Phenobarbital and The Adverse Effects in Cats

Many of you know that Phenobarbital is one of the most effective anticonvulsant drugs (AED) that we use to help control feline seizure disorders. Data we published several years ago suggested that 93% of cats obtained seizure control with serum drug concentrations between 15-40 ug/ml, regardless of the etiology. Remember, control is either a 50% reduction in seizures or 1 or less seizures every 3 months. Despite its high accolades for control, phenobarbital can cause adverse effects in cats. Phenobarbital does undergo hepatic metabolism but, unlike in the dog, it does not result in an increase in ALP. So, what adverse effects can happen?

Clinical Adverse effects
Clinical adverse effects occur in 46.7%of cats in a 2021 study (Marsh et al). These may be described as Type I or Type A adverse effects because they are secondary to the drug properties and often dose dependent. Keep that in mind!  Sedation and ataxia were the most common side effects, but not the only ones. 
Here are the adverse effects, 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. Interestingly, 26 of the 36 cats with reported adverse effects had transient signs. The majority of these only occurred in the first 4 weeks of treatment and in cats receiving multiple anticonvulsants. Adverse effects were significantly more likely in this population of cats when more than 1 AED was being used.

Biochemical Adverse Effects
A more severe, and concerning type of adverse effect is Type B. These adverse effects 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. Biochemical adverse effects are much rarer in cats than in dogs. If a cat has an elevated ALP, as a general rule, find a reason other than phenobarbital administration. In both the study we published several years ago, and the study by Marsh et al, no cats showed an elevated ALP on laboratory results.
 
Take home message:

• Talk with owners about the common adverse clinical effects in the first 2-4 weeks of treatment. These should resolve but if not, consider reducing the dose.

• Recheck the CBC and biochemistry within 4 weeks of starting phenobarbital to monitor for those rare Type B adverse effects.

• Phenobarbital is useful, but imperfect, so always look at the cat in front of you when making decisions about seizure management. When in doubt -reach out!

Thanks for reading! I hope you have a good week and are appreciating the slow shift to cold pre-winter weather that we’ve been having. I look forward to working with you soon.

Brain-Gut-Epilepsy Link

This is exciting, folks! It has been well established that comorbidities such as anxiety, ADHD and fear-behavior are present for human and veterinary epileptics. Owners of dogs with epilepsy are frequently troubled by behavioral changes AND the seizures, especially when poorly controlled. Recently, the gut biome has been an area of focus as an area of possible therapeutics for these comorbidities in humans and animals. A group of colleagues from Europe and Asia recently published data looking into this question and... it’s pretty cool! Read on to learn what they learned. 

Material and Methods
Nine dogs with drug resistant epilepsy AND behavioral changes were included in the study. A fecal donor was a dog with epilepsy that did not have behavioral comorbidities and had responded well to phenobarbital. Fecal microbiota transplantation (FMT) was performed three times, two weeks apart. Questionnaires and behavioral tests were performed at 3 and 6 months after the FMT. This, along with urine testing of neurotransmitter concentrations and routine biochemistry and hematology. 

Results
There was a significant improvement in ADHD-like impulsivity, non-social fear and chasing behavior (questionnaire based), AND seizure severity and frequency. Not surprisingly, the care-giver anxiety concurrently decreased significantly. Even more interesting (to me), the excitatory neurotransmitters glutamate and aspartate decreased and GABA, an inhibitory neurotransmitter, increased. Only 1 dog had a partial seizure response (50% reduction in seizures), and several other dogs had a reduction in cluster days during the follow-up period. No dog was seizure-free after the FMT. 

Take Home Message
This was a pilot study, so it isn't clinically applicable yet. YET. But can you imagine having access to FMT to help manage comorbidities like these? I'm sure you can think of at least 1-2 patients right now that would benefit from a decrease in ADHD-like behavior, fear or anxiety behaviors! Although we cannot use this yet to change our patient's lives, keep your ears open for the future. However, as with all new treatments out there, there will be good and bad options as this comes out. Remember that there are a lot of factors that can affect FMT. Specifically, current or historic administration of medications (antibiotics, gastroprotection’s, NSAIDs, and possibly anticonvulsants). A donor with any of these medications in their past may have an altered gut biome that makes them an unfit donor for your specific patient. So, please don't just take any gut biome and assume it will work for another patient!

Thanks for reading. I hope you can feel my excitement oozing out as you read this week, and I hope you enjoyed reading this TidBit Tuesday as much as I enjoyed reading the article. If you wish to read more, please follow the link below. Have a great week!
Link: doi.org/10.3389/fvets.2024.1385469

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 and the mailer doesn't suffice. 

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! :)

DrugWhere to submitWhen to submitStandard reference range (may vary a little by lab)PhenobarbitalAny commercial lab. Unless you regularly run QC, in-house phenobarbital analyzers aren’t recommendedAfter 14 days on the same dose15-40ug/ml (dog)
Extrapolated for cats: 15-40ug/mlLevetiracetamAuburn University
https://www.vetmed.auburn.edu/ veterinarians/clinical-labs/After 3 days on the same doseNONE verified for dogs or cats. Human range is 5-40, but target may be closer to 20 for “resistant” humans.ZonisamideCornell Animal Health Diagnostic Center https://www.vet.cornell.edu/animal-health-diagnostic-center/testing/protocols/zonisamide
After 14 days on the same dose10-40 ug/ml (human) extrapolated to dogs and catsBromideAny commercial lab.After 12 weeks on the same dose, and/or after completion of a loading dose1-3 mg/dl

DrugMy recommended reference range (pet dependent of course) Other notesCollection timePhenobarbital25-30 ug/ml dog and cat (cat is extrapolated from dog)Plain red top, serum only.Any, if on longer than 14 days of medicationLevetiracetamNone. Use this sample as an internal reference. Not sure what I mean?? Please email me for additional details.Separate serum (or plasma) into a plain red top2-4 hr. post pillZonisamideNone. I don’t think we actually know the range for dogs and cats yet!Separate the serum or plasma and store in refrigeratorJust before the next dose (i.e., trough level)BromideSolo: 2-2.5 ug/dl
Combination with phenobarbital: variable but usually around 2.0 ug/dl.NoneAny time, if at steady-state

Thanks for reading! I hope you're getting in the fall spirit and enjoying all things pumpkin, cinnamon and apple-y! Please reach out over the next few weeks if you need a consult and cannot find a suitable time on the scheduler. I have a lot of days blocked off for family events but may be able to squeeze in a consult or two as needed. 

