The blood-brain-barrier is an important player in epilepsy, even if it is an unsung hero. You may (or perhaps may not) recall from veterinary school that there are 3 parts to the BBB. 1) the tight junction (TJ) proteins between endothelial cells 2) the highly specialized and restrictive transport system in the cellular walls and 3) the capillary wall which utilizes a basement membrane, astrocyte feet (I love that they have feet) and little pericytes. The BBB is one of the best bouncers in the system and it takes extreme caution allowing molecules to pass. Over the years we have learned that the BBB plays an important role in epilepsy. For example, disruption of the TJ proteins, most notably upregulation of MMP9 (if you want to know everyone’s full name, please refer to the article) has contributed to the generation of seizures. Conversely, stabilization of the BBB can prevent seizures in experimental models. Leakage of serum albumin, through a dysfunctional BBB, has been shown to bind to TGF-beta on astrocytes and cause astrogliosis (an increase in astrocytes, or upregulation of their function). The development of astrogliosis, followed by some changes in the extracellular matrix causes a DECREASE in the inhibitory protein GABA and INCREASE in excitatory synapses in the brain. Decreasing the inhibitors and increasing the excitatory proteins. Yikes! Bring on the seizures.
A study was published outlining some novel ways to look at the BBB using MRI (Hanael E, et al from Israel. JVIM 2024). There are parts of that article that I will be skipping for this TidBit Tuesday because they aren't applicable unless an MRI is part of your practice. However, the parts that I think are good for general discussion relate to the location in the brain. Seizures are frequently generated in the piriform lobe, so the researchers looked at that lobe using MRI, histopathology and CSF. They found a significant increase in albumin and MMP9 proteins in the piriform lobe in dogs with idiopathic epilepsy, along with evidence of damage to the BBB on MRI in this region. CSF albumin was increased AND serum MMP9 activity was increased in dogs as well. All of this supports evidence that we are finding damage to the BBB, causing consequences to the brain (specifically the piriform cortex) which is then manifested physically as a recurrent seizure disorder (epilepsy). Perhaps the future will hold some therapies directed at "patching" the BBB as a treatment modality - you'll have to stay tuned!
This week's TidBit Tuesday was a bit heavy on the sciences so I hope you'll forgive me on this first full week of summer. Epilepsy is an ever changing area of study that I find fascinating and hope you don't mind coming along for the ride with me sometimes. Have a terrific week and I hope you can get out and enjoy the sunshine!
Vestibular Epilepsy
Wait, what? Did I read that correctly? Yes, you did! What do you call acute onset, transient vestibular signs? Vestibular paroxysmia (VP)! What do you call it if you have interictal spike and wave forms on EEG (which suggest an epileptic focus)? You guessed it... vestibular epilepsy (VE).
What is Vestibular Epilepsy?
In human neurology, there is a form of epilepsy in which patients have acute onset vestibular signs (drifting, rolling, nystagmus) that seconds to minutes. If the onset is associated with body position change, it is considered a paroxysmia (VP). However, when an EEG is performed, human patients with vestibular epilepsy will show classic changes consistent with seizures in the temporal and parietal lobes. The big differentiator between paroxysmia and epilepsy is the response to treatment and the presence of changes on EEG. In veterinary patients there are very few studies evaluating this form of epilepsy but clinically perhaps some of you can think of a patient (or two) with similar clinical signs? We see this, albeit rarely!
How To Diagnose Vestibular Epilepsy
Diagnosing VE in veterinary medicine can be challenging. Patients will present with repeated, transient vestibular signs and are normal on examination. Animals with underlying vestibular disease (think central or peripheral vestibular disease) often have a residual positional strabismus, or mild head tilt, or another lingering deficit. Animals with VE do not! (At least not as far as we know...yet.) In a recent study published in JVIM (2024), the authors identified 10 dogs with suspected VE. All 10 dogs were treated with an anticonvulsant drug (or 2). Five of 10 dogs received just levetiracetam, 2 of 10 received Levetiracetam + phenobarbital, and 1 of 10 received levetiracetam and gabapentin or just phenobarbital. Half of the dogs receiving levetiracetam only had resolution of seizures and the other 5 had a sustained reduction. The one dog receiving phenobarbital and levetiracetam had marked improvement after phenobarbital was added, but not before.
