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!

How to Diagnose Idiopathic Epilepsy in the Exam Room

In 2015, the International Veterinary Epilepsy Task Force (IVETF) published a list of criteria to diagnose idiopathic epilepsy in dogs (not cats). The IVETF consisted of a group of veterinary neurologists, neuropathologists, and epileptologists. If you wish to see all of the resulting publications, just let me know! (They are available open access.)

The IVETF listed several ways to make a diagnosis of idiopathic epilepsy, starting with the lowest level of confidence (Tier I) and rising to the top with the most confidence in the diagnosis (Tier III). When using this information in your daily practice, consider writing "diagnosis: idiopathic epilepsy with Tier 1 confidence" in the medical record when a patient meets the criteria for a Tier I diagnosis of idiopathic epilepsy.

Please note, idiopathic epilepsy does not mean, any seizure disorder. Idiopathic epilepsy is a specific disease, that causes repeated seizures. ANY animal with repeated seizures can be diagnosed with epilepsy, but idiopathic epilepsy is ONE form of epilepsy. Make sense?

Tier I:

A dog must have:

• A history of 2 or more seizures at least 24 hours apart

• Have the age at onset between 6 months and 6 years

• Demonstrate a normal inter-ictal physical and neurologic examination

• A normal CBC, and serum biochemistry (the IVETF lists what they consider to be standard in a serum biochemistry analysis. Let me know if you want/need this list.)

• A normal fasting bile acids and/or ammonia

• A normal urinalysis

• A familial history of IE is supportive, but not required

Tier II:

To diagnose idiopathic epilepsy with Tier II level confidence a dog must have:

• All of Tier I plus...

• A normal brain MRI

• A normal CSF analysis

• Normal fasting and post-prandial bile acids

Tier III:

• All of Tier II plus...
  

• Identification of ictal or inter-ictal EEG abnormalities suggestive of seizure disorders.

So, if a patient meets Tier I level confidence, when should MRI be performed?

• Anytime a client wishes to confirm a diagnosis of intracranial disease. (This includes idiopathic epilepsy which is diagnosed by exclusion of other causes)

• If a dog has a seizure onset of < 1 year or > 7 years of age (according to the IVETF)

• If neurologic abnormalities reflective of the prosencephalon/forebrain are identified on the neurologic examination regardless of age, breed or a familial history of seizures.

In summary, it is always worthwhile to inform clients of the option of MRI when their dog (or cat) has seizures however, if the Tier I criteria are met and MRI has a high likelihood of normal results, it is very reasonable to skip this test and begin treatment for idiopathic epilepsy.

I try to remember that MRI abnormalities were identified in 22% of dogs with a normal neurologic exam and 90% of dogs with an abnormal neurologic examination in one study.

What about CSF analysis, you ask? I'm glad you asked! Some dogs with meningitis will have a normal MRI, therefore an MRI PLUS CSF tap is often my recommendation to ensure we don't overlook those patients inappropriately by just performing an MRI.

What about cats? The IVETF recommendations do not specifically apply to cats however many neurologists, including me, extrapolate this information to cats in practice. My fingers and toes are crossed for science driven cat-specific recommendations in the near future.

Have a great week! As always stay safe, and let me know how I can help you, help your patients, with neurologic disease.

How is Sleep Linked to Seizures?

I had the privilege to be involved in a prospective study regarding the effects of sleep and epilepsy. This study was published this week in the Journal of Veterinary Internal Medicine (see below for a link).

Disrupted sleep is common in human patients with epilepsy. Is the same true for dogs with epilepsy?

Dr. Starr Cameron spearheaded a study at the University of Wisconsin-Madison, and enrolled dogs with confirmed or suspected epilepsy, fit them with a FitBark(TM) the dog equivalent of a FitBit(TM) and watched their sleep patterns over 12 weeks. This study was one part of a multi-part study using the FitBark(TM) technology.

So, what is the answer?

