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Abstract
The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs’ owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy.
Citation: Packer RMA, Shihab NK, Torres BBJ, Volk HA (2014) Clinical Risk Factors Associated with Anti-Epileptic Drug Responsiveness in Canine Epilepsy. PLoS ONE 9(8): e106026. https://doi.org/10.1371/journal.pone.0106026
Editor: Giuseppe Biagini, University of Modena and Reggio Emilia, Italy
Received: April 7, 2014; Accepted: July 29, 2014; Published: August 25, 2014
Copyright: © 2014 Packer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.
Funding: The authors have no funding or support to report.
Competing interests: Nadia K. Shihab is employed by Southern Counties Veterinary Specialists. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Introduction
Epilepsy is the most common chronic neurological condition in humans and dogs, with estimated prevalences of 0.4–1% [1] and 0.6%, respectively [2]. In human medicine, the best improvement in Quality of Life (QoL) for epilepsy patients is achieved when treatment leads to remission (seizure freedom) [3]–[5]. Indeed, in one study, no significant change in QoL was found after treatment for subjects that did not achieve seizure freedom [4]. In addition to anti-epileptic drug (AED) therapy, surgical interventions are utilised to achieve seizure freedom in medically intractable cases [6]. The dog has been considered as a naturally occurring model of human epilepsy [7], [8]. There are considerable parallels in the diagnosis of human and canine epilepsy, with similarly high levels of workup, for example and the use of advanced diagnostic imaging and in limited cases, the use of electroencephalography (EEG) [9]. However, in veterinary medicine, most epilepsy trials have primarily focused on reducing seizure frequency, rather than achieving seizure freedom. Indeed, an ≥50% reduction in seizure frequency has been the definition of AED efficacy in the majority of canine epilepsy studies (e.g. [10]–[17]). This may not be a satisfactory outcome for the carers (the owners), with nearly one third considering only complete seizure freedom as an acceptable outcome [18]. More than two thirds of dogs with epilepsy will continue to have seizures long-term [19]–[22] and around 20–30% will remain poorly controlled (<50% reduction of seizure frequency) despite adequate treatment with phenobarbitone (PB) and/or potassium bromide (KBr) [23]–[25]. Consequently, there is a need to identify those dogs that are likely to have poor outcomes so that owners have realistic, evidence-based expectations of their dog’s treatment. This has been an area of focus in human epilepsy, with analyses identifying risk factors for pharmacoresistance and poor outcome (e.g. [26]–[28]). In contrast, it has been recognised that more epidemiologic studies are needed to further document the nature and occurrence of remission of epilepsy in dogs [29], and identify risk factors associated with positive and negative outcomes. For those dogs that are unresponsive to AEDs, ‘alternative’ non-pharmacological treatment options need to be developed to improve their quantity and quality of life, for example, dietary and surgical interventions [30].
Remission with or without medication has been observed in canine epilepsy cases, demonstrating that epilepsy in dogs is not necessarily a lifelong condition. Remission rates vary between studies, for example in a study of Danish Labrador Retrievers, 24% of dogs were classed as being in remission; with only 1 (6%) of these receiving antiepileptic treatment (drug-induced remission) [21]. In a further Danish study of 63 dogs with epilepsy, the remission rate (both spontaneous remission and remission with treatment) was 15% [22]. In these studies, remission was classified as being seizure free for two years or three years seizure free, respectively. In a Swiss study of Labrador Retrievers, 30% of dogs treated with phenobarbitone became seizure-free, with an average follow-up period of 4.8 years [19]. In a study of the efficacy of phenobarbital compared with KBr as a first line treatment, complete seizure freedom was achieved in 85% and 52%, respectively, of treated dogs [31]. This study only lasted for six months however, and it is possible that the percentage of dogs experiencing seizure freedom would be lower given a longer follow-up period. In addition, higher % treatment success rates may reflect studying animals in first opinion practice environment, where seizure phenotypes are likely to be less severe than animals seen at referral practices.
