Immune-mediated polyarthritis and anterior uveitis secondary to zonisamide administration in a dog with refractory epilepsy.

The objective of this article is to describe a case of suspected zonisamide-induced immune-mediated polyarthritis (IMPA) and anterior uveitis in a dog. A 7-year-old male neutered Siberian Husky with a history of refractory idiopathic epilepsy was presented for cluster seizures. Following the addition of zonisamide to the antiepileptic regime, the dog developed new IMPA and anterior uveitis. Within a few weeks of discontinuation of the zonisamide, the dog's IMPA and anterior uveitis resolved. These immune-mediated conditions were thus presumed to be an idiosyncratic reaction to zonisamide. To our knowledge, this is the first report of IMPA and anterior uveitis in dogs associated with zonisamide administration at its recommended dose.

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.

Pathophysiology of drug-resistant canine epilepsy.

Drug resistance continues to be a major clinical problem in the therapeutic management of canine epilepsies with substantial implications for quality of life and survival times. Experimental and clinical data from human medicine provided evidence for relevant contributions of intrinsic severity of the disease as well as alterations in pharmacokinetics and -dynamics to failure to respond to antiseizure medications. In addition, several modulatory factors have been identified that can be associated with the level of therapeutic responses. Among others, the list of potential modulatory factors comprises genetic and epigenetic factors, inflammatory mediators, and metabolites. Regarding data from dogs, there are obvious gaps in knowledge when it comes to our understanding of the clinical patterns and the mechanisms of drug-resistant canine epilepsy. So far, seizure density and the occurrence of cluster seizures have been linked with a poor response to antiseizure medications. Moreover, evidence exists that the genetic background and alterations in epigenetic mechanisms might influence the efficacy of antiseizure medications in dogs with epilepsy. Further molecular, cellular, and network alterations that may affect intrinsic severity, pharmacokinetics, and -dynamics have been reported. However, the association with drug responsiveness has not yet been studied in detail. In summary, there is an urgent need to strengthen clinical and experimental research efforts exploring the mechanisms of resistance as well as their association with different etiologies, epilepsy types, and clinical courses.

Translational veterinary epilepsy: A win-win situation for human and veterinary neurology.

Epilepsy is a challenging multifactorial disorder with a complex genetic background. Our current understanding of the pathophysiology and treatment of epilepsy has substantially increased due to animal model studies, including canine studies, but additional basic and clinical research is required. Drug-resistant epilepsy is an important problem in both dogs and humans, since seizure freedom is not achieved with the available antiseizure medications. The evaluation and exploration of pharmacological and particularly non-pharmacological therapeutic options need to remain a priority in epilepsy research. Combined efforts and sharing knowledge and expertise between human medical and veterinary neurologists are important for improving the treatment outcomes or even curing epilepsy in dogs. Such interactions could offer an exciting approach to translate the knowledge gained from people and rodents to dogs and vice versa. In this article, a panel of experts discusses the similarities and knowledge gaps in human and animal epileptology, with the aim of establishing a common framework and the basis for future translational epilepsy research.

Neurosurgery in feline epilepsy, including clinicopathology of feline epilepsy syndromes.

Feline epilepsy is treated with antiseizure medications, which achieves fair to good seizure control. However, a small subset of feline patients with drug-resistant epilepsy requires alternative therapies. Furthermore, approximately 50 % of cats with epileptic seizures are diagnosed with structural epilepsy with or without hippocampal abnormality and may respond to surgical intervention. The presence of hippocampal pathology and intracranial tumors is a key point to consider for surgical treatment. This review describes feline epilepsy syndrome and epilepsy-related pathology, and discusses the indications for and availability of neurosurgery, including lesionectomy, temporal lobectomy with hippocampectomy, and corpus callosotomy, for cats with different epilepsy types.

Cannabidiol in canine epilepsy.

The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50 % reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.

Neurosurgery in canine epilepsy.

