Coughs of the brain: Seizure control in dogs with idiopathic epilepsy

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“Are the days of ‘Give two phenobarbital tablets and call me in the morning' over?” Fred Wininger, VMD, MS, DACVIM, asks the audience at one of his popular neurology sessions at Fetch dvm360 conference in San Diego. His answer: Not quite yet.

When it comes to managing seizures, veterinarians still rely on phenobarbital and potassium bromide in the majority of maintenance regimens for these dogs. But managing seizure disorders is a challenge, especially when a dog does not respond to standard phenobarbital or bromide therapy. According to Dr. Wininger, refractory cases account for 25% to 30% of all epileptics.

So what can veterinarians offer these patients? Better diagnostics and, more important, effective, safer anticonvulsants and easier-to-follow drug regimens.

A diagnosis of idiopathic epilepsy

According to Dr. Wininger, seizure disorders are common in dogs, affecting an estimated 1% of the pet dog population. Seizures are generally classified as structural, metabolic or idiopathic/heritable. Idiopathic epilepsy is by far the most common diagnosis. 

Age at the onset of seizures is an important piece of information in the patient history. Idiopathic epilepsy is usually seen in dogs between the ages of 1 and 6 years. Dr. Wininger says, “If you have a dog having seizures between the age of 1 and 6, 80% of the time it's going to be idiopathic epilepsy. If the dog is younger than 1 or older than 6, there's a 20% chance of it being idiopathic epilepsy.”

Drooling dog? That's a clue!

It's often difficult to distinguish whether a dog is presenting with a seizure rather than some sort of a movement disorder, vestibular syndrome, sleep disorder, narcolepsy or syncope. Dr. Wininger offers this tip: “One of my favorite questions to ask clients is, ‘Is your dog producing more saliva than usual?' If you see ptyalism, your confidence level that it's a seizure goes through the roof.”

Unlike what you may have learned in veterinary school, Dr. Wininger says that it is now known that dogs with idiopathic epilepsy can have violent, frequent seizures. Also, their seizures do not have to be generalized-they can be focal and can be asymmetric.

Dogs with idiopathic epilepsy also have normal interictal neurologic status. “If you have a dog between ages of 1 and 6, and it's normal in between seizures, it's appropriate to do some initial bloodwork (complete blood count and serum chemistry profile) and a bile acid stimulation test and treat them supportively. You don't have to do imaging and a spinal tap on those dogs unless they become unmanageable with anticonvulsants,” Dr. Wininger says.

However, he notes that it's always reasonable to offer a workup, potentially with imaging and a spinal fluid analysis, if the owner is interested. “We have certainly seen dogs with a presumptive diagnosis of idiopathic epilepsy surprise us with a structural brain lesion,” he says. If the dog is younger than 1 year or older than 6 years when it experiences its first seizure or if a dog between the ages of 1 and 6 has other neurologic deficits, he recommends an MRI and additional testing.

Dr. Wininger says that, when talking to his clients, “I describe seizures as ‘the cough of the brain.' They're just a clinical sign; they're not a disease. We want to get at the underlying cause.” If it's a dog that's 1 to 6 years old, it's likely idiopathic epilepsy, and there is no need to pursue other causes. However, he says, “If the dog is an outlier, we want to pick up on the cause of that cough-that seizure.”

If there's anything that would suggest that the epilepsy is not idiopathic, Dr. Wininger recommends conducting imaging right away. “If you wait for the dog to exhibit neurologic deficits, it's too late,” he says. “If you check after a seizure, before there are neurologic deficits, you're much more likely to be able to help the patient.”

The goals of therapy

With idiopathic cases, it's important to manage the expectations of pet owners. Dr. Wininger says when he talks to clients about choosing an anticonvulsant, he tells them that the goal of anticonvulsants is not to stop the seizures completely, but rather to suppress the frequency and severity of the seizures and minimize the postictal effects. Most epileptic dogs will never attain a seizure-free status. Instead, success should be considered as a reduction in the frequency and duration of the seizures. Dr. Wininger says that, of course, other goals are to limit unacceptable and serious side effects, minimize the client's financial burden, and boost the client's compliance with the treatment recommendations.

The client needs to understand that with anticonvulsant drugs, the ideal is to keep the drug in the therapeutic range, avoiding subtherapeutic and toxic ranges. “They need to know that the way to stay in that range is to give the dog the drug at a dose and frequency that enables the pet to keep the drug in its bloodstream at a steady state, so that they're not dipping or peaking outside of that range,” says Dr. Wininger.