Several factors related to the natural history of the disease and clinical factors have been implicated in both the experimental and clinical literature as influencing the likelihood of successful treatment with AEDs (either remission or <50% reduction in seizure frequency). For example, recent rodent studies found that early treatment [32] had a positive influence on the likelihood of remission being achieved in certain types of epilepsy. Indeed, in human epilepsy it was thought that patients should be treated with AEDs immediately after a seizure to increase the likelihood of achieving remission. However, evidence that remission rates in countries with and without ready access to AEDs are similar [33] implies that AEDs may act to suppress seizures, but have no influence on achieving remission. In addition, there is increasing evidence from both canine, rodent and human studies, that other aspects of disease e.g. different markers of severity can influence drug responsiveness and treatment outcome [19], [29], [34]–[36]. This includes a high seizure frequency before treatment, and the presence of cluster seizures and/or status epilepticus. Much of the canine epilepsy literature in this area is derived from single breed studies, thus the aim of this retrospective study was to investigate factors associated with remission in a large population of dogs with epilepsy treated at a multi-breed canine specific epilepsy clinic.
Materials and Methods
Data from dogs treated at a multi-breed canine specific epilepsy clinic at the Royal Veterinary College Small Animal Referral Hospital (RVC SARH) between 2005–2011 was retrospectively collected from RVC’s electronic patient records. Clinical data was originally gained via standardised owner questionnaires for epilepsy patients at their first appointment, and longitudinal follow up data was gained via telephone interview with the dogs’ owners. All dogs received a uniform diagnostic protocol (including complete blood cell count; serum biochemical profile and dynamic bile acid testing; MRI of the brain, 1.5-Tesla Gyroscan NT, Philips Medical Systems) and a neurological examination to rule out an underlying cause of the seizure activity. Only dogs which were reported in the records to be diagnosed with idiopathic epilepsy, for which a cause was not identified (no remarkable findings on interictal neurological examination, haematology, biochemistry, brain magnetic resonance imaging and cerebrospinal fluid examination), were included in the study. A genetic or hereditary basis cannot be confirmed for every case included in the study, and it is possible that the cause could have been identified with continuous EEG recording. Only dogs receiving AEDs were included in the study.
Seizures were classified according to the former guidelines of the International League Against Epilepsy, modified for veterinary patients (Berendt and Gram, 1999; Licht et al., 2002). Epilepsy was defined of at least two unprovoked seizures >24 h apart. Cluster seizures were defined as an episode where more than one seizure occurred within a 24 h period, with full recovery of consciousness between seizures. Status epilepticus was defined as seizure activity lasting longer than 10 min without gaining consciousness. Seizure activity lasting less than 10 min without gaining consciousness was classed as a single seizure episode. A consistent history was collected with the help of a questionnaire developed for a previous study [10]. The data collected included: signalment, age presented to the hospital (days), age of dog at the time of the first seizure (days), time until diagnosis (days), duration of the disorder before treatment (days), number of seizures prior to any treatment with an AED, seizure frequency per month before medication, type of seizures experienced, and experience of cluster seizures (yes/no) and status epilepticus (yes/no). Medication administered was recorded, specifically whether phenobarbitone (PB), potassium bromide (KBr) or other 3rd line drugs were prescribed, and response to these drugs recorded as responsive or unresponsive. Follow up time was recorded in days. Treatment success was recorded as:
- Seizure-free remission (with or without medication) (1/0)
- ≥50% reduction in seizure frequency (1/0)
Non-responsiveness to an AED was classified as a less than 50% reduction in seizure frequency, despite being within the reference range for the prescribed AED(s) and titrated to the maximum tolerated effective dose. As these data were derived from a clinical population, decision-making leading to the maximum dose of any AED was made by both the clinician and the owner, taking into account adverse effects of the drug and its efficacy. Serum levels of phenobarbitone and/or potassium bromide were checked by the attending clinician, and recorded from the clinical records where available, to ensure the dog was within the reference range for these AEDs and receiving adequate therapy, and to test the effect of this variable.
Ethics statement
This study was approved by the Royal Veterinary College’s Ethics and Welfare Committee. The owners of the dogs gave permission for their animals to be used in this study.
