BREAKING NEWS: Phenobarbital causes side effects in cats!

Phenobarbital and Cats

It comes as no surprise that I'm a super fan of phenobarbital for seizure control in cats. My research at the University of Wisconsin started with the development of a novel transdermal phenobarbital product, and it ended (so far) with a novel oral formulation (not published yet). Phenobarbital works WELL and for many cats. But, it still has some misconceptions which I'll enumerate below.

Misconception.... TRUTH

1) Phenobarbital causes elevated ALP enzymes in cats.....IT DOES NOT. There was one study that reported a few elevations but NONE of the 77 cats in a recent study, nor any of the cats in a prior study my resident and I conducted had elevated ALP enzymes. Elevated ALP is a dog thing!

2) Phenobarbital does not have observable side effects....FALSE! Side effects occur in 46.7%of cats (Marsh et al). Sedation and ataxia were the most common side effects, but not the only ones.
Here are the side effects (called Type A adverse events), and percent of cats affected, as reported in Marsh's study:
a. Sedation 89%
b. Ataxia 53%
c.Polyphagia 22%
d. Polydipsia 6%
e. Polyuria 6%
f. Anorexia 6%
** Perhaps the last 4 are only notable to the observant owner, or in single cat households. Also of note, side effects in cats are reported less often compared with dogs.
Type B adverse events were extremely rare in the recent study, as well as in my experience. Bone marrow suppression did occur in 1 cat (as can be seen with dogs) and it resolved with removal of the phenobarbital. Lymphadenopathy has been linked to phenobarbital use as well.

3) Phenobarbital side effects happen randomly...FALSE! They are dose dependent and predictable. Higher serum concentrations (above 35 ug/ml) result in a higher odds ratio of developing a side effect. Additionally, 20 of the 36 cats in the study by Marsh had transient signs. The majority of side effects only occured in the first 4 weeks of treatment. This is a terrific point to make when discussing the use of this drug with clients.

What is the Take Away Message?

1) Start phenobarbital at a dosage targeted to reach 20-30 ug/ml. This typically means about 3 mg/kg (or a bit less) q12h.The goal is seizure control without concerning side effects.

2) Counsel clients that side effects occur in about 1/2 of cats, and of those, the majority occur within the first 4 weeks of administration AND resolve without any dose adjustments. If side effects are present beyond 4 weeks, consider a dose reduction.

Thanks for your business, especially in these unusual times. I truly enjoy working with you, and your staff. Please stay safe, stay healthy, and keep those consults coming!

*Marsh O, Corsini G, Van Dijk J, Gutierrez-Quintana R, De Risio L. Prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats. Journal of Feline Medicine and Surgery. June 2020. doi:10.1177/1098612X20924925

*Finnerty K, Barnes Heller H, Mercier M, et al. Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004 -2013). JAVMA 2014: 244(2):195-199.

Midazolam vs. Diazepam...Which Drug is Better for At-Home Cluster Care?

Midazolam vs. Diazepam for At Home Seizure Care

History of Cluster Buster Protocols

In 1995 Dr. Michael Podell championed the idea of at-home, rectal diazepam use for canine cluster seizures. In that study, dogs that received rectal diazepam had fewer  cluster seizures compared to those that didn't receive the drug. Since then, at home cluster care has become standard practice for many veterinarians. 
According to human literature, benzodiazepine drugs (midazolam, diazepam and lorazepam) are the "best" first line anticonvulsant drugs to stop status epilepticus. As is typical, we simply adopted this idea in veterinary medicine without data to support it's use. But...the benzodiazepine drugs do show improved seizure cessation so...they probably help in some manner. 

Which Benzodiazepine is Better?

Here is where the science gets a bit muddy. We've compared rectal diazepam to intranasal midazolam and intranasal midazolam was superior. We've compared intranasal midazolam to intravenous midazolam and intranasal midazolam stopped seizures faster. However, all of these studies involved few animals and ethically we cannot have a group of untreated animals to determine true efficacy. 