Interestingly, a statistically significant change in sleep patterns was NOT noted. These were age and breed matched dogs, too. There was a trend toward poorer sleep for dogs receiving higher doses of bromide, but it was not noted at lower doses.

What is the relationship with sleep and seizures?

In human epileptic patients, seizures beget poor sleep and poor sleep can result in an increased frequency of seizures. This wasn't shown in our dog population, but that doesn't mean that it isn't a concern for some dogs. What do we take away from this? Keep an eye on the sleep pattern of your epileptic patients and consider sleep aids if they are restless. Oh, and stay tuned for more results looking at sleep and seizures in dogs - this is a hot area of research right now. :)
Article: https://onlinelibrary.wiley.com/share/JD24HPYCTIRKYTBVSJZA?target=10.1111/jvim.16205

I hope you have a great week! Let me know if you have an epileptic patient that needs a little extra assistance - I'd love to help!

Audiogenic Reflex Seizures, Anyone?

As I write this, the fireworks are blazing in my neighborhood and there is a general sense of noise in the nation. How can noise relate to seizures?

What are they?

Feline audiogenic reflex seizures (FARS) start in cats late in life (> 10 years of age) and are triggered by a sound or sounds. The seizure phenotype (appearance) has a myoclonic component, but may also have absence or generalized seizures, as well.

What causes FARS?
Any noise, but usually a high frequency sound such as clinking a spoon in a tea cup triggers the seizures. Some cats will have spontaneous seizures in addition to FARS and others will purely have FARS. If you are seeing an older cat with new onset seizures, consider having the client keep a "sound diary" for a few weeks to see if there is a correlation.

Why bother identifying this...you're going to tell me to give phenobarbital!
Au contraire mon frere! A sentinel study was published in 2017 by Lowrie, et al (https://doi.org/10.1177%2F1098612X15622806) that showed a marked improvement in cats on levetiracetam in a randomized, controlled, open-label study with phenobarbital. 100% of the cats in the levetiracetam group obtained seizure control compared to 3% in the phenobarbital group. So you're correct that I typically prefer phenobarbital for feline seizures...except for FARS!

What causes FARS?

Interestingly, the majority of cats diagnosed with FARS in the published studies have had idiopathic epilepsy with a small portion showing progressive signs suggestive of active forebrain disease (neoplasia, meningoencephalitis).

That's it for today, folks! I hope you have a safe, fun week and stay cool during this hot weather!

Update on Acute Seizure Management

"Doc, The Dog is Having A Seizure!"

No one likes to hear those words (not even neurologists). You rush into the exam room and are faced with a convulsing dog on the floor. Here is your preemptive stop and think moment (yay!):

Why do we want to stop seizures, anyway?
Prolonged seizures can result in hypertension, tachycardia, acidosis and hyperthermia with secondary neuronal cell death and hypoxia. These changes negatively affect the brain and may have systemic effects as well. The goals of acute seizure management are to stop the seizure as quickly as possible thereby limiting secondary brain and extra cranial organ damage.

Give me the "Go-To", Barnes!

Look no further than your Benzodiazepine class of drugs. Benzodiazepine drugs (Diazepam, Midazolam, Lorazepam) were introduced in the 1960s for human status epilepticus. A recent human meta-analysis identified that benzodiazepines are the “best” first line IV drugs and identified the therapeutic concentration to be between 150-300 ug/ml. To date, there have not been any veterinary studies identifying which drug is ‘best’ for acute seizure management. We’ve always used benzodiazepines so we continue to do so.

• Rectal, at home care: Home care with liquid rectal diazepam is often recommended for patients at risk for cluster seizures. Compounded suppositories are not currently recommended. Rectal midazolam and lorazepam are not! We also know that chronic phenobarbital use reduced plasma concentrations of diazepam. With this knowledge we recommend dosing rectal diazepam at 1-2 mg/kg if the patient is receiving chronic phenobarbital therapy.

