The aim of this study was to describe the phenomenology of paroxysmal involuntary movements in Border Terriers to advance our knowledge of this condition and generate hypotheses for future pathophysiology and genetic studies.
The limitations of this study were its retrospective nature and the use of information derived from a questionnaire for 36 of 53 dogs (68%). Information from clinical cases was compared by means of statistical analysis with information derived by the questionnaire and pooled together after finding no significant differences for binomial or continuous variables. The aim was to achieve a better characterization of this rare condition of Border Terrier dogs that presents with recurrent episodes of involuntary movements of brief and variable duration similar to paroxysmal dyskinesias described in humans.
Border Terriers of either gender in Europe, North America, and Australia develop attacks of involuntary movements at the median age of 3 years. Their frequency is variable from multiple attacks per day to one per year; the median duration of the attacks is 5 minutes, but in 30% of the dogs the attacks lasted between 15 minutes and 2 hours. During the episodes, the dogs appear to be disoriented, but responsive to stimuli, with dystonia, tremors affecting neck, trunk, and limbs, and titubation (see Video 1). Affected dogs are normal in between episodes, based on the results of the neurological examination in 17 of 53 dogs (32%) and owners’ evaluation in 36 of 53 dogs (68%). The clinical presentation of the described Border Terrier attacks is similar to primary or familial forms of paroxysmal dyskinesias in humans.
The phenotypic classification of paroxysmal dyskinesias in humans is based on precipitating factors and, at this time, includes three types of paroxysmal dyskinesias: paroxysmal kinesigenic (PKD); nonkinesigenic (PNKD); and exercise induced (PED). PKDs are triggered by sudden movements and the attacks are typically brief, lasting only seconds. Attacks of PNKD have a longer duration compared with PKD and are not induced by sudden movement, but can be triggered by alcohol, coffee, or strong emotions. Finally, attacks of PED are triggered by physical exhaustion after continuous exertion. Most of the attacks in Border Terriers occurred from rest (87% or 34 of 39 dogs), but some owners (67% or 29 of 43 dogs) reported that the attacks could be associated with a trigger, in particular, excitement, stress, and food. We hypothesize that, given that a kinesigenic trigger was not identifiable, the Border Terrier attacks represent a form of PNKD. Similar to the Border Terrier attacks, PNKD attacks in humans tend to occur only few times per year (up to several times per week) and last longer than in PKD (from 10 minutes up to 12 hours, although usually not longer than 1 hour). Eighty percent of genetically proven cases of human PNKD were found to have a combination of dystonia and chorea; however, 12% only had dystonia, as seen in Videos 1 and 2 of Border Terrier attacks. Primary PNKD usually has no other associated interictal signs similar to the Border Terriers in this study that had episodes of involuntary movements for a median time of 27 months without developing neurological signs between episodes. PNKD attacks in humans begin with premonitory symptoms, such as a sensation of tightness in one limb, involuntary movements of the mouth, or anxiety; when the involuntary movements ensue, they often affect only one side of the body and tend to spread or even generalize; similar observations of anxiety and stiffening of one limb preceding the attacks and generalization of the attacks were also made by owners of affected Border Terriers, as reported in Table 1.
Finally, PNKD attacks in humans occur spontaneously at rest, but more often after provocation by alcohol or coffee. Interestingly, some of the findings in our study seem to suggest an association between severity of the Border Terrier attacks and diet: Five owners reported an improvement in the frequency of the episodes after switching to a different commercial diet and, for one dog, after discontinuing rawhide chews. Similar findings were reported by Black et al., in a recent study describing this condition in 29 Border Terriers; the study was based on an owner survey and the authors reported that excitement, stress, and waking from sleep could trigger the episodes in some dogs; however, in the majority of the dogs, the episodes appeared to occur at random. In Black et al.'s study, 26 of 29 (90%) owners changed their dog's diet, suspecting an association between the attacks and diet. The majority of the owners selected hypoallergenic diets, and over 50% of the owners that participated in the survey reported a reduction in the frequency of the episodes.The limited number of dogs in our study, and the fact that the new diets were all different, does not allow conclusions to be drawn. It is possible that the response to a change in diet might be a placebo effect, as previously described in canine epilepsy trials, and induced by similar anecdotal claims reported on the World Wide Web. It is also possible that the new diets improved the Border Terriers’ general health status and reduced their stress; in fact, 28% of the dogs in this study presented recurrent skin and ear problems and 16% of the dogs had recurrent gastrointestinal problems, which may be associated with an underlying food hypersensitivity. However, there is mounting evidence of an influence of the brain-gut-microbiome axis on central nervous system neurotransmission, and enteric glial cells have been involved in the pathophysiology of gastrointestinal disease, such inflammatory bowel disease, gluten ataxia, but also Parkinson's disease.[9-11] An association between diet and severity of Border Terrier attacks, as suggested by our findings and Black et al.'s study, needs to be verified with a prospective study; however, if this hypothesis was to be confirmed, the Border Terrier dogs could represent an ideal spontaneous model to investigate the effects of diet on paroxysmal dyskinesias.
The Border Terriers included in Black et al.'s study presented with episodes of abnormal involuntary hyperkinetic movements or muscle tone; dogs with concurrent urination, defecation, and hypersalivation were excluded from the study. In our study, we found that 56% of the dogs with similar episodes of involuntary movements showed autonomic signs during the episodes, most commonly hypersalivation and vomiting reported in 48% and 24% of the dogs, respectively. The presence of autonomic signs could indicate that the episodes are part of a syndrome affecting multiple areas of the nervous systems, as in the case of some channelopathies described in humans.
The owners of five Border Terriers in this study reported that their dogs also had generalized tonic-clonic seizures with loss of consciousness, clonic movements, and autonomic signs; four of the dogs were clinical cases examined by veterinary neurologists, and the owner of the last dog (shown in Video 2) was contacted by e-mail and reported a progression toward more severe episodes and suspected generalized seizures; however, video recordings of the suspected seizures were not available for review. Further studies on this subset of Border Terriers affected by paroxysmal dyskinesia and, possibly, generalized seizures are necessary to elucidate the relation between them and their significance in terms of treatment and prognosis. This association may be coincidental given that epilepsy is commonly diagnosed in UK Border Terriers; in fact, a recent study found that in the UK, Border Terriers are 2.7 times more likely to present epilepsy than crossbred dogs. However, an association between paroxysmal dyskinesia and other neurological disorders, such as epilepsy and ataxia, has also been observed in individual human patients or families. Recently, a mutation in the KCNMA1 gene, encoding the pore forming a subunit of the large conductance calcium-sensitive potassium (BK) channel, has been discovered in a large human family with coexistent generalized epilepsy and paroxysmal dyskinesia. Sixteen affected individuals presented epileptic seizures (n = 4), PNKD (n = 7), or both (n = 5).
In this study, we described the phenomenology of paroxysms of involuntary movements with preservation of consciousness reported in Border Terriers and found clinical similarities between this condition and PNKD described in humans. The finding of a dystonia phenotype within an inbred population suggests a genetic predisposition. Purebred dogs represent an invaluable tool for mapping and cloning genes affecting human health.[15, 16] The unique history of the dog population characterized by founder effect and periodic population bottlenecks along with stringent breeding programs led to a closed genetic pool within each breed.[17, 18] This reduced genetic variation compared to humans simplifies the mapping of simple and complex diseases’ genes. Investigation of the genetic cause of the Border Terrier phenotype could improve understanding and treatment of the human condition.