Idiopathic Head Tremors

Wow, a lot of you have been seeing head tremors lately! I thought we could use this TidBit Tuesday to look more closely at Idiopathic Head Tremors and compare/contrast to seizures. 

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, if the body part that is tremoring is supported, 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. 

We're going to focus on postural tremors, and specifically head tremors. There are structural head tremors and idiopathic head tremors. Structural tremors are caused by something we see on MRI or CSF. These cases often involve pituitary lesions and are typically older pets, with neurologic deficits on neurologic exam. Contrast this with idiopathic head tremor. Animals with idiopathic head tremor can be of any age but are typically younger dogs, with a normal neurologic examination and normal MRI/CSF. 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, slightly older 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. 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 usually 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. Furthermore, rapid head movement in a bulldog is a COMMON presentation for a focal seizure so don't just disregard the information. Do a neurologic exam!! 

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 for a consult :)

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!

How do MRI lesions affect survival for MUE?

 
A study was published this week that looked at the survival times between dogs with and dogs without MRI lesions and diagnosed with meningoencephalomyelitis of unknown etiology (MUE). MUE is diagnosed if a dog has evidence of CNS inflammation (meningitis, encephalitis, myelitis or a combination of these) without evidence of infectious etiology. Signs can be focal or multifocal, and age is irrelevant. To make this diagnosis an MRI, CSF tap, and infectious disease testing are performed. There is a subset of dogs that are diagnosed with immune mediated CNS disease that do not show evidence of disease on MRI but have all of the other markers of MUE. The purpose of this paper was to determine if there is a difference in survival between the two groups of dogs.
Results
A total of 73 dogs with MUE were included in the study. This included 19 dogs with a normal MRI and 54 with an abnormal MRI. The survival time was >107 months in both groups with a significantly longer survival in the normal MRI group. Neither group reached median survival in Kaplan-Meier survival, however. Death was secondary to MUE in 1/19 dogs with a normal MRI, and 18/54 in dogs with an abnormal MRI.
Below is the breakdown comparison between the two groups:

• Remission – 68% of the normal MRI group; 53% of the abnormal MRI group.

• Death within 3 months due to disease – 5% in the normal MRI group and 13% in the abnormal MRI group.

No difference was found between dog groups regarding remission, disease-free interval, or relapse while on prednisone. The two groups received similar treatment protocol, for which corticosteroids were included in all dogs and a variation of additional immunosuppression. The total nucleated cell count (TNCC) was higher in the dogs with the abnormal MRI however this did not correlate with higher rates of death after multivariate analysis. The only significant factor associated with death was the presence of an abnormal MRI.

Why don’t they have lesions on MRI?

Perhaps we’re catching these cases early in the course of disease. This would stand to reason why they might have a lower death rate than those with more progressive disease at the time of diagnosis. Another option is that this is a different form of inflammatory brain disease. MUE is a “catch all” for inflammatory brain disease that isn’t infectious, or a specific form such as SRMA or EME. It likely includes all of the previously diagnosed cases of GME and NME.
Take away: If you have a dog with spinal pain, seizures, vestibular signs or multifocal CNS signs remember MUE! This disease can cause all of those signs, and a collection of other signs, in dogs. Early detection may = improved outcomes. So, if your patient is showing neurologic signs, please reach out to get a consult ASAP and to proceed with additional testing when able. We might just save their life!

Thanks for reading! I hope you are scratching out the very best that summer has to offer. I look forward to working with you soon!

Reference: Survival in dogs with meningoencephalomyelitis of unknown etiology with and without lesions detected by magnetic resonance imaging. Ostrager A, Bently, TR, Lewis MJ, Moore GE.
 

Levetiracetam vs. Phenobarbital for Neonatal Seizures

Thankfully, neonatal seizures are not something that we identify frequently in veterinary medicine. Unfortunately, neonatal seizures are one of the most common reasons for presentation to the ER in human medicine. Among full term infants, seizures account for 1-3.5% of the cases for infant presentation to ER. To date, phenobarbital (PB) has been the anti-epileptic drug (AED) of choice, however levetiracetam (LEV) was evaluated in a meta-analysis in 202. (REF) The findings are interesting…read on to learn more!
 
Some Background
Human infants with seizures generally have a good prognosis. Phenobarbital has been reported to control 43-80% of electrical seizures, with the added benefit of reducing brain metabolism. The downside is that it has been shown to cause neuronal apoptosis in animal models (aka our patients). LEV has a seizure control rate of 35-86% for neonatal seizures and has been shown to have a neuroprotective effect without evidence of neuronal apoptosis or synaptic development. As we well know, LEV also has a lower side effect profile in our patients. This is true for human infants however the adverse effects monitored are slightly different. In this population, blood pressure and respiratory depression are more significant and are what are reported in studies evaluating adverse effects.

The Results
Most studies reported no significant difference in efficacy between LEV and PB however 1 study showed that LEV was more effective for clinical seizures (seizures we can see) and not significantly different with electrical seizures (those we can only see on EEG). Another study reported that high dose (20-40 mg/kg/d) PB was more effective than LEV, but regular dose (20-30 mg/kg/d) was inferior to LEV. The seizure control rate in 1 study was 86% with LEV, and 62% with PB. However, the meta-analysis identified that overall, no significant difference was found between the two drugs.
Levetiracetam was the winner in terms of adverse effects! In most studies, LEV had a lower incidence of hypotension and respiratory depression than PB. Neurodevelopment scores (motor, cognitive and language scores) were similar among the two groups with a slightly higher language score in infants that had been treated with PB.
Despite all of this, PB is still the first-line treatment for neonatal seizures according to the WHO (2021) because it controls most seizures, from most etiology, and also decreases the metabolic rate. This might seem trivial, but reduced metabolic rate can improve outcome fairly strongly due to a lack of “work” that the brain must do during the post ictal phase.
 
