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.

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.

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.

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.

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.

Serum oxidant-antioxidant status and butyrylcholinesterase activity in dogs with idiopathic epilepsy - A pilot study.

Oxidative stress plays an important role in pathogenesis of idiopathic epilepsy (IE). Although IE is the most common neurological condition, oxidant-antioxidant status in epileptic dogs is still unknown. The aim of this study is to evaluate the serum oxidant-antioxidant status in dogs with newly diagnosed IE. The status in 15 dogs with IE and 15 healthy dogs is estimated through spectrophotometric determination of two oxidant markers: advanced oxidation protein products-albumin index (AOPP) and thiobarbituric acid reactive substances (TBARS); and three antioxidant markers: total thiols (R-SH) level, glutathione (GSH) level, and paraoxonase-1 (PON-1) activity. Also, butyrylcholinesterase (BChE) activity is assessed in both groups of dogs. Higher AOPP is observed in the dogs with newly diagnosed IE, while TBARS level shows no difference when compared to the healthy dogs. In contrast, lower levels of antioxidants (R-SH, GSH, and PON-1) and BChE activity are found in the dogs with IE. No significant differences are observed in the oxidant and antioxidant markers and BChE activity across the investigated IE cases with focal and generalized seizures. Our findings provide evidence that dogs with IE are characterized by an impaired serum oxidant-antioxidant balance and lower BChE activity, which may contribute to a better understanding of IE pathogenesis.

Long-term outcome of epileptic dogs treated with implantable vagus nerve stimulators.

BACKGROUND: The long-term effect of implantable vagus nerve stimulators (VNS) on seizures has not been evaluated in epileptic dogs. OBJECTIVES: Report seizure frequency in medication-resistant epileptic dogs before and after VNS implantation. ANIMALS: Twelve client-owned dogs with idiopathic epilepsy and >1 seizure day per 3 weeks despite 3 months of appropriate use of 2 antiseizure medications and seizure diaries maintained 6 months before and >12 months after VNS implantation. METHODS: Uncontrolled, open-label, before and after study. Mean monthly seizures and inter-seizure periods obtained from contemporaneous seizure diaries in the 6 months before implantation were compared with 0 to 6 months, 7 to 12 months, and subsequent 12-month periods after implantation. The number of dogs with >50% decrease in seizure frequency, >3 times increase in inter-ictal period interval, and seizure freedom for >3 months at the time of death or last follow-up were recorded. RESULTS: Five of 12 dogs were euthanized <12 months after implantation. All 7 remaining dogs showed >50% decrease in seizure frequency until last follow-up, starting at a median of 37 to 48 months after implantation (range, 0-6 to 61-72 months) and a >3-fold increase in mean inter-seizure interval starting a median of 25 to 36 months after implantation (range, 0-6 months to 49-60 months), 3/7 dogs were seizure-free at death or last follow-up. CONCLUSIONS AND CLINICAL IMPORTANCE: Monthly seizure frequencies decreased and inter-seizure intervals increased in all dogs 2 to 3 years after VNS implantation, but a high proportion were euthanized before this time point. Prospective clinical trials are required to establish causality and the magnitude of this association.

Once-a-day oral treatment with phenobarbital in cats with presumptive idiopathic epilepsy.

OBJECTIVES: Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in decreased quality of life for both cat and owner. The aim of this retrospective study was to evaluate treatment with oral PB q24h in cats with presumptive idiopathic epilepsy. METHODS: Nine cats with presumptive idiopathic epilepsy, receiving oral PB q24h, were included in a retrospective descriptive study. RESULTS: Seizure remission was achieved in 88% (8/9) of the cats and good seizure control in 12% (1/9) of the cats, treated with a mean dose of oral PB of 2.6 mg/kg q24h (range 1.4-3.8 mg/kg). No cats required an increase of their PB frequency at any time during a mean follow-up period of 3.5 years (range 1.1-8.0 years). No cats displayed side effects or issues with compliance at the last recorded follow-up. CONCLUSIONS AND RELEVANCE: Once-a-day administration of PB for feline epilepsy was safe and resulted in satisfactory seizure control for the nine cats included in this study. The results of this study justify exploring this topic further in larger prospective studies.

A retrospective evaluation of phenobarbital-induced hematologic changes in 69 cats.

