9 May 2023
Simona Radaelli
Job Title
Image: © Djomas / Adobe Stock
Seizure classification has been evolving over the years as technology has helped both visualising the manifestations at a larger scale and, consequently, the communication between practitioners and pet owners.
A seizure is a sudden, short-lasting, transient event. It can be of any nature, but often the term is used for epileptic seizures (the manifestation of an excessive synchronous, usually self-limiting activity of neurons in the brain).
Epilepsy is the tendency to have repeated seizures (at least two unprovoked epileptic seizures more than 24 hours apart).
The most common cause of seizures in dogs is idiopathic epilepsy (IE). Epilepsy is the most common neurological disorder in dogs: it is estimated that up to 0.75% of the dog population suffers from epilepsy.
A recent study on 19 dogs in Finland revealed altered trace element status in dogs diagnosed with IE and suggested that copper, selenium and chromium may be involved in the pathogenesis of seizures (Rosendahl et al, 2023).
Cortical dysplasia has been reported in two dogs and one cat as a cause of epilepsy. It is widely recognised in human medicine as a cause of seizures – often refractory to antiepileptic treatment and requiring surgical intervention.
Other causes can be divided into extracranial – as metabolic (hypoglycaemia/hyperglycaemia, liver disease, renal disease, altered electrolytes) and toxic diseases – and intracranial or structural, such as neoplasia (primary or secondary), vascular disease, inflammatory/infectious diseases, trauma and malformations.
The two main criteria for the diagnosis of epileptic seizures are:
IE is diagnosed by exclusion; it is based on the age at onset, normal inter-ictal physical and neurological examinations, and on exclusion of metabolic, toxic and structural cerebral disorders, through diagnostic investigations. The criteria for the diagnosis of IE have been grouped into three tiers of confidence levels.
Tier I includes age at onset (five months to six years), two or more unprovoked seizures at least 24 hours apart, normal inter-ictal physical and neurological examinations, and normal minimum data base (complete blood count, urinalysis and routine biochemistry, including fasting bile acids and/or ammonia).
Genetic testing can be performed in case a suspicion exists of disorders with known genetic mutation (for example, progressive myoclonic epilepsy in the miniature wire-haired Dachshund, benign familial juvenile epilepsy in the lagotto Romagnolo or L-2-hydroxyglutaric aciduria in the Staffordshire bull terrier).
Tier II includes the factors listed in Tier I, as well as normal fasting and postprandial bile acids, MRI of the brain and cerebrospinal fluid analysis (cell count and protein concentration).
MRI is the technique of choice due to its excellent soft tissue contrast and its ability to detect subtle lesions. However, CT can be useful for the identification of skull fractures secondary to head trauma, of acute intracranial haemorrhage, considerable size lesions associated with mass effect, or contrast-uptaking lesions.
Tier III includes factors listed in tier I and II, as well as the identification of ictal or inter-ictal electroencephalography (EEG) abnormalities characteristic for seizure disorders in human medicine. Unfortunately, no optimal protocol exists for EEG use in clinical veterinary practice.
Long-term seizure management seems to be most successful when therapy is started early – especially in dogs with a high seizure frequency and in breeds known to suffer from a severe form of epilepsy (such as the Australian shepherd dog, border collie, Italian spinone, German shepherd dog and Staffordshire bull terrier).
On average, 70% of epileptic dogs respond well to anti-epileptic drugs (AEDs). The aim is to reduce frequency and/or severity of the seizures, as a seizure-free status is very difficult to achieve.
Seizure control depends on several factors, including the breed of the animal, owner compliance and the correct dosage of AEDs (with serum levels within the therapeutic range). The choice of AED is based on the animal’s health, the type of seizures, AED-specific factors (including costs) and the owner’s compliance and lifestyle as, in many cases, the AED treatment has a potential lifelong duration.
Monotherapy is the initial goal when treating epilepsy, to reduce possible drug-to-drug interactions and adverse effects. Drugs such as phenobarbital and potassium bromide are broadly used; however, new drugs such as levetiracetam topiramate, felbamate gabapentin, pregabalin and zonisamide are becoming very popular as an add-on therapy in refractory cases, and/or to reduce the side effects of the other AEDs.
The main downsides of some of the newer drugs are their shorter half-lives (requiring more frequent administrations), reduced scientific data and costs.
