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! 

Do Cats Have Seizures?

Do Cats Have Seizures?

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

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

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

• 1-year prevalence for epilepsy: 0.04%

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

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

• two or more seizures, at least 24 hours apart

• Age 6 months - 6 years old

• Normal (unremarkable) neurologic examination inter-ictal

• No clinical abnormalities on CBC, serum biochemisry, urinalysis

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

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

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

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

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

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

Have a good week! 

CBD oil and Canine Epilepsy

What is the Effect of CBD oil on Canine Seizures?

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

As a neurologist, I add the following…

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

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

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

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

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

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

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

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

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

Microbiome and Epilepsy

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

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

Lactobacilli and the Influence on the Brain

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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