When does Dr. Wininger initiate therapy after a dog's first seizure? “I will usually wait until after the second or third seizure to initiate therapy,” he says. “If the seizures are more than six months apart, I will usually wait then too. The goal in treating idiopathic epilepsy is one seizure no more than every three months. If you're already there without anticonvulsants, anticonvulsants may not get you much better.” He says most neurologists concur with waiting until animals are having a seizure more frequently than every three months. Exceptions to this are if the dog's first seizure was a status epilepticus event or if the dog is an at-risk breed (like a border collie or Australian shepherd). “I don't wait on those dogs,” Dr. Wininger says. “I'll be more aggressive.”

Dr. Wininger says the client being unable to handle the pet having seizures can influence treatment decisions as well: “With initial anticonvulsant therapy, we're always shooting for monotherapy, but we have to recognize that some dogs just aren't going to be managed with a single drug.”

Utilizing levetiracetam

As mentioned, the tried and true anticonvulsant drugs remain phenobarbital and, after that, potassium bromide. But what else is available? Table 1 contains a summary of the most commonly used anticonvulsants in dogs.

Table 1. Anticonvulsant drugs commonly used to manage idiopathic epilepsy in dogs

Drug Dosage Blood levels

Half-life

Mechanism of action (MOA) Metabolism/excretion Side effects Phenobarbital 3 mg/kg orally b.i.d. starting dose, adjusted based on serum drug levels and clinical assessment

Evaluate 14 days post-dose and make adjustments based on therapeutic range and clinical response

Therapeutic range: 20-40 mg/dl

24 to 40 hours

Primary MOA: decreasing seizure onset via enhanced GABA-activated chloride conductance

Secondary MOA: decreasing seizure spread via reduced current through calcium channels and reduced glutamate-mediated excitation

Majority metabolized by the liver, with 1/3 excreted unchanged in the urine

Phenobarbital will induce hepatic microsomal enzymes (P450 enzymes) and it can be expected that elimination half-lives will decrease with time with concomitant reductions in serum levels

Hyperexcitability, restlessness, sedation in the first weeks; immune-mediated neutropenia, thrombocytopenia or anemia (reversible, occurs in first 6 months); rare idiosyncratic hepatic reactions with rapid elevation in ALT and abnormal bile acids-In such cases, phenobarbital should be stopped immediately and another drug started

With chronic dosing, polyuria/polydipsia is common and psychogenic polydipsia may develop; most common serum biochemical change is elevated alkaline phosphatase

Bromide

40 to 60 mg/kg orally once a day

Measure 8 to 12 weeks after initiating treatment

Monotherapy: 1,000-3,000 mg/L

With phenobarbital: 1,500-2,500 mg/L

20 to 46 days

Primary MOA: decreasing seizure onset via enhanced GABA-activated chloride conductance

Principally excreted by kidneys

Polyuria/polydipsia, lethargy and mild ataxia; pancreatitis and gastrointestinal intolerance reported, but infrequent

Levetiracetam

20 mg/kg orally t.i.d.

Extended release formulation: 30 mg/kg b.i.d.* Not typically performed because dose-efficacy ratio not direct

3 to 4 hours

Extended release formulation: 4.5-5 hours*

Binding with a specific synaptic vesicle protein (SV2A) in the brain

No direct effect on common neurotransmitter pathways (e.g. GABA, NMDA) or ion channels (e.g. sodium, T-type calcium)

70% excreted in urine, minimal hepatic metabolism

Lethal dose is 100x recommended dose; dosing can be increased several-fold to increase efficacy; no side effects of note

Zonisamide

5 to 10 mg/kg orally b.i.d.

Zonisamide levels can be evaluated at Auburn University; aim for 20 µg/ml (10-40 µg/ml); stable plasma concentrations achieved within 3 to 4 days

15 to 20 hours

Primary MOA: decreasing seizure spread via reduced current through calcium channels

Secondary MOA: decreasing seizure onset via enhanced sodium channel inactivation

Most excreted via the kidneys into urine; about 20% metabolized, primarily in liver

Sedation, dry eye, ataxia, inappetence and vomiting; do not give to patients with a history of sulfa drug hypersensitivity; metabolic acidosis and liver dysfunction have been reported

Topiramate

5 to 10 mg/kg orally b.i.d.

