Curtis W. Dewey

Zonisamide therapy for refractory idiopathic epilepsy in dogs.

Twelve dogs with poorly controlled idiopathic epilepsy were entered into a prospective, open-label, noncomparative study. Oral zonisamide was administered as an additional therapy at a dosage adequate to achieve serum drug concentrations of 10 to 40 microg/mL. Seizure frequency before and after initiation of zonisamide therapy was recorded. A dosing interval of q 12 hours was sufficient to maintain serum zonisamide concentrations within the therapeutic range. The mean dosage of zonisamide required was 8.9 mg/kg q 12 hours. Seven (58%) dogs responded favorably, experiencing a mean reduction in seizures of 81.3%. Five dogs had an increase in seizure frequency. Mild side effects (e.g., transient sedation, ataxia, vomiting) occurred in six dogs.

Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs

OBJECTIVE To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs. DESIGN Double-blinded, randomized, parallel, clinical trial. ANIMALS 46 AED-naïve dogs with naturally occurring epilepsy. PROCEDURES Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs. RESULTS Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 μg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], p.o., q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], p.o., q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end. CONCLUSIONS AND CLINICAL RELEVANCE Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment.

A retrospective comparison of cervical intervertebral disk disease in nonchondrodystrophic large dogs versus small dogs.

Medical records of 144 small-breed dogs (< or =15 kg) and 46 medium- to large-breed dogs (>15 kg) with surgically confirmed, Hansen type I, cervical intervertebral disk extrusions were reviewed. The most common clinical presentation was cervical hyperesthesia. The most common sites affected were the second (C(2)) to third (C(3)) cervical intervertebral disk space in small-breed dogs and the sixth (C(6)) to seventh (C(7)) cervical intervertebral disk space in the larger dogs. Following surgery, 99% of the dogs had resolution of cervical hyperesthesia and were able to ambulate unassisted. Seven (4%) dogs required a second surgery; four of these were large-breed dogs.

The seizuring cat. Diagnostic work-up and therapy

Practical relevance Although seizures occur less commonly in cats compared with dogs, they are one of the most common forms of neurological disease in the feline patient. Cats may experience both focal (partial) and generalized seizures and causes are divided into primary disorders, in which there is no underlying cause (ie, idiopathic epilepsy), and secondary disorders. Cats with secondary seizure disorders have either an underlying structural lesion or metabolic disease. Patient group Seizures affect cats of all ages. Cats with idiopathic epilepsy tend to be younger (approximately 3.5 years) than cats with secondary seizure disorders (approximately 8 years). Audience This review of feline seizures is directed at all veterinarians who treat cats, both in an emergency setting as well as in general practice. Clinical challenges Refractory seizures are often a diagnostic and therapeutic challenge. A systematic approach to the seizuring cat is described, easing the task of diagnosing the cause of the seizures. In addition, novel antiepileptics are discussed, which can be used as add-on drugs in challenging feline seizure cases. Evidence base Compared with the canine counterpart, the literature regarding treatment of feline seizures is less established. Recent clinical trials and studies are focusing on new treatment options for feline seizures. Specifically, these studies, some of which are ongoing, have led to the use of levetiracetam, zonisamide and pregabalin as add-on antiepileptics in cases that are refractory to phenobarbital.

Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy

OBJECTIVE To assess tolerability and short-term efficacy of oral administration of pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with poorly controlled suspected idiopathic epilepsy. DESIGN Open-label, noncomparative clinical trial. ANIMALS 11 client-owned dogs suspected of having idiopathic epilepsy that was inadequately controlled with phenobarbital, potassium bromide, or a combination of these 2 drugs. PROCEDURES Dogs were treated with pregabalin (3 to 4 mg/kg [1.4 to 1.8 mg/lb], PO, q 8 h) for 3 months. Number of generalized seizures in the 3 months before and after initiation of pregabalin treatment was recorded. Number of responders (>or= 50% reduction in seizure frequency) was recorded, and seizure frequency before and after initiation of pregabalin treatment was compared by use of a nonparametric Wilcoxon signed rank test. RESULTS Seizures were significantly reduced (mean, 57%; median, 50%) after pregabalin administration in the 9 dogs that completed the study; 7 were considered responders with mean and median seizure reductions of 64% and 58%, respectively. Adverse effects for pregabalin were reported in 10 dogs. Mean and median plasma pregabalin concentrations for all dogs were 6.4 and 7.3 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Pregabalin may hold promise as a safe and effective adjunct anticonvulsant drug for epileptic dogs poorly controlled with the standard drugs phenobarbital or potassium bromide. Adverse effects of pregabalin appeared to be mild. Additional studies with larger numbers of dogs and longer follow-up intervals are warranted.

