The Gut and The Brain

The gastrointestinal microbiota (GIM) is the new hot topic in neurology. This contractile organ, far distant from the brain is now considered a a possible source for drug resistant epilepsy in canine epilepsy research as well as a potential cause for behavioral disease in epileptic and non-epileptic dogs alike. A recent article by Watanangura et al highlighted the importance of the GIM in epilepsy.
The aim of their study was to investigate the effect of phenobarbital (monotherapy) on the composition of the GIM and to determine if it resulted in a change to behavior in a select group of dogs. To be included in this study, all dogs had to meet Tier II level of confidence for epilepsy (normal brain MRI, spinal tap, normal blood work and neurologic examination) and be naive on any anticonvulsant treatment. They had 12 dogs who meet these inclusion criteria. On day 1, they started phenobarbital at 2.5 mg/kg PO q12h and took fecal samples. The drug was continued without dose adjustment for 90 days at which time another fecal sample was taken. Behavioral questionnaires were submitted on day 1 and day 90 as well.

The results:

• Serum phenobarbital concentrations ranged from 19.8-18.1 mg/L (day 30 and day 90)

• Seven of 12 dogs were seizure free throughout the study and called responders.

• Five of 12 dogs were not seizure free and were called non-responders.

• Short chain fatty acids (SCFA) did increase significantly in the study, specifically propionate and butyrate.

• Butyrate was significantly higher in the responder group compared to the non-responder group. Butyrate is an anti-inflammatory fatty acid which may  benefit epileptic dogs, yielding better response to treatment. Perhaps this is due to the neuroprotective effects, or by providing an alternative energy source for the brain.

• The behavior survey showed a significant decrease in stranger-directed fear, and non-social fear with an increase in trainability! Phenobarbital has been used as an anxiolytic for humans and veterinary patients, supporting this finding. An idiosyncratic hyperexcitability and aggression has been reported with phenobarbital however it is rare. (More commonly seen with levetiracetam.)

• There was no difference in the bacterial taxa in this study except for a significant decrease in Clostridiales on day 90. The significance of this remains to be seen, however it may affect the distribution of MCFA and other products.

The Take Home Message
What do we do with this information? Well…we tuck it away in our heads and know that phenobarbital, or seizures themselves, might affect the GI microbiome and SCFA in the GI. Does this mean we should supplement? Not yet. I am not sure we know who, how and when to supplement based on this study. This was a critical step forward in our path towards understanding the GIM and I am excited to share additional information that comes forth in this area!
 
Have a wonderful week and enjoy what August has to offer us! I look forward to working with you soon.

CBD Treatment for Resistant Epilepsy in Dogs

Use of CBD Oil for Refractory Epileptic Dogs

It's baaaack! At the ACVIM conference a few weeks ago I had the pleasure of listening to researchers from Colorado State University present data from a recent double blinded, placebo controlled prospective study evaluating CBD oil in resistant epileptic dogs. 

How the Study Worked

51 client owned dogs, taking at least 1 ACD (anticonvulsant drug) and continuing to have 2 or more seizures every month, were included. Resistant epileptics are already the hardest subset to manage so this was a really tough crowd for the researchers to target. The dogs were given either placebo or CBD oil for 3 months and then switched and given the other compound for 3 months. Initially, they dosed at 2.5 mg/kg PO q12h but no effect was noted so after 12 dogs the dose was increased to 4.5 mg/kg PO q12h. 

Key Points

• ALP and ALT were elevated in this study. This is the first study to document elevated ALT during CBD administration in dogs. The researchers aren't sure why this happened but hepatocellular damage of some sort was suspected. Bile acids were normal in all dogs except 2.

• No significant difference in response (response = a > 50% reduction in seizures) was noted between the placebo and CBD administrations group.

• Total number of seizures/month and seizure days/month was reduced in the CBD group compared to the placebo group BUT over all seizures went UP with both groups

Should we use CBD to manage seizures for resistant epilepsy?

Sorry, not based on this study. It's not compelling enough to suggest that we should be using this drug PLUS it showed evidence of liver enzyme changes that could be concerning AND phenobarbital serum concentration went by 11% when the dogs were on CBD. That said, they targeted resistant epileptic dogs so could this be effective in "easier" to control dogs? Maybe. Could this increased phenobarbital concentration mean that we could lower the dose of phenobarbital in these pets? Maybe. Do we need to check out different doses? Maybe - but at least with this question I am cautious because of the new elevation of ALT at this higher dose. Can we safely increase the CBD dose? Unknown. 

This is a good step forward but alas, we still don't have enough compelling evidence to say CBD should be a part of seizure therapy and at what dose.

Keep up the good work managing epileptic dogs! I'm available if you have questions about a case or need a second opinion. Have a great week!

What is Temporal Lobe Epilepsy?

Temporal lobe epilepsy (TLE) is a newly emerging term in feline seizure discussions and one worth becoming acquainted with. TLE is not an etiology, but rather a specific seizure phenotype (appearance) caused by epileptic seizures in a specific part of the brain (hippocampus) resulting from multitudes of causes.

What does TLE look like?

Cats with TLE have 6 specific stages or appearances. Not all cats go through all 6 stages, nor are all 6 stages apparent. The stages are:

Stage 1: looking around, sniffing, attention

Stage 2: Immobility and staring (arrest)

Stage 3:Orofacial automatism (lip smacking, facial twitching, swallowing, blinking) hypersalivation, mydraisis

Stage 4: Masticatory movement, facial twitching

Stage 5: Head turning, head nodding

Stage 6: Generalized convulsive tonic-clonic seizure

Most cats are observed in stage 2 or 3, and may progress to stage 4 and 5 but stage 6 is rarely observed.