Not established at this time

2 to 4 hours

Decreasing seizure onset via both enhanced sodium channel inactivation and enhanced GABA-activated chloride conductance; decreasing seizure spread via reduced glutamate-mediated excitation

Low rate of hepatic metabolism; both unchanged topiramate and its metabolites are excreted mainly by kidneys

Sedation and weight loss; some recent studies showed elevated liver enzymes, but these patients were also receiving phenobarbital, so it's unknown if liver elevations were secondary to phenobarbital or topiramate

Gabapentin 15 mg/kg orally t.i.d. or q.i.d. Suspected blood levels are 4 to 16 mg/L; because of questionable anticonvulsant efficacy, Dr. Wininger rarely measures blood levels

3 to 4 hours

Binding to the α2δ subunit of voltage-gated neuronal calcium channels

This binding decreases intracellular calcium influx, leading to decreased synaptic release of excitatory neurotransmitters

Urine excretion; hepatic metabolism: 30% to 40% of oral dose undergoes hepatic metabolism to N-methyl-gabapentin

Sedation Pregabalin (Lyrica)

2 to 4 mg/kg orally b.i.d.

Therapeutic range: 2.8 to 7.3 µg/ml**

7 hours (11 hours in cats)

Same as gabapentin Suspected to be similar to gabapentin based on structural similarities Sedation; ataxia; possible gastrointestinal signs Felbamate

15 to 20 mg/kg orally t.i.d., with dose escalation permissible

Dr. Wininger has not performed drug levels

5 to 6 hours

Positive modulator of GABAA receptors; possible NMDA antagonist of the MR2B subunit

70% excreted in urine; remainder hepatic metabolism

Possible hepatotoxicity, blood dyscrasia and keratoconjunctivitis sicca; side effects can be severe

*Beasley MJ, Boothe DM. Disposition of extended release levetiracetam in normal healthy dogs after single oral dosing. J Vet Int Med 2015; 29(5):1348-1353.

**Bichsel P, Lyman R. A newer-generation drug to treat canine idiopathic epilepsy. 2010. Available at dvm360.com/newer-generation-drug-treat-canine-idiopathic-epilepsy

Dr. Wininger says the main secondary anticonvulsant-which is actually becoming a trusted first-line drug-is levetiracetam. “The amazing thing about levetiracetam, as opposed to phenobarbital and bromide, which are pro-inhibitory, is that it is anti-excitatory,” he says. “It affects the glutamate cells' ability to release their neurotransmitters. That's why it is less sedating and has an awesome therapeutic range. You can give the drug at well over 10 times the normal dose, and the only side effect you're likely to see is sedation. It's a very safe drug.”

Levetiracetam is available in injectable, liquid and tablet formulations, and now it is available in an extended-release formulation. Aside from sedation, there are no commonly reported side effects. Also, it's relatively affordable, doesn't require monitoring, and decreases kindling (the phenomenon in which a seizure increases the likelihood that more seizures will occur). It has minimal hepatic metabolism as well. “It's pretty much unnecessary to check blood levels because you just keep increasing the dose until it stops working, or it gets too expensive,” Dr. Wininger says. “It's great for animals that have suffered liver toxicosis but still require an anticonvulsant and can't be on phenobarbital. And it's great for portosystemic shunt cases that develop status epilepticus.”

Fact or fiction? Levetiracetam is an ineffectual solitary agent. Fiction, says Dr. Wininger. He says neurologists used to tell people that levetiracetam really didn't work well on its own. However, there's now a lot of evidence suggesting that it does.1,2 A study of 19 dogs published in 2017 showed that when levetiracetam was used as a monotherapy, it was as effective as the standard of care as phenobarbital.3 So, Dr. Wininger says, if you reach for levetiracetam as a first-line anticonvulsant, “you're not alone, and it's not a wrong thing to do.”

Fact or fiction? Levetiracetam has a frequent honeymoon effect. Dr. Wininger says this is also fiction. It used to be said that levetiracetam would work well for three to six months, and then its efficacy would decline. However, Dr. Wininger says, the evidence has not proven this concern true. “Some dogs will have a decreased response to the current dosing, but it's probably because of disease progression. If you provide them with a dose escalation, levetiracetam will often work well.”

Dr. Wininger does not usually use levetiracetam as a first-line agent, but there are certain dogs for which he makes an exception. For example, he will use it in dogs that have other neurologic deficits, often because they have postictal changes. He will also use levetiracetam in a geriatric dog that has a seizure and there's a possibility that it has a brain tumor. “If I have any suspicion that a dog is not an idiopathic epileptic, but it could be, levetiracetam is great,” says Dr. Wininger. “If you put a dog that might have a brain tumor on phenobarbital and it gets dopey, you have to wonder, is it the disease process causing it, or is it the drug? I really like levetiracetam in cases where I'm not confident of my diagnosis of idiopathic epilepsy.”