Epilepsy surgery is functional neurosurgery applied to drug-resistant epilepsy. Although epilepsy surgery has been established and achieves fair to good outcomes in human medicine, it is still an underdeveloped area in veterinary medicine. With the spread of advanced imaging and neurosurgical modalities, intracranial surgery has become commonplace in the veterinary field, and, therefore, it is natural that expectations for epilepsy surgery increase. This review summarizes current standards of intracranial epilepsy surgery in human medicine and describes its current status and expectation in veterinary medicine. Intracranial epilepsy surgery is classified generally into resection surgery, represented by cortical resection, lobectomy, and lesionectomy, and disconnection surgery, such as corpus callosotomy and multiple subpial transection. In dogs with drug-resistant epilepsy, corpus callosotomy is available as a disconnection surgery for generalized epilepsy. However, other types of disconnection and resection surgeries for focal epilepsy are limited to experimental studies in laboratory dogs and/or anecdotal case reports of lesionectomy, such as tumor or encephalocele removal, without epileptogenic evidence. Veterinary epilepsy surgery is a new and challenging neurosurgery field; with the development of presurgical evaluations such as advanced electroencephalography and neuroimaging, it may become more readily practiced.

Th17 cell-mediated immune response in a subpopulation of dogs with idiopathic epilepsy.

BACKGROUND: Canine idiopathic epilepsy (IE) is a common neurological disease with severe impact on the owner´s and the dog's quality of life. A subpopulation of dogs with IE does not respond to antiseizure drugs (non-responder). Th17 cells (T helper cells) and their proinflammatory Interleukin-17 (IL-17) are part of the immune system and previous studies showed their involvement in the pathogenesis of several autoimmune diseases. Non-responder might have an abnormal immune response against structures of the central nervous system. To discover a new aetiology of canine IE and thereby optimising the therapy of intractable IE, this prospective study aimed to investigate Th17 cells and IL-17 in dogs with IE. The underlying hypothesis was that in some dogs with IE a Th17 cell-mediated immune response could be detectable. METHODS: 57 dogs with IE and 10 healthy dogs (control group, C) were enrolled in the study. EDTA blood was taken to measure Th17 cells by flow cytometry. IL-17 was measured in 35 cerebrospinal fluid (CSF) and 33 serum samples using an enzyme-linked immunosorbent assay (ELISA). It was investigated whether there was a significant increase of stimulated Th17 cells in blood samples or of IL-17 in serum and CSF samples of dogs with IE in comparison to C. Correlations between the amount of Th17 cells/µL or IL-17 and different clinical parameters e.g. seizure frequency, seizure type, seizure severity or treatment response were evaluated. Additionally, Th17 cells/µL were randomly controlled of 17 dogs with IE and were examined for changes over time and in relation to treatment response. RESULTS: Ten dogs with IE had strongly elevated stimulated Th17 cells/µL within the blood (>100 Th17 cells/µL). A slight positive correlation between stimulated Th17 cells/µL and seizure severity (p = 0.046; rSpear = 0.27) was proven in these dogs. In addition, 4/10 dogs with elevated Th17 levels experienced cluster seizures and status epilepticus in comparison to 9% of the dogs with non-elevated Th17 levels (<100 Th17 cells/µL). Dogs with IE had significantly higher IL-17 values in CSF and serum samples compared to C (p<0.001; p<0.002; respectively). CONCLUSION: In single dogs with IE, strongly increased amounts of Th17 cells were detectable and dogs with elevated Th17 cells seemed to have a greater risk for experiencing a combination of cluster seizures and status epilepticus. Therefore, an underlying Th17-cell mediated immune response was suspected and hence anti-inflammatory drugs could be indicated in these single cases with intractable epilepsy.

Ventrolateral temporal lobectomy in normal dogs as a counterpart to human anterior temporal lobectomy: a preliminary study on the surgical procedure and complications.

Anterior temporal lobectomy (ATL) is a surgical procedure for drug-resistant mesial temporal lobe epilepsy that is commonly performed in human medicine. The purpose of this study was to determine whether ATL-like surgery, i.e., removal of the amygdala and hippocampal head, is possible in dogs, and to investigate its safety and postoperative complications. Eight healthy beagles underwent ATL-like surgery and were observed for 3 months postoperatively. Samples from the surgically resected tissues and postmortem brain were evaluated pathologically. The surgical survival rate was 62.5%. The major postoperative complications were visual impairment, temporal muscle atrophy on the operative side, and a postoperative acute symptomatic seizure. Due to the anatomical differences between dogs and humans, the surgically resected area to approach the medial temporal structures in dogs was the ventrolateral part of the temporal lobe. Therefore, the ATL-like surgery described in this study was named "ventrolateral temporal lobectomy" (VTL). This study is the first report of temporal lobectomy including amygdalohippocampectomy in veterinary medicine and demonstrates its feasibility. Although it requires some degree of skill, VTL could be a treatment option for canine drug-resistant epilepsy and lesions in the mesial temporal lobe.

