breed study from 2008, the seizure type was predominantly (83 % of dogs) defined as focal or focal epileptic seizures evolving into generalised seizures, while only 6 % of dogs experienced (primary) generalised epileptic seizures [41]. In 11 % of dogs, seizures could not be classified. Due to the high prevalence of focal seizures the authors discussed if this familial epilepsy could be compared to familial focal epilepsy in humans [41]. This large Danish Belgian shepherd family was further investigated with respect to survival and selected risk factors for premature death by a longitudinal observational study published in 2012 [37]. The life span of epileptic dogs was not significantly shortened by the presence of epilepsy. Epilepsy was the predominant cause of death in the population and epilepsy-related deaths accounted for 70 % of all deaths in the group of dogs with epilepsy. Two probable sudden unexpected deaths related to epilepsy occurred in dogs with generalised seizures. Cluster seizures occurred in 33 % but did not significantly influence the life span of epileptic dogs. Dogs with epilepsy had an epilepsy remission proportion of 13.7 % [37]. A 2012 genome wide-association study including Belgian Shepherd epilepsy cases from Denmark, Finland and USA (159 cases and 148 controls) identified a novel idiopathic epilepsy locus [34]. The mean age at seizure onset in the dogs participating in the study was 3.3 years [34], which is in line with findings of the Danish study [23]. The median seizure frequency was 5.25 seizures per year with some dogs experiencing less than one seizure per year and others up to 10 seizures per day. One third (33 %) of the affected dogs had a history of cluster seizures. The seizure type was defined as focal epileptic seizures evolving into generalised seizures in 37 % of dogs, as generalised seizures with unknown onset in 34 % of dogs, as (primary) generalised in 18 % of dogs and as focal in 7 % of the dogs. In 4 % of dogs the seizures remained unclassified [34]. Only 3 % of the dogs did not respond to antiepileptic drug treatment, while the remaining dogs all responded at least with some degree of seizure frequency reduction. A number of dogs participating in the study had an EEG examination and interictal EEG revealed epileptiform activity with variable foci in all examined dogs [34]. Multiple studies have been conducted with respect to potential modes of inheritance in this breed, however results were not always consistent and this again may reflect different study design, inclusion and exclusion criteria. In the Danish study from 2009 the mode of inheritance of epilepsy was based on segregation analysis reported to be simple mendelian with a segregation pattern resembling autosomal dominant inheritance but with possible incomplete penetrance [41]. These results contradict the findings from an older USA study in 2003, in which a polygenic mode of inheritance influenced by a single autosomal recessive locus was suggested [35]. Furthermore a study from 1997 found that a single locus model does not appear adequate as an explanation [38], but the same investigators in a 2000 study suggested a single locus with a large effect on the incidence of seizures [39]. The 1997 USA study estimated the heritability of epilepsy in the Belgian Shepherd dog at 0.77 [38], and the 1998 USA study predicted that the offspring of the mating of two non-epileptic dogs has a probability of 0.99 of never suffering from a seizure, while the offspring of the mating of two dogs who have each had one seizure has a predicted probability 0.58 of never suffering from a seizure [40]. Although, the clinical phenotype of idiopathic epilepsy in the Belgian shepherd is well described and extensive research efforts have been undertaken, it has not yet been possible to identify causative gene mutation(s) responsible for idiopathic epilepsy in the breed [34–36]. Identified risk factors: Intact dogs with idiopathic epilepsy had a significantly increased risk of being euthanised because of idiopathic epilepsy compared to neutered dogs with idiopathic epilepsy [23]. Recently, it was found that homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for idiopathic epilepsy among the investigated Belgian shepherds [34]. These data suggested that the identified ADAM23 variant is a polymorphism, but yet needs to be further confirmed. Potential breed-specific diseases that may mimic idiopathic epilepsy: In the authors’ experience the most important differential to be excluded in the Groenendael and Tervueren is a (often exercise induced) episodic involuntary movement disorder similar to paroxysmal dyskinesia described in Chinook dogs [43] and Border terriers [44]. It is recommended that the paroxysmal episode be filmed. The paroxysmal movement disorder can be distinguished from seizures because the dogs remain responsive to stimuli and their environment, for example will continue to try to play. The episodes are typically longer in duration than epileptic seizures and characterised by dystonic limb lifting (all joints in flexion). The dog may become recumbent but often remains standing (personal communication Clare Rusbridge February 2015).