What do I think? Based on this data, I would favor intravenous LEV at 30-60 mg/kg single dose for neonatal seizures in our patients FIRST, followed by diazepam + phenobarbital second if seizures aren’t controlled.
Thanks for reading! I hope you have a wonderful week and I look forward to working with you soon.

Age, The Neurologic Examination and Seizures

Age isn't a disease, right? No, it isn't but disease is associated with age. The older pet with seizures is more likely to have structural disease (i.e. neoplasia instead of idiopathic epilepsy), compared to the younger pet. That said, none of us want to diagnose a terminal disease in an older patient simply because the patient is older!

Can the Neurologic Examination Help Vets differentiate disease in Older Patients?
Let's look at the two most commonly performed parts of the neurologic examination and see how they related to disease. The menace response and paw replacement testing (previously called conscious proprioception) both assess the forebrain and are some of the most commonly performed parts of the neurologic examination. Here is what a recent group from Australia found in reference to finding evidence of forebrain disease on MRI:

Menace response
Sensitivity: 72%
Specificity: 47%
Odds ratio:  2.26

Proprioception
Sensitivity: 54%
Specificity: 72%
Odds ratio: 3.08

If age is then factored into the analysis, dogs greater than or equal to 6 years of age were more likely to have a forebrain disease detected by MRI if they had a menace or proprioceptive deficit. 

As a "field" neurologist (without a pocket MRI...yet) this tells me that I should encourage diagnostic imaging in patients with menace deficits, and possibly for those with proprioceptive deficits depending on concurrent findings. The chances (or Odds) of a patient having underlying forebrain disease is higher if they have these deficits than if they don't. Seems intuitive, but proprioceptive testing isn't as sensitive as assessing the menace response.
What's the take-away message here? If you have an older pet with seizures, and the neurologic examination is NORMAL, you might miss underlying structural brain disease if you do an MRI but, then again, you might now. If you have an older pet with seizures and a menace or proprioceptive deficit is noted you'll LIKELY MISS a structural brain disease if you skip the MRI. 

Although this TidBit is a repeat from 2020, I liked this study and thought it was worth repeating...again. 

Chan MK, Jull P. Accuracy of selected neurological clinical tests in diagnosing MRI-detectable forebrain lesion in dogs [published online ahead of print, 2020 Jul 15]. Aust Vet J. 2020;10.

Thanks for reading! I look forward to working with you soon. Have a great week!

What Role Does the BBB Play in Epileptogenisis?

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!

Zonisamide Use in Dogs

Guess what? Another study evaluating zonisamide was published recently (this one out of Japan: Saito et al. JVIM 2024). A historical paucity of data about zonisamide has made me hesitant to use this antiepileptic drug (AED) so I’m pleased that times are a changing!
On to the important stuff… This was a prospective multicenter, open-label uncontrolled study in 56 dogs. Several dogs dropped out, so the end result was that 53 dogs were assessed for efficacy and 56 dogs were included for evaluation of tolerability.

Results

To determine an appropriate dose and the target plasma concentrations, many researchers will calculate the mean drug dose and concentration for 50%, 90% and 100% of the responders. They found the following:
50%: dose range was 2.7-4.9 mg/kg PO q12h; no mean trough plasma concentration provided.
90%: mean dose 4.8 mg/kg PO q12h; mean trough plasma concentration 18.9 ug/ml
100%: mean dose 5.5 mg/kg PO q12h; mean trough plasma concentration 21.9 ug/ml
Putting all of this together, the starting dose recommendation by the authors was 2.5-5.5 mg/kg PO q12h for most dogs (reduce this for dogs with renal disease). The recommended therapeutic range is 10-40 ug/ml. However, there are a couple of things to be aware of when using this therapeutic range. First, the study design stated that the dose would be increased incrementally every 1-2 weeks for dogs with persistent seizures until adverse effects were noted OR they reached 15 mg/kg dosing. They did not exceed 15 mg/kg which could affect what is considered an appropriate therapeutic range. Secondly, the dose did not predict the serum concentration, suggesting non-linear PK. What this means is that if you start a dog on zonisamide at 5 mg/kg PO q12h, you cannot necessarily predict the plasma drug concentration. Phenobarbital in cats has predictable PK, but it doesn’t in dogs, for example. Because of this, it’s not completely clear what an “acceptable” starting dose may be for a given individual. How do you decide? It is recommended that you start with the given dose, measure drug concentrations and evaluate adverse effects. If the animal is displaying unwanted adverse effects, the dose is probably too high (regardless of drug concentration). If the animal is continuing to have seizures at an undesirable frequency, without adverse effects, the dose is likely too low. We know that adverse effects happen at higher concentrations AND that organ disease is more likely to occur at higher drug concentrations so do be cautious above 40 ug/ml plasma concentration.
Adverse effects noted in this study were minimal. They reported at least 1 adverse effect in 7 of the 56 dogs. Several dogs were withdrawn from the study due to perceived poor efficacy and adverse effects as well. Adverse effects noted include reduced activity, reduced appetite, vomiting, pelvic limb weakness, soft stools and constipation. All were mild and transient. No elevation in liver values were noted. Remember that this drug is a sulfa derivative so a patient with known sulfa sensitivity should avoid zonisamide. No renal disease or renal tubular acidosis was noted however it has been reported in other dogs receiving zonisamide. 
Seizure control was obtained in 76% of the 53 dogs. A further 55% of dogs obtained seizure freedom. These results are better than the prior study evaluating zonisamide in which about 60% of the dogs were reported to obtain seizure control. The improved results are possibly due to different dosing, or a different genetic epileptic population.

Take home message:
Zonisamide is a viable alternative for dogs either as a primary or as an add-on AED. Start at 2.5 – 5.5 mg/kg PO q12h and measure plasma drug concentrations (yay!!) at 2 weeks.
 
Thanks for reading! I hope you have a great week. Remember to check FB for last minute updates to my schedule through out the summer. Happy Father’s day to all of the dads, dads-to-be and pet-dads out there!