Statistical analysis
Differences between outcome variables were tested with a Fisher’s exact test for categorical variables with expected values <10, and the Pearson’s chi squared test for expected values >10. The Mann-Whitney U-test was used for continuous variables. Generalised linear mixed models for binary outcomes were then used to identify risk factors in a multivariate analysis for successful treatment outcomes, using the lmer function in R from the lme4 package. Treatment outcomes (i) seizure free remission with or without medication (1/0) and (ii) ≥50% reduction in seizure frequency (1/0) were used as the response variables in models. Follow-up time and serum AED values were tested in the models to verify that they did not have an effect on treatment success. Breed was included as a random effect, with all cross breeds coded plainly as ‘cross breed’ due to the unknown parentage of many of these dogs. This random effect took into account the genetic non-independence of multiple members of the same breed in the study population, and possible demographic and environmental factors. Predictors including age, sex and neuter status were tested in all models. Multicollinearity was checked for in all models, identified from inflated standard errors in the models, and thus avoided. Model fit was assessed using the deviance and Akaike’s information criterion. Data is presented as median with 25th and 75th percentiles and all tests were used two-sided with P<0.05 being considered statistically significant.
Results
Population demographics
122 dogs were lost to follow and 344 dogs were included in the analysis, of which 89.5% were pure bred and 10.5% were cross-breeds. The five most common breeds were the Labrador Retriever (14.8%), cross breed (10.5%), Border Collie (9.9%), German Shepherd Dog (8.7%) and the Staffordshire Bull Terrier (5.5%). The majority of dogs were male (70.3%), with 57% of all dogs neutered. The median age (in days) at presentation to the small animal referral hospital was 1260 days (720–2008) (approximately 3.5 years).
Clinical data
The median age at onset of seizures was 780 days (360–1447.5). The median time until diagnosis was 150 days (38–360), with the median duration of the disorder before treatment 67.5 days (30–180). The median number of seizures before the start of treatment was 4.5 (3–7.25) with a median seizure frequency (per month) before medication of 3 (1–5). The median follow up time was 656 days (330–960).
A minority of dogs had experienced status epilepticus (13.1%), whereas nearly half of dogs had experienced cluster seizures (48%). There was a significant association between the presence of status epilepticus and cluster seizures (X2 = 8.05, P = 0.004), with 9.8% of dogs experiencing both status epilepticus and cluster seizures. There was no difference between male and female dogs experiencing cluster seizures (48.9% vs. 45.8%; X2 = 0.26, P = 0.61); however, more male dogs experienced status epilepticus than female dogs (15.5% vs. 5.2%; X2 = 4.12, P = 0.041). At the univariate level (Table 1) dogs without cluster seizures were significantly more likely to go into remission, but there was no difference in dogs with or without status epilepticus.
The most common seizure type was complex-focal seizures with secondary tonic-clonic generalisation (35.7%), followed by generalised tonic-clonic (32.6%), complex-focal (14.1%), and simple-focal seizures with secondary tonic-clonic generalisation (13.7%). The rarest seizure type was simple-focal seizures with only 11 cases (3.8%).
Of the 113 dogs for which PB concentrations were available, they were well within the reference range (29.1±1.60 µg/ml, reference range from our laboratory of 15–45 µg/ml). KBr concentrations were available for 53 dogs and were 1.61±0.11 mg/ml, again well within the reference range from our laboratory of 0.5–1.9 mg/ml.
The majority of dogs were receiving PB at follow up (67.2%), with a further 38.4% of cases receiving KBr, and 27% of all cases receiving PB and KBr in combination. A minority of cases (10.2%) were prescribed a third line AED (e.g. gabapentin, pregabalin, levetiracetam and zonisamide). In addition, 5.4% of cases received emergency rectal diazepam treatment and 8.1% received pulsed intermittent treatment with levetiracetam.
Risk factors for remission
Fourteen per cent of dogs were in remission on PB treatment. When ≥50% reduction in seizure frequency is used as the outcome measure, success rates are markedly higher with 64.5% of dogs achieving this level of seizure reduction. At the univariate level, several factors were associated with an increased likelihood of achieving remission (Table 1), namely: being female, neutered, no previous experience of cluster seizures and an older age at onset of seizures. The same four factors were also associated with an increased likelihood of achieving an ≥50% reduction in seizure frequency, with the addition of an older age at presentation to hospital (Table 2).
