Phenobarbital-induced hematologic changes in cats

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July 2024

In today’s VETgirl online veterinary CE podcast, we discuss a retrospective study published in the Journal of Veterinary Clinical Pathology by Dohany et al., regarding evaluation of phenobarbital-induced hematologic changes in 69 cats. As we know, phenobarbital is a widely prescribed anti-epileptic medication used in veterinary medicine. (FYI, in case you didn’t know this, we don’t typically use potassium bromide as an anti-epileptic medication in cats due to the high prevalence of asthma secondary to its use.) But how aware are you of the cytopenias that can be associated with chronic phenobarbital administration?

At any rate, phenobarbital has been the first line therapy for recurrent seizures in cats, owing to its wide therapeutic index and a fairly short list of side effects, with the most common side effect being sedation. However, other side effects including neurologic signs, such as ataxia or paraparesis, as well as polyphagia, polydipsia and polyuria can also be seen in some patients. (On a side note, these clinical signs typically improve slowly over time!).

A couple of previous studies, including one by Bersan et al., have reported hematologic abnormalities induced by phenobarbital in dogs, with a prevalence ranging from 4 to 22%. A major side effect reported in dogs is pancytopenia, which is usually seen during the first months of treatment and has been reported to resolve with discontinuation of phenobarbital. So what about cats? Only rare studies describe hematologic changes associated with long-term phenobarbital therapy in cats. So, the goal of this present study by Dohany et al was to report the prevalence and clinical relevance of phenobarbital-induced hematologic abnormalities in cats. More importantly, we need to know as clinicians how often we need to have these cats come back for blood work while on phenobarb!

In this retrospective study entitled “A retrospective evaluation of phenobarbital-induced hematologic changes in 69 cats,” inclusion criteria included cats that were suspected of having idiopathic epilepsy – this was often based on a previous history of seizures with no interictal neurologic signs, normal physical exams, and normal baseline biochemistry blood work. Patients that had been treated with phenobarbital with or without other anti-epileptic drugs for at least 2 weeks were included in the study. In addition, at least one hematologic examination during that 2-week treatment period was required to be included in the study. Exclusion criteria included cats with structural brain diseases neoplastic diseases. A total of 69 cats were included in this study.

A complete blood count and blood smear examination was performed on all patients. The severity of the hematologic changes was classified as mild, moderate, severe, or life-threatening based on the veterinary cooperative oncology group— common terminology criteria for adverse events (VCOG-CTCAE). The references intervals were established at the institution laboratory where the study was performed. Dosage and duration of use of phenobarbital was recorded when available in the medical record. Serum concentrations of phenobarbital were also recorded if measured.

The data for hematology analyses were split into 4 groups based on the treatment days, which included ≤3 (Group 1); 4– 180 (Group 2); 181– 540 (Group 3); ≥ 541 days (Group 4). In addition, groups were assigned based on the phenobarbital serum concentrations levels, including 35 μg/mL) the therapeutic range. FIV/FeLV testing status was recorded when available.

So, what’d the authors find? In this study, the median age at presentation was 5 years with a range of 6 months to 14.7 years. 35 out of the 69 cats were male (all neutered, except one), and 34 cats were females (all spayed, except three). The most represented breed was European shorthair, with 63 out of 69 cats.

Twenty-nine cats were tested for FeLV and FIV, with all cats that were negative for FeLV, one cat with an unknown FIV status, and one cat that was positive for FIV. It is of note that the FIV-positive cat did not present with hematologic abnormalities during the duration of this study.
Patients in different treatment groups included twenty-eight cats that received only phenobarbital, while forty cats received phenobarbital in combination with levetiracetam. One cat received imepitoin in addition to phenobarbital and levetiracetam.