Phenobarbital is the first drug of choice for patients with idiopathic epilepsy. Dosage is 3mg/kg orally twice daily. Serum levels should be tested two and six weeks after initial treatment, and then every six months or any time the seizure frequency increases. Serum concentrations can be checked at any time in the dosing cycle.
It is contraindicated in dogs with hepatic dysfunction, and liver function should be monitored every 6 to 12 months with a bile acid stimulation test. Common adverse effects include sedation, ataxia, polyphagia, polydipsia and polyuria.
Potassium bromide (KBr) is the second agent in patients that are already on phenobarbital, as it has a synergistic effect, or a drug of choice in patients with hepatic dysfunction.
The oral dose is 30mg/kg to 40mg/kg once daily (evening) or divided in twice-daily doses when used as an add-on. As a solo agent, the dose is 60mg/kg once daily or divided into twice-daily doses. It takes up to three months to reach the steady state; therefore, it is used more often in cases of low seizure frequency or as an add-on treatment.
Serum concentrations should be monitored one and three months after treatment initiation (or dose change), and then every six months.
Dogs should be maintained on a constant diet and chloride intake, to prevent fluctuations in serum KBr concentrations, which could cause therapeutic failure or toxicity.
Dose-dependent adverse effects of KBr include sedation, ataxia and pelvic limb weakness, polydipsia/polyuria and polyphagia.
It is not recommended in cats due to severe side effects (including fatal allergic bronchial disease).
Levetiracetam does not have liver metabolism; therefore, it is safe to use in animals with liver pathology, and it has few side effects. The initial oral dose is 20mg/kg three to four times daily.
Adverse effects are very rarely described in dogs, except for mild sedation, ataxia, decreased appetite and vomiting.
The dose of imepitoin is 10mg/kg to 20mg/kg orally twice daily.
In recent studies, the post-treatment seizure frequency was lower with phenobarbital than with imepitoin and side effects were less frequent than with phenobarbital. No serum level monitoring is required.
Imepitoin should not be used as a primary treatment for dogs with cluster seizures and status epilepticus. It can be used as a first line anti-epileptic drug in cases of primary epilepsy.
Gabapentin can be used as a sole agent for partial seizures or an add-on for generalised seizures. It is broadly used for the management of neuropathic pain. It is partially metabolised by the liver and is excreted renally.
Gabapentin has a short half-life of two to four hours. The dose range is 10mg/kg to 20mg/kg orally three times daily.
According to the International Veterinary Epilepsy Task Force consensus proposal on medical treatment of canine epilepsy in Europe (De Risio, 2015), insufficient evidence exists to recommend the use of topiramate in dogs.
In one study in dogs, the oral dose was titrated (2mg/kg to 1mg/kg) twice to three times daily.
At present, zonisamide is licensed for use in epileptic dogs only in Japan. According to the International Veterinary Epilepsy Task Force consensus proposal on medical treatment of canine epilepsy in Europe (De Risio, 2015), insufficient studies exist to recommend the use of zonisamide as monotherapy or an add-on AED. The recommended dose in dogs is 3mg/kg to 7mg/kg orally twice daily.
It is generally considered that patients that do not respond to two conventional AEDs (normally KBr and phenobarbital) or that suffer from severe side effects are called refractory.
In some cases, despite the use of multiple medications, seizure control is not achieved. Genetic factors play a role in refractory cases, but other controllable factors may also be involved.
Inadequate blood levels and inadequate dosage, as well as drug interaction/malabsorption, can be responsible for failure of seizure control.
Discontinuation of an AED is justified in the case of remission of seizures or life-threatening adverse effects. Remission has been reported in dogs with rates between 15% and 30%.
The decision to gradually taper the dose of an AED should be taken on an individual basis, in case of seizure freedom of at least one to two years.
In case of life-threatening adverse effects, immediate cessation of AED administration and 24-hour observation are necessary. Loading with an alternative AED should be initiated promptly.
Cluster seizures are a common neurological emergency, as they can lead to status epilepticus. Cluster seizures are defined as two or more seizures in 24 hours.
Rectal diazepam should be available to the owner for emergency treatment at home and administered after the second seizure in 24 hours. Application should be carefully discussed to avoid injury to the patient.
The recommended dose is 0.5mg/kg to 2mg/kg to a maximum of three applications within 24 hours. Rectal absorption (10 minutes) is faster than oral or IM injection, although the absorption rate can be variable.
