Behavioral changes in dogs associated with the development of idiopathic epilepsy

Epilepsy & Behavior 21 (2011) 160–167

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Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

Behavioral changes in dogs associated with the development of idiopathic epilepsy Nadia Shihab a,⁎, Jon Bowen a,b, Holger A. Volk a a b

Department of Veterinary Clinical Sciences, Royal Veterinary College, Hertfordshire, UK Department of Biomolecular Medicine, Imperial College London, South Kensington Campus, London, UK

a r t i c l e

i n f o

Article history: Received 21 January 2011 Revised 4 March 2011 Accepted 14 March 2011 Available online 4 May 2011 Keywords: Canine Seizure Comorbidity Epilepsy Behavior

a b s t r a c t Objectives: The aim of the study was to demonstrate behavioral changes with the development of epilepsy in dogs, a species proposed as a naturally occurring animal model for human epilepsy. Methods: Owners of dogs diagnosed with idiopathic epilepsy (n = 80) completed a modified, previouslyvalidated behavioral and seizure questionnaire. Principal axis factor analysis identified behavioral factors, the scores for which were compared before and after the development of epilepsy. Results: Drug-naïve dogs showed an increase in the behavior factors Fear/Anxiety, Defensive Aggression, and Abnormal Perception. In dogs receiving antiepileptic medication, there were still increases in Fear/Anxiety and Abnormal Perception, but no longer in Defensive Aggression. Additional increases were observed in Abnormal Reactivity, Attachment Disorder, Demented Behavior, and Apathetic Behavior. Pharmacoresistant dogs had larger increases in Controlling Aggression, Abnormal Perception, and Demented Behavior than drug responders. Conclusion: Our data suggest that dogs, like humans and rodents, exhibit neurobehavioral comorbidities with the development of epilepsy. © 2011 Elsevier Inc. All rights reserved.

1. Introduction Epilepsy is the most common chronic human and canine neurological disorder [1–4]. In human medicine, an increasing number of studies have identified somatic and neurobehavioral or psychiatric comorbidities associated with recurrent seizure disorders [5–10]. Interestingly, recent evidence suggests not only that the presence of epilepsy increases the risk of neurobehavioral disorders, but also that a bidirectional relationship exists, with a history of major depression or anxiety increasing the risk of unprovoked seizures and epilepsy [8,11]. Neurobehavioral comorbidities have also been reported and studied in a variety of rodent models of epilepsy [12]. In a recent study, neurobehavioral changes were found to be related not only to epilepsy but also to pharmacological response, with pharmacoresistant rats having greater behavior changes [13]. There is, however, a lack of data on the comorbidities of epilepsy in dogs and the possible occurrence of behavioral changes with the development of epilepsy in this species. Most experimental rodent models of epilepsy are not naturally occurring models; seizures or epilepsy have to be induced and, therefore, these models have their limitations [12–14]. Canine epilepsy is similar in semiology to its human counterpart and has thus been proposed as a good model for human epilepsy [2,3,15]. Idiopathic ⁎ Corresponding author at: Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK. Fax: + 44 1707 649 384. E-mail address: [email protected] (N. Shihab). 1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.03.018

epilepsy in dogs is a spontaneous, naturally occurring animal model, with seizure types and pharmacological behavior similar to those in the human condition [16]. Around one-third of humans and dogs with epilepsy show pharmacoresistance to current antiepileptic drugs [17–19]. Dogs live in the same environment as humans and are exposed to similar external factors. Furthermore, epilepsy in humans has social implications and consequences, and thus, it is difficult to ascertain whether neurobehavioral changes are associated with psychosocial factors or with the epilepsy itself. In the current study we investigated whether behavior changes were associated with the development of epilepsy in dogs. If such changes could be identified, our subsequent aims were to identify seizure and patient phenotypes that might be more strongly associated with behavior changes. 2. Methods Hospital records at a veterinary referral hospital were searched for canine patients with a recurrent seizure disorder from January 2001 to January 2009. Dogs were included in the study only if they had a normal interictal neurological examination and no underlying cause for the seizure disorder had been identified. All patients had undergone a comprehensive investigation, including complete blood count, serum biochemical profile, dynamic bile acid testing, MRI of the brain, and cisterna magna cerebrospinal fluid analysis. One hundred twenty dogs were randomly selected from the 339 that met the inclusion criteria. Previous studies investigating the neurobehavioral comorbidities of epilepsy in children have used previously-validated questionnaire