Fact or fiction? Levetiracetam has to be given exactly every eight hours. Dr. Wininger says this is no longer true.4 It used to be that three-times-a-day dosing was a real problem for some clients. Administering a medication three times a day can be a daunting task and significantly reduces client compliance. However, an extended-release formulation of levetiracetam is now available. Dr. Wininger uses this formulation on almost all of his patients receiving levetiracetam. He says that in some dogs you can even administer a single daily dose of the extended-release formulation. “You can even put a toy-breed dog on an extended-release tablet two times a day,” says Dr. Wininger. “You know it's going to be over the recommended dose, but the literature suggests it's going to be OK. Use the extended-release formulation. It's much easier to manage.”

Fact or fiction? Levetiracetam has little hepatic metabolism and the levels are unaffected by phenobarbital. According to Dr. Wininger, this is also not true. “There is some hepatic metabolism of levetiracetam,” he says, “and if you have a dog concurrently on phenobarbital, you may need to bump up the dose of levetiracetam a little bit more. The numbers suggest you'll need to increase the levetiracetam dose by 25% if the dog is on phenobarbital.”

Other pharmaceutical and nutritional treatments

Zonisamide. About the same time as levetiracetam became available, zonisamide also came to market. It was used as a second-line anticonvulsant, favored over levetiracetam because it required twice-daily dosing. “I find zonisamide to be a mediocre anticonvulsant at best. Now that the extended-release formulation allows twice-daily dosing of levetiracetam, zonisamide has lost favor. The drug is just not as effective, and there is a paucity of literature to support its use.”5,6

Can cannabinoids control seizures in dogs?

Dr. Wininger gets asked about cannabinoids a lot. He says they contain interesting low-molecular-weight compounds that are similar to eicosanoids, which are precursors to prostaglandins and leukotrienes. A 2003 paper was the start of the idea that cannabis could work as an antiepileptic.1 Children with temporal lobe epilepsy were given cannabis, and their seizure frequency dropped by 50%. When cannabidiol (CBD) was studied in rats using histochemistry, normal rats didn't have many CBD receptors, but epileptic rats did. Dr. Wininger says, “So the more seizures you had, supposedly the more responsive you would become to marijuana or CBD.”

So why not use CBD oil in dogs with seizures? Dr. Wininger can list at least three reasons:

1) We don't know who's creating the CBD oils or what is in them. It's completely unregulated.

2) We don't know anything about drug interactions with the current anticonvulsants.

3) We don't have any pharmacokinetic data in dogs and no method of monitoring it.

“You're giving this oil, but you don't know how much you're giving, and you don't know frequently you should be giving it. There are all these things we don't know, which gives us reservation,” says Dr. Wininger. Since the time of this presentation, there have been continued manuscripts published supporting the mechanism and efficacy of cannabinoids. They will likely become increasingly common in the veterinary world.

Dr. Wininger has used CBD oil in some dogs, especially if the dog did not respond to all the other anticonvulsants or the NeuroCare diet and the client is contemplating euthanizing the dog, and he has seen a reduction in seizure frequency. “Placebo effect? Maybe,” says Dr. Wininger, “but perhaps there's value in cannabinoids. We just don't know yet.”

Reference

1. Stockings E, Zagic D, Weier M, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 2018. Epub ahead of print.

Topiramate. “The drug I reach for if phenobarbital, bromide and levetiracetam fail is no longer zonisamide. My new drug of choice? Topiramate,” says Dr. Wininger. Research has shown that topiramate decreases seizure onset and decreases seizure spread.7 The drug also has minimal side effects. The problem is that its half-life is only two to four hours. Theoretically, this drug should be given every four to six hours, which is very difficult for clients to achieve. Instead, Dr. Wininger recommends a dose of 5 to 10 mg/kg by mouth two or three times a day. He adds, “The drug is relatively new and its efficacy outside of case experience is poorly documented.”

Gabapentin and pregabalin. Another drug that has been used as an anticonvulsant is gabapentin. It was primarily created as an analgesic for people with fibromyalgia, but it was discovered that the fibromyalgia patients who also had seizures had fewer seizures. This led veterinarians to try it as an anticonvulsant in dogs and cats. “I've used it as a third-line agent,” says Dr. Wininger. "For those of us who've tried gabapentin as a primary anticonvulsant, it has a very poor response rate. If you have a dog that's getting gabapentin as an analgesic, maybe you'll get some antiseizure effects out of it, but it's not that effective.”