BACKGROUND: Phenobarbital (PB) is used as a first-line treatment for recurrent epileptic seizures in cats. While hematologic abnormalities are well-known side effects of antiepileptic therapy with PB in humans and dogs, little is known about such alterations in cats. OBJECTIVES: The aim of this retrospective study was to investigate the prevalence and clinical relevance of cytopenia during PB treatment in cats. METHODS: In this single-center, retrospective clinical study, 69 cats-with suspected idiopathic epilepsy admitted to the Small Animal Clinic of the University of Veterinary Medicine in Vienna (VMU)-were included. A complete blood count for each patient was performed, and changes in hematocrit, leukocytes, neutrophils, and thrombocytes were documented and graded. RESULTS: Fifty-three out of 69 cats (76.8%) showed cytopenias with a reduction of at least one cell fraction during PB treatment. The most frequent change was neutropenia (60%), followed by leukopenia (49.3%), thrombocytopenia (24.1%), and anemia (20.3%). Most of the changes were mild or moderate; only one patient (1.5%) showed severe leukopenia and neutropenia, and one was a life-threatening neutropenia (1.5%) with a serum PB concentration within or even below the therapeutic range. These patients did not present with clinical symptoms other than those related to epileptic episodes. Cats who received combination therapy showed lower hematocrits than those who received monotherapy. A tendency for leukocytes and neutrophils to decrease during PB treatment was also seen. CONCLUSIONS: Blood cytopenias may frequently occur in cats on chronic PB therapy, even when serum drug levels are within the therapeutic range. However, clinical signs are typically mild to moderate and rarely severe.

Efficacy evaluation of a commercially available MCT enriched therapeutic diet on dogs with idiopathic epilepsy treated with zonisamide: a prospective, randomized, double-blinded, placebo-controlled, crossover dietary preliminary study.

BACKGROUND: Idiopathic epilepsy (IE) is a common, chronic brain dysfunction in dogs. Recently, the effect of feeding a diet enriched with medium-chain triglycerides (MCTs) on seizure frequency has been evaluated in several studies in dogs with IE. However, most dogs with IE in previous studies were treated with phenobarbital as the main antiseizure medication (ASM). In Japan, zonisamide (ZNS) is the most prescribed ASM for dogs with IE. The interaction between ZNS and various nutrients including MCTs and the potential effects on treatment efficacy resulting from combining these therapies have not been previously studied. A prospective, randomized, double-blinded, placebo-controlled, crossover dietary study was conducted. Dogs (n = 7) treated with ZNS were fed either a placebo diet (PL) or Purina ProPlan Veterinary Diet NeuroCare (NC) for 3 months, after which treatments were crossed over and continued for another 3 months. Seizure frequency (seizures/month; sz/m), blood tests including concentrations of ZNS and ß-hydroxybutyric acid, and owner's visual analogue scale score were collected from all dogs for both treatment periods. RESULTS: There was no significant difference in the seizure frequency between PL (2.95 ± 0.80 sz/m) and NC (1.90 ± 0.57 sz/m) during the 6 months of trial. Three of 7 dogs showed ≥ 50% seizure reduction, and 1 of those 3 dogs achieved seizure freedom in NC period. However, 2 of 7 dogs had no changes in epileptic seizure frequency, 2 of 7 dogs had a deterioration in seizure frequency in the NC period. Feeding the MCT diet concurrent with ZNS showed no apparent adverse effects and did not affect ZNS concentration. CONCLUSIONS: This study indicated that the commercially available MCT-enriched diet (NC) can be safely used concurrently with ZNS for dogs with IE.

Effects of high-dose docosahexaenoic acid supplementation as an add-on therapy for canine idiopathic epilepsy: A pilot study.

Background: The anti-epileptic effects of docosahexaenoic acid (DHA) in dogs and humans remain controversial. The dosage and efficacy of DHA were various in the previous reports. Aim: The effects of high-dose DHA supplementation as add-on therapy for idiopathic epilepsy in dogs were evaluated. Methods: An open-label clinical trial was designed in this pilot study. Six dogs (median age: 6 years) with idiopathic epilepsy were included. All the patients were diagnosed with idiopathic epilepsy using magnetic MRI and cerebrospinal fluid examination (median: 2.0 years before the trial). They had 5-45 seizures and/or auras (median: 9.0) in the month before starting DHA supplementation. DHA was adjunctively administered at doses of 69-166 mg/kg/day without changing other prescriptions. Results: Four of the six patients completed the 6-month observation period. All the patients showed a decrease in seizure frequency of 50% or more within 2-3 months after the start of the administration, and three patients decreased to a frequency of 0-1 per month after 5-6 months. No clear adverse events were observed in the general condition or blood test results in any patients. Conclusion: Although the sample size was small and the study was not a randomized controlled trial, the data suggest that add-on supplementation of DHA could be useful in reducing the frequency of seizures in canine idiopathic epilepsy.

Evaluation of antiseizure medications including zonisamide in feline idiopathic epilepsy at a referral hospital in Japan.

