Use of sedation-awakening electroencephalography in dogs with epilepsy.

BACKGROUND: Electroencephalography (EEG) recording protocols have been standardized for humans. Although the utilization of techniques in veterinary medicine is increasing, a standard protocol has not yet been established. HYPOTHESIS: Assessment of a sedation-awakening EEG protocol in dogs. ANIMALS: Electroencephalography examination was performed in a research colony of 6 nonepileptic dogs (control [C]) and 12 dogs with epilepsy admitted to the clinic because of the epileptic seizures. METHODS: It was a prospective study with retrospective control. Dogs with epilepsy were divided into 2 equal groups, wherein EEG acquisition was performed using a "sedation" protocol (IE-S, n = 6) and a "sedation-awakening" protocol (IE-SA, n = 6). All animals were sedated using medetomidine. In IE-SA group, sedation was reversed 5 minutes after commencing the EEG recording by injecting atipamezole IM. Type of background activity (BGA) and presence of EEG-defined epileptiform discharges (EDs) were evaluated blindly. Statistical significance was set at P > 0.05. RESULTS: Epileptiform discharges were found in 1 of 6 of the dogs in group C, 4 of 6 of the dogs in IE-S group, and 5 of 6 of the dogs in IE-SA group. A significantly greater number of EDs (spikes, P = .0109; polyspikes, P = .0109; sharp waves, P = .01) were detected in Phase 2 in animals subjected to the "sedation-awakening" protocol, whereas there was no statistically significant greater number of discharges in sedated animals. CONCLUSIONS AND CLINICAL IMPORTANCE: A "sedation-awakening" EEG protocol could be of value for ambulatory use if repeated EEG recordings and monitoring of epilepsy in dogs is needed.

Correlation between semiautomated magnetic resonance imaging volumetry of the cingulate gyrus and interictal epileptiform discharge lateralization in dogs with idiopathic epilepsy.

BACKGROUND: Brain imaging suggests the involvement of the limbic system, particularly the cingulate gyrus (GC), in dogs with idiopathic epilepsy (IE). HYPOTHESIS: A correlation exists between the side of interictal epileptiform discharges (IEDs) and the volume of the ipsilateral GC (GCe) in dogs with IE. ANIMALS: Dogs admitted to the neurological consultation (32 with epileptic seizures and 13 control) were included. METHODS: This retrospective, blinded study followed the International Veterinary Epilepsy Task Force recommendations for diagnosing IE at the Tier III confidence level. The IE group included 18 and 14 dogs with IEDs in the left and right hemispheres, respectively (median age: 36 months, median weight: 19.5 kg), whereas the control group included 13 dogs (median age: 32 months, median weight: 20 kg). Whole-brain and GC-volumetric assessments were performed by a semiautomated method. RESULTS: In the control group, the volume of the GC was: left, from 743.63 to 1001.61 mm3, right, from 789.35 to 1015.86 mm3. In the study group, the volume of the GC was: left, from 720.88 to 1054.9 mm3 and right, from 566.29 to 987.77 mm3. In dogs with IE, GCe volume was significantly lower than the mean volume of the GC in the control group relative to total intracranial volume (TIV; P = .00044). CONCLUSIONS AND CLINICAL IMPORTANCE: Alterations in the volume of the GC provide insights into structural changes during IE. The use of semiautomatic volumetry provides an advantage by reducing the potential for human error.

Blood-brain barrier dysfunction and decreased transcription of tight junction proteins in epileptic dogs.

BACKGROUND: Epilepsy in dogs and humans is associated with blood-brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine. HYPOTHESIS: Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future. ANIMALS: Twenty-seven dogs with IE and 10 healthy controls. METHODS: Retrospective, prospective cohort study. Blood-brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase-9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe. RESULTS: The DCE-MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P = .02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin-5 in the piriform lobe of IE dogs was significantly lower than in control dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

BACKGROUND: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. ANIMALS: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. METHODS: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. RESULTS: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 µg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. CONCLUSION AND CLINICAL IMPORTANCE: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

Use of neurofilament light chain to identify structural brain diseases in dogs.

