Presumed zonisamide-induced blood dyscrasias in four dogs

1.1 Case 1

A 7-year-old neutered female Shih Tzu weighing 5 kg presented to the emergency service for 1 episode of vomiting, lethargy, and anorexia over approximately 48 hours. Pertinent past medical history included an injury at 3 weeks of age causing a right eye enucleation and a traumatic brain injury suspected to cause tonic-clonic seizures managed with zonisamide¹ (5 mg/kg, PO, q 12 h). The dog had been receiving zonisamide for 400 days. The dog had magnetic resonance imaging (MRI) 2 years prior that showed an enlarged left lateral ventricle, thickened left-sided frontal and parietal bone, and brain atrophy suspected to be secondary to the previously reported trauma.

On initial physical examination, the patient had a fever of 105.4°F (40.8°C), severe lethargy, and dullness. The dog had a grade I/VI left systolic murmur. A consultation with a board-certified neurologist revealed no new deficits, and the mentation changes were attributed to a metabolic cause, likely underlying systemic inflammation or sepsis, but a primary neurological disease could not be ruled out. On ocular examination of the left eye, there was mild serous discharge, slight corneal pigmentation, posterior immature cataract, and mild chronic vitreous changes. Consultation with a board-certified ophthalmologist confirmed mild chronic changes and no evidence of uveitis, protein, or cell deposition. There were no other physical examination abnormalities noted. Following placement of an IV catheter, the dog was hospitalized and treated with ampicillin/sulbactam² (50 mg/kg, IV, q 6 h), enrofloxacin³ (10 mg/kg, IV, q 24 h), metronidazole⁴ (15 mg/kg, IV, q 12 h), famotidine⁵ (1 mg/kg, IV, q 12 h), and maropitant⁶ (1 mg/kg, IV, q 24 h).

CBC revealed severe leukopenia characterized by decreased neutrophil, monocyte, and lymphocyte counts and a mildly low mean corpuscular hemoglobin concentration (MCHC) (Table 1). The pathologist's review of the blood smear found only 20 cells on which to base the differential cell count. The biochemistry panel revealed hypocalcemia, hypochloremia, hyponatremia, hyperbilirubinemia, and increased alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities (Table 1). There was slight hemolysis of the serum. Urinalysis revealed a specific gravity of 1.015 after the administration of IV fluids and was otherwise unremarkable. Zonisamide was discontinued on admission due to concern for a drug reaction causing bone marrow toxicity.

Thoracic radiographs were normal. Abdominal ultrasound showed mild hepatomegaly and a diffusely hypoechoic liver with gall bladder wall thickening. Echocardiography revealed a thickened mitral valve consistent with chronic degenerative valve disease and no obvious vegetative lesions. Blood cultures were not performed. The dog improved daily with supportive care and discontinuation of zonisamide, despite no identification of the septic focus. Repeat bloodwork on day 2 of drug discontinuation showed improved leukopenia with mild anemia (Table 1). The clinical pathologist's slide review identified persistent neutropenia and reactive lymphocytes.

The dog improved and started to eat on day 4 of hospitalization and was discharged with enrofloxacin (9 mg/kg, PO, q 24 h for 2 weeks) due to ongoing neutropenia. On follow-up bloodwork taken 19 days after discontinuing zonisamide, the leukopenia and anemia had resolved and were within the reference interval (Table 1). The dog was prescribed levetiracetam⁷ (25 mg/kg, PO, q 8 h) to manage seizures 69 days after discharge.

1.2 Case 2

A 1-year-old intact male Siberian Husky weighing 23.5 kg with a prior history of tonic-clonic seizures presented to the emergency service for groaning, twitching, and appearing tense. The clinical signs of twitching described were not consistent with the dog's previous seizure activity as reported by the owner. Previous seizures were described as generalized tonic–clonic seizures lasting 20–30 seconds with an approximately 1 hour postictal period. The dog had a decreased appetite for approximately 72 hours prior to presentation. Current seizure management included zonisamide¹ (17 mg/kg, PO, q 12 h), phenobarbital⁸ (4 mg/kg, PO, q 12 h), topiramate⁹ (11 mg/kg, PO, q 12 h), levetiracetam⁷ (64 mg/kg, PO, q 8 h), and a cannabinoid supplement¹⁰ (0.2 mg/kg, PO, q 12 h). The dog was on several anticonvulsants due to reported breakthrough seizures and was receiving zonisamide at this particular dosage for 29 days. There is no documentation in the dog's record as to the exact start date of zonisamide.

