Seizures in dogs under primary veterinary care in the United Kingdom: Etiology, diagnostic testing, and clinical management

Abstract Background Although seizures are common in dogs, limited published information is available on the classifications of seizures, diagnostic approaches, or clinical management of seizure‐affected patients in the veterinary primary care setting. Objectives Explore seizure etiology, diagnostic testing, and clinical management of seizure‐affected dogs in the primary care veterinary setting. Animals A total of 455 553 dogs in VetCompass. Methods Cross‐sectional analysis by cohort clinical data. Results From 2834 incident seizure cases, we identified 579 (20.5%) dogs with epilepsy based on the International Veterinary Epilepsy Task Force (IVETF) classification system, including 484 (17.1%) with idiopathic epilepsy, 95 (3.4%) with structural epilepsy, and 179 dogs (6.3%) with reactive seizures. In their clinical first opinion records, 245 (8.6%) cases were recorded with epilepsy. Overall, 1415 (49.9%) cases received diagnostic evaluation equivalent to or higher than IVETF Tier 1 diagnostic testing. Being <12 years of age and being insured were risk factors for receiving IVETF Tier 1 or higher diagnostic evaluation among seizure cases. Anti‐seizure drug (ASD) treatment was not prescribed for 1960/2834 (69.2%) dogs in association with the incident seizure event. Of the remainder, 719 (25.3%) dogs received 1 ASD, whereas 155 (5.5%) an ASD combination. Conclusion and clinical importance The differences between seizure classifications in the clinical records and those retrospectively assigned by the researchers support the need for clearer diagnostic guidelines in clinical practice. Insured dogs and dogs <12 years of age were more likely to receive advanced diagnostic evaluation, suggesting that financial and perceived prognostic factors influence case management.


| INTRODUCTION
Seizures are common in veterinary practice, affecting approximately 1 in 125 dogs annually under first opinion veterinary care. 1 Epileptic seizures are described by the International Veterinary Epilepsy Task Force (IVETF) as sudden, short-lasting, and transient events characterized by motor, autonomic, or behavioral features, or some combination of these, which can be secondary to idiopathic epilepsy (IE), structural epilepsy, or epilepsy of unknown cause. Epilepsy is defined as ≥2 unprovoked epileptic seizures separated by a minimum of 24 hours. 2 Idiopathic epilepsy is sub-classified by IVETF into 3 types: genetic (demonstrated genetic background), suspected genetic (evidence of high breed prevalence or familial association), and epilepsy of unknown origin (unidentified underlying cause and absence of structural epilepsy). 2 Structural epilepsy is characterized by the presence of underlying cerebral or intracranial pathology. 2 Reactive seizures are not considered as epilepsy but responses of the normal brain to a transient disturbance in function (ie, metabolic or toxic) that is reversible when the cause or disturbance is rectified. 2,3 Idiopathic epilepsy is a diagnosis of exclusion 4 4 The probability of first opinion caseloads achieving Tier 1 or higher diagnostic evaluation can be affected by factors including financial constraints, signalment, clinical, and other pet-related factors, owner compliance, veterinarian clinical skills, practice facilities, and predicted outcomes. 5 First-opinion clinical management for seizure cases varies between the needs of immediate emergency care compared with longer-term non-emergency management. Emergency care aims to decrease or halt current seizure activity, prevent or decrease further seizures, manage underlying seizure causes, and limit acute complications associated with the seizure event as well as decreasing long-term consequences. 6 Nonemergency longer term care aims to decrease seizure frequency, severity, and duration, but this goal must be balanced with acceptable adverse effects. 7 We aimed to explore seizure etiology, diagnostic testing, and management in the general population of dogs under primary veterinary care in the United Kingdom (UK). Specific objectives were to describe the demography, seizure classification, diagnostic testing, and treatment both overall and also for the subset of seizure cases specifically recorded as epilepsy in the clinical notes. Further objectives were to evaluate risk factors for receiving at least an equivalent of IVETF Tier 1 or higher diagnostic evaluation and risk factors for a recorded clinical diagnosis of epilepsy with special focus on breed effects.