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information obtained from parents and teachers of the children [20,21]. Similarly, the owners of the 120 selected dogs in this study were asked to complete a questionnaire designed to obtain behavioral information about the dog prior to and after the onset of epilepsy. Each questionnaire was followed up by a telephone conversation to confirm the accuracy of the data collected. Forty dogs were excluded because of either incomplete questionnaire data and/or inability to clarify data with the owners. The aim of the questionnaire was twofold: Section 1 was aimed at identifying the presence and severity of a range of behavior problems. This section of the questionnaire was based on a previously validated behavioral questionnaire [22,23]. Section 2 was aimed at obtaining a consistent, unbiased patient history. This section has previously been tested on owners of epileptic dogs [19,24] and allowed collection of such data as age of dogs at first seizure, seizure type, frequency, and antiepileptic medication. Seizure type was classified as focal, generalized, or focal with secondary generalization according to the guidelines of the International League Against Epilepsy [25] modified for veterinary patients [15,26] using the modifications described by Licht et al. [15] where standard criteria for seizure classification were provided. Information obtained from the epilepsy history questionnaire was used to identify groups of dogs that showed reduced drug response. Dogs were classified as drug nonresponsive (pharmacoresistant) if they had not exhibited a ≥50% reduction in seizure frequency on combined treatment with two first-line antiepileptic drugs in dogs (phenobarbital and potassium bromide) achieving therapeutic serum concentrations and steady state [19,27]. 2.1. Statistical analysis As the behavioral questionnaire included a number of items relating to behaviors that might be expected to share a common underlying motivation (such as different forms of aggressive behavior), principal axis factoring, using varimax rotation and Kaiser normalization, was used to explore the latent structure within the behavioral questionnaire data. This reduced the dimensionality of the data, and extracted several easily interpretable factors. Twenty-eight of the questionnaire items that were analyzed were grouped into 10 factors, each with eigenvalue N1, that accounted for 73.6% of the common variance in item scores. Variables with loadings b0.45 were excluded from the factor descriptions and the calculation of patient factor scores. In accordance with naming convention in factor analysis, and to ease interpretation, factors were given descriptive titles that reflected the variables contributing to their makeup (Table 1). The 10 factors were entitled Fear/Anxiety, Defensive Aggression, Controlling Aggression, Abnormal Perception, Territorial Behavior, Demanding Behavior, Abnormal Reactivity, Attachment Disorder, Demented Behavior, and Apathetic Behavior. The dog's score was calculated for each factor by taking the mean of the values of the variables included in that factor. Comparisons between data before and after the onset of epilepsy were performed with Kruskal–Wallis one-way analysis of variance test followed by Wilcoxon's matched pairs test. Comparisons of data between groups (unpaired) were performed with Kruskal–Wallis one-way analysis of variance test followed by the Mann–Whitney test for unpaired data. The Spearman rank correlation was used to assess for a correlation between seizure frequency and behavior. Data are expressed as means (x) ± SEM. All tests were used two-sided, and P b 0.05 was considered significant. 3. Results 3.1. Demographics/subjects Eighty dogs met the inclusion criterion for the study. Fifty-two dogs were male (29 neutered) and 28 female (21 neutered). The three