When tested in a multivariate mixed model (Table 3), two categorical variables were significantly associated with the likelihood of remission being achieved; sex and cluster seizures, with female dogs over two times more likely to achieve remission, and dogs with no previous experience of cluster seizures over six times more likely to achieve remission. No effects of neuter status or previous episodes of status epilepticus were found in any model, and were not found to improve model fit (determined by Akaike Information Criterion [AIC] and % correct classification), and as such they were not included in the final model. There were no significant effects of time until diagnosis, duration of time before treatment, the number of seizures before treatment or the seizure frequency per month before medication. No effects of follow up time or serum AED values were found. There were no significant effects of seizure type on the likelihood of remission (p = 0.208); however the seizure types with the lowest remission rates were simple-focal (0% remission) and complex-focal seizure with secondary tonic-clonic generalisation (14.1% remission).
When an ≥50% reduction in seizure frequency is used as the outcome measure (Table 2 and 4), the same two factors were found to significantly predict the likelihood of achieving remission in a multivariate model (Table 4), with the addition of age at onset of seizures. As age at onset of seizures increases, the likelihood of achieving an ≥50% reduction in seizure frequency increases.
Breeds
Dogs of fifteen different breeds achieved seizure freedom, and dogs of fifty-two breeds achieved an ≥50% reduction in seizure frequency. There was no statistically significant effect of breed on the likelihood of dogs going into remission or having an ≥50% reduction in seizure frequency when tested at the univariate level. Of the breeds with over 10 dogs for which data was available (the Labrador Retriever, Cross Breed, German Shepherd, Border Collie and Staffordshire Bull Terrier), the breed least likely to go into remission or have an ≥50% reduction in seizure frequency was the Border Collie (0% and 40% respectively), followed by the German Shepherd (11% and 35%) and Staffordshire Bull Terrier (0% and 57%). Fishers exact tests revealed only significant effects of being a Border Collie or German Shepherd on the likelihood of entering remission or experiencing an ≥50% reduction in seizure frequency (Table 5). When these breeds were included in multivariate analyses as binary variables, no significant effects were found.
Discussion
The results of this retrospective study provide evidence that the presence of cluster seizures and thus seizure density (the temporal pattern of seizure activity) is a more influential risk factor on the likelihood of achieving remission in canine epilepsy than seizure frequency or the total number of seizures prior to treatment. Nearly half (48%) of dogs in the study population had experienced cluster seizures, of which only 17.9% achieved remission and 33.5% achieved an ≥50% reduction in seizure frequency. This result has previously been found in human epilepsy [37]. The number of epileptic dogs that experience cluster seizures varies between studies, with recent reports between 38% and 64% [20], [38]. The breed least likely to achieve remission in this study was the Border Collie, a breed previously demonstrated to have a higher level of cluster seizures than other breeds (84.6% affected) [20], with similar levels reported in other studies (e.g. 94%; [29]). A remission rate of 14.2% was observed in this study, similar to a previous Danish study of canine epilepsy (15%) [22]. These were both mixed study populations; however, in studies of Labrador Retrievers in isolation, higher levels of remission have been observed (24–40%) [19], [21]. When >50% reduction in seizure frequency is used as the outcome measure, success rates are markedly higher at 64.5%.
Seizure density as well as frequency has been demonstrated to influence the likelihood of remission in humans, with individuals who experience an episode of status epilepticus [39]–[41], or cluster seizures [37] less likely to go into remission. These results were also seen in a recent study of predictors of pharmacoresistance in rats, where the average seizure frequency per day of 13 rats nonresponsive to medication was 4.31/day, indicating some rats having cluster seizures [36]. This frequency was significantly higher than 20 drug-responsive rats (mean 0.54/day). It is further notable, that of the 13 rats that were unresponsive to medication, a subgroup of six rats (18%) experienced high levels of cluster seizures, with an average of 8.94 seizures per day [36]. Intact male and female dogs have a higher likelihood of having cluster seizures [42] which may have a negative impact on their prognosis. Evidence from canine epilepsy is not clear however, with 89% (8/9) of Border Collies in remission having a history of cluster seizures, status epilepticus, or both [29]. A severe epilepsy phenotype is often seen in this breed, thus data from a larger population with a diversity of breeds represented would be valuable to gain an insight into this relationship in a wider population with a variety of disease phenotypes.