• Intranasal diazepam and midazolam: Intranasal diazepam, using an atomizer, resulted in detectable levels in about 2.5 minutes which makes this drug a viable alternative for at home anticonvulsant care. Midazolam was even more rapid and had a better outcome than rectal diazepam in one study of epileptic dogs so it is currently my drug of choice for at home (or non-IV) care.

All the "cool kids" are using levetiracetam. Should I?

Well, maybe yes, maybe no. Levetiracetam is still considered a new anticonvulsant drug, however its use has been documented in veterinary medicine since 2004. It is considered a relatively safe drug, with few reported side effects. This drug is typically used as an add-on or alternative to intravenous benzodiazepine therapy for acute seizure management at doses ranging from 30-60 mg/kg IV. Adding diazepam and levetiracetam together resulted in improved seizure control in epileptic cats so this is currently my recommended way to give IV levetiracetam. (Unless diazepam is contra-indicated such as with hepatic failure.)
Rectal levetiracetam may be on the horizon according to one study in 2014. However the first sampling time was 10 minutes therefore it is unclear if this drug will be useful in acute seizure management.

Is Propofol Still Used?

Yes, but there isn't any new information. We all like shiny, new things, but propofol does have a place in acute seizure management. There are a small number of published studies addressing this use in veterinary medicine. This drug is only recommended for intravenous use. Care must be exercised when using propofol due to its respiratory suppressive effects. Occasionally, intubation may be required if apnea is encountered during bolus therapy. Propofol withdrawal may result in distal limb twitching which may be difficult to distinguish from seizure activity. Extended exposure in cats to propofol may result in Heinz body anemia therefore a CBC analysis is recommended every 24 hours during constant rate infusion of propofol with cats.

Have a topic suggestion for TidBit Tuesdays? Please reach out!

Need a consult?
Email: barnes@barnesveterinaryservices.com
Telephone: 608-597-0077
website: www.barnesveterinaryservices.com

Happy Father's Day to all of you lucky Dads! Hope you have a safe, relaxing day.

When Should You Start Anticonvulsant Drugs (and Why)?

Following the recommendations of the International Veterinary Epilepsy Task Force I suggest starting anticonvulsive drugs if a patient meets one or more of the following criteria:

• Two or more seizures within 6 months

• History of status epilepticus (one seizure longer than 5 min)

• History of cluster seizures (cluster seizures meet the definition in the first point above)

• Post ictal signs are severe (ex: aggression) or lasting longer than 24 hours.

• Seizure frequency or duration is progressing in the last 3 interictal periods. (ex: 12 months apart, then 8 months then 6 months)

Medications are selected based on the metabolic status of the patient, seizure pattern and client constraints (administration frequency, cost, bias). Phenobarbital and bromide are considered first line treatments by the IVETF and are recommended for most forms of seizures in dogs. Phenobarbital could be considered a first line drug for cats as well (Bromide is a big NO-NO for cats). The level of evidence available to make these recommendations is, at the time of writing, more complete than for the other anticonvulsant drugs. I use the following table to as a guide for starting or changing anticonvulsant drugs; hopefully you find it useful also. Remember that these are guidelines and many animals need manipulation of their seizure control life-long.

Table 1: Indications and limitations of phenobarbital, bromide, levetiracetam, zonisamide and gabapentin as first line anticonvulsant therapy.

PhenobarbitalBromideLevetiracetamZonisamideGabapentinIndication (Dog)Generalized tonic, clonic seizuresFocal or cluster seizuresReactive seizuresGeneralized seizuresInfrequent statusIndication (cat)Generalized, focalnot recommendedReactive seizures, orofacial seizuresLimited data. Consider for generalized?Very little data. Consider as last choice.limitationsAnimals with hepatic disease should not use this drug.Give with care for dogs with renal failure, or renal tubular acidosis (or with zonisamide)Chronic administration may result in honeymoon effectDo not use in cats or dogs with known sulfa hypersensitivity, or liver diseaseNone known

Whew, it's hot out here! I hope you are staying cool, safe and enjoying this blast into summer.