| MATERIALS AND METHODS
We collected data within the VetCompass Programme 8 at the Royal Veterinary College (RVC). VetCompass collates electronic patient record (EPR) data from UK primary care practices for epidemiological research. Clinical data from participating practices are extracted from practice management systems (PMSs) by automated queries, uploaded securely to the RVC server and reformatted for entry into the VetCompass online database system. 9 The study population comprised all dogs in VetCompass with at least 1 EPR (clinical note, bodyweight, or treatment) recorded during 2013 and dogs with at least 1 EPR before and 1 EPR after 2013 or both. These dogs were defined as being under veterinary care during 2013. The year 2013 was selected because it was the latest year of full data available at the time of the study.
A cross-sectional analysis of cohort clinical data was used for risk factor analysis. A seizure was defined as an event with occurrence of signs characterized by short episodes with convulsive or focal motor, autonomic or behavioral features. 2 A seizure case was defined as any dog with at least 1 seizure event recorded in the EPR as occurring during 2013. Because the subset of seizure cases specifically diagnosed with epilepsy was of particular interest, descriptive results additionally were reported for the seizure cases recorded in the first opinion clinical notes with epilepsy. Case finding from the overall VetCompass study was as described previously. 1 The EPRs of confirmed seizure cases from the previous study were evaluated and classified as pre-existing seizure cases (≥1 seizure recorded before 2013) and "incident seizure cases" (no seizure recorded before 2013). Subsequent analyses included only incident seizure cases. The EPR of each incident seizure case was examined to extract whether or not a clinical diagnosis of epilepsy was recorded by the originating practice. Incident seizure cases additionally were retrospectively categorized based on information recorded in the EPR according to retrospective IVETF classification and diagnostic evaluation. Etiological information in the EPR was used to categorize each seizure case into 1 of 5 categories based on the IVETF classification guidelines 2 : "idiopathic epilepsy," "structural epilepsy," "reactive seizures," "unclassified," or "no cause recorded." For retrospective classification, dogs were required to have evidence of at least 2 seizures separated by a 24-hour time window for classification as epilepsy.
Data extraction and comparison to IVETF guidelines was performed by the main author (AE), who is a practicing veterinary surgeon. The extraction and classification processes were developed with the support of an expert team of veterinary neurologists and epidemiologists.
Idiopathic epilepsy was defined as dogs between 6 months and 6 years of age at first seizure that had received a minimum of an unremarkable diagnostic evaluation (clinical and neurological examination, basic diagnostic laboratory testing with investigation of CBC, serum biochemistry profile, and urinalysis (including specific gravity, protein, glucose, pH, and sediment evaluation) and for which no alternative seizure cause was recorded (IVETF diagnostic Tier 1). 4 Structural epilepsy cases were defined as dogs that had interictal neurological deficits, suspected or confirmed structural brain pathology such as neoplasm, inflammation, infection, or degenerative brain lesion, or both reported in the clinical records. Confirmed structural brain pathology required recorded evidence from neuroimaging, CSF analysis or both in the EPR whereas suspected structural epilepsy cases did not require evidence of neuroimaging, CSF analysis or both. Reactive seizure cases had clinical records that described an underlying, reversible seizure cause that was considered a reaction of the normal brain to a transient insult (eg, intoxication, metabolic disorders, electrolyte imbalance, organ dysfunction). Animals were grouped as "unclassified" if the EPR included multiple underlying causes and the animal could not be confidently categorized into any of the first 3 categories. "No cause recorded" included all remaining dogs with no information recorded on seizure causes.
Diagnostic processes recorded in the EPR were extracted and compared to IVETF standards. Cases were classified into 2 groups based on diagnostic evaluation: below IVETF Tier 1 or "IVETF Tier 1 or higher" standard. 4 Information on MRI or CSF diagnostic evaluation was extracted for each seizure case and for medications prescribed within 48 hours after the first seizure in 2013. Drugs included were diazepam, midazolam, alprazolam, zonisamide, phenobarbital, imepitoin, potassium bromide, gabapentin, levetiracetam, pregabaline, propofol, and medetomidine.
The anti-seizure drug (ASD) regimens were categorized into 3 groups: no medication, single medication or drug combinations. The ASD regimens were reported overall and also by etiological group and clinically diagnosed epilepsy and IVETF diagnostic evaluation classifications.
The "breeds" variable included individual purebred or designer breed types with ≥12 animals presenting as incident seizure cases during 2013. A designer breed type was defined as any dog with a recorded description that was a contraction of at least 2 purebred breed names. A crossbred was defined as any dog with a recorded description that was neither purebred nor designer breed. All remaining purebred and designer breed types were grouped as "other purebreds and designers breed types" and a general category of crossbred dogs also was included. A "purebred 'variable classified all dogs of a recognizable breed as' purebred," all dogs recorded with a designer breed name as "designer" 10 and all remaining dogs as "crossbred". A "KC breed group" variable described the UK Kennel Club breed groups. The mean (SD) was used to summarize data that were normally distributed whereas the median (interquartile range [IQR]) was used to summarize non-normally distributed data. 11 The age for all incident seizure cases described the age at the first seizure in 2013. An age (years) variable "age at first seizure" contained 7 age categories (0.00-≤0.50, 0.50-≤3.00, 3.00-≤6.00, 6.00-≤9.00, 9.00-≤12.00, >12.00 years, unrecorded) in accordance with IVETF protocols. 4 "Neuter status" recorded the neuter status at the final EPR and was combined with sex into a single variable "Sex-neuter." Adult was defined as >18 months of age. "adult body weight" categorized the median adult body weight (kg) into 6 groups (<10.00, 10.00-≤20.00, 20.00-≤30.00, 30.00-≤40.00, ≥40.00, unrecorded). An "adult body weight relative to breed and sex mean" variable characterized the adult body weight of individual dogs as either below or equal to or above the mean adult body weight for their breed and sex within the overall study population. This variable allowed the effect of adult body weight to be assessed within each breed and sex combination. The variable "insurance status" described whether the dog was insured, not insured or unrecorded at the final available EPR. An overview of different variables is presented in Table 1.   Dogs with seizures that were recorded as having epilepsy in the clinical notes were more likely to receive at least 1 ASD than were dogs with seizures that were not clinically diagnosed as having epilepsy (148;