On presentation, the dog had a temperature of 102.6°F (39.2°C), a heart rate of 120/min, and a respiratory rate of 20/min. There were no other physical abnormalities reported on examination. The dog was given an additional dose of levetiracetam (60 mg/kg, IV) on presentation because of suspected seizure activity, and topiramate was discontinued as the suspected cause of anorexia. The zonisamide dose was reduced to 13 mg/kg (PO, q 12 h), and all other seizure medications were continued. Along with a loading dose regimen of potassium bromide.¹² overnight, the dog developed a fever of 104.7°F (40.4°C).

Baseline laboratory evaluation revealed PCV and total plasma protein within the reference interval. Initial CBC showed leukopenia and neutropenia (Table 2). The biochemistry panel showed increased ALP activity and hypoalbuminemia. The CBC 48 hours later showed persistent leukopenia and neutropenia, with nonregenerative or preregenerative anemia and thrombocytopenia (Table 2). Two-view thoracic radiographs were normal. Abdominal ultrasound showed a mildly enlarged medial iliac lymph node and scant abdominal effusion that could not be sampled. Zonisamide was discontinued on day 2 of hospitalization due to suspected drug-induced bone marrow toxicity.

A septic source was not identified, and the dog's fever resolved during hospitalization. A bone marrow aspirate and biopsy were recommended but were declined by the owner. The dog was sent home on day 5 of hospitalization on amoxicillin/clavulanic acid¹¹ (16 mg/kg, PO, q 12 h) and enrofloxacin³ (12 mg/kg, PO, q 24 h) given the patient's persistent neutropenia (Table 2). The dog was sent home with phenobarbital (3.8 mg/kg, PO, q 12 h), levetiracetam (64 mg/kg, PO, q 8 h), and potassium bromide (20 mg/kg, PO, q 12 h) for seizure management.

On day 13, the dog returned to the hospital for a bone marrow aspirate and biopsy due to persistent pancytopenia and was not on antimicrobials at this time. CBC at this time showed leukopenia, neutropenia, nonregenerative anemia, and thrombocytopenia (Table 2). Cytology and biopsy of the bone marrow confirmed erythroid and myeloid hyperplasia with a left-shifted myeloid line. No changes to treatment were made at this time.

Recheck CBCs performed 40 days after discontinuation of zonisamide showed persistent leukopenia with neutropenia, with resolution of the anemia and thrombocytopenia (Table 2). Antimicrobials were discontinued prior to day 15 post-hospitalization.

The dog presented 180 days from initial diagnosis for a surgical consultation for a neuter, and a CBC at that time showed a leukocyte count and neutrophil count within the reference interval (Table 2). The dog was continued on phenobarbital (3.8 mg/kg, PO, q 12 h), levetiracetam (64 mg/kg, PO, q 8 h), potassium bromide (20 mg/kg, PO, q 12 h), topiramate (11 mg/kg, PO, q 12 h), and gabapentin¹³ (17 mg/kg, PO, q 8 h) for seizure management. Topiramate was restarted between days 30 and 180 to manage ongoing seizure activity.

1.3 Case 3

A 9-year-old neutered female Miniature Poodle weighing 5.9 kg presented to the emergency service for anorexia, lethargy, labored breathing, and reluctance to walk. Pertinent past medical history included seizures secondary to a hemorrhagic infarct diagnosed via MRI and managed with zonisamide¹ (8.5 mg/kg, PO, q 12 h). The dog had been receiving zonisamide for 20 days. The dog had also undergone anal sacculectomy 7 days prior to presentation to remove an apocrine gland anal sac adenocarcinoma. The dog was being treated with amoxicillin-clavulanic acid¹¹ (16 mg/kg, PO, q 12 h).