My summer 2021 hours have started! Please email me if you have a case to discuss, cannot find a time on the scheduler for a consult, or just like to chat about all things neurology. :)

I look forward to working with you, and your clients and staff, soon!

Isoxasoline Flea Treatment and Seizures

Recently published data (2020) suggests that adverse events (AE) - the new word for side effects - are higher than reported by the manufactures of isoxazoline flea treatments. Specifically, researchers looked at Bravecto (fluralane), Nexgard (afoxolaner) and Simparica (Sarolaner) in both the US and Europe.

What did they find?

This is a TidBit Tuesday-style abbreviated summary. For the full report see the link at the bottom. There is a lot of data in this report!

• The survey (called Project Jake Survey) had 2751 respondents. It was compared to the data requested of the FDA and the EMA (European Medicines Agency).

• Almost 69% gave Bravecto, 26% gave Nexgard and a small 5% gave Simparica.

• Overall, 66.6% of dogs had a reaction to treatment

• Of the 911 dogs getting Bravecto, 791 had an AE (86.8%)

• Of the 342 dogs getting Nexgard, 235 had an AE (68.7%)

• Of the 72 receiving Simparica, 44 had an AE (61.1%)
  

What about seizures??

Death and seizures were a focus for this report, however other side effects are certainly noted and were reported. I will focus on seizures.

FDA report: Overall, 5.34% of dogs experienced seizures

• 20% of dogs receiving Simparica

• 2.8% of dogs receiving Bravecto

• 6.9% of dogs receiving Nexgard

EMA report: Over all 30.3% of dogs experienced seizures (!!)

• 60.2% of dogs receiving Simparica

• 18.7% of dogs receiving Bravecto

• 46.69% of dogs receiving Nexgard

Project Jake Survey:

• 4.5% of dogs receiving Simparica

• 14.8% of dogs receiving Bravecto

• 12% of dogs receiving Nexgard
  
  

Why are the numbers SO MUCH higher in the EMA?

Perhaps it is related to genetics in the dog population, better reporting habits, or reporting by vets vs owners (or vice versa). That question wasn't answered in the report. The take home message for me was that Simparica is blowing things out of the park with seizures but that the other two still have a substantial group of dogs with seizures as an AE.
Critically, this report did NOT state if the dogs had ever had seizures prior to administration of the drugs. They did state that at least some of the dogs had novel seizures after administration of one of these drugs...but alas we don't know the details on this.

When do the majority of Adverse Events occur?

Within the first 24 hours. These are supposed to be insect specific GABA mediated chloride channel blockers that are distributed around the body in the first 24 hours so it isn't surprising that this is the highest spike of possible toxicity to the dog. Also, AE were reported as a small spike between 8-14 days.

So, what is the take away?

• Any of the drugs in this report (Bravecto, Simparica or Nexgard) can have seizures as a side effect. Are they a cause of seizures? I'd say probably yes, for at least some of the dogs. Perhaps they lowered the threshold in prone animals too?

• It looks like Simparica may have a higher incidence of seizures

• If a dog has a FIRST seizure (within 24 hours or at 8-14 days) after using an isoxazoline drug, discontinue use and try a different class or different drug in this class.

Link: https://onlinelibrary.wiley.com/doi/epdf/10.1002/vms3.285. Publication date 2020. This was a very interesting read and eye opening for me.

Keep those consults coming! The more we work together, the more we learn from each other.

This TidBit Tuesday grew from a recent spike in questions about flea/tick medications from some of YOU...so, thank you!

I look forward to working with you and your staff, soon!

Important Questions to Ask When Evaluating a Seizure Patient

Do you know the most important questions to ask a client when evaluating a seizure patient?

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!

• Clinical appearance, including a description of any autonomic signs is critical. Videos can be priceless!
  

• 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.

• How long do 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.

Your second goal here is to uncover information about possible 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 in a different TidBit Tuesday, I might add). 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.

Are you working with a seizure patient and need some backup? Please reach out, I'd love to help. It is my job to help you care for your patients with seizures more confidently. We can do it!