In the current literature, one study about idiopathic epilepsy in Bernese Mountain dogs is available [45]. This study includes 50 affected dogs from Switzerland and was published in 1999. Idiopathic epilepsy was diagnosed when physical and neurological examination, haematology, serum biochemistry, urine and CSF analysis were unremarkable. Detailed data regarding definition of idiopathic epilepsy were not provided in this study [45]. Sixty-nine healthy Bernese Mountain dogs served as control dogs and a possible gender predisposition was analysed by the use of a non-preselected population containing 4005 Swiss Bernese Mountain dogs [45]. Prevalence data have not been reported for this breed [45]. The mean age of seizure onset was 2.2 years (26.5 months) with 62 % of dogs exhibited their first seizure between one to three years of age, 20 % had an age of seizure onset of less than one year and 18 % experienced the first seizure at an age ≥ 3 years [45]. A gender predisposition for males (62 %) compared to females (38 %) was observed. The gender ratios (males to females) were 1.6:1 among epileptic dogs, 1:1.1 among non-epileptic control dogs and 1:1.4 among all dogs [45]. The seizure type was defined as generalised in 98 % of dogs and as focal in 2 % of dogs [45]. However, a detailed differentiation between (primary) generalised seizures and focal epileptic seizures evolving into generalised epileptic seizures was not conducted, hence some of the dogs may have experienced focal seizures evolving into generalisation rather than (primary) generalised seizures. The seizure frequency was not analysed in detail, but was reported to range from three seizures per week to one seizure every year, with 50 % of dogs experiencing more than one seizure every two months. The results of the pedigree analyses and binomial test were best compatible with a polygenic, recessive (possibly sex-modified) mode of inheritance [45]. The identification of a causative gene mutation has not yet been reported [45]. Identified risk factors: The age at seizure onset was significantly lower in dogs from affected parental animals than in dogs from healthy parental animals [45].
In the current literature, one specific study about idiopathic epilepsy in Border Collies is available [8]. This study – conducted in Germany – was published in 2010 and provides data regarding clinical characteristics and heritability of epilepsy among a German Border Collie population [8]. The latter study, included data of 49 Border Collies diagnosed with idiopathic epilepsy; no control dogs were included. Idiopathic epilepsy was defined as recurrent seizures (≥2 seizure days at least 4 weeks apart) with an onset between 6 months and 5 years of age in dogs with otherwise normal physical, laboratory, and neurological characteristics upon examination. Requested minimal laboratory investigations included a CBC and biochemical profile. MRI and CSF analysis were requested if age at seizure onset was < 6 months or > 5 years of age [8]. Detailed prevalence data have yet not been provided for this breed [8]. Although detailed prevalence data are not available, the Border Collie was among the most common affected breeds in several epidemiological canine epilepsy studies in the UK [17, 46, 47]. The median age at seizure onset in the German study was 2.4 years with 74 % of dogs experiencing their first seizure between 1 and 5 years. However 18 % experienced the first seizure at an age ≤ 1 year and 8 % of dogs had an age of ≥ 5 years. No gender predisposition was detected with 49 % males and 51 % females. The seizure type was defined as focal epileptic seizures evolving into generalised seizures in 78 % of dogs and as (primary) generalised in 8 % of dogs. In 14 % of dogs the seizures remained unclassified, as seizure onset was not clearly observed. In addition, 45 % of dogs also had sporadic focal epileptic seizures, which manifested as sudden uncontrolled head or facial twitching mostly associated with impaired consciousness. Active epilepsy (≥1 epileptic seizure in the last year of the study or in the year preceding death) was documented in 82 % of dogs and seizure remission was reported for 18 % of the Border Collies with idiopathic epilepsy, which is similar to reported remission rates in other dog populations [9, 11, 27, 47]. However, a recent canine epilepsy study which focussed on identification of clinical risk factors for remission revealed the Border Collie as the breed least likely to achieve seizure remission [47]. Of all affected dogs 45 % had a history of cluster seizures, 4 % had a history of status epilepticus and 49 % had a history of both. Overall, 94 % of all dogs included in the German study experienced at least one episode of cluster seizures and 60 % of all dogs had at least one episode of status epilepticus [8]. A high prevalence of cluster seizures among Border Collies was also found in a recent study about canine juvenile epilepsy in the UK [10], however, in contradiction to this data another UK study reported the Border Collie as being less affected by cluster seizures (>80 % not clustering) [46]. The median age at death among the deceased epileptic Border Collies (47 % of the study population) was 5.2 years [8], which is more than half that of the general UK Border Collie population (median age at death 13.5 years) found in another study [48]. The median survival time from seizure onset for deceased epileptic Border Collies was short being only 2.1 years in the German study [8]. This finding was supported by another study that also found a significant shorter mean survival time for Border Collies with idiopathic epilepsy (3.6 years) compared to a general dog population with idiopathic epilepsy (7.9 years) [10]. Treatment response was reported to be poor (≥1 seizure day/month) in 71 % of dogs that were treated adequately (67 % of the study population) with ≥ 2 antiepileptic drugs [8]. In summary, all above-mentioned clinical data suggest that this breed may generally have a severe epilepsy course and epileptic Border Collies are more likely to be euthanised than affected dogs of other breeds. Based on pedigree analysis, 29 affected dogs shared a common ancestor, indicating a strong genetic background for epilepsy in Border Collies. The identification of a causative gene mutation has yet to be achieved [8]. Identified risk factors: No positive impact of neutering on the course of epilepsy was detected. Comparison between dogs with active epilepsy and dogs in remission identified significant differences in age at seizure onset (older age at seizure onset in dogs that went into remission) and age at death (younger age at death for dogs with active epilepsy). Furthermore, initial seizure frequency (during the first 6 months) was significantly lower in dogs that went into remission compared to dogs with continuing epilepsy. Reduced survival times were found in dogs with young age at seizure onset (≤2 years of age) and dogs with a severe epilepsy course (occurrence of status epilepticus) [8]. No significant association between survival time and sex, reproductive status or number of administered drugs was identified. A Swiss study identified a polymorphism in the ABCB1-gene that was found to be associated with antiepileptic drug resistance (T > G variation in intron 1) in Border Collies [49]. This ABCB1-polymorphism (T > G variant) was detected in a later Japanese study with a frequency of 9.8 % among a Japanese Border Collie population [50]. In contrast to a known “loss of function” for the nt230 (del4) mutation, the T > G variation is hypothesised to have an ABCB1 drug transporter”gain of function” and therefore potentially might contribute to drug resistance. However, future research is required to investigate those associations further and also to investigate the possible mechanisms of this ABCB1-polymorphism on drug resistant epilepsy in Border Collies. Potential breed-specific diseases that may mimic idiopathic epilepsy: NCL, a neurodegenerative disorder, may also manifest with epileptic seizures and therefore may present a potential differential in young Border Collies presenting with seizures [51–53]. However, NCL is reported to manifest between the age of 15 and 22 months [51, 53] with severe and rapidly progressive neurological signs (e.g. vision impairment, gait abnormalities, dementia, behavioural abnormalities, aggression). Affected Border Collis died before the age of 3 years and the latest they were euthanized after the onset of clinical signs was 6 months [51]. A causative gene mutation for NCL in Border Collies has been identified and a gene test is available (mutation in the CLN5 gene) [54]. One study from 2011 reported 20 Border Collies diagnosed with exercise-induced collapse, but a DNM1-gene-mutation was not observed in any of these Border Collies [30]. However, in contrast to epileptic seizures, EIC usually is triggered by strenuous exercise and consciousness usually remains preserved during episodes and the dog’s behaviour suggests discomfort from heat (panting, seeking shade and/or water), which may help a clinician to differentiate between these two diseases [30]. The Border Collie breed is also affected by the ABCB1/MDR1-gene mutation (nt230 (del4)), which may need to be considered in dogs with acute seizures and potential previous exposure to neurotoxic P-gp substrates. The frequency of homozygous affected dogs is reported with 0.3 % [33]. There is one case report describing hyperammonemic encephalopathy (normal bile acids, but abnormal ammonia tolerance test) secondary to a hereditary selective cobalamin malabsorption in a juvenile Border Collie that presented with neurological signs, such as an abnormal mental state (stupor) [55]. However, although this particular dog did not seizure, hyperammonemia may carry a potential risk for reactive seizures in other Border Collies with such hyperammonemic encephalopathy.