No evidence was found to support the results of a recent rodent study that found early treatment [32] influenced the likelihood of remission being achieved. There are divergent opinions within the veterinary profession regarding time to treatment after diagnosis of epilepsy, a topic also debated in human medicine [43]. One school of thought advises treatment of seizures as soon as a dog is diagnosed as having recurrent seizures (i.e. after the second seizure episode). However, the impact of AED side effects on QoL may be considerable, with this being the top reason cited by owners for a decreased QoL in their dogs (28% of 25 owners questioned) [44]. As such, the second school of thought considers that there should be a balance between the benefits gained from using AEDs with the potential adverse effects they cause. The results of this study indicated no effect of time to treatment; however, there is mixed evidence regarding its effects on treatment outcome. In clinical studies of epilepsy in dogs, decreased time to treatment has not been observed as a positive influence upon treatment outcome, indeed, one study demonstrated that Labrador Retrievers that were in remission received medication a longer period of time after their first seizure than those dogs which continued to seizure [19]. It should be acknowledged that this result may be biased by animals with a more severe seizure phenotype receiving treatment earlier, due to owner and/or veterinarian concerns. It is currently not veterinary practice to initiate treatment after the first seizure. Early initation of treatment has also proven unsuccessful in several human studies [45]–[47]. Time to treatment is additionally likely to be influenced by disease severity, for example it was shorter in dogs with episodes of status epilepticus [48], thus being confounding factors in statistical analyses.
A large number of seizures before treatment has been identified as a poor prognostic factor in several previous human studies of epilepsy [34], [41], [49], with patients experiencing a greater number of seizures prior to initiation of treatment more likely to have refractory epilepsy. In rats, it was recently demonstrated that seizure frequency in the early phase of epilepsy is a strong predictor of refractoriness [36]. This has also been seen in dogs, with refractory dogs having a significantly higher number of seizures prior to presentation and beginning of treatment in Labradors [19] and an initially higher seizure frequency in Border Collies [29]. It has been discussed whether this initial high seizure frequency and subsequent refractoriness may be an effect of kindling (Reynolds, 1995). However, as time to treatment has not been found to be a strong predictor of refractoriness in dogs and humans, initial high seizure frequency has been considered more likely to be the result, rather than the cause of the pathophysiological changes that are later manifested as refractory epilepsy [34], [50]. Indeed, in this study and another previous study of canine epilepsy, the number of seizures before treatment was not significantly different between dogs positive vs. negative treatment outcomes [48]. In addition, no effect was found of seizure type upon the likelihood of remission; however, the most common seizure type in dogs that did not achieve remission (39.6%) was complex-focal seizures, also seen in human epilepsy [51], [52], adding evidence to the belief that focal seizures are more challenging to treat.
Males were found to be less likely to achieve remission than female dogs. Historically, male dogs are thought to seizure more than female dogs [53], and recent epidemiological studies of idiopathic epilepsy have confirmed a male overrepresentation for this disorder [2], [38]. With regard to the impact of sex upon treatment outcome, little existing data is available. One study noted that female dogs with epilepsy lived longer with the disorder than male dogs, with a median age at death two years greater (8 vs. 6 years, respectively) [22]; however, this outcome measure may be influenced by owner euthanasia decisions, so can only be a proxy of treatment success. In previous studies, male dogs were found to be more highly affected by cluster seizures than female dogs [42]. This result was not found in the current study, and indeed sex and the presence of cluster seizures were found to be independently significant risk factors, thus further investigation is warranted into the effect of sex on treatment outcome.
Age at onset of disease was found to significantly influence the likelihood of achieving an ≥50% reduction in seizure frequency, with dogs experiencing their first seizure at an older age more likely to achieve this level of reduction. This has previously been demonstrated in Border Collies, with the mean age at onset significantly higher in dogs with remission compared to those with active epilepsy [29], and in Labradors, with dogs classed as having excellent or good results (defined as those that were seizure-free, or had an improvement in their seizure frequency, strength and/or duration) having a significantly higher age at onset than uncontrolled dogs [19]. Early age at seizure onset has been previously identified in children to be a predictor of pharmacoresistance [54]. In contrast, in a study of canine juvenile epilepsy (where the first seizure occurs before the age of one year), age at onset had no influence on survival outcome [20].