BACKGROUND: Neurofilament light chain (NfL) is released into the peripheral circulation by damaged axons. OBJECTIVES: To evaluate the diagnostic value of serum NfL concentration in dogs with intracranial diseases. ANIMALS: Study included 37 healthy dogs, 31 dogs with idiopathic epilepsy (IE), 45 dogs with meningoencephalitis of unknown etiology (MUE), 20 dogs with hydrocephalus, and 19 dogs with brain tumors. METHODS: Cohort study. Serum NfL concentrations were measured in all dogs using single-molecule array technology. RESULTS: Serum NfL concentration in dogs with each structural disease was significantly higher than in healthy dogs and dogs with IE (P = .01). The area under the receiver operating characteristic curve of NfL for differentiating between dogs with structural diseases and IE was 0.868. An optimal cutoff value of the NfL 27.10 pg/mL had a sensitivity of 86.67% and a specificity of 74.19% to differentiate the dogs with IE from those with structural brain diseases. There were significant correlations between NfL concentrations and lesion size: (1) MUE, P = .01, r = 0.429; (2) hydrocephalus, P = .01, r = 0.563. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum NfL could be a useful biomarker for distinguishing IE from structural diseases in dogs and predicting the lesion sizes of MUE and hydrocephalus.

Clinical efficacy and tolerability of zonisamide monotherapy in dogs with newly diagnosed idiopathic epilepsy: Prospective open-label uncontrolled multicenter trial.

BACKGROUND: Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. OBJECTIVES: To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). ANIMALS: Study included 56 client-owned dogs newly diagnosed with IE. METHODS: This was a prospective multicenter, open-label, uncontrolled study. All dogs were ASM-naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7-14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12-week maintenance treatment period were compared with those from the 4- to 12-week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. RESULTS: Fifty-six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7-8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0-48.0) µg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that ZNS monotherapy is effective and well-tolerated in dogs with newly diagnosed IE.

Toxoplasma gondii and Neospora caninum infection in epileptic dogs.

OBJECTIVES: Studies in humans have demonstrated the role of Toxoplasma gondii, a protozoan parasite, in epileptic seizures. This study aimed to investigate the serological correlation between T. gondii and N. caninum and epilepsy in dogs. MATERIALS AND METHODS: The medical record database of the Veterinary Teaching Hospital, University of Perugia, was searched for dogs serologically tested by IFAT for T. gondii and N. caninum and following specific inclusion criteria. Dogs were stratified by having a clinical diagnosis of epilepsy or suffering different conditions. RESULTS: One-hundred and twenty-eight dogs were included, 64 with epilepsy and 64 without clinical signs of epilepsy. Seventeen of the 64 epileptic dogs (26.6%; 95% CI: 15.7% to 37.4%) and twenty-one of the 64 non-epileptic dogs (32.8%; 95% CI: 21.3% to 44.3%) tested positive for T. gondii. Eight of the epileptic dogs (12.5%; 95% CI: 4.4% to 20.6%) and three of the non-epileptic dogs (4.7%; 95% CI: 0% to 9.9%) tested positive for N. caninum. There was no statistically significant difference in the rate of T. gondii or N. caninum seroreactivity between epileptic and non-epileptic dogs. CLINICAL SIGNIFICANCE: The results obtained do not seem to support the role of T. gondii and N. caninum as causative agents of dog epilepsy.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

Evaluation of neurofilament light chain as a biomarker in dogs with structural and idiopathic epilepsy.