What are the current recommendations?

At this time, intranasal midazolam at a dose of 0.2 mg/kg up to 3 times in 24 hours is my recommendation for dogs with a cluster or status epilepticus history. Do your best to use a nasal atomizer because this has been shown to be the superior technique compared to nasal-drop application.  (I have found them at Midwest Vet:https://www.midwestvetsupply.com/products). Essentially nasal drop technique requires the client to drip the midazolam intranasal slowly during the active seizure while also avoiding getting bitten. The atomizer looks like a marshmallow that is attached to the end of the syringe and the client is then able to press the atomizer against the nare and dispense the dose in one "push". Not clear on this technique? Please ask me, I am happy to clarify! I do not have a financial incentive or disclosure for this product, or Midwest Vet Supply. :)

Hope you enjoyed the glorious weather a bit last week. I will be closed Friday October 16th, Saturday the 17th and Tuesday the 20th as we celebrate a collection of birthdays in my family. (Including mine!) 

Have a good week! 

Do Cats Have Seizures?

Do Cats Have Seizures?

You might be thinking "Has she lost her mind? Of course cats have seizures!" Naturally, we know this to be true (or half of my research is for nothing...eek!) A recent article published in the Journal of Veterinary Internal Medicine looked at a population of cats in the UK in the year 2013 to answer some  questions about feline epilepsy. I have bulleted them below for ease of reading however this is an open access article so feel free to pull the entire article if you would like to know more!

The study aims: "To estimate the prevalence of recurrent seizure disorders (RSD) and epilepsy in the wider cat population under primary veterinary care int he UK and to evaluate demographic risk factors for their occurrence. A secondary aim was to explore risk factors associated with the diagnosis of epilepsy among the subset of cats."

• 1-year prevalence (2013) for recurrent seizure disorders (not called epilepsy): 0.16%

• 1-year prevalence for epilepsy: 0.04%

* Note these are lower than the listed prevalence for referral institutions (and mobile veterinary neurologists) for the obvious reason that referral hospitals have a different caseload!

Diagnosing epilepsy in cats is not defined, as it is in dogs, by the International Veterinary Epilepsy Task Force (IVETF). Many neurologists, myself included, extrapolate from the IVETF recommendations but also realize the limitations in data for cats.
The IVETF recommendations for dogs to diagnose epilepsy (Tier 1 - aka without diagnostic testing) are:

• two or more seizures, at least 24 hours apart

• Age 6 months - 6 years old

• Normal (unremarkable) neurologic examination inter-ictal

• No clinical abnormalities on CBC, serum biochemisry, urinalysis

A diagnosis of epilepsy was made in this study in 24.89% of the cats with recurrent seizure disorders. There was a disturbing sentence that I quote "It is conceivable that general veterinary practitioners may feel reluctant to formally diagnose epilepsy or idiopathic epilepsy in cats because of a combination of factors, including their limited confidence in performing a complete neurological examination in cats, the longstanding traditional belief that cats do not commonly have idiopathic epilepsy, and a believe that access to advanced imaging is essential to exclude other causes."  This sentence is the reason I chose this article for our TidBit Tuesday this week. First, if you're not diagnosing a cat with epilepsy (and presumable starting appropriate care or recommending appropriate testing) because of a lack of confidence in the exam, know that you are not alone! Please call me for a neurologic examination with your feline patient - I too understand the limitations of cats in assisting with their own health care. (To put it mildly.) Let's not let a lack of confidence in the examination block us from doing what is right by the pet. Secondly, idiopathic epilepsy does occur and in this study it was almost 1/4 of the cases of recurrent seizures (if they diagnosed it correctly, of course). It has been reported that up to 12% of cats can have a normal neurologic examination and have structural disease, but that shouldn't stop us from attempting appropriate treatment. Please, let's remove this thought from our practices. Finally, you do NOT need access to advanced imaging to make a presumptive diagnosis of idiopathic epilepsy. The Tier I recommendations were designed expressly to meet the needs of making this diagnosis (in dogs) without MRI or spinal tap. Whew...okay, back on track. 