In case of cluster seizures or status epilepticus, the recommended emergency anti-epilepsy protocol includes the use of benzodiazepines either as boluses (diazepam 0.5mg/kg IV or 2mg/kg intra-rectal, or midazolam 0.2mg/kg IV, IM or SC up to three times) or a constant rate infusion (CRI; diazepam 0.5mg/kg/hr or midazolam 0.2mg/kg/hr), together with a loading dose of phenobarbital, KBr or levetiracetam.
It is recommended to start AED treatment when:
In case of emergency treatment, in patients not on medication and with no known liver pathology, phenobarbital is the loading drug of choice.
The dose is 18mg/kg to 24mg/kg IV, IM or orally, divided in multiple doses within 24 to 48 hours. Serum concentrations can be measured one to three days after loading.
The loading dose of KBr is 125mg/kg/day, divided into three to four doses, for five days. The dog needs to be hospitalised.
After the five loading days, a daily maintenance dose can be started (20mg/kg to 40mg/kg) from day six. Serum levels should be monitored one month after loading.
A pulse protocol with levetiracetam can be used IV or orally. The dose is 60mg/kg once, followed by 20mg/kg three to four times daily until seizure free for 48 hours.
This protocol can be used also by the owners at home in case of patient with known cluster seizures. In case of poor response, a CRI with propofol is normally recommended. A recent study (Roynard et al, 2021) highlighted the use of ketamine instead of propofol, in refractory cases that do not respond to the use of benzodiazepines.
The dose is 5mg/kg IV, given once (author’s emphasis) as a bolus.
Some studies have reported genetic mutations associated with idiopathic epilepsy in the lagotto Romagnolo (focal, juvenile remitting epilepsy), Belgian shepherd dog and Rhodesian ridgeback (photosensitive myoclonic epilepsy), but the hypothesis is that epilepsy represents a complex disease with interaction of multiple genes and environmental factors. Studies are ongoing to prove a genetic predisposition in the border collie and Italian spinone (author’s note).
Lafora disease in the miniature wire-haired Dachshund belongs to the group of structural disorders, as the gene defect (mutation in the EPM2 gene) results in a storage disease that causes seizures and other neurological deficits.
Genetic testing to investigate pharmacoresistance to AEDs are also under way – especially in individuals that show resistance to most AEDs, raising the suspicion of a more complex cause than simple drug metabolism (for example, multi-drug transporter hypothesis and drug target hypothesis of pharmacoresistance).
A study has shown the benefit of a ketogenic medium-chain TAG diet (MCTD) as an adjunctive method in dogs on anti-epilepsy treatment. The MCTD resulted in a reduction in seizure frequency per month compared to the placebo-standardised diet (Law et al, 2015).
A commercial diet is now available, or medium-chain triglyceride oil can be added to the normal diet at 1 teaspoon/10kg bodyweight of the dog twice daily.
Vagal stimulation is used in humans that are refractory to AED treatment.
A pacemaker-like device, implanted subcutaneously, can be activated to stimulate the vagus nerve in the neck. This will stimulate the solitary nucleus and several cortical and subcortical areas to interfere with the seizure activity.
Vagal stimulation can be a treatment option for the future in refractory dogs, but further studies are required, and the device is still very expensive for veterinary use.
Surgery to resect the corpus callosum or focal cortical areas (seizure focus, identified by EEG) in refractory patients has been described in human medicine, but use in veterinary medicine still needs large-scale reports and standardised EEG protocols.
Acupuncture is based on the implantation of gold bead implants or acupuncture needles in specific locations (acupoints) to stimulate the nervous system. This practice is rarely used in veterinary medicine.
A seizure diary is very useful for monitoring the response to treatment. This should include dates, frequency, duration and description of the episodes. Once therapy is initiated, dates of dosage changes and blood monitoring should be added.
Manual recordings of seizures in epileptic patients, using apps specifically designed to track seizure activity and medication requirements, have been used since 2015. Accelerometers on specifically designed collar devices could help improve the monitoring of seizures also in absence of the owners, as well as video recordings, EEG or mattress sensors.
These methods have limitations and peer-reviewed studies to confirm their efficacy in veterinary medicine do not exist.
It is key that the clinician recognises, diagnoses and intervenes promptly when dealing with seizures, and that the owner’s education and compliance are given priority and value.
At present, several studies are ongoing to improve our understanding of the pathophysiology of seizures and of the potential genetic involvement in their occurrence and pharmacoresistance. The results of genetic studies could benefit breeding regulations through screening and prevention of diseases.
These studies should ultimately favour development of new therapeutic approaches targeted to each individual patient.