Also, a super big thank you to those of you that have contributed head tremor cases to the database!! If you're not sure what I'm talking about please email me or check out last week's TidBit Tuesday mailer for more details.

Stay safe, stay healthy and keep those consults coming!

Idiopathic Head Tremor VS Seizures

Idiopathic Head Tremors vs. Focal Seizures

Wow, a lot of you have been seeing head tremors lately and sending them my way! I thought we could take this TidBit Tuesday to look more closely at Idiopathic Head Tremors and compare/contrast to seizures. Please read or skip to the end - there is a plea for data collection and I need your help!

What are Idiopathic Tremors?

Good question!

• Tremors are action-related in veterinary medicine.

• Two classes are: Postural (example is orthostatic tremor, idiopathic head tremors, and hypomyelination) and Kinetic (Intention tremors with cerebellar disease, others)

• Postural tremors happen NOT AT REST. Meaning, the body part isn't supported by the ground/bed/etc. If it is, the tremor stops.

• Further, idiopathic head tremors STOP WITH MOTION. Distract the dog, get it walking, eating, etc, the movement stops.

• Kinetic tremors DO NOT STOP WITH MOTION. They get worse. The classic example is a cat with cerebellar hypoplasia. As they move, the tremor becomes more obvious. This is a kinetic tremor.

So, what causes idiopathic head tremors? We...ahem...don't know. They are classified as a movement disorder but that means it could be from CNS or PNS lesion localization. Movement disorders are a huge box of diseases that are lumped together but may be anything associated with specific movements, or not. There is a really nice, recently published article by Dr. Mark Lowrie that outlines the different types of tremors if you'd like to read more.
(https://bvajournals.onlinelibrary.wiley.com/doi/epdf/10.1002/inpr.3)

How do you differentiate tremors from seizures?

Look for classic evidence of seizures such as autonomic signs, changes in mentation or a lack of stopping when moved, distracted or completely recumbent. Even the head must be recumbent for idiopathic head tremors to stop.

How do you diagnose idiopathic head tremors?

I'm sorry to say that we don't have any diagnostic tests available to make the diagnosis. Also, it is idiopathic, so even if we do brain MRI/CSF all testing is normal. There is a suspected genetic sire in Doberman dogs that idiopathic head tremors can be traced back to, but as of yet there isn't a genetic test available. Stay tuned.

Because we cannot reliably differentiate these from focal seizures AND seizure disorders can be progressive and life-limiting if left unchecked AND some movement disorders do respond to anticonvulsant drugs I always, always, recommend doing a trial of an anticonvulsant medication before simply stating that they are a movement disorder and ignoring them.

One of the tenants of idiopathic head tremors is that they don't respond to anticonvulsant medications but please read this line cautiously. Up to 30% of dogs and cats with seizure disorders do not respond to anticonvulsants (1 or multiple) either so a lack of response to anticonvulsant drugs still does not rule out a seizure disorder.

If the animal has autonomic signs (drooling, lacrimation, urination, defecation, vomiting) concurrent with the movement, they cannot be distracted easily from the movement OR it is present at rest consider this a seizure disorder and keep trying to treat. Or call your local, friendly, mobile neurologist.

DATA COLLECTION

I am looking into the seasonality of head tremors. If you have a case that you have seen with a postural tremor, such as a head tremor, (not cerebellar animals) please consider filling out the short form found online to contribute data to this study. It shouldn't take long to fill out. If you've sent me an email about a tremor, please consider filling out the online questionnaire so I have your permission to include your data. Thank you!!
Link:https://barnesveterinaryservices.com/head-tremor-database
Password: VET2021

I am here to help you, help your patients, live their best lives with neurologic disease. You don't need to be "good" at neurology - that's my job - you just need to be willing to advocate for your patient!

Stay safe. I look forward to working with you soon!

Bromide!!

Bromide tablets received conditional FDA approval this month so I thought this was a good time for us to review Bromide and the do's and don'ts of this drug. 