BACKGROUND: Neurofilament light chain (NfL) is a frequently used biomarker in humans for both diagnostic and therapeutic monitoring purposes in various neurologic diseases. HYPOTHESIS/OBJECTIVES: It was hypothesized that dogs with diagnosed structural epilepsy (SE) would have a significantly higher serum NfL concentrations compared to dogs with idiopathic epilepsy (IE). The secondary hypothesis was that dogs would have a significantly higher serum NfL concentrations when measured within 7 days after a seizure compared to being seizure-free for at least 30 days. ANIMALS: Fifty client-owned dogs presented to the neurology service for evaluation of seizures were enrolled. Fourteen dogs had SE and 36 dogs had IE. METHODS: Prospective cohort study performed on 52 serum samples obtained for NfL concentration measurement using single molecule array technology. RESULTS: The median serum concentration of NfL in dogs with SE was significantly higher (109 pg/mL; range, 11.4-741.3 pg/mL) than in dogs with IE (17.7 pg/mL; range, 5.8-188 pg/mL; Wilcoxon rank sum test, P = .001). No significant relationship was found between serum NfL concentration and time of sampling in relation to the most recent seizure in dogs with IE. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum NfL may serve as an adjunctive biomarker for the differentiation of SE and IE.

Clinical features and outcome of 10 dogs with suspected idiopathic vestibular epilepsy.

BACKGROUND: In humans, vestibular epilepsy (VE) is described as focal seizures with transient signs of vestibular disease. In dogs, 2 cases of vestibular episodes, called vestibular paroxysmia, are reported. HYPOTHESIS/OBJECTIVES: The objective of this study was to define the clinical features, phenotypical manifestation, and outcome of suspected VE in dogs. ANIMALS: Ten dogs with recurrent vestibular episodes. METHODS: Retrospective study. Medical records between 2009 and 2023 were reviewed, and dogs with a normal neurological examination, a history of transient signs of vestibular disease, absence of abnormalities detected on blood exams and brain magnetic resonance imaging (MRI) or computed tomography (CT), besides a minimum 10-month follow-up were included. Clinical improvement was defined as a ≥50% reduction in frequency or the cessation of clinical signs after the onset of antiseizure medications (ASMs). RESULTS: Pugs were the most prevalent breed (5/10; 50%). In 2 cases, additional generalized tonic-clonic (GTC) seizures were reported. MRI exam was performed in most cases (9/10; 90%), whereas 1 dog underwent a CT scan (1/10; 10%). Electroencephalography (EEG) was carried out in 3 dogs that showed interictal spikes in the fronto-temporal and fronto-parietal areas. All cases received ASMs, with clinical improvement in 10/10 dogs (100%). CONCLUSION AND CLINICAL IMPORTANCE: The presence of GTC seizures, EEG interictal spikes, and responsiveness to ASMs supported the hypothesis of an epileptic origin of vestibular episodes and thus the existence of VE in these dogs, with a presumed idiopathic cause and apparent favorable outcome.

Serum concentrations of complement C3 and C4 in dogs with idiopathic epilepsy.

BACKGROUND: High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy. OBJECTIVES: To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE). ANIMALS: The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs. METHODS: In this case-control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine-specific ELISA kit. RESULTS: Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915-6.673] mg/mL, P < .001; C4, 0.327 [0.134-0.557] mg/mL, P = .03) than in healthy control dogs (C3, 3.550 [3.075-4.191] mg/mL; C4, 0.267 [0.131-0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192-5.715] mg/mL; C4, 0.427 [0.143-0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702-7.132] mg/mL; C4, 0.258 [0.130-0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695-8.735] mg/mL; P < .01) and C4 (0.451 [0.163-0.675] mg/mL; P = .01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464-5.142] mg/mL; C4, 0.161 [0.100-0.325] mg/mL). CONCLUSIONS AND CLINICAL IMPORTANCE: Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency.

A retrospective study of the efficacy of zonisamide in controlling seizures in 57 cats.