Following multivariate analysis, the only variable that stood out as a risk factor for a diagnosis of epilepsy was age. Cats 3-6 years of age had a 3.32 times higher odds of developing epilepsy then cats less than 3 years of age.

Insurance was also a risk factor but that doesn't apply to the majority of the pets that I interact with so I have left that portion of the study out. Breed and sex were not associated risk factors. 

*O'Neill, DG, Phillipps, SA, Egan, JR, Brodbelt, D, Church, DB, Volk, HA. Epidemiology of recurrent seizure disorders and epilepsy in cats under primary veterinary care in the United Kingdom. J Vet Intern Med. 2020; 1– 13. https://doi.org/10.1111/jvim.15881

I hope you are doing well and staying safe. I appreciate what you do to help clients and their pets. Let me know how I can help you manage your patients with neurologic disease.

On site consultation is available Monday through Saturday at variable times throughout the week. Email consults are completed in evenings. 

Have a good week! 

CBD oil and Canine Epilepsy

What is the Effect of CBD oil on Canine Seizures?

Yes, I'm opening a proverbial can of worms today! As a neurologist, vets often ask me if CBD can be used as an anti-epileptic drug (AED). As a practicing veterinarian in Wisconsin I say I cannot recommend or prescribe CBD containing products.

As a neurologist, I add the following…

In June 2019 a study was published that attempted to answer the question:
“What effect does CBD oil have on seizure control?”1
 According to the authors:

• CBD is metabolized through the cytochrome system in the liver in humans, and probably dogs. The ALP increased in all dogs receiving CBD oil in that study. What is the clinical significance? Unknown, currently.

• There was no difference in seizure response between the CBD group or the placebo group (Response = dogs that had a 50% or greater reduction in seizures during the 12-week observation period.) Do we need a different dose? Different formulation? Or did it simply not work for this group of dogs?

• Drugs that are metabolized through the liver (e.g. phenobarbital, zonisamide) may be affected by CBD. This means that the adverse clinical effects could be more pronounced in dogs concurrently receiving these drugs.

• What adverse clinical effects does CBD have? We don't know yet. Several dogs in the CBD group developed ataxia, however they were concurrently on other anti-epileptic drugs. Was the ataxia due to CBD, or because of increased serum concentrations of concurrent AED?

So, although my response to clients remains that I don’t recommend it. My reasoning includes all of the reasons listed above in addition to the recommendations by the government officials in Wisconsin.

What if a client wants to give it anyway? As a veterinarian, I would thoroughly document the discussion, and then recommend monitoring at least liver values (ideally the entire biochemistry panel) every 4-6 months while the pet receives the product. It may be that CBD is the magical seizure potion we are searching for to help our drug-resistant seizure patients. However, history would tell us that the newest “catch all” tonic is typically not as universally perfect as we wish it to be. Be educated, be careful, and be observant when we walk into this yet uncharted territory of CBD oil and seizures.

1. McGrath S. et al Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. JAVMA 2019; 254(11): 1301-1308.

 Are you working with a patient with seizures and need some expert help? I'd love to! Please reach out via email, telephone or schedule an appointment online.

Microbiome and Epilepsy

Microbiotia-Gut-Brain axis...say what?

There has been growing evidence in human, and veterinary, medicine to suggest that what is in the gut can influence brain development, function and even the course of disease. Many clients have a firm belief that food plays a role in a dog's epilepsy however it has been less clear to me what this role may be. Is it the gluten in the diet (as with some Border Terriers)? Or, is it the microbiome? Maybe both? Maybe neither?