What should clients (and vets) know about bromide?

Bromide is one of my favorite anticonvulsant drugs for dogs. Seizures happen when there is too much excitability or too little inhibition in the brain therefore neurons fire. Making neurons' less able to "fire" reduces seizures. Below are answers to common client questions about bromide.

How does it work?
This drug makes neurons more negative making it harder to fire a nerve. Less firing = fewer seizures. It does not eliminate seizures, nor does it "cure" an epileptic dog.

Has this drug been shown to be safe in dogs (or cats)?
This medication should ONLY be used for dogs. Cats do not tolerate bromide!

How long does it take to be effective?
Bromide has a long half-life, therefore it takes about 3 months to reach the point of maximal expected efficacy (steady-state). You may notice side effects, and clinical improvement sooner than 3 months however, it won't be fully stable (or fully effective) until at least 3 months. Furthermore, this means that when the dose is adjusted, it won't be fully realized until 3 months after the dose adjustment is made. Key point: Don't give up too soon on this drug. It is slooooowww.

Side note for vets: Please try to take a therapeutic serum concentration at 3 months even if the dog is doing well. This is valuable information should they loose that seizure control in the future.

What side effects are common?
Some pets do not demonstrate any clinical side effects. In those that do,sedation, ataxia, weakness, increased drinking, urinating, appetite and occasionally vomiting can be noted. It is important to understand that bromide and phenobarbital have very similar side effects so if the dog is already on phenobarbital and we're adding bromide, side effects may be additive! Don't blame the bromide! Vets: try reducing the phenobarbital a bit and often side effects will improve. We're adding bromide because we think it may help the dog so don't play with the dose too much (if at all) in the first 3 months.

What other life-style changes do I need to make for my dog?
Bromide must be given every day, at about the same time each day. It isn't as picky as some other anticonvulsant drugs so little adjustments in the administration time is usually okay. Vets: I prefer this medication is given 20 mg/kg PO q12h, but it can also be give as 40 mg/kg PO q24h.
Additionally, this drug will be confused with chloride during excretion through the kidney. This means that your dog must be maintained on a "stable" salt diet. Not restricted, just consistent. In other words, feed the same food, and if you must give "treats" give the same treats, every day. A sudden increase in salt consumption can result in a serious decrease in bromide in the body, resulting in seizures. (Think: 4th of July BBQ when the dog steals a hot dog from the table...)

Incidentally, "bromide" also means: a trite and unoriginal idea or remark, typically intended to soothe or placate. Hmmm, I wonder if I can put this in a sentence in everyday life? :)

For some of you, this was a repeat TidBit Tuesday from November 2019. This is one of those topics I think is worth repeating and I hope you agree.

Stay safe, stay warm and be healthy. I'm available Mon-Sat, if you have a question, or a case that needs evaluation.

Seizures vs Syncope

In honor of Valentine's day this past weekend, I thought we might discuss when the heart tries to act like the brain...known as syncope vs. seizures.

Seizures and syncope are both described as a temporary loss of consciousness. Clinical signs of seizures often include collapse, some form of somatic movement, and a display of autonomic activation (e.g. urination, defecation, salivation, pupillary dilation) but these signs can be subtle in some patients. Clinical signs of syncope may also include collapse with occasional loss of bladder or bowel function. However, the pathophysiology, differential diagnoses, diagnostic testing and treatment plans are markedly different therefore differentiation between seizures and syncope is critical! What are my top 5 ways to differentiate between seizures and syncope?

1. Autonomic signs: Loss of bladder control has been reported with syncope and is a common finding with seizures. Other autonomic changes such as loss of bowel function, salivation, lacrimation and dilation of pupils have not been reported with syncope and are regularly reported with seizure disorders.

2. Post ictal phase: blindness, disorientation and at times, aggression can be seen for minutes to hours following a seizure. Animals with syncope may appear momentarily disoriented but typically they are back to normal within seconds of a return to consciousness.

