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.

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.

Out-of-hospital rescue medication in dogs with emergency seizure disorders: an owner perspective.

Background: Emergency seizure disorders such as status epilepticus and cluster seizures are unlikely to cease spontaneously while prolonged seizure activity become progressively more resistant to treatment. Early administration of rescue medication in canine epileptic patients, in particular benzodiazepines, at seizure onset by the owners can be life-saving and brain protecting. Clinical studies in dogs evaluating the use of rescue medication in hospital environment exist, however, the owner perspective has not been assessed to date. Hypothesis or objectives: To evaluate the use of rescue medication in dogs with seizure emergencies by the owner at home. Method: Observational study based on online surveys of owners of dogs with emergency seizure disorders. Results: The questionnaire was answered by 1,563 dog owners, of which 761 provided complete and accurate answers suitable for analysis. Of these, 71% administered diazepam, 19% midazolam, 6% levetiracetam, 3% lorazepam, and 4% more than one rescue or other medication. Overall, the success rates based on owners' perspective for intranasal midazolam and rectal diazepam were 97 and 63%, respectively. Owners reported a compliance level of 95 and 66% for intranasal midazolam and rectal diazepam administration, respectively. Conclusions and clinical importance: Even though rectal diazepam was the most used rescue medication in this survey population, intranasal midazolam was perceived by the owners as a better option regarding effectiveness, time to seizure cessation and owner compliance.

Investigating Owner Use of Dietary Supplements in Dogs with Canine Cognitive Dysfunction.

Canine cognitive dysfunction (CCD) is becoming increasingly recognized in veterinary medicine, as dogs live longer and with CCD being highly prevalent among the elderly dog population. Various studies have shown that diet and dietary supplementation can positively influence the clinical signs of CCD, especially if given at an early stage. The aim of this study was to investigate owner use of dietary supplements (DSs) in dogs with age-related behavioral changes. An observational study based on an online questionnaire for owners of dogs with age-related behavioral changes was performed. Out of a total of 394 owners who completed the survey, after noticing age-related behavioral changes, over half of the dogs received DSs (54%), whereas only 8% reported changing their dog's base diet. The most used DS was fish oil (48%). The use of DSs should be discussed with and monitored by veterinary surgeons since many geriatric patients have multi-morbidities, may have specific nutritional requirements and receive multi-faceted medications.

"Resistance Is Futile": A Pilot Study into Pseudoresistance in Canine Epilepsy.

Epilepsy is a common neurological disorder in veterinary practice, complicated by frequent occurrence of medication-resistant epilepsy. In human medicine, it has been noted that some patients with medication-resistant epilepsy have in fact other reasons for their apparent medication-resistance. The aim of this retrospective study was to describe the issue of pseudoresistance using as an example a population of dogs presented with presumed medication-resistant epilepsy and provide an in-depth review of what is known in human medicine about pseudoresistant epilepsy. One-hundred fifty-two cases were identified with medication-resistant epilepsy, of which 73% had true medication-resistant epilepsy and 27% patients had pseudoresistance. Low serum anti-seizure medication levels were the most common cause of pseudoresistance, present in almost half of the cases (42%), followed by inadequate choice of drugs or dosages (22%), misclassification (22%) or misdiagnosis (9%) of epilepsy and poor compliance (9%). All cases of pseudoresistance, except for one, responded to a modification of the initial therapy protocol. Pseudoresistance can bias clinical trials, misinform the clinical decision-making process, delay diagnosis and treatment, and misinform owners about their pets' prognosis. A substantial proportion of these cases can have improvement of their seizure frequency or achieve seizure freedom upon modification of their therapeutic protocol.

Canine olfactory detection of SARS-CoV-2-infected humans-a systematic review.

PURPOSE: To complement conventional testing methods for severe acute respiratory syndrome coronavirus type 2 infections, dogs' olfactory capability for true real-time detection has been investigated worldwide. Diseases produce specific scents in affected individuals via volatile organic compounds. This systematic review evaluates the current evidence for canine olfaction as a reliable coronavirus disease 2019 screening tool. METHODS: Two independent study quality assessment tools were used: the QUADAS-2 tool for the evaluation of laboratory tests' diagnostic accuracy, designed for systematic reviews, and a general evaluation tool for canine detection studies, adapted to medical detection. Various study design, sample, dog, and olfactory training features were considered as potential confounding factors. RESULTS: Twenty-seven studies from 15 countries were evaluated. Respectively, four and six studies had a low risk of bias and high quality: the four QUADAS-2 nonbiased studies resulted in ranges of 81%-97% sensitivity and 91%-100% specificity. The six high-quality studies, according to the general evaluation system, revealed ranges of 82%-97% sensitivity and 83%-100% specificity. The other studies contained high bias risks and applicability and/or quality concerns. CONCLUSIONS: Standardization and certification procedures as used for canine explosives detection are needed for medical detection dogs for the optimal and structured usage of their undoubtful potential.

