In cases of epileptic seizures in dogs, survival is often more dependent on quality of life and financial issues than actual disease manifestations. As such, the burden is on the veterinarian to balance seizure control and owner perception of patient quality of life.
The temporal distribution of seizures is often as clinically relevant as overall seizure frequency. An animal that experiences one day of seizures per year may be considered fairly well controlled, but if the seizures occur in a flurry or cluster, this episode may result in an expensive emergency visit. The terms “acute repetitive seizures”, “cluster seizures” (CS), “serial seizures” and “flurry seizures” describe a condition characterised by multiple generalised tonic, clonic or tonic-clonic seizures, or even multiple focal seizures, occurring over 24 hours (Monteiro et al., 2012; Berendt et al., 2015).
There is no definitive clinical definition for a cluster of seizures. Studies examining clinically defined seizure clustering patterns have used varying empiric definitions, including two to four seizures in less than 48 hours; three seizures per 24 hours; or two generalised tonic-clonic or three complex focal seizures in four hours (Patterson, 2014). Non-specific definitions, such as “those having several convulsions within a day or two” (Patry, 1931) have also been described.
Limited data exists documenting the prevalence of cluster seizures in veterinary medicine. Studies have suggested that anywhere between 38 percent to 77 percent of dogs with epilepsy can experience CS at some point (Monteiro, 2012; Packer et al., 2014). Some canine breeds appear predisposed to CS. Up to 94 percent of Border Collies (Hülsmeyer et al., 2010; Kwiatkowska et al., 2018) and nearly 50 percent of Australian Shepherd dogs, diagnosed with idiopathic epilepsy, have been reported to experience CS. German Shepherd Dogs, Rottweillers and Boxers have also been noted with a higher prevalence of CS compared to other breeds with idiopathic epilepsy (Monteiro et al., 2012; Packer et al., 2016). Limited work has been done evaluating the prevalence of seizure clustering in cats. One study evaluating 125 cats with primary and secondary causes of seizure activity documented CS in 53 percent and 59 percent of cases, respectively (Pakozdy et al., 2010).
Dogs experiencing CS are less likely to achieve long-term seizure remission, and experience a decreased survival time and an increased likelihood of euthanasia compared to dogs with single epileptic seizure episodes (Packer et al., 2014).
Three broad options exist for the treatment of CS in dogs and cats, which are not mutually exclusive. These are firstly to improve long-term seizure control; secondly administer short-acting treatment at the time of a cluster with the aim of reducing possible “follow on” seizures in the next few minutes; and lastly administer long-acting medication with the aim of reducing “follow on” seizures over the subsequent few hours. These treatments may all be necessary when the animal is presented to the veterinary clinic with CS, but some of them can be advised with the appropriate cautions in the at-home environment for the client to administer to avoid therapeutic delays (Figure 1).
Short-acting treatment at the time of a cluster event
Benzodiazepines (diazepam, midazolam) are potent, fast-acting anticonvulsants and are therefore often the preferred initial therapy for emergency seizures. When skilled technicians, veterinary nurses or veterinarians are present, IV administration is preferred. However, if IV access is not available, the recommendation for emergency seizures in a dog or cat is to immediately consider IM midazolam. Benzodiazepines can also be administered via rectal, nasal or buccal routes when parenteral therapy is not feasible, such as in the at-home environment. It has been well established that absorption of lipid-soluble drugs by the membranes of the colon and rectum is rapid and complete (Podell, 1995). Diazepam can be administered into the rectum using plastic administrators such as teat infusion cannulas or tom-cat catheters with a water-soluble lubricant. The efficacy of rectally delivered diazepam depends on several factors, not least the time that it takes for the drug to reach the therapeutic concentration (Probst et al., 2013). Rectal diazepam (0.5 to 2.0mg/kg) has been evaluated for treatment of cluster seizures in dogs proving a significant decrease in the number of CS in a 24-hour period as well as a significant decrease in the total cost of emergency care (Podell, 1998).
The intranasal route has been investigated extensively and has not only been found to be more convenient and socially acceptable than rectal diazepam, but also yielded equal or better results in regards to anti-epileptic activity and onset of action (Charalambous, 2017). Diazepam and midazolam administered intranasally (IN) to dogs have both been shown to rapidly reach high concentrations (Charalambous et al., 2019).
Continuous benzodiazepine infusion may be a necessary and effective mode of in-hospital therapy for frequent CS. The dose should be calculated hourly (diazepam 0.1 to 0.5mg/kg of body weight, q1hr) and is usually diluted in 0.9% saline or in 5% dextrose in water (D5W), with the volume used being equal to the maintenance fluid requirement over the hour (Patterson, 2014). The dose can be delivered with an infusion pump. The dosage rate should be reduced by 50 percent every six hours for at least two reductions before discontinuing the drug. Midazolam is completely water-soluble and has been shown to be an effective and safe therapy when administered by constant rate infusion.