What causes TLE?

Because TLE is not an etiology, but a description of a seizure syndrome located in one part of the brain, any cause of non-TLE seizures can cause TLE seizures as well. This list could include vascular causes, neoplasia, meningoencephalitis (infectious or non-infectious), or idiopathic.

How is TLE diagnosed?

When orofacial automatisms are observed, TLE should be suspected. To confirm TLE, an MRI with changes in the hippocampus is needed. There may be evidence of the seizure etiology such as neoplasia, or vascular disease as well, but the hippocampus must show specific MRI changes. Histopathology can reveal hippocampal sclerosis or necrosis. Some authors think sclerosis precedes necrosis but this sequence isn’t fully established. I won’t bore you with the detailed differences between sclerosis and necrosis, especially since the difference is detected on necropsy.

Can we treat TLE?

Yes! Treat seizures with antiepileptic drugs (AED) as you would any feline or canine seizure disorder. Any 1 seizure more than every 3 months, or longer than 3 minutes warrants a discussion of starting AEDs. Recently, hippocampectomy (removal of part of the hippocampus) has bene published in a cat as a treatment for TLE. This is a well-established treatment for human TLE (a common form of AED-resistant epilepsy in humans) and it carries an extremely high success rate for seizure elimination. Unfortunately, the procedure in cats needs a bit more work before we start considering it standard treatment. The hippocampus is the memory storehouse therefore loss of the hippocampus can cause difficulty with motivation, spatial memory, and learned behavior. Some researchers have described the effect to be similar to feline cognitive disorder in geriatric cats. Hippocampectomy was extensively performed in the 1960s during the time of rapid, although sometimes perhaps unethical, knowledge acquisition of how the brain works in animals and humans. We must acknowledge this work, even if we might find it ethically repulsive today.

Key Points

·         Temporal lobe epilepsy is a syndrome, resulting in damage to the hippocampus and a classic seizure presentation.

·         Temporal lobe epilepsy can be treated, but may be progressive and unresponsive to treatment once the necrosis stage has been reached. How do we know we reached this stage? No one knows antemortem….stay tuned!

·         Cats should take phenobarbital or levetiracetam. These are currently (2023) the only two drugs with enough literature to support their use and predict a reasonable efficacy. (Sorry my zonisamide-using friends.)

Seizures, Quality of Life and Side Effects, oh my!

A study published in JAVMA (Gristina BR et al. JAVMA 2023)  just recently caught my eye and I thought, perhaps it might interest you as well. The study evaluated 100 dogs with , with Tier I or Tier II level confidence of idiopathic epilepsy and assessed owner satisfaction, seizure control and adverse effects (the fancy name for side effects) of various drugs. 
*Tier I = normal CBC, serum biochemistry, neurologic examination and bile acid test
* Tier II = all of tier I plus normal brain MRI and CSF analysis

How was the Seizure Control?

Improvement in seizure control was reported in 86% of dogs with phenobarbital, 76% in the levetiracetam and 65% in the zonisamide group. Treatment failure, due to inadequate seizure control, was 48% for phenobarbital, 32% for  levetiracetam and 35% for zonisamide. Importantly, they didn't corelate seizure control with serum drug concentrations because we don't have target serum concentrations for levetiracetam and zonisamide. HTerefore, some dogs could have been under medicated, and thus poorly controlled. Interestingly, 88% of dogs were still on their original antiepileptic drug (AED) at the time this study was performed. Mean daily doses for phenobarbital, levetiracetam and zonisamide were 4.9  mg/kg, 53.8 mg/kg and 12.4 mg/kg, respectively. 

What side effects made a splash?

Phenobarbital had the highest reported adverse effects at 77%, followed by levetiracetam at 59% and zonisamide at 39% of dogs. The most common adverse effects are listed below for each drug:

• Phenobarbital: polyphagia, polydipsia, ataxia, sedation and polyuria

• Zonisamide: sedation, ataxia, hyporexia

• Levetiracetam: Sedation, ataxia, hyporexia, diarrhea, behavioral changes.

What was the perceived Quality if Life?

Owners perceived a significant improvement in quality of life, regardless of the anticonvulsant used, between pre and post treatment assessment. This is important for us to realize: clients can tolerate adverse effects if they perceive improved seizure control and quality of life! Although this retrospective, owner-perception study has limitations (all studies do), I felt it was worth repeating a bit of the information for you to add to your knowledge when addressing seizure management with your clients. 

Have a wonderful week! Remember, early bird registration ends May 31st for the July CE event so register soon if you are planning to do so! Details are available on my website. 

Reference: doi.org/10.2460/javma.22.10.0469

How to Question an Owner

Careful questioning of the owner is required to determine if the episodes described ARE seizures. Syncope, vestibular signs, neck pain, and movement disorders (think Scottie cramp) have episodic presentations with similarities to seizures. Nothing is fool proof, even an EEG, but here are some tips to get you going in the right direction. 

Describe the event, please!

Discrete episodes, with a finite start and stop, combined with autonomic signs often indicate a seizure. Level of mentation can be confusing and difficult to determine (especially for those pesky night time seizures) so don't spend too much time grilling an owner on this one. Videos can be priceless. I have evaluated many dogs and cats for seizures that actually have something else after reviewing the video. Neck pain, movement disorders, and syncope are the most common pretenders that I've seen. Finally, ask how long the events are lasting. This question is subject to tremendous bias, but if the owner says "all day" I start wondering about other non-seizure events. 