Background: Idiopathic epilepsy in cats is a more common disease than previously thought, but little information is available about the medical treatment of feline idiopathic epilepsy. Aim: To assess the therapeutic efficacy and safety of antiseizure medication (ASM) for a minimum of 6 months, including zonisamide (ZNS), in feline idiopathic epilepsy at a referral hospital in Japan. Methods: Twenty cats diagnosed with idiopathic epilepsy treated with ASMs were retrospectively included. Results: Nine cats that were finally treated with phenobarbital (PB) monotherapy reached the primary goal (the seizure frequency after the treatment intervention was less than one seizure every 3 months). Three cats were treated with ZNS monotherapy and two reached the primary goal. Eight cats finally received combination therapy. Two of the three cats receiving PB and ZNS therapy achieved the primary goal, but one was considered no responder. Five cats [PB + diazepam (DZP), ZNS + DZP, and ZNS + levetiracetam + DZP] decreased the seizure frequency and reached the primary goal in all but one cat reached the secondary goal. Adverse events were observed in eight patients, but these were curable. Two patients had vomiting after ZNS monotherapy, one had diarrhea, and another was an increase in sleeping hours. Conclusion: PB was frequently used and seemed effective as both monotherapy and combination therapy. Some cats were treated with ASM protocols containing ZNS. ZNS may be available to treat idiopathic epilepsy in cats. However, ZNS administration may cause adverse events, such as gastrointestinal toxicity, in cats.

DYRK1B haploinsufficiency in a Holstein cattle with epilepsy.

In this study, epilepsy with focal seizures progressing to generalized seizures was diagnosed in a 6-month-old Holstein heifer. The seizures were characterized by a brief pre-ictal phase with depression and vocalization. During the ictal phase eyelid spasms, tongue contractions, nodding and abundant salivation were observed, rapidly followed by a convulsive phase with bilateral tonic, clonic or tonic-clonic activity and loss of consciousness. Finally, during the postictal phase the heifer was obtunded and disorientated, unable to perceive obstacles and hypermetric, and pressed its head against objects. In the inter-seizure phase, the heifer was clinically normal. Neuropathology revealed axonal degeneration in the brainstem and diffuse astrocytic hypertrophic gliosis. Whole genome sequencing of the affected heifer identified a private heterozygous splice-site variant in DYRK1B (NM_001081515.1: c.-101-1G>A), most likely resulting in haploinsufficiency owing to loss-of-function. This represents a report of a DYRK1B-associated disease in cattle and adds DYRK1B to the candidate genes for epilepsy.

The role of neuroinflammation in canine epilepsy.

The lack of therapeutics that prevent the development of epilepsy, improve disease prognosis or overcome drug resistance represents an unmet clinical need in veterinary as well as in human medicine. Over the past decade, experimental studies and studies in human epilepsy patients have demonstrated that neuroinflammatory processes are involved in epilepsy development and play a key role in neuronal hyperexcitability that underlies seizure generation. Targeting neuroinflammatory signaling pathways may provide a basis for clinically relevant disease-modification strategies in general, and moreover, could open up new therapeutic avenues for human and veterinary patients with drug-resistant epilepsy. A sound understanding of the neuroinflammatory mechanisms underlying seizure pathogenesis in canine patients is therefore essential for mechanism-based discovery of selective epilepsy therapies that may enable the development of new disease-modifying treatments. In particular, subgroups of canine patients in urgent needs, e.g. dogs with drug-resistant epilepsy, might benefit from more intensive research in this area. Moreover, canine epilepsy shares remarkable similarities in etiology, disease manifestation, and disease progression with human epilepsy. Thus, canine epilepsy is discussed as a translational model for the human disease and epileptic dogs could provide a complementary species for the evaluation of antiepileptic and antiseizure drugs. This review reports key preclinical and clinical findings from experimental research and human medicine supporting the role of neuroinflammation in the pathogenesis of epilepsy. Moreover, the article provides an overview of the current state of knowledge regarding neuroinflammatory processes in canine epilepsy emphasizing the urgent need for further research in this specific field. It also highlights possible functional impact, translational potential and future perspectives of targeting specific inflammatory pathways as disease-modifying and multi-target treatment options for canine epilepsy.

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing.

The common marmoset ( Callithrix jacchus) has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies. Epileptic marmosets have been independently reported in two Asian primate research centers. Nevertheless, the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated. Here, we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing. We identified 14 558 184 single nucleotide polymorphisms (SNPs) from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples. Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers. In addition, SNP and copy number variation (CNV) analyses suggested that the WW domain-containing oxidoreductase ( WWOX) and Tyrosine-protein phosphatase nonreceptor type 21 ( PTPN21) genes may be associated with epilepsy in marmosets. Notably, KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets. This study provides valuable population genomic resources for marmosets in two Asian primate centers. Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers, while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.