BACKGROUND: Evidence-based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures remain inadequately controlled by administration of phenobarbital alone or for cats that cannot safely receive phenobarbital. OBJECTIVE: To compare seizure frequency in cats before and after oral administration of zonisamide and describe adverse clinical or clinicopathologic effects in this cohort. ANIMALS: Fifty-seven cats with a history of seizures. METHODS: Multicenter, retrospective study. Median number of seizures per month and number of seizure days per month were compared before and after administration of zonisamide in all cats, a subgroup of cats with idiopathic epilepsy (IE), and a subgroup of cats receiving zonisamide as sole therapy. Clinical and clinicopathologic adverse effect data were also reported. RESULTS: A median decrease of 1 (P = .001, 95% confidence interval (CI) [-1.0, -0.5]) seizure per month, and 1 (P = .003, 95% CI [-1.5, -0.2]) seizure days per month was found across all cats after oral administration of zonisamide. The subgroup with IE showed median decreases of 1 (P = .03, 95% CI [-2.0, -0.5]) and 2 (P = .01, 95% CI [-2.5, -1.0]), respectively. The most common clinical adverse effects were sedation (17%), ataxia (11%), hyporexia (17%), and emesis (5%). One cat developed mild nonregenerative anemia, 2 cats developed mild metabolic acidosis, and 6 cats showed mild increases in ALT and ALP. CONCLUSION: Zonisamide was well tolerated and efficacious in controlling seizure activity in most cats.

Ketogenic diets: A systematic review of current scientific evidence and possible applicability in dogs and cats.

Ketogenic diets (KD) have been used in the treatment of epilepsy in humans for around a century and, more recently, they have been implanted for cancer patients, as well as in the treatment of obesity. This type of diet consists of high-fat levels, an adequate amount of protein and restricted carbohydrates, or high medium-chain triglycerides. Recently, the ketogenic diet has gained attention in veterinary medicine and studies were published evaluating the effects of KD in dogs with epilepsy. The objective of this review was to highlight recent studies about the application of KD in dogs and cats, to describe the neurobiochemical mechanisms through which KD improves epilepsy crisis, and their adverse effects. Studies were identified by a systematic review of literature available on PubMed, Embase, and Scopus. All cohort and case-control studies were included, and all articles were exported to Mendeley® citation manager, and duplicates were automatically removed. Seven articles and three conference abstracts conducted with dogs were included in the present study. There is evidence that the consumption of diets with medium-chain triglycerides increases the concentration of circulating ketone bodies and improves epilepsy signs, although these diets have higher carbohydrate and lower fat content when compared to the classic KD.

ACVIM Consensus Statement on the management of status epilepticus and cluster seizures in dogs and cats.

BACKGROUND: Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive drug-resistant and self-sustaining character, and high morbidity and mortality. Current treatment approaches are characterized by considerable variations, but official guidelines are lacking. OBJECTIVES: To establish evidence-based guidelines and an agreement among board-certified specialists for the appropriate management of SE and CS in dogs and cats. ANIMALS: None. MATERIALS AND METHODS: A panel of 5 specialists was formed to assess and summarize evidence in the peer-reviewed literature with the aim to establish consensus clinical recommendations. Evidence from veterinary pharmacokinetic studies, basic research, and human medicine also was used to support the panel's recommendations, especially for the interventions where veterinary clinical evidence was lacking. RESULTS: The majority of the evidence was on the first-line management (ie, benzodiazepines and their various administration routes) in both species. Overall, there was less evidence available on the management of emergency seizure disorders in cats in contrast to dogs. Most recommendations made by the panel were supported by a combination of a moderate level of veterinary clinical evidence and pharmacokinetic data as well as studies in humans and basic research studies. CONCLUSIONS AND CLINICAL RELEVANCE: Successful management of seizure emergencies should include an early, rapid, and stage-based treatment approach consisting of interventions with moderate to preferably high ACVIM recommendations; management of complications and underlying causes related to seizure emergencies should accompany antiseizure medications.

A review of the pharmacology and clinical applications of levetiracetam in dogs and cats.