There are recognised limitations to studying epilepsy in a veterinary referral population [20] due to a bias towards a more severe seizure phenotype, and thus may not be representative of the whole canine epilepsy population. As such, further studies of epilepsy in the first opinion practice population may be warranted, although the level of diagnostic work up may be lower owing to availability of equipment and specialist expertise, and thus confidence in diagnosis may be variable. A further limitation of this study is the varied follow up time of cases. In previous studies, remission was strictly classified as dogs that were seizure free for two or three years [21], [22]. In human epilepsy, seizures may re-occur after a period of months of seizure freedom, without alterations to treatment [55]. As such, some of the dogs classified as seizure free in this study may have later experienced seizures. This may be due to a variety of factors including drug tolerance, deterioration of the epilepsy phenotype, acquired drug resistance and poor owner compliance [55]. The median follow up time, however, was 656 days and thus is in line with the follow-up standards of comparable epilepsy studies in the veterinary environment. There are limitations to which variables could be controlled for in this study, introduced by data being collected in a clinical environment with naturally occurring disease in client owned animals. Due to the expense of medication it is possible that clients may decline third line AEDs that may affect the response rate, which may mean the figures here are an underestimate of how many dogs could biologically achieve remission. In addition, EEG is not routinely used in the Canine Epilepsy Clinic data were sourced from, or in veterinary medicine in general at present, and thus there is no confirmation that the ‘seizure’ episodes reported by owners was indeed seizure activity. A further limitation of this study is that serum AED levels were not available for all dogs; however, clinicians contributing to this dataset routinely checked AED serum levels were within the reference ranges and thus, this is naturally standardised across the sample. Furthermore, not all serum levels were conducted at the same laboratory and therefore could not be analysed in the same dataset. No statistical association between AED levels and treatment outcome were found; however, future studies could include this variable to check this result was not due to the lower power of this sub-sample.
Conclusions
In conclusion, the present provides evidence that it is not merely the absolute number of seizures prior to treatment that predicts refractoriness, but their temporal pattern, with those patients experiencing cluster seizures (more than one seizure within a 24 h period) more likely to be pharmacoresistant. Whether this result is an effect of cluster seizures promoting epileptogenesis and causing brain damage that results in seizures resistant to medication, or is actually a reflection of a more aggressive disease phenotype that is harder to treat is unknown, and warrants further investigation. The present study further demonstrates similarities between this naturally occurring model of epilepsy and both experimental rodent models [36], and human clinical studies [37]. The similarity between clinical environments, high level of diagnostic work up, and shared living environments between humans and dogs further strengthens the use of this readily available animal model.
Author Contributions
Conceived and designed the experiments: NKS BBJT HAV. Performed the experiments: NKS BBJT. Analyzed the data: RMAP. Contributed reagents/materials/analysis tools: RMAP. Contributed to the writing of the manuscript: HAV RMAP.
References
- 1. Sander JW, Shorvon SD (1996) Epidemiology of the epilepsies. Journal of Neurology, Neurosurgery, and Psychiatry 61: 433–443.
- 2.
Kearsley-Fleet L, O’Neill DG, Volk HA, Church DB, Brodbelt DC (2013) Prevalence and risk factors for canine epilepsy of unknown origin in the UK. Veterinary Record 172.
- 3. Poochikian-Sarkissian S, Sidani S, Wennberg R, Devins G (2008) Seizure Freedom Reduces Illness Intrusiveness and Improves Quality of Life in Epilepsy. The Canadian Journal of Neurological Sciences 35: 280–286.
- 4. Birbeck Gretchen L, Hays Ron D, Cui X, Vickrey Barbara G (2002) Seizure Reduction and Quality of Life Improvements in People with Epilepsy. Epilepsia 43: 535–538.
- 5. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, et al. (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51: 1069–1077.
- 6. Ramey WL, Martirosyan NL, Lieu CM, Hasham HA, Lemole Jr GM, et al. (2013) Current management and surgical outcomes of medically intractable epilepsy. Clinical Neurology and Neurosurgery 115: 2411–2418.
- 7. Löscher W, Schwartz-Porsche D, Frey HH, Schmidt D (1985) Evaluation of epileptic dogs as an animal model of human epilepsy. Arzneimittelforschung 35(1): 82–7.