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Table 1 Results of factor analysis. Item Factor 1: Fear/Anxiety Dog acts anxiously or fearful When approached by unfamiliar dogs When in new or unfamiliar surroundings When an unfamiliar person enters the house When there are sudden or unpredicted movements Factor 2: Defensive Aggression Dog acts aggressively When being handled When approached by other dogs When people or dogs walk past the house When approached by people on walk Does your dog ever snap at or bite/try to bite Other dogs Unfamiliar people Factor 3: Controlling Aggression Dog acts aggressively When food, bones, or toys are taken away When being corrected or punished When approached while eating Factor 4: Abnormal Perception Dog is seen Barking without any apparent cause Chasing light spots or shadows Aimlessly pacing or wandering Staring into space Factor 5: Territorial Behavior Dog acts aggressively When a familiar person enters the house When a stranger enters the house Factor 6: Demanding Behavior Dog shows loss of interest in receiving affection Dog is seen barking at familiar object or person Factor 7: Abnormal Reactivity Dog shows anxious behavior If there are sudden or unpredicted movements If there is a loud or sudden noise Factor 8: Attachment disorder Dog acts anxiously When left alone in the house or when a particular family member leaves Factor 9: Demented behavior Dog fails to recognize family members or familiar people Dog is seen pacing aimlessly or wandering Factor 10: Apathetic behavior Dog is agitated if disturbed from sleep Dog shows reduced interest in activities

Loading

0.616 0.726 0.884 0.489

0.489 0.818 0.492 0.669 0.598 0.643

0.825 0.693 0.800

0.674 0.544 0.470 0.627

0.624 0.726 0.686 0.689

0.644 0.594

0.630

0.879 0.464 0.457 0.630

Note. The table lists the 28 questionnaire items that were analyzed, grouped into 10 factors. The loading shown for each questionnaire item refers to the degree of correlation of an item with the behavior factor.

breeds with the highest representation were Labradors (n = 12), German Shepherds (n = 8), and Border Collies (n = 7). The age of the dogs at seizure onset was 37.3 ± 3.5 months (range: 4–107), and the age at the time of data collection was 63.75 ± 3.5 months (range: 12–142). An accurate seizure frequency was available for 53 dogs: 2.7 ± 0.7 seizures per month. There were 57 dogs (71%) that showed a change in their score for at least one behavior factor with the onset of epilepsy. 3.2. Behavior changes in dogs with epilepsy (drug naïve) Twenty-six dogs did not receive antiepileptic drugs. In this group a significant increase was identified between the pre-epilepsy and post-onset-of-epilepsy scores for the following behavior factors: Fear/Anxiety (xpre = 0.27 ± 0.09, xpost = 0.42 ± 0.13), Defensive Aggression (xpre = 0.30 ± 0.09, xpost = 0.39 ± 0.11), and Abnormal Perception (xpre = 0.04 ± 0.02, xpost = 0.14 ± 0.06) (Fig. 1A). Removing the seven dogs under the age of 2 years (age of maturity) from the analysis did not alter the aforementioned significant changes.

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Fig. 1. Behavior changes in drug-naïve and -treated dogs. (A) Weighted score for each behavior factor for drug-naïve dogs both before and after the development of epilepsy. An increase in behavioral score is observed for all behavioral factors. Significant increases were seen for Fear/Anxiety, Defensive Aggression, and Abnormal Perception. (B) Weighted score for each behavior factor for dogs that were receiving antiepileptic medication. An increase in score was again demonstrated with respect to all behavioral factors, but with a greater number of factors showing a significant increase (*P b 0.05).

The possible influence of seizure frequency on behavior was also assessed in this group of drug-naïve dogs. A verifiable seizure frequency was available for 19 drug-naïve dogs. A significant positive correlation with seizure frequency was identified only for Defensive Aggression (r = 0.52). 3.3. Behavior changes in dogs with epilepsy receiving treatment Fifty-four dogs were receiving antiepileptic medication. Phenobarbital alone was used as monotherapy in 22 dogs, potassium bromide alone in 7 dogs, and a combination of these two drugs in 16 dogs. Phenobarbital and potassium bromide were dosed to achieve therapeutic range. In conjunction with phenobarbital and potassium bromide 9 dogs were receiving additional second-line antiepileptic medications (levetiracetam, n = 2; levetiracetam and topiramate, n = 2; zonisamide, n = 1; phenytoin, n = 1; gabapentin, n = 3). As with the drug-naïve dogs, the 54 dogs receiving antiepileptic