A drug similar to gabapentin that Dr. Wininger has found to have more significant anticonvulsant effects is pregabalin (Lyrica-Pfizer). However, Dr. Wininger says, “Though it's an excellent anxiolytic, it's not confirmed as the best anticonvulsant, and it's currently extremely expensive.”

Felbamate. Felbamate is frequently used in human medicine, but it's fallen out of favor in veterinary medicine. “The reason it's not used in veterinary medicine is it causes hepatotoxicity and blood dyscrasias,” says Dr. Wininger. “When these side effects happen, they are bad enough that I don't know any [veterinary] neurologists who use felbamate any longer.”

Imepitoin. You won't see the drug imepitoin (Pexion-Boehringer Ingelheim) listed in Table 1. Dr. Wininger says he has no familiarity with the drug except what he's read. It's been used in Europe for more than 15 years, and there's a lot of evidence supporting its use as an anticonvulsant. It's a partial benzodiazepine that is less sedating than the full agonists like diazepam, has less risk of tolerance than diazepam, is less effective but more easily tolerated than phenobarbital, and has some partial calcium-channel-blocking effects. It was recently approved for use in dogs as model for human epilepsy. “Hopefully, in the next few years, we'll have access to imepitoin [in the United States], and there is already a body of evidence to support its efficacy,” says Dr. Wininger.

NeuroCare Diet. Dr. Wininger is routinely asked about the Purina ProPlan Veterinary Diet NC NeuroCare Canine Formula. “[The diet] is in line with the theory that ketogenic diets can decrease seizure frequency in people,” he says. A recent report suggested there was a 50% decrease in seizure frequency in 50% of the dogs given the food.8 However, there've been studies of ketogenic diets in the veterinary literature that showed no evidence to suggest that these diets helped these animals.9

“So, if a dog is presenting with seizures for the first time, and if it's not severely affected, perhaps you can give the NeuroCare instead of starting the dog on phenobarbital or potassium bromide,” Dr. Wininger says. He personally has not seen the diet work in any of the dogs he's fed it to, but he sees the worst cases-much worse than general practitioners typically see. Nevertheless, he says, “I would encourage you to try it. It's nutritionally sound. But as to whether this diet is going to stop seizures, the jury's still out.”

A new therapeutic algorithm

Dr. Wininger says that the old algorithm recommended starting with monotherapy: “Pick phenobarbital. Pick bromide. If that doesn't work, go to polytherapy, adding on a second-line agent. But everything's been turned on its head now with levetiracetam.” He says levetiracetam may replace phenobarbital, but the two drugs have different mechanisms of action and can thus work well together. “You have a pro-inhibitory drug and an anti-excitatory drug. I think it makes sense to use them in concert,” he says.

As researchers continue to explore pharmaceutical, surgical, nutritional and alternative therapies, the options should continue to grow to manage “the cough of the brain” in your veterinary patients.

References

Fredsø N, Sabers A, Toft N, et al. A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy. Vet J 2016;208:44-49.

Packer RM, Nye G, Porter SE, et al. Assessment into the usage of levetiracetam in a canine epilepsy clinic. BMC Vet Res 2015;11:25.

Kelly D, Raimondi F, Shihab N. Levetiracetam monotherapy for treatment of structural epilepsy in dogs: 19 cases (2010-2015). Vet Rec 2017;181(15):401.

Beasely MJ, Boothe DM. Disposition of extended release levetiracetam in normal healthy dogs after single oral dosing. J Vet Intern Med 2015;29(5):1348-1353.

Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy-a systematic review. BMC Vet Res 2014;10:257.

Potschka H, Fischer A, Löscher W, et al. International veterinary epilepsy task force consensus proposal: outcome of therapeutic interventions in canine and feline epilepsy. BMC Vet Res 2015;11:177.

Kiviranta AM, Laitinen-Vapaavuori O, Hielm-Björkman A, et al. Topiramate as an add-on antiepileptic drug in treating refractory canine idiopathic epilepsy. J Small Anim Pract 2013;54(10)512-520.

Law TH, Davies ES, Pan Y, et al. A randomised trial of a medium-chain TAG diet as treatment for dogs with idiopathic epilepsy. Br J Nutr 2015;114(9):1438-1447.

Muñana KR, Zhang D, Patterson EE. Placebo effect in canine epilepsy trials. J Vet InternMed 2010;24(1):166-170.