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Rectally administered levetiracetam in dogs with cluster seizures | VETgirl Veterinary Continuing Education Podcasts

In this VETGirl podcast, we discuss the efficacy of the anti-epileptic medication, levetiracetam, when given rectally in dogs. There are few things more frightening for an owner than witnessing a seizure in their dog, and cluster seizures (CS) and status epilepticus (SE) are particularly scary! Unfortunately as veterinarians, we have somewhat limited emergency interventional options that we can offer to owners when CS or SE occurs at home. The administration of oral medications is problematic due to risks of an inadvertent bite, difficulty or inability for the patient to swallow, and of course the risk of aspiration. Perhaps the most common emergency therapy for SE in dogs is rectally administered diazepam, which is the preferred rectally-administered emergency medication in human medicine as well (Podell, Brophy). Levetiracetam has become an increasingly popular maintenance therapy for seizure management in small animal medicine, and recent studies have demonstrated that rectally-administered levetiracetam at 40 mg/kg effectively reaches target concentrations in both healthy and epileptic dogs (Peters, Cagnotti). That said, no studies have investigated how well rectal levetiracetam performs clinically, which is what we really care about, right?

So, Cagnotti et al wanted to evaluate this in a study entitled Open-label clinical trial of rectally administered levetiracetam as supplemental treatment in dogs with cluster seizures. In this study, the authors investigated the clinical efficacy of rectal levetiracetam at reducing seizure activity in dogs presenting with CS or SE. This was a prospective, open label, clinical trial performed between September 2016 and May 2018. Dogs that presented to a veterinary teaching hospital during this time period for CS or SE were included. Just as a quick reminder, the International Veterinary Epilepsy Task Force (IVETF) defines SE as continuous epileptic seizures lasting more than 5 minutes, or as having 2 or more discrete epileptic seizures where the patient does not experience a complete recovery of consciousness in between episodes (Berendt). They then define cluster seizures as 2 or more seizures taking place within a 24 hour time period (Berendt). These definitions are what the authors used to define SE and CS in this study. Dogs were excluded if they were already receiving levetiracetam for seizures or if diagnostics suggested that the seizure was occurring in response to a metabolic or toxic insult. All dogs had a CBC, biochemistry profile with electrolytes, blood ammonia level, and pre and postprandial bile acid levels performed. Dogs received a neurologic examination by either a supervised neurology resident or a boarded neurologist. The patients were classified as having idiopathic epilepsy or structural epilepsy, but neither advanced imaging nor cerebrospinal fluid analysis were required to diagnose structural epilepsy. This diagnosis was made when reactive causes were eliminated and when the patient had neurologically abnormal examinations between seizure episodes.

On presentation to the hospital, either rectal or intravenous (IV) diazepam was given at 1-2 mg/kg if the patient was actively seizing. Then the dog received IV phenobarbital at 4-5 mg/kg every 8 hours. At this point, patients were divided into 2 study groups. One group received rectal levetiracetam at 40 mg/kg in addition to their phenobarbital, and the control group received only the phenobarbital. Unfortunately, this was not randomized assignment, as the owners made the final decision of which protocol their dog would receive. The investigators defined responders as dogs that did not have a seizure over the following 24 hours. A total of 57 dogs met the inclusion criteria and continued into the study, with 21 dogs assigned to the rectal levetiracetam group and 36 assigned to the control group. No statistically significant differences were observed between groups in terms of age, sex, weight, presenting complaint, or seizure etiology, and mixed breed dogs were the most highly represented breed in each group. The authors used the IVETF consensus statement’s guidelines to define idiopathic epilepsy, and by the confidence levels described in these guidelines, they used Tier I and Tier II confidence levels to diagnose idiopathic epilepsy (Berendt). By these standards, idiopathic epilepsy was diagnosed in 57% of the rectal levetiracetam group and 44% of the control group. In contrast, 43% of dogs were either suspected to have or were diagnosed with structural causes of seizures in the rectal levetiracetam group and in 56% of the control group. In both the control and the rectal levetiracetam group, approximately 14% of dogs presented with SE, and the remaining 86% presented with CS. Given such low numbers of dogs presenting with SE, the authors performed statistics only on patients presenting with CS.

Okay, so let’s talk about how the levetiracetam performed. Well to cut to the chase, it did pretty well! Remember that responders were defined as dogs that did not have a seizure for 24 hours, whereas non-responders were dogs that had additional seizure activity. In this study, 94% of dogs in the rectal levetiracetam group were classified as responders, as compared to 48% of dogs in the control group. As you may expect, that difference was determined to be statistically significant. Interestingly, there was not a significant difference in the response rate between dogs with idiopathic epilepsy versus structural epilepsy.

One of the limitations of the study that the authors discuss is the lack of a placebo-controlled group. However, they also discussed that in human medicine, there has been a movement away from placebo exposure due to the suggestion that adding effective anti-epileptic therapies would more effectively reduce adverse outcomes. Other limitations the authors discuss include the lack of randomization to study groups (recall that owners made the final decision regarding treatment group assignment), the few cases of SE, the lack of serum levels of phenobarbital or potassium bromide for some patients receiving these therapies prior to presentation, and finally the lack of a definitive diagnosis of structural epilepsy in some cases.

So, what can we take away from this VETgirl podcast? Based on this study, rectal levetiracetam appears to be an effective therapy when combined with a standard treatment protocol in preventing seizures in dogs presenting with CS. Hopefully additional studies will be performed to further evaluate how rectal levetiracetam performs in dogs with SE, and the authors recommend a double-blinded placebo-controlled clinical trial to further validate these findings. At this point, however, it appears that rectal levetiracetam may have a future in small animal medicine as one more tool for helping with those scary seizure emergencies!

References:

Cagnotti G, Odore R, Bertone I, et al. Open-label clinical trial of rectally administered levetiracetam as supplemental treatment in dogs with cluster seizures. J Vet Intern Med 2019;33:1714-1718.

Podell M. The use of diazepam per rectum at home for the acute management of cluster seizures in dogs. J Vet Intern Med 1995;9(2):68-74.

Brophy GM, Bell R, Classen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23.

Peters RK, Schubert T, Clemmons R, Vickroy T. Levetiracetam rectal administration in healthy dogs. J Vet Intern Med. 2014;28(2):504-509.

Cagnotti G, Odore R, Gardini G, et al. Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus. BMC Vet Res. 2018;14:189.

Berendt M, Farquhar RJ, Mandigers PJ, et al. International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals. BMC Vet Res. 2015;11:182.

Abbreviations:
CS – Cluster seizures
IV – Intravenous
IVETF – International Veterinary Epilepsy Task Force
LEV – Levetiracetam
SE – Status epilepticus

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