Levetiracetam (LEV) (20 to 60mg/kg IV, IM or rectal) is a rapidly acting and safe anticonvulsant which can be used parenterally when benzodiazepines are considered ineffective (Packer et al., 2015). It can be effective for eight hours, at which time it can be repeated. It causes minimal sedation and is not metabolised in the liver, representing a very suitable option for older dogs and cats. In addition to its seizure-suppressing activity, previous experiments in chronic epilepsy models in rodents suggested that LEV might also possess anti-epileptogenic or disease-modifying activity (Packer et al., 2015). A randomised, placebocontrolled, double-masked study including 19 dogs with status epilepticus or CS has shown that administration of IV levetiracetam in addition to diazepam resulted in a significantly higher responder rate compared to just diazepam (Hardy et al., 2012).
The distribution of PB to the central nervous system may take up to 30 minutes, because of weaker lipophilicity in comparison with diazepam. If the patient is refractory to benzodiazepines and levetiracetam, it may require a loading dose of PB if it is currently not already being maintained on this drug. The recommended
loading dose is 12 to 24mg/kg IV if immediate therapeutic concentrations are desired but this can induce a profound stupor with concurrent suppression of the cardiovascular and respiratory system (Patterson, 2014). Alternatively, the dose can initially be 2 to 6mg/kg IV, repeating the dose every 20 to 30 minutes to effect and to a maximum total 24-hour dose of 24mg/kg (Patterson, 2014). The parenteral form can also be given IM, which is recommended if diazepam has already been administered. This will avoid the potentiation of profound respiratory and cardiovascular depression.
Cluster seizures that do not respond to a benzodiazepine, levetiracetam or PB may be considered refractory and require more aggressive treatment (Platt, 2014). Short-acting anaesthetic drugs are the most commonly used agents for treating resistant SE, as they have a rapid onset of action, short half-lives and cause reductions in cerebral metabolic rates. These drugs should be used only in an intensive care setting because of the need for continuous blood pressure monitoring and, ideally, central venous pressure monitoring. Propofol, ketamine and dexmedetomidine have all been suggested as being effective for animals with refractory emergency seizures when used IV at standard doses (Platt, 2014).
Long-acting treatment at the time of a cluster event
The following options should be viewed as at-home therapies for those animals that are known to exhibit cluster seizures. The treatments are not intended as a method to avoid veterinary care and counselling but offer an “on the spot” therapy that may prevent cluster seizures from occurring or at least reduce the amount of seizures exhibited within a 24-hour period. As such, the owners can be advised to attempt one of the below options at the time of the first seizure.
Clorazepate (clorazepate dipotassium) is a benzodiazepine pro-drug that acts by enhancing GABA activity in the brain. Oral doses between 0.5 and 2mg/kg every eight hours can result in sedation and ataxia but such signs may resolve three to four days after treatment (Platt, 2014). In essence this drug is a short-term anticonvulsant that can be effective when administered orally. Anecdotally, this drug can be given as a pulsed therapy adjunctively to the maintenance medication which the animal is on, beginning at the lower end of the recommended dose. The success of this approach may depend on the tolerance of the owner to the ensuing sedation and the ability to predict a cluster based on the first seizure event (Platt, 2014). The duration of treatment can be short (one to three days). The author does not recommend the use of this drug in dogs receiving phenobarbital or in cats unless absolutely necessary.
Oral or rectal levetiracetam
The pharmacokinetics of levetiracetam appear favourable for oral administration during CS. The bioavailability of oral administration is nearly 100 percent. The use of an interval or pulsed oral dosing regimen of levetiracetam can be used as in the treatment of at-home cluster seizures. If the animal is already on phenobarbital, a higher dose of levetiracetam is advised (more than 20mg/kg) (Packer et al., 2015). Similar to the use of clorazepate, in this situation, the success of this approach may depend on the prediction of cluster activity but in this drug’s case, there will be limited sedation and liver metabolism is not a concern. A documented protocol is the administration of an initial dose of approximately 60mg/kg after a seizure has occurred or pre-ictal signs are recognised by the owner, followed by approximately 20mg/kg every eight hours until seizures do not occur for 48 hours (Packer et al., 2015). If the dog is already being prescribed this drug for maintenance seizure control, then a lower dose can be used which should be tailored to the drug’s sedative effects; approximately 40 percent of dogs receiving 60mg/kg orally will be ataxic and/or sedated. The use of a levetiracetam pulse treatment protocol has actually been suggested as an alternative to levetiracetam maintenance therapy in an attempt to reduce the tolerance that can be seen with this drug when used long term (Packer et al., 2015).
The oral route can be easily employed by owners at home. However, the postictal phase in epileptic patients can impair swallowing ability, preventing use of this route because of aspiration risk, thus delaying the initiation of treatment. For this reason, rectal delivery of this drug has been investigated and proven successful for CS in dogs when used at 40mg/kg (Cagnotti et al., 2018; Cagnotti et al., 2019). In the majority of cases, target plasma concentrations are reached after rapid absorption within 30 minutes after administration of the drug (Peters et al., 2014).