medication showed significant increases in the behavior factors Fear/Anxiety (xpre = 0.18 ± 0.05, xpost = 0.37 ± 0.09) and Abnormal Perception (xpre = 0.13 ± 0.04, xpost = 0.51 ± 0.07) before and after the onset of epilepsy (Fig. 1B). In the treated group, however there were additional significant increases after the onset of epilepsy in the following behavior factors when compared with the pre-epilepsy values: Abnormal Reactivity (xpre = 0.46 ± 0.09, xpost = 0.79 ± 0.12), Attachment Disorder (xpre =0.26±0.06, xpost =0.48±0.08), Demented Behavior (xpre = 0.08 ± 0.03, xpost = 0.42 ± 0.07), and Apathetic Behavior (xpre = 0.11 ± 0.04, xpost = 0.27 ± 0.05). In this group there was no longer a significant difference between the pre- and postepilepsy scores for Defensive Aggression (xpre = 0.32 ± 0.06, xpost = 0.38± 0.06). Removing the 21 dogs under the age of 2 years (age of maturity) from the analysis did not alter the aforementioned significant changes. The possible influence of seizure frequency on behavior was also assessed in this group of dogs receiving antiepileptic medication.

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A verifiable seizure frequency was available for 34 dogs receiving antiepileptic medication. A positive correlation with seizure frequency was identified for Demented Behavior (r = 0.58) and Abnormal Perception (r = 0.50). A significant correlation was no longer present for Defensive Aggression.

3.4. Difference in behavior changes between drug responders and pharmacoresistant dogs For the dogs who had received antiepileptic medication an accurate account of response to treatment was available for 46 dogs to enable classification into responders (n = 26) and nonresponders (n = 20). Changes in behavior factor scores with the onset of epilepsy were compared between responders and nonresponders (Fig. 2A). A significant difference was identified in the following behavior factors: Controlling Aggression (xresp = 0.13 ± 0.09; xnonresp = −0.03 ± 0.03), Abnormal Perception (xnonresp = 0.49 ± 0.1, xresp = 0.22± 0.05), and Demented Behavior (xnonresp = 0.58 ± 0.14, xresp = 0.10± 0.06).

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3.5. Effect of seizure type on behavior change Thirty-four of the 80 dogs in the study had primary generalized seizures and the remaining 46 dogs had focal seizures with or without secondary generalization. These two groups of dogs were compared with respect to the degree of change in each behavior factor that was seen with the onset of epilepsy (Fig. 2B). No significant differences were identified between these two groups in any behavior factor.

3.6. The effect of sex on behavior change There were 52 male dogs and 28 female dogs. There was no significant difference between their behavior factor scores prior to the onset of epilepsy. The degree of change for each behavior factor score with the onset of epilepsy was then compared between the male dogs and female dogs. A significant difference was identified in the following behavior factors: Abnormal Perception (xM = 0.35 ± 0.06, xFe = 0.18 ± 0.05), Attachment Disorder (xM = 0.24 ± 0.06, xFe = 0.02 ± 0.02), Apathetic Behavior (xM = 0.17± 0.04, xFe = 0.05 ± 0.04), with

Fig. 2. Effect of seizure type and pharmacoresponse on the degree of behavior change. Shown here is the change in each behavior factor score that was seen with the development of epilepsy in dogs classified as nonresponders or responders (A) and in dogs with primary generalized seizures and dogs with focal seizures with or without secondary generalization (B). It can be seen in (A) that significantly greater increases in Controlling Aggression, Abnormal Perception, and Demented Behavior were seen in dogs that did not respond to antiepileptic medication. Graph (B) demonstrates that no significant difference was observed in the degree of change in behavior factor score between dogs with primary generalized seizures and dogs with focal seizures with or without secondary generalization (*P b 0.05).