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.

The Postictal Phase in Canine Idiopathic Epilepsy: Semiology, Management, and Impact on the Quality of Life from the Owners' Perspective.

BACKGROUND: Dogs with idiopathic epilepsy experience not only the preictal and ictal seizure phases but also the postictal phase. To date, research has primarily focused on the preictal and ictal semiology and therapeutic control of ictal events. Research into the postictal phase's pathophysiology, as a therapeutic target and how it impacts the quality of life, is sparse across different species. Interestingly, even if anecdotally, owners report the postictal period being an impactful negative factor on their quality of life as well as their dog's quality of life. HYPOTHESIS/OBJECTIVES: We aimed to assess the semiology and the impact of postictal signs on the quality of life of owners and dogs. METHOD: This observational study was carried out using surveys of owners of dogs with seizure disorders. RESULTS: The questionnaire was filled out by 432 dog owners, 292 of whom provided complete responses that could be analysed. More than nine out of ten owners (97%) reported the presence of various postictal clinical signs. The dog's and the owner's quality of life was mainly affected by specific postictal signs, i.e., disorientation (dog: 31%; owner: 20%), compulsive walking (dog: 17%; owner: 22%), ataxia (dog: 12%; owner: 6%), and blindness (dog: 17%; owner: 10%). Nearly 61% of the owners felt that the severity of postictal signs was moderate or severe. Rescue antiseizure medications did not have an effect on controlling the postictal signs based on 71% of the responders. In contrast, 77% of the respondents reported that other measures such as rest, physical closeness, and a quiet and dark environment had a positive impact on the postictal phase. CONCLUSIONS AND CLINICAL IMPORTANCE: Overall, this survey shows that specific postictal signs are common and have a notable impact on the perceived quality of life of both dogs and their owners. According to the respondents, antiseizure medication might have no influence on the postictal phase in most cases, in contrast to other nonpharmacological measures. Further research on the management of the postictal phase is vital for improving the quality of life of dogs with seizure disorders and their owners.

Surgical treatment of cranial cruciate ligament disease in dogs using Tibial Plateau Leveling Osteotomy or Tibial Tuberosity Advancement-A systematic review with a meta-analytic approach.

Tibial Plateau Leveling Osteotomy (TPLO) or Tibial Tuberosity Advancement (TTA) are commonly used surgical techniques for correction of cranial cruciate ligament (CCL) rupture in dogs. This systematic review aims to investigate whether one technique is superior to the other. Seventy-two studies on surgical management of CCL rupture have been identified and evaluated in regard of subjective and objective gait analysis criteria, development of osteoarthritis (OA), thigh circumference measurements, goniometry, joint stability, pain and complication rates. Almost half (47.2 %) of the studies were considered of low quality of evidence, leading to high heterogeneity in quality among studies; this posed a major limitation for an evidence-based systematic review of both surgical techniques. Out of 72 studies, there were only eleven blinded randomized clinical trials, of which five were rated with a low overall risk of bias. However, both techniques were considered to be successful management options. Subjective and objective gait analysis revealed no lameness at long-term evaluation for the majority of the patients. However, it appeared that TTA lead to better OA scores up to 6 months postoperatively, while TPLO had a lower rate of surgical site infections. In summary, no method can be clearly preferred, as most of the study evaluated were subpar. Studies with a high level of evidence are therefore urgently needed for such a common surgical procedure.

Ondansetron in dogs with nausea associated with vestibular disease: A double-blinded, randomized placebo-controlled crossover study.