Morphometric features of the craniocervical junction region in dogs with suspected Chiari-like malformation determined by combined use of magnetic resonance imaging and computed tomography

OBJECTIVE To objectively describe morphometric features of the craniocervical junction region of Cavalier King Charles Spaniels (CKCSs) and non-CKCS dogs with suspected Chiari-like malformation (CLM) and identify associations between these features and the presence of other malformations in this region. ANIMALS 216 CKCSs and 58 non-CKCS dogs. PROCEDURES Magnetic resonance and computed tomographic images of the head and craniocervical junction region of patients evaluated because of suspected CLM were assessed for cerebellar compression (CC), ventral spinal cord compression at the C1-C2 articulation (medullary kinking), and dorsal spinal cord compression at the C1-C2 articulation (dorsal compression). A compression index was calculated for each of these 3 locations in each dog. Multiple logistic regression analysis was performed to determine whether breed (CKCS vs non-CKCS) and compression index values were associated with the presence of other craniocervical junction abnormalities. RESULTS All 274 dogs had CC; medullary kinking was identified in 187 (68.2%) and dorsal compression was identified in 104 (38.0%). Atlantooccipital overlapping (AOO) was identified in 76 (27.7%) dogs. Breed of dog (CKCS vs non-CKCS) and value of CC index were the only significant predictors of AOO. The CKCSs had an almost 5-fold decrease in risk of AOO, compared with the non-CKCS dogs, and the risk of AOO nearly doubled for every 10% increase in CC index. CONCLUSIONS AND CLINICAL RELEVANCE The anatomic abnormality responsible for CC was AOO in a substantial percentage of dogs suspected to have CLM. The CC index value may be used to help differentiate subtypes of craniocervical junction abnormalities in dogs.

Pharmacokinetics of single-dose oral pregabalin administration in normal dogs

OBJECTIVE To describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose. STUDY DESIGN Prospective experiment. ANIMALS Six adult Labrador/Greyhound dogs (four females and two males) aged 2.6 (2.6-5.6) years old (median and range) weighing 33.4 (26.8-42.1) kg. METHODS After jugular vein catheterization, the dogs received a single oral dose of pregabalin ( approximately 4 mg kg(-1)). Blood samples were collected at: 0 (before drug administration), 15 and 30 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours after drug administration. Plasma pregabalin concentration was measured by HPLC. Noncompartmental analysis was used to estimate pharmacokinetic variables. RESULTS No adverse effects were observed. The median (range) pharmacokinetic parameters were: Area under the curve from time 0 to 36 hours = 81.8 (56.5-92.1) microg hour mL(-1); absorption half-life = 0.38 (0.25-1.11) hours; elimination half-life = 6.90 (6.21-7.40) hours; time over 2.8 microg mL(-1) (the presumed minimal effective concentration) = 11.11 (6.97-14.47) hours; maximal plasma concentration (C(max)) = 7.15 (4.6-7.9) microg mL(-1); time for C(max) to occur = 1.5 (1.0-4.0) hours. Assuming an 8-hour dosing interval, predicted minimal, average, and maximal steady state plasma concentrations were 6.5 (4.8-8.1), 8.8 (7.3-10.9), and 13.0 (8.8-15.2) microg mL(-1). The corresponding values assuming a 12-hour interval were 3.8 (2.4-4.8), 6.8 (4.9-7.9), and 10.1 (6.6-11.6) microg mL(-1). CONCLUSIONS AND CLINICAL RELEVANCE Pregabalin 4 mg kg(-1) PO produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to suggest that a twice daily dosing regime would be adequate. Further study of the drugs safety and efficacy for the treatment of neuropathic pain and seizures in dogs is warranted.

Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy.

OBJECTIVE To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to phenobarbital treatment in cats with poorly controlled suspected idiopathic epilepsy. DESIGN-Open-label, noncomparative clinical trial. ANIMALS 12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects when treated with phenobarbital. PROCEDURES Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded. RESULTS Median maximum serum levetiracetam concentration was 25.5 microg/mL, median minimum serum levetiracetam concentration was 8.3 microg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in seizure frequency of >or=50%). Two cats had transient lethargy and inappetence. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to phenobarbital treatment in cats with idiopathic epilepsy.

Mycophenolate mofetil treatment in dogs with serologically diagnosed acquired myasthenia gravis: 27 cases (1999-2008).

OBJECTIVE-To compare clinical outcome in dogs with serologically diagnosed acquired myasthenia gravis (MG) treated with pyridostigmine bromide (PYR) with that of dogs treated with mycophenolate mofetil (MMF) and PYR (MMF + PYR). DESIGN-Retrospective case series. ANIMALS-27 dogs. PROCEDURES-Medical records from August 1999 through February 2008 were reviewed to identify dogs with serologically diagnosed acquired MG treated with PYR or MMF + PYR. Data collected for each dog included signalment, whether the dog had megaesophagus or pneumonia (or both), thyroid hormone concentration, remission, time to remission, and survival time. Rates for detection of clinical signs and survival time were compared. Survival time was estimated via the Kaplan-Meier method. Influence of drug treatment protocol on likelihood of remission, time to remission, and survival time was examined. Effects of MMF treatment, megaesophagus, pneumonia, and low serum thyroid hormone concentration on time to remission and survival time were also analyzed. RESULTS-12 dogs were treated with PYR, and 15 were treated with MMF + PYR. Mortality rates were 33% (PYR) and 40% (MMF + PYR). There was pharmacological remission in 5 and 6 dogs in the PYR and MMF + PYR groups, respectively. No significant differences were detected between treatment groups for remission rate, time to remission, or survival time. Megaesophagus, pneumonia, and low serum thyroid hormone concentration had no significant effect on time to remission or survival time for either treatment group. CONCLUSIONS AND CLINICAL RELEVANCE-The results did not support routine use of MMF for the treatment of dogs with acquired MG.