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male dogs showing a significantly larger change in these factors with the onset of epilepsy. 4. Discussion Psychiatric comorbidity with epilepsy has long been identified in human medicine and has been shown to have a major impact on patient quality of life [28–31]. These disturbances include depression, anxiety, psychotic disorders, and cognitive and personality changes [8]. The prevalence of psychiatric disorders is greater in patients with epilepsy than in either the general population or patients with other chronic medical diseases [6,32,33]. Twenty to seventy percent of patients with epilepsy have a comorbid psychiatric condition, depending on the patient group investigated [34]. In the current study it was found that at least one behavior changed in 71% of all the dogs in this study. The most common psychiatric disorders in people with epilepsy are depression and anxiety disorders, followed by psychoses and attentiondeficit disorders [8,31,32,34,35]. In this study, dogs with epilepsy that were currently not treated showed changes in Fear/Anxiety, Defensive Aggression, and Abnormal Perception. With epilepsy these dogs began to act more anxious or fearful when approached by unfamiliar dogs or people, when in unfamiliar surroundings, or when faced with sudden or unpredicted movements. They acted more aggressively when being handled, when approached by other dogs or unfamiliar people, or when strangers passed by the house. Fear/Anxiety-type behaviors and display of Defensive Aggression may be comparable to the anxiety disorders seen in people with epilepsy [8]. The Abnormal Perception changes seen in these dogs with epilepsy included barking without apparent cause, chasing shadows or light spots, aimless pacing, and staring into space. Psychosis is a common psychiatric comorbidity in people with epilepsy and can be accompanied by hallucinations, delusions, reduced connection to reality, and impaired thought [36]. Similarities between the Abnormal Perception changes seen in the dogs and the symptoms of psychosis in people could be considered. The causal mechanisms underlying the association between epilepsy and behavioral and psychiatric conditions are poorly understood; however, their existence has led to the hypothesis that common pathogenic mechanistic pathways might exist. It has been proposed that GABAergic and glutaminergic neurotransmitter disturbance or abnormalities in serotonergic, noradrenergic, and dopamine transmission may play a role in the comorbidity of psychiatric disease and epilepsy [34,37]. Defects in the serotonin system of patients with epilepsy, for example, may lower seizure threshold while increasing the risk of depression [38]. Additional suggested pathogenic linkages between epilepsy and mood dysfunctions include a hyperactive hypothalamic– pituitary–adrenal axis or disordered corticotropin-releasing hormone (CRH) release; for example, excessive CRH release from neurons within the brain may result not only in seizures but also in mood dysfunctions [37,39]. Recently, the role of altered neurosteroid levels in both patients with epilepsy and patients with psychiatric and emotional disorders has been described, providing a further example of a potential common pathogenic mechanism [40–42]. The existence of common pathogenic mechanisms is further supported by the existence of a bidirectional relationship. Humans with a history of depression or suicide are reported to have up to a seven times greater risk of developing epilepsy [8,43]. In addition, drugs traditionally regarded as antiepileptic medications have been used in the management of psychiatric disease, and several antidepression drugs also have antiseizure properties [37]. The possibility of a similar bidirectional relationship in epileptic dogs was not investigated in this study because of the absence of a control, nonepileptic population. The finding of behavior changes in concurrence with epilepsy in animal models such as the dog strengthens the concept of a link between epilepsy and psychiatric disease. Behavioral alterations have