How often have the events occurred?

Okay sorry, I need to harp on this one. My pet peeve is hearing "about once a month" as an answer! This is an easy one and something we should encourage ALL clients with seizure pets to do. Keep a calendar! Tell owners to write it down, put it in a spreadsheet, mark it on their phone, keep a list - the choices are as varied as the seizures they record! You will NEED this to be in place to help you direct treatment. The single biggest reason to change treatment is that the seizures do not meet the seizure goals for epileptic pets. What are the seizure goals? Animals should have 1 seizure or less every 3 months. 

Your second goal here is to learn about cluster seizures. If the animal has 2 or more seizures in 24 hours that is defined as cluster seizures. Cluster seizures need at home cluster seizure management (another topic for another day). Furthermore, some drugs work better for dogs with cluster seizures than those with single seizures. I personally believe that bromide is a terrific option for cluster seizures and will readily use it for patients with this type of pattern. 

How long is each seizure? 

This question is utilized to learn about status epilepticus. Any seizure longer than 3-5 minutes (people argue about what is the correct time) is considered status. Status warrants emergency management with injectable solutions (intranasal, intravenous, other). Untreated status can set an animal up for systemic side effects as well as increase the risk of permanent brain damage. 

What does the animal do after the event is finished?

Your goal here is to evaluate the post ictal phase so that you can decide if a change in treatment is needed. Based on the rules outlined by the International Veterinary Epilepsy Task Force, severe post ictal changes (such as aggression) warrant treatment even if the other parameters for treatment haven't been met. I also use this question to determine how the owner is feeling about the event. Answers such as "he was fine" or "he paced and paced and seemed really upset" give me a window into how they feel about as much as how the dog did. Helping owners cope with seizures is also part of our job!

Do you have a seizure case that isn't meeting your seizure goals? Let me know! My favorite part of neurology is long-term seizure management so I'd love to help you, help your patients!

I'm headed to Chicago Vet Conference on Friday for a few talks on seizures, the neuro exam and lesion localization. I'd love to see you if you're at the conference so stop by and say "hi" if you have time!

Trace Minerals and Canine Epilepsy

Trace elements are the micronutrients found throughout live animals that are essential for organ function and brain health. They keep mitochondria running smoothly, improve neurotransmission and aid with enzyme function. Deficiency or excess has been linked to multiple neurologic diseases including neurodegenerative diseases, behavior diseases and inflammation in humans and animal species. A recent study evaluated the levels of several trace elements in hair samples of dogs with epilepsy and compared them to dogs without seizures.
 

What Trace Elements were Abnormal?

In this study, by Rosendahl et al, there were 10 epileptic dogs without any treatment, 53 epileptic dogs currently undergoing treatment for epilepsy, and 42 control dogs (no seizure history).

• Phosphorus: lower in epileptic dogs

• Copper: Higher in epileptic dogs

• Zinc: higher in epileptic dogs

• Copper/zinc ratio: higher in epileptic dogs. Specifically, higher in dogs treated with phenobarbital, in one previous study. Studies have shown that copper homeostasis is an important preventative for some neurodegenerative diseases. More work needs to be done in veterinary species to determine if this holds true for our patients, too.

• Selenium: higher in epileptic dogs

• Arsenic: higher in epileptic dogs but also much higher in dogs receiving potassium bromide!

Some of these findings were significant, some were significant only when comparing control dogs with either treated, or untreated dogs, and others were significant for both subgroups of epileptic dogs.

This study is likely to be a stepping stone for either this group, or others, studying trace minerals and their relationship to seizures. It was important work to identify differences, but the clinical significance remains unknown. Treatment, or correction of these deficits or elevations of trace minerals has not been evaluated in epileptic dogs. Stay tuned!
 

Thanks for reading! I hope you have a great week and enjoy what I hope is our final push out of winter, into spring, weather.

 
Reference: https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.16698?campaign=wolearlyview

Hypophosphatemia in Seizures Vs. Syncope

We've all been there, right? An elderly small breed patient with a grade II or III heart murmur presents to you with a history of "passing out". Clients aren't more descriptive than that, and they didn't catch a video. Is this syncope or was this a seizure?

You have several things to ask and look for (see prior TidBit Tuesday on syncope) but recent research has given us one more tool in our belt to help differentiate between these two diseases. 

Human patients with generalized tonic-clonic seizures demonstrate a reduced phosphate level within several hours of the event and patients with syncope do not. A study from Israel published data in January that strongly suggested a link between hypophosphatemia and seizures in dogs, as well. According to this study, 87 dogs with seizures and 26 dogs with syncope were included. Phosphate was evaluated within 3 hours of the "event" in question and noted to be decreased in 28 (32%) of dogs with seizures. None of the dogs with syncope had a low phosphate level. Dogs were excluded from the study if their creatinine was above the normal range to eliminate those cases with hypophosphatemia from renal causes. Median phosphate levels were significantly different between the two groups!

Key point: With an optimum cutoff value of 0.97 mmol/L (about equal to 3.0 mg/dl), evidence of hypophosphatemia has a 100% specificity and 44% sensitivity to diagnose seizures. 

Importantly, this tool should not be used as a stand alone finding to differentiate between seizures and syncope! However, identification of hypophosphatemia, within 3 hours of the witnessed event, could suggest a generalized seizure was more likely than a syncopal event if all other historical, physical examination and biochemical findings are concurrently evaluated. Important note: This has not been verified in dogs with focal seizures or complex partial seizures OR cats! 

This week's TidBit Tuesday is short and sweet. I hope you have a wonderful start to March 2023! 

