ShapeShapeauthorShapecrossShapeShapeShapeGrouphamburgerhomeGroupmagnifyShapeShapeShapeShape
Distance
learning
New Distance Learning Programmes New programmes starting in 2021 Find out more

A guide to managing cluster seizures in the clinic and at home

Epileptic seizures are a common neurologic disorder in dogs with short- and long-term management challenges

09 July 2020, at 7:55am

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.

Prevalence

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).

Prognosis

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).

Treatment

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).

Content diagram
FIGURE (1) Overview of therapeutic options for cluster seizures in the veterinary clinic and in an at-home environment

Short-acting treatment at the time of a cluster event

Benzodiazepines

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

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).

Phenobarbital (PB)

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.

Oral clorazepate

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).

References
Author Year Title
Berendt, M., Farquhar, R., Mandigers, P., Pakozdy, A., Bhatti, S., De Risio, L., Fischer, A., Long, S., Matiasek, K., Muñana, K., Patterson, E., Penderis, J., Platt, S., Podell, M., Potschka, H., Pumarola, M., Rusbridge, C., Stein, V., Tipold, A. and Volk, H. 2015 International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals. BMC Veterinary Research, 11, 182
Cagnotti, G., Odore, R., Bertone, I., Corona, C., Dappiano, E., Gardini, G., Iulini, B., Bellino, C. and D'Angelo, A. 2019 Open‐label clinical trial of rectally administered levetiracetam as supplemental treatment in dogs with cluster seizures. Journal of Veterinary Internal Medicine, 33, 1714-1718
Cagnotti, G., Odore, R., Gardini, G., Amedeo, S., Bertone, I., Guerriero, G., Lentini, L., Dappiano, E. and D’Angelo, A. 2018 Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus. BMC Veterinary Research, 14, 189
Charalambous, M., Bhatti, S., Van Ham, L., Platt, S., Jeffery, N., Tipold, A., Siedenburg, J., Volk, H., Hasegawa, D., Gallucci, A., Gandini, G., Musteata, M., Ives, E. and Vanhaesebrouck, A. 2017 Intranasal midazolam versus rectal diazepam for the management of canine status epilepticus: a multicenter randomized parallel-group clinical trial. Journal of Veterinary Internal Medicine, 31, 1149-1158
Charalambous, M., Volk, H., Tipold, A., Erath, J., Huenerfauth, E., Gallucci, A., Gandini, G., Hasegawa, D., Pancotto, T., Rossmeisl, J., Platt, S., De Risio, L., Coates, J., Musteata, M., Tirrito, F., Cozzi, F., Porcarelli, L., Corlazzoli, D., Cappello, R., Vanhaesebrouck, A., Broeckx, B., Van Ham, L. and Bhatti, S. 2019 Comparison of intranasal versus intravenous midazolam for management of status epilepticus in dogs: A multi‐center randomized parallel group clinical study. Journal of Veterinary Internal Medicine, 33, 2709-2717
Hardy, B., Patterson, E., Cloyd, J., Hardy, R. and Leppik, I. 2012 Double-masked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs. Journal of Veterinary Internal Medicine, 26, 334-340
Hülsmeyer, V., Zimmermann, R., Brauer, C., Sauter-Louis, C. and Fischer, A. 2010 Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. Journal of Veterinary Internal Medicine, 24, 171-178
Kwiatkowska, M., Tipold, A., Huenerfauth, E. and Pomianowski, A. 2018 Clinical risk factors for early seizure recurrence in dogs hospitalized for seizure evaluation. Journal of Veterinary Internal Medicine, 32, 757-763
Monteiro, R., Adams, V., Keys, D. and Platt, S. 2012 Canine idiopathic epilepsy: prevalence, risk factors and outcome associated with cluster seizures and status epilepticus. Journal of Small Animal Practice, 53, 526-530
Packer, R., Nye, G., Porter, S. and Volk, H. 2015 Assessment into the usage of levetiracetam in a canine epilepsy clinic. BMC Veterinary Research, 11, 25
Packer, R., Shihab, N., Torres, B. and Volk, H. 2014 Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy. PLoS ONE, 9, e106026
Packer, R., Shihab, N., Torres, B. and Volk, H. 2016 Risk factors for cluster seizures in canine idiopathic epilepsy. Research in Veterinary Science, 105, 136-138
Pákozdy, Á., Leschnik, M., Sarchahi, A., Tichy, A. and Thalhammer, J. 2010 Clinical comparison of primary versus secondary epilepsy in 125 cats. Journal of Feline Medicine and Surgery, 12, 910-916
Patry, F. 1931 The relation of time of day, sleep, and other factors to the incidence of epileptic seizures. American Journal of Psychiatry, 87, 789-813
Patterson, E. 2014 Status epilepticus and cluster seizures. Veterinary Clinics of North America: Small Animal Practice, 44, 1103-1112
Peters, R., Schubert, T., Clemmons, R. and Vickroy, T. 2014 Levetiracetam rectal administration in healthy dogs. Journal of Veterinary Internal Medicine, 28, 504-509
Platt, S. R. 2014 Pathophysiology and management of cluster seizures. In: De Risio L. and Platt S. (eds.) Canine and feline epilepsy. Diagnosis and management. Cabi Publishing, pp. 503-518
Podell, M. 1995 The use of diazepam per rectum at home for the acute management of cluster seizures in dogs. Journal of Veterinary Internal Medicine, 9, 68-74
Podell, M., Smeak, D. and Lord, L. K. 1998 Diazepam used to control cluster seizures in dogs. Journal of Veterinary Internal Medicine, 12, 120-121
Probst, C., Thomas, W., Moyers, T., Martin, T. and Cox, S. 2013 Evaluation of plasma diazepam and nordiazepam concentrations following administration of diazepam intravenously or via suppository per rectum in dogs. American Journal of Veterinary Research, 74, 611-615

Simon R. Platt, BVM&S, Diplomate ACVIM (Neurology), Diplomate ECVN, FRCVS, qualified from the University of Edinburgh in 1992 and completed a residency in neurology and neurosurgery in 1998 at the University of Florida. Simon is currently a professor at the University of Georgia and an American, European and RCVS Recognised Specialist in Veterinary Neurology.

More from this author