BACKGROUND: Nausea and emesis can be, among other signs, common manifestations of acute vestibular system dysfunction in dogs. Currently, antiemetic drugs, such as maropitant and metoclopramide, are used commonly, but do not appear to control nausea. A non-placebo-controlled preliminary study suggested good efficacy of 5-HT3-receptor antagonists, such as ondansetron, against nausea in dogs with vestibular syndrome. OBJECTIVES: To assess and confirm the effect of ondansetron on behavior suggestive of nausea in dogs with vestibular syndrome. ANIMALS: Fourteen dogs with vestibular syndrome and clinical signs of nausea presented to a neurology service. METHODS: Placebo-controlled, double-blinded, crossover study. Behavioral assessment was performed hourly for 4 hours using an established numerical rating scale. The criteria salivation, lip licking, vocalization, restlessness, lethargy, and general nausea were scored. The occurrence of emesis was recorded. After scoring at T0 (pre-dose) and T2 (2 hours post-dose) either ondansetron (0.5 mg/kg) or placebo was injected IV. Two hours post-dose, treatments were switched. Blood samples were collected to measure serum arginine vasopressin (AVP) concentration, which previously has been shown to correlate with clinical signs of nausea. RESULTS: Clinical resolution of nausea was observed 1 hour after administration of ondansetron, whereas serum AVP concentration decreased 4 hours after ondansetron administration. CONCLUSION AND CLINICAL IMPORTANCE: Administration of ondansetron IV is beneficial for dogs with nausea secondary to acute vestibular syndrome. Ondansetron substantially and rapidly decreased clinical signs of nausea behavior and stopped emesis.

Neurostimulation as a Method of Treatment and a Preventive Measure in Canine Drug-Resistant Epilepsy: Current State and Future Prospects.

Modulation of neuronal activity for seizure control using various methods of neurostimulation is a rapidly developing field in epileptology, especially in treatment of refractory epilepsy. Promising results in human clinical practice, such as diminished seizure burden, reduced incidence of sudden unexplained death in epilepsy, and improved quality of life has brought neurostimulation into the focus of veterinary medicine as a therapeutic option. This article provides a comprehensive review of available neurostimulation methods for seizure management in drug-resistant epilepsy in canine patients. Recent progress in non-invasive modalities, such as repetitive transcranial magnetic stimulation and transcutaneous vagus nerve stimulation is highlighted. We further discuss potential future advances and their plausible application as means for preventing epileptogenesis in dogs.

Pharmacokinetics of Cannabidiol Following Intranasal, Intrarectal, and Oral Administration in Healthy Dogs.

The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3-8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL*h, respectively. The maximal plasma CBD concentration (Cmax) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (Tmax), respectively. Significant differences between IN and PO administration were found in the Tmax (p = 0.04). Higher AUC and Cmax were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and Cmax (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.

Defining and overcoming the therapeutic obstacles in canine refractory status epilepticus.

Status epilepticus (SE) can be effectively resolved if diagnosis and treatment are addressed at an early stage, although this is not always possible in clinical practice. If untreated, continuous seizure activity leads to refractory SE which does not respond to antiseizure medication. Although refractory SE is a life-threatening emergency, there is a lack of veterinary consensus on its appropriate management. Classical therapeutic approaches often fail to prevent the progression of SE. One of the main reasons for failure or inadequate response, is a lack of understanding of the fundamental progressive pathophysiology occurring during SE. If the therapeutic approach is focussed on the specific pathophysiologic alterations responsible for initiating and maintaining continuous seizure activity, SE could be successfully resolved during its early stages, preventing progression to a refractory state. The aim of this review is to detail the underlying pathophysiology of SE at its different temporal stages in order to determine a more effective therapeutic approach.

Evaluation of the effect of phenobarbital administration on the biochemistry profile, with a focus on serum liver values, in epileptic cats.