Now on to the most exciting part of this study… the major hematologic abnormalities associated with phenobarbital use in cats! Cytopenias were reported in fifty-three (of 69) cats (or 76.8%) while on phenobarbital therapy. A single cytopenia was found in 16 cats, bicytopenia in 27 cats, and pancytopenia in 9 cats. Neutropenia was one of the major findings and was found in 60% of the cats, with leukopenia being recorded in 49.3% cats, followed by thrombocytopenia in 24.1% and anemia in 20.3% cats. Wow! I don’t know if I would have clinically noted those findings! Neutropenia and leukopenia were found to be mild in most of the cases, except in 5 cases where they were interpreted to be moderate, with one being classified as severe and one being life-threatening. The one patient with life-threatening neutropenia tested negative for FeLV/FIV, and had normal hematocrit and platelet counts; however, the patient was euthanized due to worsening neurologic symptoms. Histopathologic examination of the brain post-mortem later revealed an intraventricular meningioma. Anemia was documented in 14 patients, including mild anemia in 11.6% of cases and moderate anemia in 8.7% of cases. The anemia was non-regenerative in all cases. Thrombocytopenia was present in 7 out of 29 patients who had platelet counts performed, while none of the patients showed any signs of bleeding.

Next, let’s talk about the phenobarbital doses that these patients were prescribed (please note that a dose was recorded for all patients in the study). The median phenobarbital dose was 6.15 mg/kg, ranging from 0.88 to 27.17 mg/kg. Patients who received levetiracetam in addition to phenobarbital had significantly lower hematocrits as compared to the ones that received only phenobarbital. No difference was observed in leukocyte, neutrophil, or thrombocyte count between these two groups (in other words, phenobarbital monotherapy vs. combination therapy).

As you know, phenobarbital concentrations are often measured for monitoring purposes in these patients. In this study, measurement of serum concentrations of phenobarbital was measured in 67 of 69 patients. A median of 27.5 ug/mL was recorded, with a range of 6 to 79.2 ug/mL. Interestingly, the leukocyte counts were lower in patients with phenobarbital concentrations that were in the therapeutic range of 25-35 ug/mL as compared to the phenobarbital concentrations that were either below or above this range. No significant difference was found in hematocrit, neutrophil, or thrombocyte counts between different therapeutic ranges. Of note, a decrease in leukocyte and neutrophil counts was noted as the treatment time increased. The time to severe leukopenia and neutropenia was between 25 and 114 days in this study.

The authors highlighted several limitations of this study, the most important one being the “cause-effect relationship” between phenobarbital and hematologic cytopenias. They noted that to truly attribute the cytopenias to phenobarbital use, the therapy would have to be discontinued to see if recovery from the cytopenias occurs in these patients. However, it is usually not feasible to withdraw these medications as that can be life-threatening. In addition, use of combination therapy confounds the interpretation of effects of phenobarbital on hematologic changes as well. The authors also noted the limitation of not having bone marrow examinations performed, which limits the interpretation of primary bone marrow disease vs. peripheral disease resulting in cytopenias. That said, this is a comprehensive retrospective study looking at trends in hematologic changes in cats on long-term phenobarbital therapy which haven’t been extensively described in cats previously.

So, what do we take away from this VETgirl podcast? The biggest take home point is that cytopenias can occur commonly in cats on phenobarbital — even when the phenobarbital concentrations are within the therapeutic range! This stresses the importance of routine CBC monitoring in these patients. It’s important to warn cat owners about the most frequently documented hematologic changes, including neutropenia, leukopenia, thrombocytopenia, and anemia. These cytopenias were mild in most of the cases, with rare cases showing severe decrease in one or more cell lines; that said, almost 78% of cats had a cytopenia while on chronic phenobarbital. And lastly, it is interesting to note that patients on combination therapy had lower hematocrits as compared to patients on phenobarbital therapy. Ultimately, even though the hematologic changes in most cases seem to be mild, close monitoring of patients with moderate to severe neutropenia is warranted.

References:
1. Bersan E, Volk HA, Ros C, De Risio L. Phenobarbitone-induced haematological abnormalities in idiopathic epileptic dogs: prevalence, risk factors, clinical presentation and outcome. Vet Rec. 2014;175(10):247. doi:10.1136/vr.102158.
2. Dohány A, Guija-de-Arespacochaga A, Fux D, Silberbauer C, Pákozdy Á. A retrospective evaluation of phenobarbital-induced hematologic changes in 69 cats. Vet Clin Pathol. 2023;52(4):601-606. doi:10.1111/vcp.13259.

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