Use of Zonisamide for Cats

Use of Zonisamide in Cats

Zonisamide has been recommended for use in cats and dogs with seizures for almost 20 years despite a lack of efficacy studies. Not that this is surprising -we love to extrapolate from human and canine medicine to cats – but it was frustrating to say the least. Well, that has been improved recently after a study evaluating the effectiveness of add-on zonisamide OR single agent zonisamide in a population of cats with seizures. (https://doi.org/10.1111/jvim.16984). This was a retrospective study of 57 cats, with seizures of any etiology that were prescribed zonisamide as part of their treatment plan. Of this group, 16/57 were diagnosed with idiopathic epilepsy (Tier II level confidence), 4/57 neoplasia, 4/57 had congenital brain disease, 2/57 head trauma and 1/57 with metabolic encephalopathy. The remainder (30 cats) did not under go diagnostic testing to obtain a diagnosis and were treated for presumptive disease based on the clinician’s assessment.

Results

Prior to treatment, the majority of cats were reported to have generalized seizures with both focal and generalized seizures taking second place. Focal only seizures were a distant third place with only 12 cats. The cats in this study demonstrated a significant reduction in seizure days (number of days having a seizure) and seizures (total count) per month following administration of zonisamide. Within the confirmed idiopathic epilepsy group, this group had a reduction in seizures/month of 1, with a total of 69.2% of cats with idiopathic epilepsy responding to zonisamide treatment. This equates to 9 of 13 cats for whom they had efficacy data. Add-on zonisamide was noted in 33 cats for whom 56% responded to treatment. Lastly, for cats whom zonisamide was the only AED, a 70% response rate was noted. A few cats had an increase in seizures after starting zonisamide. This may have been related to disease progression or resistant epilepsy. The retrospective nature, along with the lack of diagnostic testing in all cats, makes assumptions difficult.

The median daily dose of zonisamide was 7.55 mg/kg (range 3.8-17.7 mg/kg) and it was given q12h most commonly (36/57 cats). This drug can be given q12 or q24h based on the PK available.

Adverse effects were noted in 15/57 (26%) which is relatively low compared to the reported adverse effects for, say, phenobarbital. The adverse effects included inappetence (n=10), transient sedation (n=6), ataxia (n=4), vomiting (n=3). The adverse effects appeared dose related therefore higher doses resulted in more frequent adverse effects. The adverse effects lasted for variable amounts of time but typically 2-4 weeks. Mild changes to CBC were noted but significance was unknown due to concurrent disease. Liver enzyme elevation including ALT, ALP and ASK was noted but increases were mild.

What’s the take home message?
Zonisamide appears to control 56- 70% of seizures for cats, regardless of etiology. This number is closer to 70% for idiopathic epileptic cats.
Zonisamide has a low incidence of adverse effects, however the nausea/vomiting/anorexia adverse effects should be closely monitored.
Zonisamide is metabolized through the liver and is a sulfa derivative so use caution in patients with a known sensitivity.
 
I hope you enjoyed this week’s TidBit and will join me in celebrating the publication of solid data about zonisamide! I hope you have a great week and look forward to working with you soon.

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!

Cardiac Changes with Idiopathic Epilepsy?

A recent study from Brazil (www.veterinaryworld.org/Vol.17/February-2024/13.pdf) evaluated 10 dogs diagnosed with Tier I level idiopathic epilepsy to determine if changes to the EKG were present. The rationale for doing this study was initiated by the human epileptic syndrome of "sudden death in epilepsy, or SUDEP". SUDEP is a devastating syndrome wherein human patients are found dead after recovery from a recent seizure. This is most traumatic for the parents of pediatric epileptics who may help their child through a seizure, see that they are recovered and then find them deceased a short while later without any signs of additional seizures. The cause of SUDEP is debated however a cardiovascular cause appears most likely. This syndrome is rarely identified and poorly published in veterinary medicine. 

During a seizure, a tremendous release of catecholamines occurs which may stimulate hypertension, as well as intoxicate the cardiac muscle causing poor relaxation and cardiomyopathy. The study reported findings in 10 dogs with epilepsy and compared them to 11 dogs without epilepsy who were apparently healthy on laboratory testing, physical and neurologic examination and without a seizure history. 

Results

The QRS complex was significantly longer in dogs with epilepsy compared to the control group suggesting left ventricular enlargement or left bundle branch block. Additionally, the QT interval was prolonged, and this was attributed to the below reference range ionized calcium concentrations in the epileptic dogs. Interestingly, the control dogs also had lower ionized calcium concentrations so one might question the validity of this test. What do these cardiac changes mean for us? It means that even "well controlled, healthy" epileptic dogs may have occult cardiac damage. Use caution when providing anesthesia to this group and perhaps reach for a preoperative EKG for this population even if their breed or age wouldn't otherwise spur you to do so. Lastly, I found it interesting that the serum glucose concentration was significantly higher in dogs with idiopathic epilepsy compared to the control group. This likely harkens back to the high sympathetic response and catecholamine release mentioned above but another idea crosses my mind as well. Many internet sites still recommend giving glucose or honey to a pet after a seizure, even without evidence of hypoglycemia. Ice cream, popsicles, and honey are frequent additions to post-ictal care in many of our patients. If given prior to the laboratory samples, it could falsely increase the serum glucose concentration. What's the take away here? Don't rule out hypoglycemia as a seizure etiology on a single blood sample. Consider a second one 4-6 hours later, during hospitalization, and note if the glucose drops below the therapeutic range. (Oh, and make sure your clients are advised against giving sugar products postictal. No one needs a sugar rush when you're on a catecholamine rush!)

Thanks for reading! This little article crossed my radar this week and I thought it was good enough to share with all of you! I hope you have a great first full week of Spring (anyone else looking at snow on their forecast??) and I look forward to working with you soon.

How Effective is Zonisamide in Cats?

Seizures are a common reason for me to evaluate cats and therefore (I assume) something you encounter frequently. Seizures originate from the forebrain (prosencephalon) and can be secondary to idiopathic epilepsy, structural epilepsy (such as congenital disease, neoplasia, meningoencephalitis, cerebrovascular events, head trauma, and on goes the list), or metabolic seizures (hypoglycemia, thiamine deficiency, etc.).

