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. 

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!

Midazolam as a Constant Rate Infusion (CRI)

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

1. Prevent brain damage

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

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

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

The findings, in a nutshell:

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

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

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

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

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

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

Take Home Message

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

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

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

• Phlebitis is not expected, unlike with diazepam!

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

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

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

20% of dogs receiving AEDs have dermatologic reactions??

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

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

What signs are seen?

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

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

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

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

• Pruritus and/or alopecia (3 dogs)

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

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

How was it managed?

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

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

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

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