Reference: https://doi.org/10.1016/j.tvjl.2022.105914

Levetiracetam use in Cats

We all know cats are not small dogs, so how does levetiracetam (leh-vuh-tr-A-suh-tam) differ between species?

Metabolism
The mechanism of action (modification of the SV2A receptor) is the same for cats and dogs. This mechanism of action (MOA) is unique to levetiracetam and different that the MOA for phenobarbital. 

Formulations
There are two formulations available 1) standard release (SRL) and 2) extended release (XRL). The dosage of 20 mg/kg PO q8h for the SRL formulation, comes from pharmacokinetic analysis of this drug in a cohort of healthy cats. A therapeutic range has not yet been developed for cats therefore if seizure control is poor, the dosage is often increased until signs of toxicity are noted and then reduced to the highest effective dose with minimal side effects. When doing that, the prescriber is using the individual animal as a guide for toxicity rather than an established therapeutic range. Reported side effects include hypersalivation (mild, transient), inappetence and mild lethargy. There are very few efficacy studies for cats, however in 2008, a single study reported a greater than 50% reduction in seizures  in 7 of 10 cats when levetiracetam was added to phenobarbital. Liquid formulations are readily available through compounding pharmacies and can be used interchangeably with the 250 mg size tablets. Use caution when prescribing the liquid formulation to ensure it does not have xylitol as an added ingredient. 

Extended release levetiracetam is available in 500 mg and 750 mg size tablets. Historically, this has limited its use in cats. In 2017, I decided it was high time we changed that thinking so we evaluated the pharmacokinetics of a single dose of 500 mg XRL in healthy cats and found that it was well tolerated with minimal side effects. Furthermore, we identified that a reduce dosing interval from q8hr (SRL) to q24h when using XRL was appropriate for cats! The serum levetiracetam concentrations were really high therefore we subsequently evaluated the use of levetiracetam over 10 days to monitor for drug accumulation. Thankfully, none was identified! No efficacy studies have been performed using 500 mg PO XRL q24h in cats, to date, however I do recommend this dosage for cats, when levetiracetam is needed and q8h dosing isn't an option.

The story doesn't end there! Medicating cats is such a terrible thing to do to a cat (and horrifying for some owners) that I then explored the idea of transdermal levetiracetam (TD).The dosage of 20 mg/kg transdermal q8h resulted in serum concentrations similar to those of the oral route with minimal side effects. We have not evaluated TD levetiracetam long-term so efficacy remains unknown. Do I use TD levetiracetam? Yes. I ensure that the clients know that this is cutting edge research and therefore long-term efficacy studies have not been performed; purely that it is well tolerated. 

That's all for now! Please reach out with any suggested topics and stay tuned for a super fun neurology CE event coming this summer. Shhhh...it's still in the planning stages! 

Have a great week!

Exercise and Seizure Control

Last year we talked about a temporal relationship between seizures and exercise. It has been shown that seizures rarely occur DURING exercise.

Recently, I was involved in a study, performed at the University of Wisconsin, evaluating increased activity and it's relationship to seizure development. In this study, dogs were tracked using a FitBark(tm) exercise tracker for 3 months and then prescribed a 20% increase in activity over the next 3 months. Seizure frequency and "seizure days' (the number of days that a dog has a seizure) per month were evaluated. Unfortunately, many of the dogs did not actually do the exercise increase as prescribed (ugh!) but even accounting for that, exercise was not associated with a statistically significant reduced seizure frequency or number of seizure days during the study period.

Why didn't this work? There are many possible reasons why prescribed exercise didn't change the seizure frequency. The most obvious reason is that not enough pets made the change to show a statistical difference. The other, more concerning option, is that exercise really doesn't have an effect on overall seizure performance. There are mixed results in the human epilepsy studies. Although it is rare to have seizures during activity, it can happen. Furthermore, some studies showed a lower seizure frequency when exercise was added to a treatment plan and other studies did not.

What is the take home message? Increased activity cannot (yet) be used as an adjunctive treatment for seizure management. It is still a healthy choice, and should be encouraged in all pets but especially our dogs with epilepsy but not, sadly, as a means to seizure control. This was a small study, so my hope is that future studies will yield more robust results.

Thanks for reading! If you want to read the whole study you can find it here: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jsap.13568

Have a great week. Happy Thanksgiving! Enjoy exercising with your pets, friends, and family this holiday week!

Renal Tubular Acidosis and Zonisamide

Ahh, it is time to examine Zonisamide again. A recent article in Veterinary Medicine and Science described a single dog with lethargy and distal renal tubular acidosis following administration of zonisamide. (https://onlinelibrary.wiley.com/doi/epdf/10.1002/vms3.905)
Distal renal tubular acidosis (RTA) has been defined as a normal anion gap metabolic acidosis with alkaline urine.

What should I look for to diagnose RTA?

The dog in this report had hypochloremia and hyperkalemia on initial blood work. This, coupled with a mild acidosis on blood gas and a urine pH of 7.73, suggested RTA. We're not sure of the consequences of RTA in dogs, yet. In pediatric human epileptic patients, there is some concern for future renal disease with RTA but this hasn't been well established (to my knowledge) for dogs. In this case, the link between the RTA and the dog's clinical lethargy was made, which is what drove the clinicians to pursue treatment.

How is it treated?