| DISCUSSION
We report on the etiology, diagnostic evaluation, and clinical management of dogs under primary veterinary care affected with seizures in the UK. Our study of retrospective primary care data identified a seizure incidence risk of 0.62%. Using a slightly different case definition, a Swedish study by pet insurance data identified a similar 0.75% incidence risk for epilepsy in 2014. Both of these retrospective studies used large databases of pre-existing health information and each was susceptible to different selection biases on the dogs included. The slightly higher epilepsy rates in insured dogs 13 could reflect higher diagnostic efforts for insured dogs compared to uninsured dogs .
Retrospective classification identified that 20.5% (idiopathic epileptic 17.1% and structural epileptic 3.4%) of the incident seizure cases met the IVETF criteria for epilepsy compared with just 8.6% of incident seizure cases that were recorded clinically with epilepsy by the veterinary teams. Furthermore, the relatively small overlap Dogs with a higher body weight compared to their sex and breed mean had a higher probability of a higher diagnostic seizure evalua-  24 In a referral population in Tokyo, Japan Chihuahua, Miniature Dachshund, and mixed breed were the 3 most common breeds diagnosed with epilepsy. 21 Another study from a German referral clinic identified the Border Collie as a breed with a high prevalence of idiopathic epilepsy. 25 The predominant breed status among the structural epilepsy group in our study was purebred. Breed distribution among dogs with structural epilepsy in our study was affected by the overall breed distribution in the UK dog population, and therefore commonly affected breeds are not necessarily predisposed to structural epilepsy. However, results from the multivariable analysis did take into account the different counts of breeds in the study and therefore provide information on breed predisposition, regardless of the popularity of these breeds overall. 26 When considering the background population, crossbreds presented the highest number of dogs with structural epilepsy followed by the Labrador Retriever, Staffordshire-Bull-Terrier, and Jack Russell Terrier. A study in a referral setting reported crossbreds as being the most common group with structural epilepsy followed by Labrador Retrievers and Boxers. 27 In addition, mean age at the first seizure event among dogs with structural epilepsy in a previous study was 9.99 years, emphasizing that structural epilepsy is more common in older patients. 4 Consistent with this finding, dogs ≥9 years of age in our study accounted for 63.1% of structural epilepsy cases. Two retrospective studies support these findings and reported increased age at first seizure onset for dogs with structural epilepsy compared to those with idiopathic epilepsy. 28,29 The influence of sex and neuter status on seizure activity is the subject of ongoing VetCompass research, with several investigations suggesting a seizure protective effect of androgens, 30 Our study had several limitations, which have been discussed previously. 1 Retrospective seizure identification is based on the reporting veterinarians notes collected in the VetCompass Program, and cases might be mis-or un-classified because of a potential lack of information because veterinary caregivers write notes for the individual management of each case, and not for research purposes; these records then are adapted by VetCompass as secondary data for research approach.
Consequently, these data are expected to be formatted to conform with good clinical practice and professional conduct code, 37 and to meet the needs of the note-writing veterinarian to optimize patient care but might not include all data fields or meet levels of data completeness required for research. 38 Conversely, a surplus of recorded patient information on potential seizure causes might explain the number of unclassifiable cases.
Given the evidential data gap on seizure management for the general dog population, our study provides useful benchmarking information for practitioners on the etiologies, diagnostic evaluation and management of seizures currently used in general practice in the UK 39 and also provide an evidence-based context for other studies that report on cases derived from primary care caseloads. Our study analyzed data from 2013, 2 years before IVETF published their recommendations for classification, diagnostic evaluation and treatment. 2,4,7,36 Future research could repeat the current study to explore the impact of the IVETF on seizure management by first opinion practitioners.

| CONCLUSION
The substantial differences identified in our study between seizure

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.