Levetiracetam and Dogs with Chronic Renal Disease

Levetiracetam and Chronic Renal Disease in Dogs

I dislike starting sentences with “Little is known…” but alas, that is how I wish to start this TidBit Tuesday. Little is known about the effect of levetiracetam on the kidneys of dogs with chronic kidney disease (CKD). Human epileptics with concurrent CKD have a longer levetiracetam half-life than patients without CKD. Therefore, the dose is often adjusted (lowered) to account for poor renal function. Thanks to a colleague, I was reminded of a paper from 2021 on this very subject in vet med. Gim SY et al (2021: Veterinary Sciences doi.org.10.3390/vetsci8110263) published data about 20 dogs with CKD and compared them to 17 dogs without CKD. I thought you might find a quick review of the data valuable:

CKD group

• Mean age 12.5 +/- 3.78 yrs

• Mean weight 5 +/- 2.78 kg

• Many breeds

• CKD IRIS stage 1: 60%

• CKD IRIS stage 2: 40%

• Initial dose 21.9 +/- 8.36 mg/kg q8-12h

Non-CKD group

• Mean age 10.26 +/- 3.73 years

• Mean weight 5.44 +/- 5.56 kg

• Initial dose 20.58 +/- 8.72 mg/kg q8-12h

Results

The authors note that the typical starting dose for levetiracetam is 20 mg/kg PO q8h (30 mg/kg PO q12h if using extended release) in dogs. Therefore, the dogs with CKD had a mean starting dose HIGHER than the standard dose, which is odd. One would expect a reduced dose for animals with CKD. Sadly, the authors did not obtain serum levetiracetam concentrations to document a difference in drug accumulation in the two populations. Not surprisingly, dogs with CKD were reported to have more adverse effects (85% vs 53%) than dogs without CKD. Adverse effects most commonly reported were ataxia, sedation and anorexia. Although a known adverse effect, anorexia may have been worsened by the underlying CKD. Throughout the study period, a clinically relevant, statistically significant increase in serum BUN, serum creatinine or both was noted in the CKD group. The authors postulate that sedation may have contributed to reduced water consumption, worsening the renal disease, however this was not objectively measured or observed.

Take away message

Based on our knowledge of renal elimination of levetiracetam, the authors suggest starting with a dose lower than 20 mg/kg PO q8h in dogs with CKD. Based on clinical experience I recommend starting at a 20% reduction (16 mg/kg PO q8h)  and monitoring BUN/creatinine every 2-3 weeks for several rounds. If seizures are poorly controlled and BUN and creatinine do not increase, an increase in levetiracetam could be considered.
I hope you have found this helpful! It isn’t a very robust study, but it brings to light the discussion of monitoring dogs with CKD who are taking levetiracetam, a worthy topic.

On a different note, I’m having issues with my phone carrier and therefore texting isn’t available for at least the next 3-4 weeks. I can see texts that you send me, but I cannot respond. For the time being, please email me with all nonurgent questions and use the old fashioned telephone to call with any urgent questions. I’ll do my best to respond to the phone calls as timely as possible! Thanks for your patience as I work through this stupid new regulation.

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.

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

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

How was the Seizure Control?

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

What side effects made a splash?

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

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

• Zonisamide: sedation, ataxia, hyporexia

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

What was the perceived Quality if Life?

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

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

Reference: doi.org/10.2460/javma.22.10.0469

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!

Paroxysmal Dyskinesia

These words are not uttered by many of us on a regular basis (unless you are studying for boards and talking in your sleep). So, why do you need to know what this is? So that we remember that not all things that twitch have seizures.

Paroxysmal dyskinesia's are one, of a group, of movement disorders characterized by abnormal muscle movements UNRELATED to epileptic discharges. If you take one thing away from this email it is this: movement disorders are not seizures. Not that I suggest you stop reading...

How do I identify a Paroxysmal Dyskinesia (PD)?

This group of movement disorders manifest as sudden cramping in muscles and limbs. It has been identified in several breeds, with increased incidence in Terrier breeds. Notably there is no loss of consciousness, no autonomic signs, and upon recovery from the cramping the dogs return to normal function immediately. These cramping episodes can be triggered with specific activities in some patients (activity or exercise is a common trigger) and may last for minutes to hours. When performed, no EEG abnormalities consistent with epileptic discharges are noted.

What diagnostic testing should I run?

Cramping syndromes may be triggered from metabolic causes as well as genetic causes. A CBC, serum biochemistry and urinalysis are a wonderful way to rule out metabolic causes. If normal, assessment of a video can determine if additional testing for seizure disorder should be pursued.

Are there any treatment options?

Yes! Many movement disorders improve with anticonvulsant drugs such as the benzodiazepine class of drugs. One recent report (reference below) detailed successful treatment of a Welsh Terrier with levetiracetam (20 mg/kg PO q8h) to control signs.

Do you suspect you have a patient with a movement disorder? Please reach out for a consultation - I'm happy to help. I truly love working with you and your staff to help patients live their best lives, with neurologic disease. Keep up the good work!

Stay safe - it's almost spring time and we can make it!

Reference:
Green S, Olby N. Levetiracetam-responsive paroxysmal exertional dyskinesia in a Welsh Terrier. JVIM 2021: https://doi.org/10.1111/jvim.16068