Apparent Acute Idiosyncratic Hepatic Necrosis Associated with Zonisamide Administration in a Dog

A4-year-old, 6.5-kg, castrated male Boston Terrier was referred to the Cornell University Hospital for Animals for evaluation of seizures. Seizure activity was characterized by unconsciousness, tonic-clonic limb movements, and hypersalivation, with each seizure lasting approximately 1 minute. Three seizures had occurred during the 24 hours preceding presentation. Otherwise, the dog had been clinically healthy. No drugs were administered and toxin exposure was unlikely. Laboratory assessment completed by the referring veterinarian included CBC and serum biochemistry (sodium, potassium, chloride, total protein, albumin, globulin, BUN, creatinine, glucose, calcium, phosphorus, total bilirubin, and cholesterol concentrations; alkaline phosphatase [ALP], alanine aminotransferase [ALT], and amylase activities). Results disclosed eosinopenia (0.09 9 10 cells/lL; reference range 0.1–1.49 9 10/lL) and mildly increased ALT activity (124 U/L; reference range, 10–100 U/L). On presentation, the dog was bright and alert with modest upper airway stridor attributable to brachycephalic conformation. Neurologic examination demonstrated decreased menace OD and equivocal cervical pain. Multiplanar magnetic resonance imaging of brain and cervical spinal cord performed under general anesthesia (preanesthetic medications included hydromorphone [0.05 mg/kg SC], dexmedetomidine [2.0 lg/kg SC], and glycopyrrolate [5.2 lg/kg SC]; induction with propofol [4.6 mg/kg IV] and thiopental [6.0 mg/kg IV]; general anesthesia maintained with sevofluorane and oxygen; post-anesthetic administration of dexamethasone SP [1.7 mg SC]) using a 0.2T superconducting magnet revealed multifocal, asymmetrical ill-defined intra-axial hyperintense areas in the cerebral cortex; these regions were slightly hyperintense to brain on T2-weighted images and fluid attenuated inversion recovery, but lacked contrast enhancement. A linear intra-axial lesion with the same signal intensity as cerebrospinal fluid (CSF) that did not contrast enhance was noted within spinal cord parenchyma at C1 and C2, consistent with mild syringohydromyelia. The CSF collected from the lumbosacral subarachnoid space was colorless and clear with normal nucleated cell count (3/lL; reference range, <5/lL) and total protein concentration (21 mg/dL; reference range, <45 mg/dL); cytologic examination disclosed 63% small lymphocytes and 37% macrophages. Collective findings were interpreted as changes secondary to the recent seizure activity and mild syringohydromyelia. The dog was prescribed the anticonvulsant zonisamide (7.7 mg/kg PO q12h) for presumed idiopathic epilepsy. After 10 days of zonisamide administration, the dog was presented again for inappetence and vomiting. No seizure activity had occurred since instituting zonisamide. Results of CBC and serum biochemistry disclosed lymphopenia (0.5 9 10/lL; reference range, 0.9–4.7 9 10/lL), eosinopenia (0.0 9 10/lL), mild thrombocytopenia (176 9 10/lL; reference range, 186–545 9 10/lL) with platelet clumps, few acanthocytes and keratocytes, marked increases in activities of ALT (16328 U/L) and aspartate aminotransferase (AST; 5908 U/L; reference range, 16–50 U/L), modest increases in activities of ALP (354 U/L; reference range, 12–122 U/L) and gamma-glutamyl transferase (GGT, 61 U/L; reference range, 0–10 U/L), and hyperbilirubinemia (2.3 mg/dL; reference range, 0–0.3 mg/ dL). Urine was concentrated (specific gravity 1.050) with bilirubinuria, 2+ proteinuria, pH 7.5, and sediment demonstrated crystals consistent with sulfonamide drug-related crystalluria. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged beyond measurable range. Abdominal ultrasound examination was within normal limits. Treatment with PlasmaLyte A (90 mL/kg/d) supplemented with potassium chloride (15 mEq KCl/L) and B vitamin complex (2 mL/L), fresh frozen plasma (FFP; 10 mL/kg IV), vitamin K1 o (0.5 mg/kg SQ q12h for 3 doses), N-acetylcysteine (140 mg/kg IV loading dose followed by 70 mg/kg IV q12h), ondansetron (0.1 mg/kg IV q12h) and levetiracetam (20 mg/kg IV q8h) were initiated, and zonisamide was discontinued. Two hours after the FFP transfusion, PT (86 s; reference range, 12–17 s) and aPTT (>102 s; reference From the Departments of Clinical Sciences, Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York (Miller, Center, Randolph, Cautela, Dewey, Lepherd). Corresponding author: Meredith Miller, DVM, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; e-mail: mlm64@cornell.edu. Submitted April 29, 2011; Revised May 29, 2011; Accepted July 6, 2011. Copyright