One specific study about epilepsy in Border Terriers that was conducted in Germany and published in 2008 is available in the current literature [56]. This study included 47 affected dogs and 318 non-affected control dogs collected by questionnaires send to owners of dogs registered in the German Terrier Club. Detailed data regarding epilepsy definition were not provided [56]. The prevalence of epilepsy was estimated at 13.1 % among the investigated population [56]. In line with this high prevalence, a UK epilepsy prevalence and risk factor study reported the Border Terrier with a 2.7 times increased odds of epilepsy compared with crossbred dogs [17]. A gender predisposition was not detected with 53 % males and 47 % females in the German study. The mean age at seizure onset was 3.2 years. The clinical course was assessed as mild in most of the dogs (70 %) with only occasional seizures per year; only 27 % of dogs suffered from multiple seizures per month. Cluster seizures were documented in 8.5 % of dogs. The seizure type was defined as generalised epileptic seizures in 68 % of dogs and as focal epileptic seizures in 32 % of dogs, however a differentiation between (primary) generalised epileptic seizures and focal epileptic seizures evolving into generalised seizures was not performed. In 17 % of dogs autonomic signs (urination, defecation) were reported during a seizure and some of the dogs (27.6 %) experienced preictal signs, such as restlessness, disorientation, behaviour suggesting fear or seeking owners’ attention [57]. Hence, according to the new classification guidelines some of those dogs with a “preictal phase” (27.6 %) might be reclassified as having focal seizures evolving into generalised seizures. The seizures were defined as tonic in 46.8 % of dogs, as clonic in 14.9 % of dogs and as tonic-clonic in 38.3 % of dogs. In 51 % of dogs seizures occurred when they were in a resting position [57]. One important finding was that in most of the dogs (79 %) consciousness was assessed as preserved during a seizure, and only 21 % of dogs experienced an ictal loss of consciousness. Thirty per cent of dogs were treated with phenobarbital, and in 23.4 % of dogs, owners subjectively reported at least some clinical improvement [57]. The identification of a causative gene mutation has not yet been reported [56]. Potential breed-specific diseases that may mimic idiopathic epilepsy: Canine epileptoid cramping syndrome (CECS) is proposed as paroxysmal dyskinesia affecting Border Terriers. Recently, detailed data regarding typical clinical phenotypes of 29 CECS-affected Border Terriers have been published [44]. Based on the similarities regarding clinical semiology and typical age of disease manifestation, CECS is an important differential to epileptic seizures in this breed; even for experienced clinicians CECS may mimic a seizure disorder and vice versa. Distinct phenotypic characteristic of the paroxysmal events in CECS are generalised tremor, dystonia and difficulty walking. Episodes were reported to last from 2–30 min in the majority of dogs and in some up to 150 min [44]. In addition, some owners report signs of gastrointestinal distress associated with the episodes, including borborygmi during the episode and vomiting and diarrhoea before or after the episode in almost 50 % of the dogs. From a clinical point of view, the assessment of consciousness and the occurrence of autonomic signs such as urination, defecation or salivation during an episode may help to differentiate between both diseases, with CECS usually being characterized by a normal conscious state and absence of above mentioned autonomous signs [44]. However, as 79 % of epileptic Border Terriers were reported to have preserved consciousness during an epileptic seizure in the German study [56] and 62 % of Border Terriers diagnosed with CECS showed some kind of “pre- and postcramping” signs (such as eating grass, vomiting, or seeking to be near owners) [44] diagnosis still may remain challenging and potential overlapping of both diseases needs to be further elucidated in the future (e.g. with ambulatory ictal EEG examinations). With regard to response to therapy, therapeutic trials with phenobarbital, potassium bromide, diazepam, butylscopolamin resulted in no improvement in the majority of CECS affected dogs, but 50 % of the owners felt improvement after a dietary change (e.g. change to hypoallergenic diet) [44].
For several years it has been suggested that idiopathic epilepsy may occur as an independent disease in this breed and may not be the consequence of the frequently occurring Chiari-like malformation [58]. This hypothesis was supported by a study from 2013 that did not find a significant association between the degree of the Chiari-like malformation, (such as degree of ventriculomegaly) and the occurrence of epileptic seizures [59]. However, an overlapping of the two diseases cannot be entirely excluded. According to the findings of the study published in 2013 the seizure type was defined as (primary) generalised epileptic seizures in 39 % of the dogs, as focal epileptic seizures in 36 % and as focal epileptic seizures evolving into generalised seizures in 25 % of dogs [59]. No detailed data regarding potential modes of inheritance are available; however, epilepsy was found more frequently in lines originating from whole-colour dogs [58]. Potential breed-specific diseases that may mimic idiopathic epilepsy: Cavalier King Charles Spaniels are also known to suffer from Episodic Falling (paroxysmal exercise-induced dyskinesia) [60]. Episodic falling is a movement disorder that typically manifests between the age of 4 months and four years. Falling episodes are induced by physical activity, stress and excitement and manifest with hypertonicity of the limbs resulting in inability to move or even complete collapse. In contrast to epileptic seizures consciousness usually is not affected during these episodes [60]. A gene test is available for episodic falling that is based on evidence of a BCAN (brevican) mutation [61, 62]. Older Cavalier King Charles spaniels (>5 years old) have a high prevalence of myoclonus, which manifests most commonly as a brief jerking of the head and forelimbs when the dog is standing or sitting. Initially the syndrome is relatively benign but can be progressive with affected dogs suffering frequent jerks which may interfere with function, for example cause the dog to fall or stumble [63]. The syndrome can be confused with focal epileptic seizures but generally does not respond to AEDs licenced for dogs although may respond to levetiracetam (personal communication Clare Rusbridge February 2015). The pathogenesis of the myoclonus is as yet undetermined.
What breed of dog is prone to seizures?
Most pet owners probably don’t know this, but dogs can have seizures just like humans. Few things are worse than seeing your four-legged friend suddenly flop to the ground and tread water that isn’t even there, but for some dogs, this is their reality.
So how do you know if your dog has or may get seizures? And what should you do if they start experiencing them?