- 8. Potschka H, Fischer A, von Rüden E-L, Hülsmeyer V, Baumgärtner W (2013) Canine epilepsy as a translational model? Epilepsia 54: 571–579.
- 9. Berendt M, Høgenhaven H, Flagstad A, Dam M (1999) Electroencephalography in dogs with epilepsy: similarities between human and canine findings. Acta Neurologica Scandinavica 99: 276–283.
- 10. Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE (2008) The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. The Veterinary Journal 176: 310–319.
- 11. Platt SR, Adams V, Garosi LS, Abramson CJ, Penderis J, et al. (2006) Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Veterinary Record 159: 881–884.
- 12. Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducoté JM, et al. (2009) Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. Journal of the American Veterinary Medical Association 235: 1442–1449.
- 13.
Dewey CW, Guiliano R, Boothe DM, Berg JM, Kortz GD, et al.. (2004) Zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of the American Animal Hospital Association 40.
- 14. von Klopmann T, Rambeck B, Tipold A (2007) Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of Small Animal Practice 48: 134–138.
- 15.
Andrew SE (2008) Immune-mediated canine and feline keratitis. Veterinary Clinics of North America-Small Animal Practice 38: 269-+.
- 16. Muñana KR, Nettifee-Osborne JA, Bergman RL Jr, Mealey KL (2012a) Association between ABCB1 genotype and seizure outcome in collies with epilepsy. Journal of Veterinary Internal Medicine 26: 1358–1364.
- 17. Muñana KR, Thomas WB, Inzana KD, Nettifee-Osborne JA, McLucas KJ, et al. (2012b) Evaluation of levetiracetam as adjunctive treatment for refractory canine epilepsy: a randomized, placebo-controlled, crossover trial. Journal of Veterinary Internal Medicine 26: 341–348.
- 18. Wessmann A, Volk H, Parkin T, Ortega M, Anderson TJ (2012) Living with canine idiopathic epilepsy: a questionnaire-based evaluation of quality of life. Proceedings of the 24th Symposium ESVN-ECVN. J Vet Intern Med 26: 823–852.
- 19. Heynold Y, Faissler D, Steffen F, Jaggy A (1997) Clinical, epidemiological and treatment results of idiopathic epilepsy in 54 labrador retrievers: a long-term study. Journal of Small Animal Practice 38: 7–14.
- 20. Arrol L, Penderis J, Garosi L, Cripps P, Gutierrez-Quintana R, et al. (2012) Aetiology and long-term outcome of juvenile epilepsy in 136 dogs. Veterinary Record 170: 335.
- 21. Berendt M, Gredal H, Pedersen LG, Alban L, Alving J (2002) A Cross-Sectional Study of Epilepsy in Danish Labrador Retrievers: Prevalence and Selected Risk Factors. Journal of Veterinary Internal Medicine 16: 262–268.
- 22. Berendt M, Gredal H, Ersbøll AK, Alving J (2007) Premature Death, Risk Factors, and Life Patterns in Dogs with Epilepsy. Journal of Veterinary Internal Medicine 21: 754–759.
- 23. Trepanier L, Schwark W, Van Schoick A, Carrillo J (1998) Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992–1996). J Am Vet Med Assoc 213: 1449–1453.
- 24. Schwartz-Porsche D, Löscher W, Frey H (1985) Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther 8: 113–119.
- 25. Podell M, Fenner W (1993) Bromide therapy in refractory canine idiopathic epilepsy. Journal of Veterinary Internal Medicine 7: 318–327.
- 26. Cockerell O, Johnson A, Sander J (1994) Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 346: 140–144.
- 27. Bonnett LJ, Tudur Smith C, Smith D, Williamson PR, Chadwick D, et al. (2014) Time to 12-month remission and treatment failure for generalised and unclassified epilepsy. Journal of Neurology, Neurosurgery & Psychiatry 85: 603–610.
- 28. MacDonald BK, Johnson AL, Goodridge DM, Cockerell OC, Sander JWAS, et al. (2000) Factors predicting prognosis of epilepsy after presentation with seizures. Annals of Neurology 48: 833–841.
- 29. Hülsmeyer V, Zimmermann R, Brauer C, Sauter-Louis C, Fischer A (2010) Epilepsy in Border Collies: Clinical Manifestation, Outcome, and Mode of Inheritance. Journal of Veterinary Internal Medicine 24: 171–178.