On initial physical examination, the dog had a temperature of 101.1°F (38.4°C), a heart rate of 140/min, and a respiratory rate of 60/min. Overnight, a fever of 103.3°F (39.6°C) developed. The incision site lateral to the dog's anus was clean, dry, and intact. There were no other physical examination abnormalities noted. The dog was treated with Lactated Ringer's,¹⁵ maropitant⁶ (1 mg/kg, IV, q 24 h), zonisamide (8.5 mg/kg, PO, q 12 h), amoxicillin/clavulanic acid (15 mg/kg, PO, q 12 h), clopidogrel¹⁴ (1 mg/kg, PO, q 24 h), and gabapentin¹³ (7.5 mg/kg, PO, q 8 h). The dog received a single dose of clopidogrel due to concern that another vascular event had occurred at home. Approximately 12 hours after admission, zonisamide and clopidogrel were discontinued, amoxicillin/clavulanic acid was changed to ampicillin/sulbactam² (50 mg/kg, IV, q 6 h), and enrofloxacin (10 mg/kg, IV, q 24 h) and levetiracetam⁷ (20 mg/kg, PO, q 8 h) were initiated. Zonisamide was discontinued due to a suspected idiosyncratic drug reaction, and clopidogrel was discontinued as the dog's previous vascular events were due to a hemorrhagic, rather than ischemic, infarct.

CBC after discontinuing zonisamide showed severe leukopenia and neutropenia. The chemical panel showed increased ALP activity and hyponatremia (Table 3). Thoracic radiographs on day 2 of hospitalization showed a normal thorax. Repeated CBC on day 3 showed improved leukopenia, but a neutrophil count of 0 persisted, with mild nonregenerative or preregenerative anemia. Repeated CBC on day 5 of hospitalization showed improved leukopenia and neutropenia, with progressive nonregenerative or preregenerative anemia and severe platelet clumping and large platelets noted on the manual blood smear, decreasing the automated platelet count (Table 3).

CBC 6 days after discontinuing zonisamide showed a WBC count and neutrophil count within the reference interval with slight toxic change, improved nonregenerative or preregenerative anemia, and severe platelet clumping and large platelets noted on manual blood smear, decreasing the automated platelet count (Table 3). A septic process was not found during the workup, and the dog improved with supportive care after zonisamide was discontinued. The dog was discharged with levetiracetam (21 mg/kg, PO, q 8 h), metronidazole¹⁶ (8.5 mg/kg, PO, q 12 h), and amoxicillin/clavulanic acid (21 mg/kg, PO, q 12 h). On follow-up exam for a surgical incision check 6 days postdischarge, the dog had returned to normal at home with no further clinical signs after discontinuation of zonisamide.

1.4 Case 4

A 5-year-old neutered male Miniature Poodle weighing 8.9 kg presented to the emergency service for vomiting, lethargy, and anorexia. Past pertinent history included tonic-clonic seizures from suspected idiopathic epilepsy, managed with zonisamide¹ (8.4 mg/kg, PO, q 12 h) and levetiracetam⁷ (14 mg/kg, PO, q 12 h), and a partially torn right cruciate ligament. The dog had been receiving zonisamide for 1,196 days.

On initial physical examination, the dog had a fever of 104.9°F (40.5°C), heart rate of 96/min, and respiratory rate of 54/min. Following placement of an IV catheter, the dog was hospitalized and treated with amoxicillin/clavulanic acid (14 mg/kg, PO, q 12 h), recombinant human granulocyte colony-stimulating factor¹⁷ (filgrastim, 5 μg/kg, SC, q 24 h, for 3 days), and levitiracetam⁷ (28 mg/kg, PO, q 8 h). Zonisamide was discontinued.

CBC showed severe leukopenia characterized by neutropenia and mild thrombocytopenia. The biochemistry panel showed increased ALP activity, hyponatremia, hypokalemia, hypochloremia, and hypercholesterolemia (Table 4). Urinalysis showed a specific gravity of 1.030 with no evidence of bacteria or WBCs. A 4Dx test was negative.

Complete blood count on day 2 of hospitalization showed improved leukopenia and neutropenia and a mild nonregenerative or preregenerative anemia and progressive thrombocytopenia. The CBC on day 3 of hospitalization showed leukocyte and neutrophil counts within the reference interval, with progressive nonregenerative anemia and improved platelet counts. The CBC 4 days after discontinuing zonisamide showed a WBC and neutrophil count within the reference interval and improved anemia and thrombocytopenia (Table 4).

No specific diagnostics were performed to determine the origin of febrile neutropenia given rapid improvement and strong suspicion of neutropenia due to a drug reaction. The patient was discharged with amoxicillin/clavulanic acid¹¹ (14 mg/kg, PO, q 12 h) and levetiracetam (28 mg/kg, PO, q 8 h) for seizure management. At a follow-up appointment with a board-certified neurologist 48 days postdischarge, the patient's exam was normal, having returned to normal activity at home following discontinuation of zonisamide.