The authors described a very slow infusion of bicarbonate (please don't do this unless you have 24 hour monitoring capability!) which reversed the clinical lethargy and normalized the blood gas imbalance for 3 days. They did try to reduce the dose of zonisamide prior to treating the acidosis and achieved mild clinical improvement of sedation when the serum zonisamide concentration went from 38.6 ug/ml to 15.1 ug/ml. No change in biochemical status was noted. If you don't have the option to do a bicarbonate infusion, slowly tapering down or off of zonisamide is recommended to reverse the RTA. It is unknown, in dogs, if sustained RTA has negative health consequences. For many patients, another anticonvulsant drug must be substituted prior to removing zonisamide from the treatment plan.

Another short, but sweet TidBit Tuesday. Please let me know if you have any questions!
I hope those of you here in Wisconsin enjoyed the wonderful weather we had this past weekend and have found your winter hats and gloves in preparation for this coming weekend. Bring it on, am I right??

Midazolam vs. Diazepam for At-home 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 our canine patients 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. So, which is better? They all work, but intranasal is perhaps faster and easier than other non-intravenous routes when IV access is restricted.

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 and also carry them in my car. Ask, when I'm at your clinic, if you need one!).

Nasal drop vs. Atomizer?

The 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 conical shaped 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. :)

I hope you're enjoying summer and all it has to offer! I am at the Dane County 4-H Fair cheering on my kids so my hours are a bit limited. Please reach out if you need me and cannot find a suitable consult time online. Have a great week!

Zonisamide Induced Blood Dyscrasia in Dogs

Really, zonisamide? You couldn't just let this one slide? Phenobarbital already has dibs on blood dyscrasias and I'm struggling to like you as it is. Why did you go and have to do THIS to dogs, too??

If you've been a TidBit Tuesday reader for awhile you'll know I struggle to love zonisamide. Yes, it has it's place in movement disorder management. Yes, it can be a wonderful anticonvulsant. in some dogs. But in my hands, in my experience, it either hasn't worked well or I've seen undesirable side effects that I've attributed to zonisamide. And it is a Sulfa antibiotic. So, there's that worry, too.

New this week, we can read about 4 dogs with blood dyscrasias likely secondary to zonisamide administration.

Dog 1: 7 year old Shih Tzu. Presented for vomiting, lethargy and fever. He had received Zonisamide (ZNS) for 400 days at a dose of 5 mg/kg q12h. Severe leukopenia with neutropenia, monocytopenia and lymphopenia were noted along with an elevated ALP, ALT, hypocalcemia, hypochloremia, hyponatremia, and hyperbilirubinemia. ZNS was discontinued and antimicrobials were started. 19 days later, the leukopenia was resolved.

Dog 2: 1 year old Siberian Husky. Presented for a history of groaning, and appearing tense. He had received ZNS for 29 days at a dose of 17 mg/kg q12h. On presentation the dog was also febrile, had a leukopenia with neutropenia, and increased ALP and hypoalbuminemia. Zonisamide was discontinued and the leukopenia persisted through 40 days. On day 180 from discontinuation, the WBC was within the reference range.

Dog 3: 9 yr old Miniature Poodle. She presented for lethargy, anorexia, labored breathing and reluctance to walk. She had received zonisamide for 20 days at a dose of 8.5 mg/kg q12h. No fever was noted on presentation however overnight a fever developed. Severe leukopenia with neutropenia was documented after the zonisamide was discontinued (within 24 hours, I think) along with increased ALP activity and hyponatremia. Leukopenia and neutropenia resolved by day 6.

Dog 4: 5 year old Miniature Poodle. He presented for vomiting, lethargy and anorexia as well as fever. ZNS was started 1,196 days prior to presentation at a dose of 8.4 mg/kg q12h. Again, CBC showed a leukocytosis with neutropenia and mild thrombocytopenia. Serum biochemistry showed increased ALP, hyponatremia, hypokalemia, hypochloremia and hypercholesterolemia. Zonisamide was discontinued and leukopenia improved within 2 days, and normal by day 3.

The authors attributed the blood dyscrasia to an idiosyncratic drug reaction. Idiosyncratic, of course, means that it is unpredictable in scope and severity and not reliably related to dose. Other idiosyncratic reactions to ZNS include hepatopathies, skin eruptions and rental tubular acidosis. Perhaps all of these reactions are because this is a sulfonamide derived anticonvulsant? Discontinuing the drug is the best way to try to reverse the blood dyscrasia. I found it interesting that in one of the cases they continued phenobarbital (a drug also known to have a risk of idiosyncratic blood dyscrasia) and the bone marrow was still able to regenerate.

Key point: If you find an abnormal CBC for a pet receiving ZNS, please consider an idiosyncratic blood dyscrasia and discontinue the drug (safely).

Reference: https://doi.org/10.1111/vec.13222

Have a great week and thanks for reading!

Abrupt Benzodiazepine Withdrawal in Dogs

Abrupt withdrawal of benzodiazepine drugs can result in withdrawal seizures. A recent report describes withdrawal seizures in 3 young dogs and I thought we could take this opportunity to review this concept.

What is a benzodiazepine drug?

Benzodiazepine class drugs commonly include diazepam, midazolam and lorazepam. These drugs are GABA agonists in the CNS which results in suppression of activity. GABA activation causes inhibition in the forebrain, cerebellum, and in other parts. So, if you activate an inhibitor, you will suppress activity. Got it?

How long is too long?