been shown to occur with epilepsy in poststatus rodent models of temporal lobe epilepsy [13,44]. Pilocarpine-induced epilepsy in mice is associated with a significant increase in anxiety-related behavior and changes in learning and memory [45]. Such models also exclude confounding psychosocial factors in the human condition, for example, stigmatization, loss of autonomy, and the higher unemployment rate of people with epilepsy. 4.1. Effect of treatment Antiepileptic drugs can cause psychiatric symptoms and behavioral disturbances in people. However, conflicting reports exist, and differentiating adverse drug effects from the effects of epilepsy is problematic. Depression has been linked particularly to those drugs with GABAergic properties, and psychotic disorders have been reported as toxic effects in association with several antiepileptic drugs [8]. Positive psychotropic effects have also been seen, especially with drugs that have mood-stabilizing properties, and psychiatric disorders can follow discontinuation of some antiepileptic drugs [8,34,46]. Differentiating psychiatric comorbidities from drug-related effects is challenging when evaluating humans with epilepsy [47]. In the present study, the group of 26 dogs that were not receiving antiepileptic medication showed significant changes in Fear/Anxiety, Defensive Aggression, and Abnormal Perception. In the treated group, a significant change in behavior scores was also seen for Fear/Anxiety and Abnormal Perception with the onset of epilepsy, but with a loss of significance of change in Defensive Aggression. Additionally, however, there were significant differences in the scores for Abnormal Reactivity, Attachment Disorder, Demented Behavior, and Apathetic Behavior. These dogs showed anxiety with unpredicted movement or with sudden or loud noises; signs of separation anxiety; agitation if not allowed to sleep; reduced interest in activities; reduced ability to recognize family members or familiar people; and aimless pacing or wandering. The occurrence of a significant difference in the Abnormal Reactivity, Attachment Disorder, Demented Behavior, and Apathetic Behavior scores and the loss of significance of the change in Defensive Aggression in this treatment group may represent the side effects of antiepileptic medication on behavior. Behavioral changes in dogs may occur after starting antiepileptic medication. The antiepileptic drugs phenobarbital and potassium bromide can result in sedation or lethargy in dogs [48]; however, in some cases, restlessness and hyperexcitability can be observed with phenobarbital [49,50]. To the authors’ knowledge only one study has explored the possibility of the effect of antiepileptic drug treatment on quality of life and behavior in dogs with epilepsy [50]. All 25 dogs in that study were receiving antiepileptic medication (potassium bromide, phenobarbital, or both) and the observed behavior changes of restlessness and lethargy were postulated to be side effects of the medication. The origin of these changes cannot be definitively determined; nevertheless, owners considered them to impact the perceived quality of life of the dogs. This study also identified that owners consider the dog's quality of life to be of greatest importance above seizure frequency. The likelihood that behavior changes will impact the dogs’ perceived quality of life further exemplifies the importance of the finding of comorbid behavior changes. In people an extensive range of potential behavioral disturbances have been reported with antiepileptic medication including depression, psychosis, and anxiety [8]. Although the behavior changes seen in the treated dogs in this study are not drug side effects that have been specifically reported before, the possibility that the changes could be attributed to the medications has to be considered. 4.2. Age at seizure onset The onset of idiopathic canine epilepsy normally occurs between the ages of 6 months and 6 years; therefore, some dogs in this study

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were younger than their age of maturity when they were diagnosed with idiopathic epilepsy. Thus, some of the behavior changes seen could be attributed to the normal behavioral maturing process of a dog. Furthermore, it is known that children with epilepsy are at higher risk of developing psychiatric and behavioral problems than adults [5]. In human medicine it is considered possible that both cortical development and mental functions are negatively influenced by seizures and that the use of antiepileptic drugs may also have adverse effects on the developing brain by interfering with neuronal migration, differentiation, and plasticity [51]. With these considerations, the analysis was repeated with the dogs under the age of 2 years removed from the drug-naïve and -treated groups. Because this did not alter the results it was not considered necessary to exclude these young dogs from the investigation. 4.3. Influence of seizure frequency on behavior The finding in this study that certain behaviors show a correlation with seizure frequency may be in agreement with some findings in human patients with epilepsy; however; the relationship between seizure frequency and seizure control and psychiatric disorders is known to be complex. A higher prevalence of mood disorders has been identified in human patients with poorly controlled epilepsy [52]. Seizure frequency has been considered an important predictive factor for psychiatric disorders in children with epilepsy by some authors; however, this finding has not always been replicated in subsequent studies [53,54]. Other authors have also failed to find that variables such as seizure frequency are associated with depression, which is the most common psychiatric comorbidity [34]. The complexity of the relationship is further demonstrated by the rare phenomenon of forced normalization. In this situation there is an inverse relationship between seizure control and the occurrence of psychiatric symptoms, especially at the beginning of treatment with abrupt cessation of seizures [36]. In this study there also appears to be a complex relationship between seizure frequency and behavior changes in dogs. The factor Fear/Anxiety showed a significant increase in both drug-naïve and drug-treated groups; however, its occurrence, like depression in people, appears to be the result of epilepsy and does not appear to be correlated with seizure frequency. Interestingly, there was a loss of correlation of seizure frequency with Defensive Aggression in the treated group. This is consistent with the hypothesis that the antiepileptic medication may be reducing or modulating the Defensive Aggression behavior traits. This is also further demonstrated by the finding that this behavior factor showed a significant increase with epilepsy in the drug-naïve group, but the increase was no longer present in the treated group. Finally, the appearance of a correlation between seizure frequency and Demented Behavior and Abnormal Perception in dogs receiving treatment further demonstrates the complexity of the relationship, with combined influence of seizure frequency, drug treatment, and epilepsy on these behavior factors. 4.4. Pharmacoresistance and behavior change In human patients with epilepsy, psychiatric comorbidities have been associated with a lack of response to antiepileptic drug therapy [29,55]. This is also a common finding in rodent epilepsy models. In a rat model of temporal lobe epilepsy more severe behavioral alterations were seen in antiepileptic drug-resistant rats than in drug-responsive rats. Different responses were seen in tests of anxiety, behavioral hyperexcitability, and learning/memory [13]. The results in the dogs in this study showed some similarities to these findings in human patients and rat models with respect to the association of behavior changes with lack of response to antiepileptic medication. The 20 dogs that were classified as nonresponders showed significant differences in Controlling Aggression, Abnormal Perception, and Demented behavior,

