The Case: Breakthrough Cluster Seizures
Initial Presentation
A 10-year-old female spayed Irish setter mix with a 4-year history of seizures presented to the emergency department after having 4 seizures at home over 4 hours, each lasting 1 minute or less. She had 2 seizures, ate dinner and took her prescribed zonisamide and S-adenosylmethionine/silybin, and then had 2 additional seizures.
Seizures had previously been controlled with phenobarbital, but a recent predental serum chemistry profile (10 days prior to emergency presentation) had revealed an alkaline phosphatase >2400 IU/L (range, 5–131); it was then decided to transition to zonisamide from phenobarbital and begin S-adenosylmethionine/silybin. The owners had been advised to start zonisamide (7.3 mg/kg q12h PO) and discontinue phenobarbital (2.2 mg/kg q12h PO) after 3 days of zonisamide therapy. The remainder of the CBC and serum chemistry panel 10 days prior, including alanine aminotransferase, was within normal limits. A serum bile acids test and abdominal ultrasound were recommended but declined.
The dog also had a history of hyperadrenocorticism that was controlled with trilostane (5 mg/kg q24 hours PO). Alkaline phosphatase had traditionally been moderately elevated in this patient at 700–800 IU/ L (range, 5–131), but the recent chemistry finding signified a marked increase in this parameter.
Physical Examination
On presentation, the patient was recumbent with generalized weakness, had bilateral nuclear sclerosis and mydriatic pupils, and had normal bilateral pupillary light responses.
Temperature: 101.4⁰F
Pulse: 130 bpm
Respiration: 50 bpm, mildly increased respiratory effort, increased bronchovesicular sounds bilaterally
Cardiac: Grade II/VI systolic murmur with left parasternal PMI, normal rhythm. This was a new finding in this patient.
A 5th seizure occurred shortly after the exam and was treated with 0.5 mg/kg diazepam IV. After the seizure, the dog exhibited opisthotonus, further tachypnea, mildly increased respiratory effort, and gagging. The gagging and opisthotonus resolved after 5 to 10 minutes, but the tachypnea persisted.
Pulse oximetry (on room air): unreliably 91% with poor waveform.
When repeated a short time later, the reading was 96% with a more reliable waveform. Chest radiographs were recommended to rule out aspiration pneumonia vs noncardiogenic pulmonary edema vs heart failure, but were declined at the time of admission.
Diagnostics
Owners declined further blood analysis; serum chemistry profile had been performed 10 days earlier.
Treatment
The patient was admitted for seizure watch and a partial phenobarbital load (total dose administered to achieve adequate seizure control: 8 mg/kg IV). Since the phenobarbital had been discontinued just 10 days prior, it was expected that some level of the drug remained in her system. Her breakthrough seizures were assumed to be secondary to abrupt discontinuation of phenobarbital and increased clearance of zonisamide given in the presence of phenobarbital. Overnight the patient continued to be tachypneic. Thoracic radiographs were performed to rule out cardiac causes and revealed pulmonary edema that was most prominent in the right caudodorsal lung field. This was presumed to be noncardiogenic. She was administered oxygen by cage overnight at 40%. Pulse oximetry readings continued to be 96% to 97% on room air.
The patient had no further seizures overnight and was eating and drinking well. Oral medications were begun in the morning once the patient was less sedate: Two 4 mg/kg doses of phenobarbital, 5 hours apart as a continued partial loading dose, and the zonisamide dose increased to 10 mg/kg q12h. The owners were advised to continue the phenobarbital (2.2 mg q12h) for 2 weeks and then begin a slow taper, decreasing the dose by 25% every 2 weeks until discontinuation. They were also advised to maintain the higher dose of zonisamide for at least 2 weeks after discontinuation of phenobarbital before decreasing, since phenobarbital can increase clearance of zonisamide.
Outcome
Patient returned for a recheck 2 weeks after the cluster seizures, and was seizure free and doing well at home. Bile acid testing was performed at that time and results were elevated; slow tapering of phenobarbital with the goal of eventual discontinuation was continued as previously recommended.
The Generalist’s Opinion
Barak Benaryeh, DVM, DABVP
There are many occasions in veterinary medicine when we either change prescribed medications or choose to combine drugs. This case is a very good example of why it is important to be aware of drug interactions: Up-regulation of hepatic enzymes by phenobarbital increases the clearance of many drugs, including zonisamide. For this reason, if the two drugs are given concurrently, a higher dose of zonisamide is needed. In addition, because of the long half-life of phenobarbital, even after it is discontinued, a higher dose of zonisamide may be needed for as long as 10 weeks.1 This situation is in contrast to that with many other medications, which when combined often have a synergistic effect, thus necessitating a lower dosage of each.
Drug Monitoring
The dog in this case was taken off phenobarbital in response to elevated hepatic enzymes noted on a predental blood screen. It’s good practice both medically and financially to have a protocol in place for monitoring blood values with any drug taken on a long-term basis. Practice management software can be set to generate appropriate reminders.