Abrupt withdrawal resulting in seizures and other signs of CNS overstimulation can occur after constant rate infusion (CRI) use, or chronic oral use. Use of a benzodiazepine drug as a CRI for more than 12 hours usually warrants tapering. The three dogs in the recent report received one of these drugs for 39, 64, and 48 hours, respectively. After abrupt withdrawal of the drugs they experienced ataxia and seizures within 4- 48 hours. A return of the benzodiazepine CRI at a low dose, followed by a 12-24 hour taper, resulted in a successful wean from the medication and no additional neurologic events. All three of these dogs were also undergoing mechanical ventilation, and received other medications, so there is always the questions about a direct link between the benzodiazepine withdrawal and the seizures, however the authors suggest this link follows an expected pattern with abrupt withdrawal in humans and in animals. I agree.

As a general rule of thumb (based on human literature), if I prescribe a benzodiazepine drug for oral use longer than 7 days I taper the medication. Abrupt withdrawal is sometimes called "Jim jams" which, honestly, is a pretty fantastic term but probably not a fantastic feeling. Withdrawal ataxia, cerebellar signs and seizures can be seen from abrupt discontinuation of a benzodiazepine drug.

How do I taper to avoid withdrawal seizures?

CRI:

• Typical dosing range is 0.1-0.5 mg/kg/hr. I reduce the dose by 50% every 12 hours until the pet would be receiving less than 0.1 mg/kg/hr. For example, if we are at 0.25 mg/kg/hr and wish to taper I would start with a reduction to 0.12 mg/kg/hr x 12 hours, then stop, because the dose would then be less than 0.1 mg/kg/hr.

Oral dosing

• Typical dosing is 0.25-0.5 mg/kg PO q8-12hours. If the dog receives the drug for more than 7 days, I would recommend a 50% taper for 3-5 days, followed by another 50% reduction for another 3-5 days and the stop. Cats are at risk of acute hepatic necrosis with oral diazepam administration so I rarely use this medication. However, if you find yourself treating a cat on chronic benzodiazepine drugs, a similar taper can be employed.

Thanks for reading and enjoy your summer! Remember, if you're working with a dog or cat with neurologic disease, I'm an email or telephone call away! Better yet, schedule a consult and we can work through the case side-by-side.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/vec.13221

Client Communication Surrounding Seizure Management

Client Communication Surrounding Seizure Management

Client communication is critical during the initial seizure consultation. Many clients arrive in my exam rooms with one or more of the following expectations:

• Their pet will not have any more seizures (this is a common one)

• Medications should not have side effects (yes, this is often requested)

• Inexpensive medication 

• Easy to administer, once to maybe twice daily medication (this is key for cat owners)

These goals do not align with our expectations, do they? Here are my goals:

Seizures will likely continue, if they've had 2 or more already.
Realistically, everybody gets 1 free seizure in their life. If you've had 2, or more, we probably should see your dog or cat and have a chat. If we place the pet on anticonvulsant drugs (ACD), our goal is to have 1 seizure or less every 3 months. That is a reasonable goal. The other option is to have a 50% reduction in seizure activity. This means that we need to know the interval of the seizures before treatment, and then calculate what a 50% reduction looks like for that individual. I am a goal oriented person and most clients also respond favorable to setting appropriate goals. This allow us to feel a sense of success when we achieve them, and a reason to continue to modify treatment if we don't. 

Side effects WILL happen.
Any ACD has side effects, our goal is to have tolerable side effects for that family and pet. Tolerable may mean that they are okay with PU/PD, or it may mean that a level of sedation is acceptable. Each family is unique so this approach is tailored directly to the family I am working with. I am diligent outlining known side effects of the drugs at the time they are prescribed. Be sure to tell the client that many side effects improve or resolve by the time the pet reaches steady-state. This means we can set goals for resolution of signs, too. If the time to steady-state is 14 days (phenobarbital) then give clients that information so that when they see side effects (they will) they know to hang in there for 14 days and it is likely to get better. If it isn't,  we can adjust after evaluating the serum drug concentration at steady-state (when applicable for the drug prescribed).

Cost
The cost of ACD varies over time. Phenobarbital when through a period where it was difficult to obtain and was, therefore, very expensive compared to previous and subsequent years. The fluctuation in cost is really due to production, availability and (as with all things right now), shipping costs. It can be helpful to outline the cost of the drug up front, but ensure that the client knows this can change over time depending on the aforementioned causes. 

Administration is key!
If an owner cannot administer the medication, it doesn't matter how effective it SHOULD be because the pet isn't taking it. This concept is especially near and dear to cat owner's. In human medicine, when a prescription was recommended 1x daily, the compliance was over 80% (the drug was given as prescribed over 80% of the time). However, when the prescription was recommended at a 3-4x daily dosing, the compliance dropped as low as 10-15% in some studies. This becomes especially true in the pediatric world, in which an individual is having something given TO them. I think it is reasonable to translate this to our veterinary world and realize that three times a day levetiracetam, even if the perfect drug for other reasons, may not be a good option for some clients simply because compliance will be low. It has been well established in neurology that the variation between peak and trough can be just as important as one serum concentration at one time point. If there is a wide swing between peak and trough, there may be a greater chance of breakthrough seizures or poor control. Missed doses can result in wide swings of the peak and trough serum concentrations and therefore should be avoided. 

So there you have it! I hope this pep talk has been helpful for you as you help clients navigate the (at times) choppy water of seizure management. If you need help with a seizure case, or feel the client would benefit from a second opinion, please reach out. Seizure management is one of my favorite aspects of neurology!

Have a great week and keep those consults coming!

Status Epilepticus

Status epilepticus (SE) is defined as continuous seizure activity for more than 5 minutes or two seizures in which consciousness isn't resumed in between. SE has a potentially fatal outcome in dogs and humans and is devastating to watch, try to fix, and explain to clients. I wish it wasn't so.