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when compared with the responders. In each case, the nonresponders showed a greater increase in the behavior abnormality with epilepsy. The finding of more marked behavioral changes in people, rats, and now dogs with pharmoacoresistant epilepsy is in accordance with the suggestion that pharmacoresistant epilepsy is a distinct clinical entity [13,56,57], possibly with distinct premorbid genetic differences leading to distinct conditions with the development of epilepsy. In people it has been postulated that neurobiological processes that result in depression, anxiety, and psychosis interact with those processes producing seizures to increase the extent of brain dysfunction and thereby increase the likelihood of development of pharmacorestisant epilepsy [55]. Current theories of drug resistance in patients with epilepsy include changes in blood–brain barrier permeability, such as overexpression of P-glycoprotein, changes in GABAA receptor characteristics, and development of functional and structural neuropathological brain alterations [58–60]. Similar processes may contribute to the development of psychiatric disorders; for example, GABAergic deficits have been associated with depression in people and with behavioral and cognitive changes in mouse models [61]. Functional changes in the blood–brain barrier change the neuronal environment and have been suggested to play a role in disturbed cognition, mood, and behavior [62]. It is therefore possible that some or all of the functional and structural pathologies of the brain seen with pharmacoresistant epilepsy are the bases for the observed comorbid neurobehavioral changes. An additional consideration is that the observed behavioral differences seen between drug responders and nonresponders could be due to a lack of response to antiepileptic medication accompanied by a lack of the drug's potential effect on behavior. 4.5. Effect of seizure type on behavior change In people, focal epilepsies have been associated with a higher prevalence of psychiatric disorders, particularly in association with temporal lobe epilepsy [8,34,63]. Some authors have found a higher prevalence of depression [8,64] and anxiety disorders [63] in focal rather than in generalized epilepsies. The suicide rate, which is reported to be five times greater in patients with epilepsy, is 25 times greater than expected in patients with complex focal seizures of temporal lobe origin [52]. In the present study only 34 dogs had primary generalized seizures. This is in agreement with the previous finding that focal onset seizures are more common than generalized onset seizures in populations of presumptive idiopathic epileptic dogs [15,65]. We did not, however, find an association between seizure type and behavioral change. There was no significant difference between the behavior changes seen with the development of primary generalized seizures and those seen with the focal seizure disorders. There may be several explanations for this negative result. It is possible that the dogs represent a heterogeneous group of focal epilepsies with different epileptic foci and, therefore, are not directly comparable to the human patients with specific focal epilepsies studied. Temporal lobe epilepsy is the most common of the focal epilepsies in humans, with a high frequency of clinical occurrence. Depression and anxiety disorders have been reported to occur more frequently in association with temporal lobe epilepsy than other focal epilepsies [63]. It is possible that in temporal lobe epilepsy, involvement of the temporomesial limbic structures may be associated with the psychiatric comorbidities observed [8]. Several authors have suggested that temporal lobe epilepsy may also occur in dogs; however, it has so far proved impossible to confirm that the seizure types and syndromes seen are analogous to temporal lobe epilepsy in people [3]. In humans, this seizure type is often refractory to antiepileptic medication and characteristic neuropathological changes are seen in the hippocampus dentate gyrus. In a study of six dogs with epilepsy refractory to antiepileptic medication, similar neuropathological hippocampal changes were not found, and it was concluded that temporal lobe epilepsy is unlikely to be a common cause of refractory epilepsy in dogs