What Is The Take Away Message?
1) Be aware of transient vestibular signs - maybe your patient has seizures!?
2) If seizures are suspected, try levetiracetam (22 mg/kg PO q8h standard release; 30 mg/kg PO q12h extended release)
3) The dogs in this study had idiopathic vestibular epilepsy (because the study selected for those cases) but vascular disease (such as transient ischemic attacks; TIA) can cause transient vestibular disease and maybe vestibular epilepsy (according to a different study).
Not sure what your patient has? Catch a video and set up a consultation! I'm always happy to rule OUT neurologic disease and I am here to help when we rule it IN. Have a great week! I hope those of you celebrating Easter had a nice, relaxing holiday. I look forward to working with you soon!
Trace Minerals and Canine Epilepsy
Trace elements are the micronutrients found throughout live animals that are essential for organ function and brain health. They keep mitochondria running smoothly, improve neurotransmission and aid with enzyme function. Deficiency or excess has been linked to multiple neurologic diseases including neurodegenerative diseases, behavior diseases and inflammation in humans and animal species. A recent study evaluated the levels of several trace elements in hair samples of dogs with epilepsy and compared them to dogs without seizures.
What Trace Elements were Abnormal?
In this study, by Rosendahl et al, there were 10 epileptic dogs without any treatment, 53 epileptic dogs currently undergoing treatment for epilepsy, and 42 control dogs (no seizure history).
Phosphorus: lower in epileptic dogs
Copper: Higher in epileptic dogs
Zinc: higher in epileptic dogs
Copper/zinc ratio: higher in epileptic dogs. Specifically, higher in dogs treated with phenobarbital, in one previous study. Studies have shown that copper homeostasis is an important preventative for some neurodegenerative diseases. More work needs to be done in veterinary species to determine if this holds true for our patients, too.
Selenium: higher in epileptic dogs
Arsenic: higher in epileptic dogs but also much higher in dogs receiving potassium bromide!
Some of these findings were significant, some were significant only when comparing control dogs with either treated, or untreated dogs, and others were significant for both subgroups of epileptic dogs.
This study is likely to be a stepping stone for either this group, or others, studying trace minerals and their relationship to seizures. It was important work to identify differences, but the clinical significance remains unknown. Treatment, or correction of these deficits or elevations of trace minerals has not been evaluated in epileptic dogs. Stay tuned!
Thanks for reading! I hope you have a great week and enjoy what I hope is our final push out of winter, into spring, weather.
Reference: https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.16698?campaign=wolearlyview
Bile Acid Testing For Dogs with Seizures
Case scenario: You are presented with a 2 year old Labrador retriever with a history of 3 seizures in the past 1 month. The seizures are consistent with generalized seizures and last less than 1 minute. Further questioning of the client reveals the dog to have normal activity, appetite, and mobility at home between seizures. You perform a neurologic examination (yay!) and no abnormalities are found.
What is the likelihood of idiopathic epilepsy in this dog?
According to the International Veterinary Epilepsy Task Force, a diagnosis of idiopathic epilepsy can be made, at a Tier I level of confidence, if a dog is between the ages of 6 months and 6 years, has had 2 or more seizures, has a normal interictal neurologic examination AND has normal CBC, serum biochemistry and dynamic bile acid testing (that means pre and post feeding testing). We know Labs are commonly diagnosed with idiopathic epilepsy and that a genetic inheritance is known or suspected for most of the breed. So, do we really need to do a bile acid test?
First, a little background. Minimum data base (MDB) pseudohepatic function tests include glucose, BUN, albumin, ALP and ALT. A pre-prandial bile acid test alone, called a resting bile acid test, is different than a dynamic bile acid test which includes both pre and postprandial samples.
Do we Reallllly Need to Perform Dynamic Bile Acid Testing?
An article from England recently addressed this question in a publication in the Veterinary Record (DOI: 10.1002/vetr.2585).