The mainstay treatment for cats has been phenobarbital for many years and not without good reason. Phenobarbital controls seizures in over 90% of cats, regardless of the etiology, and has predictable clinical side effects. When cats cannot tolerate phenobarbital, or have seizures in excess while on phenobarbital, other antiepileptic drugs (AED) are added; one of those is zonisamide. Very little data has been published to date about zonisamide use in cats. A recent study out of UW (go Bucky) was published recently. I thought it was worth a quick summary, TT style.

How many cats were enrolled in this retrospective, multicenter study? 57

The median age of seizure onset was 7 years (range 0.17-22) and the median age of onset for cats diagnosed with idiopathic epilepsy was 8 years. Note the difference between cats and dogs! Dogs have a lower median age at onset! Importantly, note that 30 cats did not have advanced diagnostics (52%) which means a final diagnosis was not reached and therefore their disease may have affected their response to zonisamide (but we don’t know!).
How did the cats on zonisamide respond to treatment?

• There was a significant decrease in seizures/month AND seizures/day after starting zonisamide. Note: we don’t know how long the seizures were monitored before starting zonisamide.

• 70% of cats responded to zonisamide monotherapy (had less than 1 seizure per 3 months)

• 56% of cats responded to zonisamide as add-on therapy

• Almost 70% of cats diagnosed with idiopathic epilepsy responded to zonisamide but it isn’t clear if these cats were on monotherapy or add-on therapy.

• The median dose was 7.5 mg/kg/day with about 1/3 of the cats receiving the drug once daily and 2/3 receiving it twice daily.

• More cats obtained seizure control on twice daily dosing than once daily dosing but the side effects were more profound on twice daily dosing.

• Side effects were noted in 15/57  cats and they included inappetence (10 cats), sedation, ataxia and vomiting for most reports. The duration of the side effects was up to 4 weeks after starting the medication. This is surprising and warrants further investigation. Anorexia has been the side effect I note more commonly but

• No clinically significant CBC or biochemistry changes were noted on the cats in this study

So what’s the take home message? Would I use zonisamide in a cat? A qualified, yes. Phenobarbital still has a better reported seizure control compared to this cohort of cats on zonisamide. BUT it is worth a try if the cat fails treatment with phenobarbital and the don’t have a history of a sulfa drug reaction (zonisamide is a sulfa derivative). Starting dose should be less than 10 mg/kg daily, and side effects appear dose dependent…but last awhile!

Thanks for reading this week’s, TidBit Tuesday! I hope you learned a little something – I know I did! Keep those consults rolling. Have a great week and stay warm and safe out there.
 
 Reference: https://doi.org/10.1111/jvim.16984

Anesthesia for Pets with Seizures

It’s a Tuesday morning, and on your schedule is a 6 year old Maltese dog with a 3 year history of seizures that appear well controlled on phenobarbital monotherapy. She has a history of 1 seizure every 6-8 months and each seizure is less than 3 minutes in length. No interictal signs noted by the owners and she continues to have a normal neurologic exam. Today, they would like to discuss doing a dental for their dear little dog. What should you consider? How does general anesthesia for a patient with neurologic disease differ from those without?

The Risks of Anesthesia

General anesthesia is not necessarily bad. 😊 The biggest two risks of general anesthesia for dogs or cats with seizures are (1) hypotension and (2) negative effect on the seizure threshold. Let’s talk hypotension.
Your goals are to preserve cerebral blood flow, which is largely controlled by the cereal perfusion pressure, which is largely controlled by the mean arterial blood pressure (MABP). MABP is directly related to intracranial pressure (ICP). Thankfully there is a wide range at which MABP will have little negative effect on ICP. MABP between 50-150 mm HG should result in constant ICP, if other parameters are equal. Hypotension can be caused by some of the medications used (I’m looking at you acepromazine) or caused by CO2 levels. If the PaCO2 levels are above 50, a risk of vasodilation occurs which may decrease MABP. Monitoring CO2 can be quite useful to avoid this. If vasodilation occurs, and consequently decreased MABP, perfusion to the brain can be compromised. Hyperventilation will decrease the PaCO2, result in vasoconstriction and maybe lower the ICP. Some references suggest that PaCO2 should be between 30-35 for “appropriate” cerebral perfusion. Big disclaimer today – I am not an anesthesiologist so specific questions about anesthetic protocols should be directed to your local anesthesiologist! Long-standing, serious, hypotension can affect neuronal membranes and in rare situations could cause neuronal cell membrane damage, or a worsening seizure disorder. Thus, try to keep the PaCO2 in a normal range, and monitor blood pressure for pets with seizures undergoing anesthesia. 
With respect to the seizure threshold, isoflurane, diazepam, midazolam, and possibly propofol are neuronal protective. If you have the luxury of choice, consider using one (or all!) of these medications in your anesthetic protocol. If you have a patient with poorly controlled seizures, administration of IV phenobarbital 20 minutes before starting anesthetic recovery may be useful to add seizure protection during the recovery process. ALWAYS go slow! Give the phenobarbital over 20-30 minutes as a slow infusion to avoid severe cardiovascular or respiratory suppression. This drug is closely related to pentobarbital, our common euthanasia solution. Most patients can receive benzodiazepine medication if active seizures are noted during the recovery process. Paradoxycal hyperactivity following benzodiazepine adminsitration occurs rarely but would be a reason to avoid using the drug in the future if a patient exibited these signs. Patients with significant hepatic disfunction such as those with portosystemic shunts should either avoid benzodiazepine drugs due to inadequate metabolism, or be adiminsered a 25% dose. 

Any anesthetic event, even an uneventful one, can put a patient with a known seizure disorder at risk for seizure breakthrough. This risk persists for at least 24 hours following anesthesia but in rare patients it can be longer. Owners should avoid leaving the pet alone for extended periods of time such as traveling by airplane, boarding the pet or other unobserved time in the first 24 hours after anesthesia. Never withhold chronic anticonvulsant medications prior to anesthesia. Bromide can cause vomiting therefore it should be given with a small meal. Patients receiving bromide (liquid) can receive it rectally if they are anesthetized early in the morning and a small snack with their bromide is not possible. Phenobarbital, levetiracetam and zonisamide can be given on an empty stomach without high risk of GI upset.