A recent study out of the UK (see below) outlined risk factors for short term mortality (death during hospitalization for SE) and long-term recurrence of SE in dogs. Here are some key points but, as always, if you want more depth please read this open access article.

Short-term mortality:

• 124 cases included, 87 survived to discharge (70%)

• Increasing age, shorter duration of hospitalization, onset of SE before hospitalization and SE being caused by a potentially fatal etiology were related to mortality.

• Of the survivors - 42 had idiopathic epilepsy ( this was the first seizure in 6 dogs), 21 had structural epilepsy (first seizure in 12 of the dogs) and 8 had reactive seizures (first seizure in 10 of the dogs).

Recurrence of SE

• 74 of 87 dogs had follow-up information after discharge. Recurrence happened in 20 of 74 dogs.

• Pharmacoresistant epilepsy and having focal seizures were the only significant risk factor identified. .

• 50% of recurrence was within 2 months from discharge

What do we make of this?
Status epilepticus is a serious form of a seizure. We cannot fully prevent it, but we can counsel clients on the possibility if their animal has one of the predisposing factors identified above (advancing age, fatal etiology or focal seizures). Do not delay on treatment of seizures. Waiting and seeing can result in SE and avoidance is definitely the best policy for management of SE.

JVIM (2022): 36: 353-662.

Thanks for reading! Happy Easter and Passover to those of you that celebrate. Safe fast to those of you in the midst of Ramadan. I look forward to continuing to work with you and your staff to help pets with neurologic disease.

Seizures in the Post Operative Period

Seizures in the immediate post operative period can indicate a poor prognosis for humans undergoing brain surgery. The same is suspected for dogs, but isn't known. A recent article (see below) recently discussed this question and I thought you might be interested in reading some key points from the article.

Key points:

• 88 dogs underwent 125 procedures. Most had either a brain biopsy or a brain surgery, but some had both.

• All included surgeries were rostro tentorial because caudal tentorial surgery and tumors have a very low incidence of seizures.

• Most dogs (72%) had seizures before brain surgery was performed, therefore diagnosed with structural epilepsy.

• All types of seizures were noted (35% generalized only, 29% focal and generalized and 17% focal only)

• Forty-one of 88 dogs (46%) had a normal interictal neurologic examination. This is MUCH higher than some other studies have shown and is worth noting in general practice. The neurologic examination can help guide you towards advanced diagnostic testing, or not. According to this study, almost 1/2 of the dogs had a normal exam and had a brain tumor!

• About 42% of dogs had an abnormal neurologic examination consistent with a focal lesion and 11% had examination findings consistent with multifocal disease.

What I learned from this article

This article was full of data, so if you're a practicing brain surgeon, it is worth a full read. That said, there were a few points that may benefit the non-neurosurgeons amongst us. I've summarized them below and included a link to the open access article at the bottom if you'd like to read more yourself.

• Early post-operative seizures in humans, are diagnosed in the first month after brain surgery. One of the hypotheses was that dogs receiving anticonvulsant drugs (ACD) would have a lower incidence of post-operative seizures. Interestingly, this article did not detect a difference in post operative seizures between dogs with or without ACD pre-operatively!

• Tumor location nor brain herniation were associated with the development of post operative seizures.

• Curative intent surgery carried a higher risk of post operative seizures when compared to biopsy procedures.

• Dogs with glioma had a higher incidence of seizures compared to other tumor types, except meningioma.

• Dogs with early post operative seizures were less likely to survive to discharge.

• Early post operative seizures occurred in the first 24 hours for all dogs, and were associated with longer hospitalization.

Take Away Message

What does this mean? It means that seizures are a small, but mighty way for the brain to express it's displeasure with human touch. Even the most careful surgeon risks causing seizures that could be life threatening for their patients. I still give ACD pre-operatively but am compelled, by this data, to consider stopping that practice. Why administer an ACD if it isn't associated with a lesser chance of seizures? For most of you, brain surgery is not a part of your daily practice, so I would suggest that the most important take away from this article might be that almost half of dogs had a normal neurologic exam and yet were diagnosed with a brain tumor. Also, if a client asks you about post operative seizures, you can refer to this article! Thank you, Science.

Thanks for reading all the way through! I hope you have a great week and look forward to working with you, and your patients, soon.

Article links: https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.16391

What do CBD and Phenobarbital Have in Common?

Phenobarbital and CBD are known to both use the Cytochrome P450 system for hepatic metabolism therefore it stands to reason that co-administration could result in altered metabolism of one or both of these drugs.

In a recent study by Doran et al (https://doi.org/10.2460/ajvr.21.08.0120), changes in CBD pharmacokinetics (PK) were discussed, in reference to phenobarbital. Interestingly, no apparent changes in PK of phenobarbital or CBD were noted when each drug was given ONCE (not chronic dosing).

Significant changes in serum ALP were noted during chronic (3 week) CBD dosing at 10 and 20 mg/kg/d. More dogs had a chance in serum ALP concentration at the higher dose, but the sample sizes were very small so it is difficult to extract too much information from that finding.

Also interesting, the maximal concentration of CBD was higher in fed animals, than in those fasted at the time of CBD administration. Food for thought...

What is the take away?
1. CBD alone can cause elevated ALP in dogs. Significance? Not addressed in this study.
2. We don't know how phenobarbital serum concentrations are affected by chronic or single dose exposure to CBD, because this wasn't studied as a separate question.
3. This study didn't tell us anything about dose escalations so if you are using CBD oil in your practice, please look elsewhere for dosing recommendations for efficacy!