3. Timing of the event – It is more common for seizures to occur when the pet is at rest, and syncope to occur when the pet is in motion or accelerating. We know this doesn't apply 100% of the time but can be a very helpful to ask what the pet was doing immediately before it collapsed.

4. Evidence of metabolic disease: Evidence of metabolic diseases known to cause seizures such as hypoglycemia, hypocalcemia or hepatic failure concurrently identified in a patient with a history of acute collapsing episodes should lead the clinician to consider a seizure disorder. Without a doubt, patients with metabolic diseases can also have concurrent metabolic derangement however I will use this as a tool when trying to sort between seizures and syncope.

5. Neurologic examination abnormalities. This one is obvious. If the pet has neurologic abnormalities that localize to the prosencephalon (forebrain) it is reasonable to consider this lesion localization over syncope. You could turn this upside down and say that if the pet has evidence of a cardiac arrhythmia or cardiac disease, syncope may be considered more likely. I have seen several patients that have been unfortunate enough to have BOTH syncope and seizures but, thankfully, that is rare.

I hope this helps you differentiate between seizures and syncope. Let me know if you have any other ways to differentiate between seizures and syncope in your practice.

Thanks for reading and stay warm, my friends! 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.

Midazolam as a Constant Rate Infusion (CRI)

We Tell Clients: Seizures Should Be Stopped ASAP. But...Why?

1. Prevent brain damage

2. Prevent secondary systemic problems such as hypoperfusion, acidosis and possibly hypoglycemia if prolonged.

Okay, fine that's reasonable. But how, and when do I use a CRI?

My rule of thumb for dogs and cats with seizures is to recommend hospitalization with placement of an IV catheter and initiation of a constant rate infusion if a pet has more than 3 seizures in 24 hours. (At home cluster buster care is another TidBit Tuesday.) Once seizure control has failed at home, it is time for hospitalization.
Diazepam is the mainstay drug intervention however diazepam shortages and a growing recognition of phlebitis secondary to IV diazepam has lead to a greater use of midazolam. Full disclosure, I have used midazolam without hesitation for more than 12 years but...sigh...we didn't have scientific literature to support it's use, until now!
A study out of North Carolina State University by Dr. Bray and colleagues (two of whom were my resident mates way back...) described the use and safety of midazolam CRIs in dogs with status epilepticus and cluster seizures.

The findings, in a nutshell:

• 106 dogs including 40 with idiopathic epilepsy, 16 unknown seizure etiology, 43 structural epilepsy and 7 with reactive seizures. --> I suggest that this heterogenous population provides us challenges with efficacy studies but at least we have something!

• Median start dose was 0.25 mg/kg/hr., range 0.1-0.75 mg/kg/hr. (Remember it has a 20% higher binding affinity than diazepam)

• Seizure control was obtained in 82 dogs (77% of the population) including 49 in which no dose adjustment was needed and 25 in which dose escalation was required to control signs and a further 8 in which 1 single additional seizure occurred but they still considered it control. (Hmmm, this group doesn't meet their criteria very well.)

• Adverse effects were reported in only 24 dogs (22.6%) which included sedation, vomiting/diarrhea, hyperexcitability, ataxia and polyphagia. No reports of phlebitis, as expected.

• Median time to control was 13 hours and CRI duration was 25 hours.

The main limitation to the study, from my point of view, is the heterogenous population. We suspect poorer seizure control in dogs with structural epilepsy than those with idiopathic epilepsy. This was also noted in the study wherein control was obtained in 85% of dogs with idiopathic epilepsy and 74% of dogs with structural epilepsy. This difference, however was not statistically significant.

Take Home Message

• Continue to use midazolam, with a starting dose of 0.2 mg/kg/hr. (Now with data to support it's use!!)

• Expect success in most patients, regardless of the underlying cause

• Plan to use it for at least 12 hours, but possibly longer

• Phlebitis is not expected, unlike with diazepam!