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[66]. The different frequencies of occurrence of the various focal seizure types in humans and dogs may have contributed to the disparity of findings in this study, compared with reports in humans. Two final issues that should not be overlooked are the challenge of identifying focal onset seizures in dogs and the challenge of developing clear classification guidelines [15]. Patients with focal seizures and focal onset seizures with secondary generalization were grouped together and compared with those with generalized seizures without a focal onset. This classification system was aimed at separating dogs according to the underlying processes leading to seizure generation, that being focal onset versus generalized onset. It is, however, possible that different categorization would have led to identification of a different set of associated behavior changes. 4.6. The effect of sex on behavior change Prior to the onset of epilepsy there was no difference in behavior between male and female dogs. However, with the development of epilepsy, male and female dogs differed in the degree of behavior change. Male dogs had greater increases in Abnormal Perception, Attachment Disorder, and Apathetic Behavior. This is in agreement with findings in human clinical neurology where sex has been identified as an important factor relating to the occurrence of comorbid depression [67]. Although idiopathic depression is more common in women, depression as a comorbidity of epilepsy has been identified more commonly in men [68]. 5. Conclusions Behavior changes are seen with the development of epilepsy in dogs. This finding is in accordance with the consideration that canine epilepsy is similar in semiology to its human counterpart. The use of canine epilepsy as a naturally occurring model of seizures removes the need to induce seizures as in other animal models, and is without the psychosocial factors that complicate the human condition. The finding of behavior changes with the development of epilepsy in dogs is consistent with the concept of common pathogenic mechanisms underlying seizures and comorbid psychiatric disorders. Additionally the finding that behavioral changes with the onset of epilepsy differed between drug responders and nonresponders raises the possibility of the development of behavioral markers of pharmacoresistance in dogs that have already developed epilepsy. Acknowledgments The authors thank Kate Chandler for her contributions. We also thank the owners of the dogs, the referring veterinary surgeons, and the nurses involved in the care of the dogs involved in this study. References [1] Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy: a review. Epilepsy Res 2009;85:31–45. [2] Berendt M, Gredal H, Alving J. Characteristics and phenomenology of epileptic partial seizures in dogs: similarities with human seizure semiology. Epilepsy Res 2004;61:167–73. [3] Chandler K. Canine epilepsy: what can we learn from human seizure disorders? Vet J 2006;172:207–17. [4] Zarrelli MM, Beghi E, Rocca WA, Hauser WA. Incidence of epileptic syndromes in Rochester, Minnesota: 1980–1984. Epilepsia 1999;40:1708–14. [5] Austin JK, Caplan R. Behavioral and psychiatric comorbidities in pediatric epilepsy: toward an integrative model. Epilepsia 2007;48:1639–51. [6] Gaitatzis A, Carroll K, Majeed A, Sander JW. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45:1613–22. [7] Jalava M, Sillanpaa M. Concurrent illnesses in adults with childhood-onset epilepsy: a population-based 35-year follow-up study. Epilepsia 1996;37:1155–63. [8] LaFrance Jr WC, Kanner AM, Hermann B. Psychiatric comorbidities in epilepsy. Int Rev Neurobiol 2008;83:347–83.

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