By Simon R. Platt, BVM&S, Diplomate ACVIM (Neurology), Diplomate ECVN, FRCVS, RCVS & EBVS Recognized Specialist of Veterinary Neurology • PRN Pharmacal As practitioners, we are reminded that there is a vital need for more effective therapies and management strategies with approximately 30% of idiopathic epilepsy dogs being treatment-resistant to one or several antiepileptic medications.1 Refractory epilepsy refers to seizures that persist despite the use of at least two appropriate anti-seizure drugs (ASDs) at the correct doses. This condition, sometimes referred to as drug-resistant epilepsy can be frustrating for both the dog and its owner, significantly affecting the owner’s and animal’s quality of life. While it has been emphasized that partial therapeutic success with a reduction in seizure frequency, seizure severity, or reduction in the occurrence of seizure clusters or status epilepticus can be of relevance for canine patients and their owners, seizure freedom is the main aim of clinical management.2 The severe impact of drug-resistant epilepsy highlights the importance of aiming for complete seizure control in all dogs experiencing seizures. It's crucial to enhance our understanding of the reasons behind drug resistance and how they relate to various causes, progression of the disease, and affected breeds. Additionally, we need to focus on developing and evaluating new pharmaceutical and non-pharmaceutical treatment approaches, as well as combinations of these methods. (See Table 1 below: Refractory Epilepsy in Dogs: At a Glance Causes) Factor Key Point 1. Causes and Seizure Severity Certain breeds and high early seizure frequency can be a predictor of refractory epilepsy 3-9 2. Drug Tolerance or Resistance Drug resistance reflects failure of appropriately dosed ASDs to control seizures.3 Tolerance (“honeymoon effect”) has been reported with phenobarbital and levetiracetam, with phenobarbital inducing its own hepatic clearance over time.10,11 3. Pseudo resistance Apparent treatment failure may result from misdiagnosis, suboptimal drug or dose selection, or owner compliance. Only 1 in 5 owners achieve full compliance.12 4. Other Health Issues Metabolic disorders, organ dysfunction, and systemic infections can worsen seizure control; E. coli UTIs have been linked to seizure deterioration in dogs with idiopathic epilepsy.12 5. Drug Choice Certain epilepsy syndromes have different responses to drugs, emphasizing the importance of appropriate drug selection in refractory cases.3,13 Treatment Options for Refractory Epilepsy Dogs with refractory epilepsy require ongoing care, regular vet visits, and consistent medication monitoring. While seizures may not be completely eliminated, they can often be reduced to improve the dog’s quality of life. Keeping a detailed seizure log is imperative to fine-tune the treatment plan. While managing refractory epilepsy is challenging, there are several treatment strategies available. Adjusting Medication: The initial step in managing seizures in dogs often involves increasing the dosage, adjusting the dose frequency, or adding a second or third antiepileptic drug. Recent work has shown that increasing the frequency of phenobarbital from 2 to 3 times daily may be beneficial in some refractory dogs.11 Dietary Management and the Gut Microbiome: There is evidence that diets enriched with medium-chain triglycerides (MCT) have been shown to improve seizure control in dogs with epilepsy that is resistant to at least one anticonvulsant.14 The reasoning suggested for the benefit of MCTs include (i) providing energy to epileptogenic brain areas which can have impaired glucose metabolism; (ii) a direct anticonvulsant action being non-competitive AMPA receptor antagonists and (iii) microbiome modulation.15 Cannabidiol (CBD): The anticonvulsant effect of cannabidiol (CBD) has been confirmed by findings from animal models and human trials and has attracted the interest of veterinary practitioners and dog owners. Additionally, there is renewed awareness of cannabinoids, which have been used for epilepsy since ancient times, due to social media and public pressure. While research is still in its early stages, some studies have shown promising results in reducing seizure activity when used in conjunction with traditional anticonvulsants.18 Vagus Nerve Stimulation (VNS): If a dog with epilepsy does not respond to multiple anticonvulsants and dietary modifications, there are other non-pharmacological treatment options to consider. These include vagal nerve stimulation (VNS), deep brain stimulation, and transcranial magnetic stimulation. Some evidence suggests that individual dogs may benefit from these treatments, but more studies are needed to determine if they can improve long-term seizure control and if they are cost-effective. VNS involves surgically implanting a device that sends electrical impulses to the brain via the vagus nerve, which may help reduce seizure frequency19, although hand-held devices may also be successful.20 Acupuncture and Alternative Therapies: Some pet owners turn to holistic treatments like acupuncture, herbal supplements, or homeopathy. While the evidence supporting these treatments is limited, some dogs may benefit from these approaches. Potassium Bromide: Managing IE Seizure Control With or Without Combination Therapy Potassium bromide has been used as an anticonvulsant for over a century and is particularly effective in managing seizures in dogs. Its mechanism of action differs from that of phenobarbital, zonisamide and levetiracetam, making it an excellent candidate for combination therapy.21 Improved Seizure Control: For many dogs, phenobarbital alone may not completely control seizures, especially in refractory epilepsy. Adding potassium bromide to the treatment regimen can provide additional seizure control. Studies suggest that potassium bromide is effective in reducing seizure frequency in approximately 50-80% of dogs when used alongside phenobarbital22 Lower Phenobarbital Dosages: Phenobarbital