This topic was suggested by one of your colleagues - thanks for the suggestion! Do you have a topic you wish I’d cover? Please reach out!  Thanks for reading and have a great day!

Non-Convulsive Seizures in Dogs

Non-Convulsive Seizures in Dogs and Cats With Cluster Seizures

This week we're going to dig into non-convulsive seizures in dogs a bit before we jump off of the seizure bandwagon and back into other topics in neurology next week. (Sorry to the surgeons that read these!) A recent study out of Germany by Tastensen et al (DOI: 10.1111/jvim.16953) evaluated nonconvulsive seizures in dogs and cats with cluster seizures. A few definitions, first....

Cluster seizures: 2 or more seizures within 24 hours in which pets regain consciousness between seizures. 
Status Epilepticus (SE): Seizures lasting for longer than 5 minutes or 2 or more seizures in which consciousness is not regained. 
Nonconvulsive seizures (NCS): no visible somatic or autonomic manifestation of seizures with evidence on EEG. 
Nonconvulsive status epilepticus (NCSE): no visible somatic or autonomic manifestation of seizures, with evidence on EEG and the seizures are lasting longer than 5 minutes. (yikes!)

This study evaluated 26 dogs and 12 cats with EEG monitoring following cluster seizures and found 11 of the animals (9 dogs, 2 cats) had NCS. Of these 11 dogs and cats, 4 dogs and 2 cats (16%) had NCSE. They found repeated doses of benzodiazepine drugs and levetiracetam did not break the seizures. Only inhalant anesthesia with propofol induction resulted in a return to baseline EEG. 

Six of 11 animals had a decreased level of awareness and a few of them had mild twitching of an ear which could have represented the somatic movement of the seizure. Sadly, this group had a much higher mortality rate (73% NCS; 67% NCSE) than the general population of dogs without NCS or NCSE (27%). Overall, cluster seizures have a higher mortality rate than for dogs or cats without cluster seizures (~40%) as well. None of these patients died as a result of NCSE or NCS however several were euthanized. 

The seizure etiology was more often structural epilepsy (neoplasia, encephalitis, malformation, vascular cause or trauma) and accounted for 22/38 (58%) of the animals in the study. About 18% (7/38) had idiopathic epilepsy, 11% (4/38) had unknown epilepsy and about 18% (7/38) had reactive seizures. Does this mean that dogs and cats with structural epilepsy are more likely to have cluster seizures, or does it mean that the prognosis is inherently poorer for animals with structural epilepsy? If the prognosis is poorer, do clients elect humane euthanasia when in a situation of NCSE more readily, driving up the mortality rate, or does the disease make it harder to treat? Non-convulsive epilepsy is more common in humans with cluster seizures as well, and has a higher mortality rate than people without NCE or NCSE. I don't have the answers to these questions but pose them as a way of critically reviewing the data provided.

Take home message:
If you have a dog or cat with a history of cluster seizures and they are persistently, mentally inappropriate (obtunded, stupor or coma) after stopping the physical appearance of the seizure consider nonconvulsive seizures. Inhalant anesthesia would be recommended however without additional diagnostic testing (such as MRI or spinal tap) it would be unknown if there is high intracranial pressure from the underlying disease which could increase the risk of complication with anesthesia. So what do you do in general practice? If the owner wants a referral for 24 care - start there. If not, consider a bolus of diazepam or midazolam. OR you could monitor for 1-2 hours to determine if the change in behavior is secondary to postictal changes. 

Not sure how to manage a seizure case? Feel free to email or call me or schedule a neurology consult! Please always text or call if it is an emergency; I don't check my email very often during the day.  Have a great rest of your day!

Once Daily Phenobarbital for Cats?

A study by Dr. Mojarradi et al, out of Sweden, was recently published in the Journal of Feline Medicine and Surgery reporting on once daily phenobarbital administration for cats with seizures. The reported half-life of phenobarbital in cats is 43-72 hours which could suggest once daily treatment is possible, however based on pharmacokinetic data twice daily dosing has been the standard of care. This retrospective study questioned if this was necessary. 

This study was a retrospective review of 9 cats up to 3 years from enrollment. They tracked the number of seizures before starting phenobarbital (unfortunately for an unknown amount of time) and compared that to the number of seizures after starting phenobarbital. The cats were required to have 2 or more seizures, separated by at least 24 hours, prior to starting phenobarbital however the frequency and duration of the seizure disorder for each cat isn't known. They do comment that 6/9 cats had 1 or more per month prior to starting phenobarbital. Phenobarbital was started at a mean dose of 1.8 mg/kg PO q24h, the mean serum concentration of phenobarbital was 11 ug/ml (range 6-17) at about 1 month (range 19-54 days). All but 1 cat was seizure-free at that first follow-up. The second and third follow-up appointments, roughly 1 year apart, showed a few more seizures in the time range however overall 8/9 cats were considered to be in seizure remission (no seizures for more than 12 months) at the end of the study. Seizure remission, as defined in this study, was less than 1 seizure every 12 months. If they started at 1 seizure/month, and ended at 1 per year that is a pretty remarkable improvement! So remarkable, I wonder if the phenobarbital is responsible for that shift, or not.
My questions:

• Could such a low serum phenobarbital concentration cause such a dramatic response?

• Could this be the natural regression to the mean (shifts that are unrelated to intervention)?

• Did the retrospective nature of the study include only cats that did well on once daily phenobarbital, otherwise they would have taken twice daily phenobarbital and therefore been excluded from the study? Was this group of cats bound to do well, in other words, and it wasn't due to medication?

Another study by Pakozdy (https://doi.org/10.1177/1098612X12464627) noted that over time, most cats have a natural reduction in seizures while on anticonvulsant drugs. They tracked seizures in cats over a 10 year period and noted that most improved, some were seizure-free and some stopped medication. About 16% of the cats that stopped medication needed to have it restarted due to a return of seizures. 