**Disclaimer: the State of Wisconsin forbids prescribing or recommending CBD containing products by veterinarians. Please consider this TidBit informative and not a recommendation for treatment with CBD containing products for pets.**

Short and sweet this week! Have a great week and I hope to work with you soon!

How to Use Phenobarbital Serum Concentrations

The 5 year old Golden Retriever

The set up...
Decker presented to me with a history of 3 seizures in the preceding 2 weeks. The seizures were consistent with generalized, tonic-clonic seizures of a duration about 30 seconds to 2 minutes (depending on the parent reporting the seizure). Decker was a very big boy. Not fat...just one of those super large Goldens that we occasionally see. He had a pretty healthy history prior to the seizures other than occasional ear and skin issues that the primary veterinarian had addressed. He wasn't taking any current treatment, was up to date on vaccines, hadn't traveled out of Wisconsin in the last 6 months, did not have a history of head trauma and wasn't a working dog. Yes, I do ask all of those questions during a seizure consult, every time. Unless I forget. But I try not to forget.

The Exam...
Decker's exam was normal. Normal physical (other than his giant, wonderful self) and a normal neurologic examination. So his lesion localization was... (you fill in this blank. Look at the bottom to check your answer).

The Plan...
Decker needed anticonvulsants. More than 1 seizure every 3 months is a good reason to start anticonvulsant therapy according to the IVETF. So, we did! We started phenobarbital at about 4 mg/kg PO q12h and requested a serum phenobarbital concentration in 14 days.

The Serum Concentration...
14 days after starting phenobarbital the serum phenobarbital concentration was 22 ug/ml (reference range: 15-40 ug/ml)

What do you do with this information?
Well, to answer that question you must first ask yourself why you took the serum phenobarbital concentration in the first place? Was it...
1. To document that it was therapeutic for Decker?
2. To ensure it wasn't toxic?
3. To show if the client wasn't giving it right?
4. To document if the serum concentration was too low?

How do you know if the dose was appropriate for Decker? You look at the seizure calendar, which we cannot do until Decker has been on phenobarbital for at least 3 "seizure cycles". What is a seizure cycle? It is the interval between seizures. In his case, it is less than 2 weeks (3 seizures within 2 weeks). So, we must evaluate efficacy by looking at about a 6 week interval of time.

Toxicity is seen by clinical adverse effects in the pet, which we cannot truly evaluate until the drug reaches steady-state. Steady-state is about 14 days in dogs, therefore signs of toxicity (or that the dose is too HIGH) should be assessed at the 14 day visit, or shortly thereafter. If adverse clinical effects are problematic after 14 days, the dose may be too high.

If the client isn't giving the drug, the serum concentration will be lower, but how much lower really depends on how often they miss a dose. This is not an appropriate way to ensure the client is giving the drug, in my opinion.

So, why take a serum concentration at all?? I do it to determine if the dose is too LOW. Serum concentrations below 15 ug/ml are outside of the accepted canine therapeutic range and therefore the dose should be increased. I would argue that serum concentrations below 25 ug/ml are clinically less desirable and typically advocate a dose increase for many pets (depending on clinical adverse effects).

What is the take away message?
Take the serum concentration to ensure it is not too low, use the dog to determine if the side effects are too high, and use the seizure calendar to determine if the dose is effective.

Thanks for reading! If reading this makes you groan, please reach out! I'm happy to help you manage your patients and love doing seizure consults. (Yes, for real!)

I am on vacation until Friday February 18th and ask for your patience if you reach out this week. I will reply but it probably won't be as quickly as you are used to!

What If We Could See a Seizure Focus?

Idiopathic epilepsy is something we all see on a regular basis. However, when we diagnose something by exclusion, I often wonder what we are missing. Currently idiopathic epilepsy is diagnosed if dogs meet the following criteria:

Tier I

• Normal neurologic examination

• Normal CBC, serum biochemistry and bile acid test

Tier II

• All of the above PLUS

• Normal brain MRI

• Normal CSF analysis results

(There is a Tier III, but it is rarely used.)

What if we could actually see a seizure focus?

This is the stuff of science-fiction, folks! A recent article in JVIM (https://doi.org/10.1111/jvim.16270) utilized an MRI technique that has been used in human epilepsy to try to visualize a seizure focus in dogs with idiopathic epilepsy. MRI works by affecting magnetic fields in the brain. With this new technique, neuronal currents are mapped with a specific oscillating magnetic field. This has been shown to be an effective mapping technique for humans with idiopathic epilepsy. The researchers applied the technique to a group of control dogs (those without seizures) and dogs diagnosed with idiopathic epilepsy with Tier II level confidence.

Results

There were three different frequencies used in the protocol however the authors combined the results from the different frequencies and found that 11 of 12 dogs with idiopathic epilepsy had a bright spot identified in their brain, with this technique. Even cooler, 4 of the 5 control dogs did NOT have any bright spots visualized in their brains. Perfect? No. Super cool? Yes!

Take Home Message

What does this mean for you and me? It means that as we test this new protocol a bit more we are one step closer to "seeing" the seizure focus in the brain. Who cares, you may ask? We all should!! If we can see it, we can remove it surgically (maybe), target it with radiation (already being done but this will improve accuracy), or start to identify different "types" of idiopathic epilepsy and assess how our drug protocols are affecting animals with specific forms of epilepsy. All of this allows us to target epilepsy much more specifically, and ultimately improve quality of life.

Thanks for reading! Hopefully you can use this new information to give your clients hope, when faced with a diagnosis of canine idiopathic epilepsy. Researchers (vets!) are working tirelessly to find a way to make life better for owners, and their pets with epilepsy.

Have a great week and be safe!