is metabolized by the liver and can lead to hepatotoxicity in some dogs. By adding potassium bromide, veterinarians can often reduce the dosage of phenobarbital, decreasing the risk of liver damage while still maintaining adequate seizure control. Non-Hepatotoxic: Unlike phenobarbital, potassium bromide is primarily excreted by the kidneys, making it an attractive option for dogs that are prone to liver problems or already showing signs of liver damage. GettyImages/Gilaxia Administering Potassium Bromide to Dogs on Phenobarbital When transitioning a dog to a combined therapy of potassium bromide and phenobarbital, careful planning is essential to avoid complications and ensure optimal seizure control. Loading Dose vs. Maintenance Dose One of the most important considerations when starting potassium bromide is whether or not to administer a loading dose. Potassium bromide has a long half-life (up to 24 days in dogs), so it can take weeks or even months to reach steady-state levels when given at a standard maintenance dose. To accelerate this process, a loading dose may be used. Loading Dose: A high dose of potassium bromide given over several days to rapidly raise blood bromide levels to a therapeutic range. The loading dose (400-600mg/kg) is typically divided over 3 to 5 days to minimize gastrointestinal upset, which is a common side effect during this phase.23 Maintenance Dose: Once the loading phase is complete, potassium bromide is given at a dose to maintain therapeutic levels in the blood. This maintenance dose is usually administered once-daily.The recommended dosage of potassium bromide for dogs is generally in the range of 30-50 mg/kg/day when used as an adjunct to phenobarbital. The exact dose will depend on the individual dog's response and tolerance to the medication. Close monitoring of blood levels is required to adjust the dose and avoid toxicity. Monitoring Therapeutic Levels: Blood bromide levels should be measured periodically to ensure they remain within the therapeutic range, typically between 1.0 and 3.0 mg/mL. Monitoring should be done every few weeks initially and then every 3 to 6 months once stable. Adjusting Phenobarbital Dosage: After potassium bromide has been added and is hopefully effective in controlling seizures, the phenobarbital dosage may be tapered to minimize side effects. Reducing phenobarbital should be done gradually under veterinary supervision to avoid triggering rebound seizures. Monitoring and Long-Term Care The use of potassium bromide in combination with phenobarbital requires ongoing monitoring to ensure therapeutic effectiveness and avoid side effects. Key aspects of monitoring include: Regular Blood Tests: Blood levels of both potassium bromide and phenobarbital should be measured regularly to ensure they remain in the therapeutic range. Kidney and liver function tests are also recommended to monitor for any signs of organ damage and assess the need for dose changes. Maintaining a Stable Diet: Chloride and bromide compete for renal tubular reabsorption, with bromide being more readily reabsorbed and chloride more readily excreted. An increase in dietary chloride intake can enhance bromide renal elimination.24 Changes in chloride intake can occur with changes in dietary salt (sodium chloride) content, so it is advised to keep the diet stable by avoiding treats and table scraps. Seizure Diary: Owners should keep a detailed record of their dog’s seizures, noting frequency, duration, and severity. This information is invaluable for adjusting medication dosages and assessing the effectiveness of the treatment plan. A brand new seizure tracking and medication reminder app is now available to help owners with this task - https://www.petspieceofmind.com/. Behavioral and Physical Changes: Owners should watch for signs of sedation, lethargy, ataxia, or gastrointestinal distress and report them to the veterinarian. Adjusting the dosage or changing the treatment plan may be necessary if side effects become problematic. As part of patient monitoring, we should ensure that we focus on the pet’s quality of life (QoL). Idiopathic epilepsy significantly impacts the QoL of both canine patients and their owners, a consideration that becomes critically important in cases of refractory epilepsy. A systematic review by Pergande et al. identified key QoL determinants, including seizure frequency, severity, cluster activity, and anti-epileptic drug side effects.25 Owner-perceived QoL is equally vital; Wessmann et al. demonstrated a strong correlation between owner stress levels and their assessment of the dog's QoL, highlighting the bidirectional nature of the disease's impact.26 Furthermore, Chang et al. found that while ASDs like phenobarbital are effective, persistent side effects (sedation, ataxia) significantly detract from QoL, often necessitating therapeutic adjustments.27 In refractory cases where seizure control is elusive, these factors are amplified. Therefore, management must extend beyond seizure frequency to include meticulous assessment of ASD tolerability and proactive support for owner burden, as optimizing these domains is essential for preserving QoL when complete seizure freedom is not achievable. Dr. Simon Platt qualified from the University of Edinburgh, Scotland, in 1992. Dr. Platt was a professor of neurology and neurosurgery at the University of Georgia until 2022. Simon currently runs a neurology consulting and training company, co-leads the teleneurology team at VetOracle, and is the Medical Director for Hallmarq Advanced Veterinary Imaging and co-founder of Web-Vet Neurology Specialists (www.web-vetneurology.com). Dr. Platt has authored or co-authored over 250 journal articles and 70 book chapters and is the co-editor of Manual of Small Animal Neurological Emergencies. Currently, Simon also serves as Editor in Chief of the NAVC journal Today’s Veterinary Practice. Dr. Platt was made a fellow of the Royal College of Veterinary Surgeons in 2018 for meritorious contributions to the veterinary profession.