The data reported in the study from Sweden suggests that we could administer phenobarbital once daily but the results are so remarkable (marked seizure improvement in a short period of time, low serum drug concentrations) that I feel compelled to repeat this study with a different, perhaps large, cohort of cats and make sure this is reliable. My advice: don't switch to once daily just yet!

Thanks for reading! I love managing seizures so please schedule a consult if you have a case that you'd like more assistance with seizure management. I'm happy to help!

Status Epilepticus in Cats

Last week we looked at the ACVIM consensus statement for the treatment of status epilepticus and focused on the different stages, and the treatment algorithm outlined by the committee. This week, I thought we should look at this statement through the lens of cat care. Please refer to the article for more details - it's a good one! (DOI 10.111/jvim.16928)
As a reminder, all available literature was reviewed and classified according to it's level of evidence. Studies with a high level of confidence for or against a specific treatment included treatments in which 2 or more clinical studies with a high quality score (more about that in a minute) evaluated this specific intervention. Moderate level of evidence for a treatment needed 2 or more studies with moderate quality score or 1 study with high quality score. A label of low evidence for a specific intervention was used in situations where 2 or more studies with low-quality score were reviewed or 1 with a moderate quality score without any high quality score articles identified. A label of conflicting evidence was used when 2 or more studies, usually with a high quality score, were reviewed and found to have results in conflict. Finally, the label "absence of evidence" is pretty self explanatory. The quality scores were numeric scores assigned each study based on clearly defined criteria such as EEG or clinical confirmation of seizure cessation for each study reviewed. 

Definitions
The definitions are the same for cats as they are for dogs. Any seizure longer than 5 minutes is considered status epilepticus (SE). Similarly, cluster seizures are 2 or more seizures within 24 hours in which consciousness is regained between the seizures. Okay, off to a good start. 

Antiseizure Therapy for Cats
Figure 3, in the aforementioned article, is a pyramid of hierarchy for therapy recommendations for cats in status epilepticus. Sadly, there are no studies with a high level of confidence for any intervention. This means that no high quality studies, evaluating seizure cessation in cats, were identified. We need to fix this! Intravenous bolus or CRI of midazolam, intravenous bolus of diazepam, intravenous levetiracetam, intravenous phenobarbital and inhalant anesthetics were considered to have moderate level of confidence for cats. This suggests that there is at least clinical evidence (if not EEG evidence) that supports these treatments for SE management in cats. Oral levetiracetam, intravenous bolus or CRI of phenobarbital and propofol had low level of evidence suggesting that giving these drugs, via these routes, to cats with seizures is not supported by the literature. Oral midazolam, intravenous CRI, oral or endotracheal diazepam were not supported by the literature. Not surprisingly, there were many drugs that were withheld from analysis due to a lack of evidence for cats. 

As I mentioned last week, the authors made the following statement:
"Although both benzodiazepine drugs are potent and safe for the management of SE in dogs and cats, midazolam may be considered a more potent or safer benzodiazepine drug than diazepam."
Based on this, and my own clinical impression, if you aren't carrying injectable midazolam yet, now is a good time to consider adding this to your cabinet!

The authors also specifically addressed CRI reduction and recommended reducing by 25-50% every 4-6 hours after a cat (or dog) has been seizure free for at least 12 hours, preferred 24 hours. It is always preferred to taper the medication, not stop abruptly, whenever feasible. 


I think that is enough for today. I hope you had a good holiday, didn't go too crazy on Black Friday, and I look forward to working with you soon!

As always, the holidays bring many challenges. If you cannot find a suitable time for a consult using my online scheduler please reach out to me via email. I will always try to accommodate your request if I can. 

Status Epilepticus Consensus Statement 2023

Status Epilepticus and Acute Seizure Management Consensus Statement 2023

The ACVIM Consensus statement about status epilepticus (SE) was published this past summer (2023) and I felt it was applicable to all of us faced with acute seizure management. They dove right in and addressed the need for a definition of a prolonged seizure as one occurring for longer than 5 minutes. The human equivalent of our International Veterinary Epilepsy Task Force (IVETF) is the International League Against Epilepsy (ILAE). The ILAE has recently also revised their definition of SE to any seizure longer than 5 minutes as well. Previously, SE was defined as anything between 5-30 minutes. Thirty minutes was the cut off because at that point, brain damage is common. The reason for adopting the 5 minute rule was to 1) minimize the risk of systemic and brain complications associated with continuous seizure activity reaching up to 30 minutes; 2) prevent worsening of the prognosis and drug resistance associated with increasing duration of uncontrolled seizure activity and 3) limit any potentially unfavorable outcomes and adverse effects associated with the prolonged administration of multiple therapeutic interventions. 

Status Epilepticus is divided into 4 stages:
1) Impending (occurs at 5-10 minutes of seizures) - there is neurotransmitter imbalance and ion channel opening/closing. Animals are likely to be responsive to first line anticonvulsant drugs (ACD) during stage 1. 
2) Established (occurs at 10-30 minutes)- Inhibitory neurotransmitters are reduced, the receptors for the inhibitory neurotransmitters are internalized and there is upregulation of NMDR and AMPAR. Some animals may still be responsive to first line ACD, but most will be responsive to second line ACD.
3) Refractory - (occurs > 30 minutes) - There is a sustained imbalance between inhibitory and excitatory neuropeptides with BBB drug transporter upregulation. Most pets will not be responsive to first or second line ACD, but should be responsive to third line ACD. 
4) (Super)refractory - (occurs > 24 hours) - There are gene expression alterations and animals are expected to be refractory to all ACDs. 

What were considered first line ACDs? IV benzodiazepine drugs were considered the most effective and safest for in-hospital use and intranasal benzodiazepines are the preferred treatment for out-of-hospital treatment. "Although both midazolam and diazepam are potent and safe for the management of SE in dogs and cats, midazolam may be considered a more potent or safer benzodiazepine drug than diazepam." There we go!

They provided a list of the steps to follow, based on the evidence reviewed, when treating SE. I have repeated it here, but encourage you to read the entire article if you treat SE regularly as there are loads of pearls of wisdom peppered throughout the paper.