OBJECTIVE: To review and summarize the pharmacology of the antiepileptic drug (AED), levetiracetam (LEV), and to discuss its clinical utility in dogs and cats. DATA SOURCES: Veterinary and human peer-reviewed medical literature and the authors' clinical experience. SUMMARY: LEV is an AED with mechanisms of action distinct from those of other AEDs. In people and small animals, LEV exhibits linear kinetics, excellent oral bioavailability, and minimal drug-drug interactions. Serious side effects are rarely reported in any species. LEV use is gaining favor for treating epilepsy in small animals and may have wider clinical applications in patients with portosystemic shunts, neuroglycopenia, and traumatic brain injury. In people, LEV may improve cognitive function in patients with dementia. CONCLUSION: LEV is a well-tolerated AED with well-documented efficacy in human patients. Although its use is becoming more common in veterinary medicine, its role as a first-line monotherapy in small animal epileptics remains to be determined. This review of the human and animal literature regarding LEV describes its role in epileptic people and animals as well as in other disease states and provides recommendations for clinical usage.

Juvenile idiopathic epilepsy in Egyptian Arabian foals, a potential animal model of self-limited epilepsy in children.

BACKGROUND: Juvenile idiopathic epilepsy (JIE) is categorized as a generalized epilepsy. Epilepsy classification entails electrocortical characterization and localization of epileptic discharges (ED) using electroencephalography (EEG). HYPOTHESIS/OBJECTIVES: Characterize epilepsy in Egyptian Arabian foals with JIE using EEG. ANIMALS: Sixty-nine foals (JIE, 48; controls, 21). METHODS: Retrospective study. Inclusion criteria consisted of Egyptian Arabian foals: (1) JIE group diagnosed based on witnessed or recorded seizures, and neurological and EEG findings, and (2) control group of healthy nonepileptic age-matched foals. Clinical data were obtained in 48 foals. Electroencephalography with photic stimulation was performed under standing sedation in 37 JIE foals and 21 controls. RESULTS: Abnormalities on EEG were found in 95% of epileptic foals (35 of 37) and in 3 of 21 control asymptomatic foals with affected siblings. Focal ED were detected predominantly in the central vertex with diffusion into the centroparietal or frontocentral regions (n = 35). Generalization of ED occurred in 14 JIE foals. Epileptic discharges commonly were seen during wakefulness (n = 27/37 JIE foals) and sedated sleep (n = 35/37 JIE foals; 3/21 controls). Photic stimulation triggered focal central ED in 15 of 21 JIE foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Juvenile idiopathic epilepsy has a focal onset of ED at the central vertex with spread resulting in clinical generalized tonic-clonic seizures with facial motor activity and loss of consciousness. Electroencephalography with photic stimulation contributes to accurate phenotyping of epilepsy. Foals with this benign self-limiting disorder might serve as a naturally occurring animal model for self-limited epilepsy in children.

Epilepsy is more than a simple seizure disorder: Parallels between human and canine cognitive and behavioural comorbidities.

Psychiatric and cognitive comorbidities have been known to play a major role in human epilepsy for a long time. People with epilepsy (PWE) frequently express signs of varying psychiatric and cognitive disorders affecting their quality and quantity of life (QoL/QaoL). Over the last few years, research on behavioural comorbidities and their effect on the underlying disease have been performed in canine epilepsy. The following article reviews manifestations of comorbidities in canine epilepsy with an emphasis on patterns of clinical signs and their effects on QoL and QaoL. Cognitive and behavioural alterations in epileptic dogs are mainly represented by fear-/anxiety related behaviour and cognitive impairment (CI). Reduced trainability and altered reactions to daily situations are common results of comorbid changes posing obstacles in everyday life of owners and their dog. In addition, clinical signs similar to attention deficit hyperactivity disorder (ADHD) in humans have been reported. Canine attention-deficit-hyperactivity-disorder-like (c-ADHD-like) behaviour should, however, be evaluated critically, as there are no official criteria for diagnosis of ADHD or ADHD-like behaviour in dogs, and some of the reported signs of c-ADHD-like behaviour could be confused with anxiety-associated behaviour. Many intrinsic and extrinsic factors could potentially influence the development of behavioural and cognitive comorbidities in canine epilepsy. In particular, seizure frequency/severity, signalment and factors concerning disease management, such as pharmacotherapy and nutrition, are closely linked with the presence of the aforementioned comorbid disorders. Further studies of behavioural alterations in epileptic dogs are needed to comprehend the complexity of clinical signs and their multifactorial origin.