Localization of cerebral hypoperfusion in dogs with refractory and non-refractory epilepsy using [99mTc] ethyl cysteinate dimer and single photon emission computed tomography.

To evaluate the localization of functional deficit area in epileptogenic zones of the brain in seven refractory and seven non-refractory epilepsy dogs using technetium 99m labeled with ethyl cysteinate dimer and interictal single photon emission computed tomography [99mTc-ECD SPECT] co-registration with Magnetic Resonance Imaging (MRI). Regions showing perfusion deficits in the SPECT images were analyzed by using the standard semiquantitative evaluation method to compare the level of cortical perfusion to the maximum number of counts within the cerebellum (max C), considered the area of reference. This study showed that SPECT imaging revealed abnormalities in several regions of the brain in both epilepsy groups. The refractory epilepsy dogs showed more frequency area of hypoperfusion in temporal lobe than non-refractory group with not statistically significance (P=0.28). The result suggests the lesion in temporal might be relevance with refractory epilepsy in canine patients.

ABCB1 c.-6-180T>G polymorphism and clinical risk factors in a multi-breed cohort of dogs with refractory idiopathic epilepsy.

Epilepsy is the most common chronic neurological disorder in dogs. Approximately 20-30% of dogs do not achieve satisfactory seizure control with two or more anti-epileptic drugs at appropriate dosages. This condition, defined as refractory epilepsy, is a multifactorial condition involving both acquired and genetic factors. The P glycoprotein might play and important role in the pathophysiological mechanism and it is encoded by the ABCB1 gene. An association between a single nucleotide variation of the ABCB1 gene (c.-6-180T>G) and phenobarbital resistance has previously been reported in a Border collie population with idiopathic epilepsy. To date, the presence and relevance of this polymorphism has not been assessed in other breeds. A multicentre retrospective, case-control study was conducted to investigate associations between ABCB1 c.-6-180T>G, clinical variables, and refractoriness in a multi-breed population of dogs with refractory idiopathic epilepsy. A secondary aim was to evaluate the possible involvement of the ABCB1 c.-6-180T>G single nucleotide variation this population. Fifty-two refractory and 50 responsive dogs with idiopathic epilepsy were enrolled. Of these, 45 refractory and 50 responsive (control) dogs were genotyped. The G allele was found in several breeds, but there was no evidence of association with refractoriness (P=0.69). The uncertain role of the c.-6-180T>G variation was further suggested by an association between the T/T genotype with both refractoriness and responsiveness in different breeds. Furthermore, high seizure density (cluster seizure) was the main clinical risk factor for refractory idiopathic epilepsy (P=0.003).

Closed-Loop Neurostimulators: A Survey and A Seizure-Predicting Design Example for Intractable Epilepsy Treatment.

First, existing commercially available open-loop and closed-loop implantable neurostimulators are reviewed and compared in terms of their targeted application, physical size, system-level features, and performance as a medical device. Next, signal processing algorithms as the primary strength point of the closed-loop neurostimulators are reviewed, and various design and implementation requirements and trade-offs are discussed in details along with quantitative examples. The review results in a set of guidelines for algorithm selection and evaluation. Second, the implementation of an inductively-powered seizure-predicting microsystem for monitoring and treatment of intractable epilepsy is presented. The miniaturized system is comprised of two miniboards and a power receiver coil. The first board hosts a 24-channel neurostimulator system on chip fabricated in a [Formula: see text] CMOS technology and performs neural recording, on-chip digital signal processing, and electrical stimulation. The second board communicates recorded brain signals as well as signal processing results wirelessly. The multilayer flexible coil receives inductively-transmitted power. The system is sized at 2 × 2 × 0.7 [Formula: see text] and weighs 6 g. The approach is validated in the control of chronic seizures in vivo in freely moving rats.