Steps to follow for SE:

• Give midazolam or diazepam IV. A benzodiazepine bolus is effective if the seizure stops < 5 minutes after administration and no relapse occurs <10 minutes

• If seizure activity is controlled with a benzodiazepine drug but recurs 10-60 minutes later is considered recurrent SE

• Recurrent SE, or those that don't respond to the first bolus of benzodiazepine, should get a second IV dose of benzodiazepine drug

• If seizures persist after two bolus, administer a 3rd dose immediately followed by a CRI. Dogs = midazolam or diazepam CRI is acceptable; Cats = diazepam should be avoided. 

• If seizures still persist, administer a 4th dose of benzodiazepine and administer a second line ACD

• Second line ACD include levetiracetam IV, followed by phenobarbital IV and lastly fosphenytoin IV. Only administer the subsequent drug if the prior failed to stop the seizures. 

Note: Levetiracetam or phenobarbital IV can be started after step 2 above if long-term maintenance is desired for either medication. They do not need to be reserved for second line use only. 

I think that is enough for today. I'll go through some more data from the study in another TidBit Tuesday. I hope you enjoy the rest of this week, have a safe, relaxing holiday and look forward to working with you soon!

Does the Duration of Diazepam and Propofol CRI in Dogs Matter?

Does the Duration of CRI Matter?

If you work in a 24-hour facility, odds are high that you've employed a constant rate infusion (CRI) to control seizures in dogs with cluster seizures or status epilepticus. A recent article evaluated the duration of a CRI of diazepam and propofol to see if there was a superior choice.

Why could duration matter?

On one side, the longer a pet is on a CRI (12 h or 24 h), the longer they must remain in hospital which incurs more charges. However, most dogs will have a recurrence of seizures within 12 hours of hospitalization according to prior studies, so if you run a CRI longer perhaps the less chance they have to have another one and thus return to hospitalization. 

Materials and Methods

Cagnotti et al (Frontiers, 2023) collected 73 dogs and separated them into two experimental groups. The first group received diazepam CRI for 12 hours, the second propofol for 12 hours. No standard dosing was employed for either group, just the duration. These were compared to a prior study of dogs with identical inclusion criterial in which the CRI was continued for 24 hours. 

Results

No difference in outcome, or hospital duration was noted between the 12 hour CRI group (both diazepam and propofol) and the 24 hour group. Surprisingly, the dogs receiving the 12 hour CRI still had a 56 hour hospitalization! I cannot locate any data on breakthrough seizures after stopping CRI in either group but one might suspect this occurred to result in a 56 hour hospitalization for the 12-hour group. Either that, or the CRI dose was much higher and therefore had more step down doses compared to the 24 hour CRI? Those are my suppositions, not verified by data in this study. 

Take Home Message:
It is well established that a CRI should be employed for dogs having cluster seizures or status epilepticus and that 2 step-down doses are typically recommended to avoid withdrawal seizures when stopping. That said, this paper suggests that a 12 hour CRI is comparable to a 24 hour CRI. Personally, I typically start with 0.25 mg/kg/hr diazepam CRI for 12 hours and then step down in 50% increments until the dose is below 0.1 mg/kg/hr. This data would suggest that this is an appropriate approach but I think it is 'loosely' supportive!

Reference: Cagnotti G, Ferrini S. Duration of constant rate infusion with diazepam or propofol for canine cluster seizures and status epilepticus. Frontiers in Vet Sc Aug 2023. 

Thanks for reading! I hope you have a great week and I look forward to working with you next week when we're back stateside again!

To Seize is to Grab, to Seizure is to Convulse

Seizures and Deficits...What to Do?

Today, we have, back by popular request, another lesion localization practice case! Enjoy!!

Signalment: 7 year old MC Pitbull-X (maybe Boxer dog?)
History: The dog presented with a history of 2 seizures, 1 day apart. Since the seizures, the dog has been walking compulsively to the left, and appears to bump into objects. Although a decreased appetite has been appreciated, the dog is still eating when hand fed. 

Physical Examination: unremarkable

Neurologic Examination:
Mentation: Obtunded
Cranial nerves: Absent menace OD, intact PLR OU, mild head turn left, remainder normal. 
Gait: Ambulatory with intermittent compulsive circling to the left. He is able to walk to the right when asked but will not continue the circles without inspiration. 
Postural reactions: normal all limbs.
Reflexes: Normal all limbs.
Palpation: no spinal pain and normal cervical ROM  and tail jack. 

Neuroanatomic lesion localization (NALL) Practice

Let's look at the examination is sequence as it is listed above. If you wish to use the table format that I prefer, please look at the tables provided in the Small Animal Neuroanatomic Lesion Localization Practice Book (publisher CABI, date 2022 by yours truly). We'll discuss it in conversation format for this TidBit Tuesday. 

Seizures: Seizures ALWAYS localize to the forebrain and are not readily lateralized (left or right side). 

Obtunded: reduced mentation is noted with lesions in the forebrain and brainstem. This is NOT a clinical sign of cerebellar, spinal cord or neuromuscular disease, nor a non-neurologic finding. This narrows our lesion localization to forebrain or brainstem.

Cranial nerves: The menace pathway, in it's most basic sense, involves CN 2, the forebrain and CN 7. PLR involves CN 2, midbrain and CN 3. The blink reflex is not states as being abnormal above (blink reflex: CN 5 and CN 7) therefore by process of elimination, the menace deficit OD is most likely due to a forebrain lesion. The second part of the story is lateralization. Only the right eye is affected. This is a crossing tract (mostly) which means that the lesion should be on the left side of the forebrain.

Gait: The compulsive circling to the left is localized to the forebrain and, rarely, vestibular system. Localization to the vestibular system is most likely when a head tilt is present. Without a head tilt, I would consider a forebrain lesion most likely and they circle TOWARDS their lesion. This would further support a left forebrain lesion. 

NALL: Left forebrain

How'd you do? Did anything surprise you with the NALL? If you enjoyed this case, thank your colleagues for suggesting a seizure NALL case for practice. :)

As a reminder, I will be out of the country starting next week through November 14th. I will be available by email ONLY (no cell phone service) and will be doing my best to keep up on emails. Please expect minor delays in my response because I will be lecturing and we'll be on different time zones but I will do my best to be as responsive as possible. Have a great week!