Epilepsy is more than a simple seizure disorder: Causal relationships between epilepsy and its comorbidities.

This review draws connections between the pathogenesis of canine epilepsy and its most commonly recognised comorbidities: cognitive impairment (CI), attention deficit hyperactivity disorder (ADHD)-like behaviour, fear and anxiety. Uni/bidirectional causalities and the possibility of a common aetiology triggering both epilepsy and the associated diseases are considered. Research on this topic is sparse in dogs, so information has been gathered and assessed from human and laboratory animal studies. Anatomical structures, functional connections, disrupted neurotransmission and neuroinflammatory processes collectively serve as a common foundation for epilepsy and its comorbidities. Specific anatomical structures, especially parts of the limbic system, such as the amygdala and the hippocampus, are involved in generating seizures, as well as cognitive- and behavioural disorders. Furthermore, disturbances in inhibitory and excitatory neurotransmission influence neuronal excitability and networks, leading to underlying brain dysfunction. Functional magnetic resonance imaging (fMRI), interictal epileptiform discharges (IEDs), and electroencephalography (EEG) have demonstrated functional brain connections that are related to the emergence of both epilepsy and its various comorbidities. Neuroinflammatory processes can either cause or be a consequence of seizures, and inflammatory mediators, oxidative stress and mitochondrial dysfunction, can equally evoke mood disorders. The extensive relationships contributing to the development and progression of seizures and comorbid cognitive and behavioural conditions illustrate the complexity of the disease that is epilepsy.

Quantitative serum proteome analysis using tandem mass tags in dogs with epilepsy.

This study included four groups of dogs (group A: healthy controls, group B: idiopathic epilepsy receiving antiepileptic medication (AEM), group C: idiopathic epilepsy without AEM, group D: structural epilepsy). Comparative quantitative proteomic analysis of serum samples among the groups was the main target of the study. Samples were analyzed by a quantitative Tandem-Mass-Tags approach on the Q-Exactive-Plus Hybrid Quadrupole-Orbitrap mass-spectrometer. Identification and relative quantification were performed in Proteome Discoverer. Data were analyzed using R. Gene ontology terms were analyzed based on Canis lupus familiaris database. Data are available via ProteomeXchange with identifier PXD041129. Eighty-one proteins with different relative adundance were identified in the four groups and 25 were master proteins (p < 0.05). Clusterin (CLU), and apolipoprotein A1 (APOA1) had higher abundance in the three groups of dogs (groups B, C, D) compared to controls. Amine oxidase (AOC3) was higher in abundance in group B compared to groups C and D, and lower in group A. Adiponectin (ADIPOQ) had higher abundance in groups C compared to group A. ADIPOQ and fibronectin (FN1) had higher abundance in group B compared to group C and D. Peroxidase activity assay was used to quantify HP abundance change, validating and correlating with proteomic analysis (r = 0.8796). SIGNIFICANCE: The proteomic analysis of serum samples from epileptic dogs indicated potential markers of epilepsy (CLU), proteins that may contribute to nerve tissue regeneration (APOA1), and contributing factors to epileptogenesis (AOC3). AEM could alter extracellular matrix proteins (FN1). Illness (epilepsy) severity could influence ADIPOQ abundance.