Questions asked:
1. If a dog has a normal MDB, how likely are we to finding an elevated postprandial bile acid test?" Answer: 24 dogs out of 202 dogs
2. How likely is a dog with a normal MDB and a normal pre-prandial bile acid test to have an elevated postprandial bile acid test? Answer: about 9 out of 100 dogs
3. What is the prevalence of a clinically significant hepatopathy in a dog with a normal MDB and normal pre-prandial serum bile acid test (if we don't do a post-prandial bile acid test)? Answer: 1.29%
The authors compared this to the risk of missing a significant brain lesion in a dog less than 6 years of age with a normal neurologic exam in which an MRI is not performed. (About 2.2% of cases would have had a brain lesion missed.) The question always begs, how much of a risk taker are you, or your client?
Based on the information from this study, here is what I propose we do:
ALWAYS check CBC, serum biochemistry for every dog with a history of 2 or more seizures.
ALWAYS recommend a pre AND post bile acid test for every dog presenting with a history of 2 or more seizures, even if CBC and serum biochemistry are normal. When making this recommendation I suggest that we make clients aware of the less than 2% chance that their dog could have a significant hepatopathy that will be undiagnosed if we do not perform these tests. This hepatopathy may be the reason for their seizures or, and perhaps more importantly, it could affect how they metabolize many of the anticonvulsants that we use. I'm looking at you phenobarbital, zonisamide and diazepam! Poor hepatic function could result in poor metabolism of these anticonvulsant drugs even if the hepatopathy isn't severe enough to be the seizure etiology.
ALWAYS perform a neurologic examination to document any abnormalities before starting any medications for seizures. (Okay, so this wasn't part of the study but I still think this is a must!)
Thanks for reading! This was a very informative article so check it out for more detail!
Have a seizure patient that you need a little backup for? Seizure management is my passion so I'd love to help! Email me or hop on my website to schedule a consult. Have a great week!
Levetiracetam use in Cats
We all know cats are not small dogs, so how does levetiracetam (leh-vuh-tr-A-suh-tam) differ between species?
Metabolism
The mechanism of action (modification of the SV2A receptor) is the same for cats and dogs. This mechanism of action (MOA) is unique to levetiracetam and different that the MOA for phenobarbital.
Formulations
There are two formulations available 1) standard release (SRL) and 2) extended release (XRL). The dosage of 20 mg/kg PO q8h for the SRL formulation, comes from pharmacokinetic analysis of this drug in a cohort of healthy cats. A therapeutic range has not yet been developed for cats therefore if seizure control is poor, the dosage is often increased until signs of toxicity are noted and then reduced to the highest effective dose with minimal side effects. When doing that, the prescriber is using the individual animal as a guide for toxicity rather than an established therapeutic range. Reported side effects include hypersalivation (mild, transient), inappetence and mild lethargy. There are very few efficacy studies for cats, however in 2008, a single study reported a greater than 50% reduction in seizures in 7 of 10 cats when levetiracetam was added to phenobarbital. Liquid formulations are readily available through compounding pharmacies and can be used interchangeably with the 250 mg size tablets. Use caution when prescribing the liquid formulation to ensure it does not have xylitol as an added ingredient.
Extended release levetiracetam is available in 500 mg and 750 mg size tablets. Historically, this has limited its use in cats. In 2017, I decided it was high time we changed that thinking so we evaluated the pharmacokinetics of a single dose of 500 mg XRL in healthy cats and found that it was well tolerated with minimal side effects. Furthermore, we identified that a reduce dosing interval from q8hr (SRL) to q24h when using XRL was appropriate for cats! The serum levetiracetam concentrations were really high therefore we subsequently evaluated the use of levetiracetam over 10 days to monitor for drug accumulation. Thankfully, none was identified! No efficacy studies have been performed using 500 mg PO XRL q24h in cats, to date, however I do recommend this dosage for cats, when levetiracetam is needed and q8h dosing isn't an option.
The story doesn't end there! Medicating cats is such a terrible thing to do to a cat (and horrifying for some owners) that I then explored the idea of transdermal levetiracetam (TD).The dosage of 20 mg/kg transdermal q8h resulted in serum concentrations similar to those of the oral route with minimal side effects. We have not evaluated TD levetiracetam long-term so efficacy remains unknown. Do I use TD levetiracetam? Yes. I ensure that the clients know that this is cutting edge research and therefore long-term efficacy studies have not been performed; purely that it is well tolerated.
That's all for now! Please reach out with any suggested topics and stay tuned for a super fun neurology CE event coming this summer. Shhhh...it's still in the planning stages!
Have a great week!
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!
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!
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!