- 30. Martlé V, Van Ham L, Raedt R, Vonck K, Boon P, et al. (2014) Non-pharmacological treatment options for refractory epilepsy: An overview of human treatment modalities and their potential utility in dogs. The Veterinary Journal 199: 332–339.
- 31. Boothe DM, Dewey C, Carpenter DM (2012) Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc 240: 1073–1083.
- 32. Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, et al. (2008) Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49: 400–409.
- 33. Placencia M, Sander JWAS, Shorvon SD, Roman M, Alarcon F, et al. (1993) Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment. Epilepsy Research 14: 237–244.
- 34. Kwan P, Brodie MJ (2000) Early Identification of Refractory Epilepsy. New England Journal of Medicine 342: 314–319.
- 35. Weissl J, Hulsmeyer V, Brauer C, Tipold A, Koskinen LL, et al. (2012) Disease progression and treatment response of idiopathic epilepsy in Australian Shepherd dogs. Journal of Veterinary Internal Medicine 26: 116–125.
- 36. Löscher W, Brandt C (2010) High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia 51: 89–97.
- 37. Sillanpää M, Schmidt D (2008) Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy. Brain 131: 938–944.
- 38. Short AD, Dunne A, Lohi H, Boulton S, Carter SD, et al. (2011) Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach. Veterinary Record 169: 48.
- 39. Hauser WA (1990) Status epilepticus: epidemiologic considerations. Neurology 40: 9–13.
- 40. Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA (2007) Likelihood of seizure remission in an adult population with refractory epilepsy. Annals of Neurology 62: 382–389.
- 41. Sillanpää M (1993) Remission of Seizures and Predictors of Intractability in Long-Term Follow-Up. Epilepsia 34: 930–936.
- 42. Monteiro R, Adams V, Keys D, Platt SR (2012) Canine idiopathic epilepsy: prevalence, risk factors and outcome associated with cluster seizures and status epilepticus. Journal of Small Animal Practice 53: 526–533.
- 43. Marson AG (2008) When to start antiepileptic drug treatment and with what evidence? Epilepsia 49: 3–6.
- 44. Chang Y, Mellor DJ, Anderson TJ (2006) Idiopathic epilepsy in dogs: owners’ perspectives on management with phenobarbitone and/or potassium bromide. Journal of Small Animal Practice 47: 574–581.
- 45. Musicco M, Beghi E, Solari A, Viani F (1997) Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. Neurology 49: 991–998.
- 46. Camfield C, Camfield P, Gordon K, Dooley J (1996) Does the number of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is 10 or less. Neurology 46: 41–44.
- 47. Avanzini G, Depaulis A, Tassinari A, de Curtis M (2013) Do seizures and epileptic activity worsen epilepsy and deteriorate cognitive function? Epilepsia 54: 14–21.
- 48. Saito M, Muñana K, Sharp N, Olby N (2001) Risk factors for development of status epilepticus in dogs with idiopathic epilepsy and effects of status epilepticus on outcome and survival time: 32 cases (1990–1996). J Am Vet Med Assoc 219: 618–623.
- 49. Collaborative Group for the Study of Epilepsy (1992) Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study of the Effects of Monotherapy on the Long-Term Course of Epilepsy. Epilepsia 33: 45–51.
- 50. Berg AT, Shinnar S (1997) Do Seizures Beget Seizures? An Assessment of the Clinical Evidence in Humans. Journal of Clinical Neurophysiology Secondary Epileptogenesis 14: 102–110.
- 51. Regesta G, Tanganelli P (1999) Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Research 34: 109–122.
- 52. Reynolds EH, Elwes RDC, Shorvon SD (1983) Why Does Epilepsy Become Intractable - Prevention of Chronic Epilepsy. Lancet 2: 952–954.
- 53. Bielfelt SW, Redman HC, McClellan RO (1971) Sire- and sex-related differences in rates of epileptiform seizures in a purebred beagle dog colony. American Journal of Veterinary Research 32: 2039–2048.
- 54. Cockerell OC, Johnson AL, Sander JW, Shorvon SD (1997) Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 38: 31–46.
- 55. Löscher W, Schmidt D (2006) Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs. Epilepsia 47: 1253–1284.