OBJECTIVES: Phenobarbital (PB) is the most common antiseizure drug (ASD) used for the management of feline epilepsy. In dogs, PB is known to cause serum liver enzyme induction and hepatotoxicity, especially after administration long term or in high concentrations. In cats, insufficient evidence is available to draw similar conclusions. The aim of this study was to evaluate the effect of PB administration on the serum biochemistry profile of epileptic cats. As an additional objective, other adverse effects arising, related to PB treatment, were recorded. METHODS: Medical records of four veterinary centres were retrospectively reviewed for epileptic cats receiving PB treatment. Cats were included if they had a diagnosis of idiopathic epilepsy or structural epilepsy; a normal baseline serum biochemistry profile; at least one follow-up serum biochemistry profile; no concurrent disease or had not received medication that could possibly influence liver function or lead to serum liver enzyme induction. Alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase and gamma-glutamyl transferase activities, and total bilirubin, bile acids, glucose, albumin, total protein, urea and creatinine concentrations before and during PB administration were recorded. PB serum concentration was also recorded, when available. RESULTS: Thirty-three cats (24 males, nine females) with a median age of 3 years (range 2 months to 12 years) met the inclusion criteria. Idiopathic or structural epilepsy was diagnosed in 25 (76%) and eight (24%) cats, respectively. The follow-up period ranged from 9 to 62 months. This study found an increase in ALT in three cats, possibly related to a PB serum concentration >30 µg/ml. No statistically significant increase in serum liver enzymes or other evaluated biochemistry parameters was found by comparing pre- and post-treatment parameters. CONCLUSIONS AND RELEVANCE: PB administration did not result in hepatic enzyme induction or other biochemical abnormalities in cats. This strengthens the safety profile of PB as an ASD in cats.

Long-term follow-up of spinal segmental stabilization for surgical treatment of dorsal hemivertebrae associated with kyphosis in brachycephalic dogs.

The aim of this study is to report chronic complications (> 2 mo after surgery) following spinal segmental stabilization (SSS) to treat myelopathy associated with thoracic congenital vertebral malformations in brachycephalic dogs. Follow-up medical records (years 2006 to 2020) of 12 cases that underwent SSS at 3 university hospitals were retrieved and analyzed with a minimum follow-up period of 1 y. Five dogs showed no chronic complications and 7 dogs had chronic complications which are reported here. This case series demonstrates that the rate of chronic complications associated with SSS was high (58%) but most of these were minor and did not require revision surgery.

Suivi à long terme de la stabilisation segmentaire rachidienne pour le traitement chirurgical des hémi-vertèbres dorsales associées à la cyphose chez le chien brachycéphale. Le but de cette étude est de rapporter les complications chroniques (> 2 mois après chirurgie) suite à la stabilisation segmentaire rachidienne (SSS) pour traiter la myélopathie associée aux malformations vertébrales congénitales thoraciques chez les chiens brachycéphales. Les dossiers médicaux de suivi (années 2006 à 2020) de 12 cas qui ont subi un SSS dans trois hôpitaux universitaires ont été récupérés et analysés avec une période de suivi minimale de 1 an. Cinq chiens n'ont présenté aucune complication chronique et sept chiens ont présenté des complications chroniques qui sont rapportées ici. Cette série de cas démontre que le taux de complications chroniques associées au SSS était élevé (58 %) mais que la plupart d'entre elles étaient mineures et n'ont pas nécessité de reprise chirurgicale.(Traduit par Dr Serge Messier).

Repetitive transcranial magnetic stimulation in drug-resistant idiopathic epilepsy of dogs: A noninvasive neurostimulation technique.

BACKGROUND: Although repetitive transcranial magnetic stimulation (rTMS) has been assessed in epileptic humans, clinical trials in epileptic dogs can provide additional insight. OBJECTIVES: Evaluate the potential antiepileptic effect of rTMS in dogs. ANIMALS: Twelve client-owned dogs with drug-resistant idiopathic epilepsy (IE). METHODS: Single-blinded randomized sham-controlled clinical trial (dogs allocated to active or sham rTMS) (I) and open-labeled uncontrolled clinical trial (dogs received active rTMS after sham rTMS) (II). Monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were evaluated for a 3-month pre-TMS and post-rTMS period and safety was assessed. The lasting effect period of rTMS was assessed in each dog treated by active stimulation using the MSF ratio (proportion of post-TMS to pre-rTMS MSF) and treatment was considered effective if the ratio was <1. RESULTS: No adverse effects were reported. In trial I, MSF and MSDF decreased significantly (P = .04) in the active group (n = 7). In the sham group (n = 5), no significant changes were found (P = .84 and .29, respectively). Cluster seizures did not change significantly in either group. No significant differences were detected between the groups. In trial II, previously sham-treated dogs (n = 5) received active rTMS and significant decreases in MSF and MSDF were noted (P = .03 and .008, respectively). The overall effect of rTMS lasted for 4 months; thereafter, the MSF ratio was >1. CONCLUSIONS AND CLINICAL IMPORTANCE: Repetitive transcranial magnetic stimulation may be a safe adjunctive treatment option for dogs with drug-resistant IE, but large-scale studies are needed to establish firm conclusions.