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Canine status epilepticus (SE) is a naturally occurring condition, not a model, and may provide a setting in which proof of principle studies of new therapies for both humans and canines can be evaluated. Current treatment of human SE is based on clinical studies performed decades ago using drugs developed before the 1970s (Cranford et al., 1978). Successful treatment rates in a comprehensive clinical study were only 67% with lorazepam and 51% with phenytoin (Treiman et al., 1998). These drugs now form the basis of international treatment guidelines (Kalviainen, 2007). In a recent international workshop, it was stated “regulations in their current form for undertaking studies in the emergency situations in patients unable to give consent pose serious obstacles for future research” (Shorvon et al., 2008). There is an urgent need for developing treatments for SE using newer agents. Two new intravenous antiepileptic drugs (levetiracetam and lacosamide) are now available and two are being developed (carbamazepine and topiramate). These may have significant advantages over current therapies, but evidence is required before they can be incorporated into guidelines. A major obstacle for performing studies with drugs for SE is that although it is possible to obtain “continuing consent” in emergency treatment situations, the institutional review boards (IRBs) allow this only if there is some evidence to indicate that the test drug has potential for being superior to accepted therapy. This is a high bar for new drugs if the only evidence for efficacy and safety is based on SE studies performed in small animals with experimental SE. These experimental models of SE have two shortcomings that make it difficult to apply results to treating SE in humans: (1) none of the models have counterparts in the human condition; and (2) they are usually induced by various chemicals or use of electrical kindling (Sloviter et al., 2007). These laboratory models are inadequate to support applications for human studies presented to the U.S. Food and Drug Administration (FDA) for an Investigational New Drug (IND) application or to obtain support from local IRBs.

There are many similarities between human and canine epilepsy (Berendt et al., 2004). Canine SE is commonly encountered in veterinary practice, and the causes are similar to those seen in humans (Platt & Hagg, 2002; Bateman & Parent, 1999; Saito et al., 2001). This naturally occurring SE is comparable to the human condition in terms of underlying pathophysiology, clinical course, and response to conventional therapy. Evaluating drugs for SE in dogs has three advantages: (1) studies could provide proof of principle evidence for efficacy and safety; (2) the doses and plasma drug concentrations needed to control canine SE provide much more relevant information about the design of effective dosing regimens in humans; and (3) being able to perform a placebo-controlled study in dogs significantly increases the power of the study. We were able to obtain approval for a double-blind placebo controlled study of levetiracetam (LEV) in canine SE because there is no widely accepted treatment or successful treatment for this condition. Approximately 4–6 dogs per month present at the University of Minnesota Veterinary Hospital, but because of the cost of the ICU stay, most owners have chosen not to participate, instead electing to have their dogs euthanized. Informed consent is obtained from the owner. If seizures continue after phenobarbital or diazepam, the canine subject is randomized to a loading dose of LEV or saline and admitted to the ICU. The primary end points are number of hours from admission until 24 h without an observed seizure, number of seizures until 24 h seizure free, number of episodes of status epilepticus (five or more minutes of seizure activity), and percentage all-cause mortality while hospitalized. After administration of the study agent, further therapy may be used for refractory SE. Secondary endpoints are hours of hospitalization, number of bolus injections of diazepam given, percentage of dogs receiving a constant rate infusion (CRI) of diazepam, hours of CRI of diazepam, percentage of dogs receiving either propofol or pentobarbital treatment, and hours of propofol or pentobarbital treatment. Power analysis calculations indicated that 10 dogs in the active and 10 in the placebo group would detect a 40% difference in the number seizure free at the end of a 24-h observation period with an alpha of 0.05 and beta of 0.20. In the LEV study, dogs were randomized in blocks of 10, 5 LEV and 5 placebo receiving 30 mg/kg LEV or saline. Interim analysis without unblinding found a group difference: in one group, three of five (60%) had no more seizures for 24 h and in the other group 1 had no more seizures (20%). The second group of 60 mg/kg is now underway.

Another development in the United States that will facilitate studies of SE is the existence of the Neurological Emergencies Treatment Trial (NETT) Network. Severe neurologic illnesses or injuries such as SE require immediate intervention to preserve life or reduce mortality. The NETT has been funded by the National Institute of Neurological Disorders and Stroke. The NETT conducts multicenter clinical trials of potential new therapies for a wide range of neurologic problems. The NETT includes not only academic centers, but also community and rural sites, in order to enroll patients who are cared for in diverse settings. The NETT consists of a Clinical Coordinating Center, located at the University of Michigan and a Statistical and Data Management Center at the Medical University of South Carolina. Patient enrollment into clinical trials occurs at 11 “hubs,” which, in turn, coordinate the activity of between 3 and 10 “spokes.” The hub provides local resources, support, and administration of the activities of the NETT, and ensures proper patient enrollment and adherence to protocols and regulatory requirements. Each spoke is a hospital the emergency department of which is involved with the acute care of patients with neurologic emergencies. By performing proof of concept studies in canine SE and then utilizing the NETT for human studies, it may be possible to advance the treatment of SE in humans.

Acknowledgment

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Disclosure: None of the authors has any conflict of interest to declare.

References

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