Many drugs, including NSAIDs, psychotropic medications, and antiseizure agents, can have deleterious effects when given for long periods. Knowing what the possible side effects are and monitoring for them is critical. We cannot be expected to remember every interaction and side effect of all the drugs we prescribe. We can, however, check a quick reference if we are uncertain and keep ourselves and our patients out of trouble.
Elevations in hepatic enzymes do not necessarily mean there is liver disease or damage. Recommending bile acid testing was appropriate, as was changing antiseizure drugs. The issue was not the decision to change, but rather how best to have made that change.
Non-cardiogenic Pulmonary Edema
Non-cardiogenic––or in this case neurogenic––edema can be self-limiting. The clinicians decided not to give this dog furosemide despite radiographic evidence of pulmonary edema. Since non-cardiogenic edema is not a result of an increase in pulmonary and venous capillary pressure as occurs with heart disease, it is questionable whether furosemide would have been of benefit.2 Supportive care is often all that is needed. This patient did well with oxygen support alone; in hindsight this was clearly the correct decision.
Related Article: Noncardiogenic Pulmonary Edema
Antiseizure Drugs
There are several pharmacologic choices to combat seizures. Regardless of which is chosen, it’s important to be familiar with the various side effects, drug monitoring needs, and drug interactions involved. This dog had a good outcome, maintaining good seizure control, which is not always easy to achieve. Even on the human side, neurologists struggle to get control of seizures in some patients.
Barak Benaryeh, DVM, DABVP, is the owner of Spicewood Springs Animal Hospital. He graduated from University of California–Davis School of Veterinary Medicine in 1997 and completed an internship in Small Animal Medicine, Surgery, and Emergency at University of Pennsylvania. Dr. Benaryeh has also taught practical coursework to first-year veterinary students and was a primary veterinary surgeon for the Helping Hands Program, which trains assistance monkeys for quadriplegic people. Dr. Benaryeh is certified by the American Board of Veterinary Practitioners in Canine and Feline Practice.
The Specialist’s Opinion
Gretchen Statz, DVM, DACVECC
It was a reasonable decision to switch the dog in this case from phenobarbital to zonisamide. It is difficult to be certain whether an elevated alkaline phosphatase is being caused by phenobarbital, and switching to another medication may help to make that determination. The main issue here is that the phenobarbital was stopped abruptly, and the zonisamide was started at a slightly low dose for a dog on phenobarbital.
Phenobarbital Side Effects & Monitoring
Phenobarbital has been around for years and is an effective and reliable antiseizure medication, but it does have side effects of which veterinarians and owners must be aware. The most obvious include increased thirst, urination, and hunger. Phenobarbital can also cause benign elevations in liver enzymes, specifically alkaline phosphatase and sometimes alanine aminotransferase (ALT). This side effect does not necessarily mean that the medication must be discontinued; however, it can be a challenge to determine whether the elevation is a result of a disease process (ie, hepatic disease or hyperadrenocorticism) or a benign effect of the medication. Phenobarbital at high doses over time can also lead to hepatotoxicity, so elevated enzymes in such cases cannot be ignored. It is wise to monitor liver values, phenobarbital levels, and bile acids yearly when a patient is receiving the drug.
Laboratory value changes that should prompt further workup or a change in medication could include:
A jump in liver enzymes from one year to the next with no change in medication
Liver values (especially ALT) more than 4 to 5 times above the reference range
Increased bile acids
Phenobarbital levels above 30 μg/mL
In cases of abnormal liver function, when there is concern about hepatoxicity, or side effects are bothersome, it is advisable to switch to a different antiseizure medication. Newer agents that are gaining popularity include zonisamide and levetiracetam (Keppra®). When switching an animal from phenobarbital to one of these medications, it is best to wait at least one week before starting to taper the phenobarbital to allow for achieving steady state levels. Phenobarbital increases metabolism of zonisamide and levetiracetam via induction of hepatic enzymes, which results in lower blood concentrations. It is advisable to start zonisamide on the high end of the dose initially (10 mg/kg q12h PO). The dose can always be decreased if the dog is doing well; however, most dogs will continue to tolerate this dose even after the phenobarbital is discontinued.
Phenobarbital should not be stopped abruptly if at all possible. Breakthrough seizures can occur with rapid withdrawal. It is advisable to wean the patient over several weeks to months (by 25% every 2 to 4 weeks) until the medication is discontinued.
Gretchen Statz, DVM, DACVECC, is an internal medicine consultant for Antech Diagnostics and a clinician at Veterinary Emergency and Specialty Care in Indianapolis, Indiana. A graduate of University of Wisconsin–Madison, Dr. Statz interned at VCA West Los Angeles and then worked for several years at two emergency/referral hospitals in the Boston area. After completing a residency at VCA Veterinary Referral Associates in Gaithersburg, Maryland, she became boarded in emergency and critical care. Having a strong interest in internal medicine, she has been practicing in that field for the past several years.