Lactobacilli and the Influence on the Brain

Research suggests that Lactobacillus sp. can play a role on brain function in humans through it's anti-inflammatory properties and perhaps through the production of GABA, an inhibitory neurotransmitter. What about dogs with epilepsy? Dr. Karen Munana investigated Lactobacilli in fecal samples of dogs with epilepsy and compared them to fecal samples of dogs without epilepsy. (See reference below)

No difference in absolute ore relative numbers of Lactobacillus species were found in drug-free epileptic dogs compared to healthy dogs. Furthermore, Lactobacilli were not killed in culture when exposed to phenobarbital, potassium bromide, zonisamide and levetiracetam. 

For now, this means we don't see a difference in this important bacterial species. This DOESN'T mean that we may not find a difference in the future, and it DOES NOT mean that gut health isn't linked to canine epilepsy. I will keep my ear to the ground on this one and keep you posted on any breaking news on GI health-brain health linking.

Stay safe, stay healthy, and keep me posted on how I can help you, help your patients with neurologic disease!

*Muñana KR, Jacob ME, Callahan BJ. Evaluation of fecal Lactobacillus populations in dogs with idiopathic epilepsy: a pilot study. Anim Microbiome. 2020;2(1):19. 

What drug, route and dose should you use for at home acute seizure management?

I hope you had a wonderful and safe 1st and 4th of July (my American and Canadian friends)! Enjoy this week's TidBit Tuesday...

What drug, route and dose do you use for at home acute seizure management?

For most of us, benzodiazepine drugs (diazepam, midazolam, lorazepam) are our first choice drugs for acute seizure cessation.

Not all benzodiazepine drugs are equal!
What routes can you give the drugs? What routes shouldn’t you give the drugs?

Benzodiazepine drugs were introduced in the 1960s for human status epilepticus. A 2015 human meta-analysis identified that benzodiazepines are the “best” first line IV drugs. To date, there have not been any veterinary studies identifying which drug is ‘best’ for acute seizure management. We’ve just always used benzodiazepines so we continue to do so. Furthermore, limited data regarding efficacy is available for veterinary patients. So, what do we know?? The table below outlines the approved routes for each of the common benzodiazepine drugs. This should be printable. 

DiazepamSafe for dogs ☒Safe for cats ☒            Okay if given:IV ☒IM ☐ Not recommended!Rectal ☒  Preferred drug!Intranasal ☒MidazolamSafe for dogs ☒Safe for cats ☒            Okay if given:IV ☒IM ☒Rectal ☐ (nope).Intranasal ☒  Preferred drug!LorazepamSafe for dogs ☒Safe for cats ☒            Okay if given:IV ☒IM ☐ No dataRectal ☐ Nope, not absorbedIntranasal ☒

In 2017 a randomized veterinary clinical trial determined that intranasal midazolam was superior to rectal diazepam for controlling seizures in some dogs. As such, intranasal midazolam (0.2 mg/kg intranasal) is currently my treatment recommendation for at home anti-convulsant care. Guess what? It works great in hospital too when you cannot access a vein fast enough. 

My current recommendations for at home care are:
1) Intranasal midazolam at 0.2 mg/kg IN up to 3x in 24 hours. Use a nasal atomizer - it's a game changer. 
2) Rectal diazepam at 1 mg/kg PR up to 3x in 24 hours. Make sure to prescribe the BOTTLE, this drug is light sensitive so dosing it in a syringe makes it useful for up to 30 minutes and then it may loose potency. 

Other choices, such as rectal or IV levetiracetam, have been evaluated for acute seizure management too. We have more data about benzodiazepine drugs, and I'm more accustomed to using them (over the past 20 years!) therefore they are still my preference. I'll keep you posted if data surfaces suggesting we should change to using levetiracetam, or another drug, instead of the benzodiazepine class. 

Stay safe and keep those consults coming! For July my days of operation should remain Monday-Saturday. The schedule will change at the end of August once we sort out what kind of schooling we will be doing for the kiddos - I will keep you posted or you can always check the website or Facebook.  Thanks for reading!