Want more? The full article can be found online (open access):
Bray, KY, Mariani, CL, Early, PJ, Muñana, KR, Olby, NJ. Continuous rate infusion of midazolam as emergent treatment for seizures in dogs. J Vet Intern Med. 2020; 1– 9. https://doi.org/10.1111/jvim.15993

Welcome to 2021!! I look forward to continuing to work with you, and your staff.

Seizure management is my passion - please call/email or have me out for a consult if you have a seizure case!

The Nuts and Bolts of Anticonvulsant Drug Monitoring

The following information is contained in these two tables:
1. What drugs can I run therapeutic drug monitoring levels?
2. Where do I submit samples?
3. When do I draw blood for sampling?
4. What is the standard reference interval?
5. What is MY (i.e. Dr. Heidi Barnes Heller's) recommended reference range
6. How should I collect this sample? Note - all samples for therapeutic drug monitoring should be spun and separated into a plain red top tube. Do not use serum separator tubes! Plasma can be used for some samples also. Please separate the plasma into a plain red top tube as well.
7. What time of the day should I collect the sample?
*** The format became a little messy with the mailer so email me directly if you want a printable PDF of these tables.

What is not contained in these tables?
How do I use this information obtained from a drug serum concentration?? Stay tuned for that in a separate TidBit Tuesday! :)

As always, please stay safe, and mentally and physically healthy out there. I love working with you and look forward to continuing to do so.

Please note that I am performing consults through December 25th and then I will be modifying my schedule through January 16th because of my concern for increasing COVID numbers following the holidays. As many of you know, I have an at risk kiddo so I am super-duper cautious. If you need a consult between December 25th and January 16th please email me to discuss options.

Happy Hanukkah to those of you also celebrating!

20% of dogs receiving AEDs have dermatologic reactions??

Up to 20% of dogs taking AEDs may have a drug reaction that manifests as a dermatologic reaction.

Wow! That number is higher than I remember from residency; what's your experience?? I dug into this statistic this week after consulting on a case about a possible dermatologic drug reaction in a dog receiving an anti-epileptic drug (AED).

What signs are seen?

During a prospective study, 15 dogs (of 137 dogs) were identified as having a dermatologic condition after starting an AED. However, three may have had signs before starting the AED. All 15 were treated with phenobarbital!

9 dogs were seen by a dermatologist and the following signs were documented:

• Extensive erosions or epidermal necrosis leading to skin detachment (4 dogs)

• Papules, pustules, erythema, crusty lesions (8 dogs)

• Pruritus and/or alopecia (3 dogs)

How do they *know* it is related to the drug?

They utilized an index based assessment, which is used for drugs in which withdrawal or drug challenges may be unethical (AEDs!). The index is called the Naranjo intext. I'm not terribly familiar with the nuances of using this index, so forgive my lack of a more detailed explanation. When they applied this, they considered 6 dogs to have probable cutaneous drug reactions, possible drug reactions in 8 dogs and doubtful in 1 dog. We all know these indexes can be wrong, but those numbers sound pretty compelling, and concerning.

How was it managed?

The AED therapy was withdrawn in 7 cases and 5 subsequently resolved completely with 2 weeks. Another dog had partial improvement after withdrawal of the drug and the rest received supportive or directed treatment such as anti-inflammatory, antimicrobial topicals, ant parasitic agents, or systemic prednisolone. All dogs had resolution of signs with the above treatments, but improvement wasn't complete and appeared temporary.

Key Point: Do a thorough physical examination on your patients before starting any AED and document new dermatologic changes if they arise. Can they still be coincidental? Yes. But, maybe we're are missing some that are not.

Do you need help with an epileptic patient? I am especially fond of helping with seizure management so I'd love to help! Call, text or email. Please note that I respond to emails at night (most days) so if you have an urgent question please call or text.

*Reference: Koch T, Mueller BD, et al. Cutaneous adverse drug reactions in dogs treated with antiepileptic drugs. Frontiers in Veterinary Science 2016: 3: 1-10.

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!