Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide in epileptic dogs

Fifteen dogs with idiopathic epilepsy were included in a 9-month clinical trial to determine the therapeutic serum concentrations of primidone and its active metabolites, phenobarbital and phenylethylmalonamide. Dogs with a seizure frequency greater than 1/mo or with a record of multiple seizures greater than 1/day were chosen for the study. Each dog was given primidone 3 times daily at dosages intended to maximize seizure control and to minimize undesired side effects. Maintenance period blood samples were taken from fasted dogs 7 hours after dosing in the 3rd, 5th, 7th, and 9th months of the trial to determine therapeutic serum concentrations of primidone and its metabolites. Two blood samples also were taken from all dogs 7 hours after dosing, during an enforced drowsy period, to establish upper limits of desirable serum concentrations of the drug. Seizure frequencies during the trial were controlled in 13 dogs, 7 of which had no seizures during the 9-month trial. The mean percentage reduction in seizure frequency from pretrial frequency was 85%. Two dogs appeared refractory to primidone therapy. Serum phenobarbital was the best metabolite of primidone to use to assess therapeutic serum concentrations. The therapeutic antiepileptic serum concentration of phenobarbital was found to be between 25 and 40 micrograms/ml of serum. Serum phenobarbital concentrations greater than 40 micrograms/ml resulted in side effects in most dogs.     

Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison

The efficacy of phenobarbital and primidone against canine epilepsy was compared in a controlled study. Thirty-five dogs showing generalized tonic-clonic seizures (grand mal), treated for a minimum of 6 months, were included in the study; fifteen of these were treated with phenobarbital, the other twenty with primidone. Both drugs were dosed according to the clinical requirement; the daily doses ranged from 5-17 mg/kg phenobarbital and from 17-70 mg/kg primidone. The plasma concentrations of phenobarbital, or of primidone and its metabolites phenobarbital and phenylethylmalondiamide (PEMA), were routinely monitored. Complete control of tonic-clonic seizures for 6 months, at least, was attained in six out of fifteen dogs of the phenobarbital group, and in five out of twenty dogs in the primidone group. A further six dogs on phenobarbital, and seven dogs on primidone, were classified as 'improved', i.e. the rate of seizures was reduced by at least 50%. The rest of the dogs were not improved by the treatment. The difference between the efficacy of phenobarbital and primidone was not significant, but primidone gave rise to signs of liver toxicity in fourteen out of twenty dogs, as indicated by considerable elevations of liver enzyme values (alanine transferase, glutamate dehydrogenase, alkaline phosphatase). Phenobarbital is, therefore, regarded as the drug of first choice for the treatment of canine epilepsy.     

Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study

A new antiepileptic and anxiolytic drug, ELB138, was evaluated in a clinical pilot study in dogs with newly diagnosed or chronic idiopathic epilepsy. The purpose was to verify clinically the anticonvulsant effectiveness of this substance, which had already been demonstrated experimentally. Data from 29 dogs treated with ELB138 were compared with results obtained retrospectively from 82 dogs treated with conventional antiepileptic medication. The reduction in seizure frequency using ELB138 in dogs with newly diagnosed idiopathic epilepsy was comparable to the reduction in dogs treated either with phenobarbital or primidone. In dogs with chronic epilepsy and add-on therapy with either ELB138 or potassium bromide, such supplementation reduced the seizure frequency and the duration and severity of seizures. The most obvious difference between ELB138 treatment and conventional medications became clear in the evaluation of side effects, which in those dogs treated with ELB138 were rare, and consisted mostly of transient polyphagia. This pilot study confirmed that ELB138 has a potent anticonvulsant effect in dogs with idiopathic epilepsy. These results will form the basis for a multicentre, blinded study.     

Propofol for treatment of refractory seizures in dogs and a cat with intracranial disorders

Twelve dogs and one cat that were presented with seizures due to various disorders of intracranial origin were treated with one or several boluses of propofol (2 to 8 mg/kg). All the animals had received previous medication, including diazepam alone or in combination with phenobarbital and/or pentobarbital. Seizure control with prevention of further convulsions was achieved in 11 patients. In one dog, seizures kept recurring after periods of successful control following administration of propofol. Another dog with continuing seizures resistant to barbiturate therapy died following administration of propofol. This retrospective study suggests that propofol may be an effective drug in controlling status epilepticus resistant to conventional medication and may be used as an alternative to pentobarbital administration.     

Low concentrations of cerebrospinal fluid GABA correlate to a reduced response to phenobarbital therapy in primary canine epilepsy

In this study, we investigated whether pretreatment cerebrospinal fluid (CSF) neurotransmitter concentrations of gamma-aminobutyric acid (GABA) and glutamate (GLU) were correlated with response to phenobarbital treatment in dogs with primary epilepsy. Eleven untreated dogs, 6 males and 5 females, with a median age of onset of seizures of 3 years (range: 0.5-5 years) were selected for therapy based on progressive or serious seizure patterns. The median interval between the first observed seizure and start of phenobarbital therapy was 485 days (range: 101-1,765 days). All dogs were purebred, with the exception of I male dog. Oral phenobarbital was started at 2.5 mg/kg every 12 hours. Trough serum phenobarbital concentrations were measured at 15, 45, 90, 180, 360, 540, and 720 days after the start of treatment. There was no difference in the mean trough serum concentration or in the mean number of seizures recorded between each time period of phenobarbital measurement over the 2-year evaluation. No correlation was found between CSF GLU, GABA, or GLU: GABA ratio and the total number of seizures recorded before or after initiation of phenobarbital therapy. Lower CSF GABA concentration, however, was correlated with a lower seizure frequency difference (the total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy for an identical time period of evaluation) and lower percentage reduction in seizures: ([total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy] divided by the total number of seizures before phenobarbital therapy) x 100. There was no correlation between CSF GLU and the seizure frequency difference and percentage reduction in seizures. A negative correlation between the CSF GLU:GABA ratio and seizure frequency difference was found. Thus, dogs with an initial lower CSF GABA concentration before phenobarbital therapy did not respond as well as did dogs with a higher CSF GABA concentration.     

Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs

The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client‐owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital‐treated dogs, significantly increased levels of alkaline phosphatase, gamma‐glutamyl‐transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no‐observed‐adverse‐event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs.     

Effectiveness of a therapeutic drug monitoring service as an aid to the control of canine seizures

The results presented were derived from an anticonvulsant monitoring service, provided for two years to practising veterinary surgeons, in which samples of serum were taken from dogs treated with either primidone or phenobarbitone. Of the 19 patients assessed, 13 were controlled after the recommended changes in dose had been made. Of the six patients not completely controlled after changes in dose, four had a much lower incidence of seizures but two did not respond to treatment in spite of having high serum phenobarbitone levels. There were large variations between the doses of anticonvulsant drugs required to reach therapeutic serum levels; these variations underlined the value of routine monitoring for improving the control of canine seizures.     

Effects of phenobarbital treatment on serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs.

OBJECTIVE: To determine whether phenobarbital treatment of epileptic dogs alters serum thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations. DESIGN: Cross-sectional study. ANIMALS: 78 epileptic dogs receiving phenobarbital (group 1) and 48 untreated epileptic dogs (group 2). PROCEDURE: Serum biochemical analyses, including T4 and TSH concentrations, were performed for all dogs. Additional in vitro analyses were performed on serum from healthy dogs to determine whether phenobarbital in serum interferes with T4 assays or alters free T4 (fT4) concentrations. RESULTS: Mean serum T4 concentration was significantly lower, and mean serum TSH concentration significantly higher, in dogs in group 1, compared with those in group 2. Thirty-one (40%) dogs in group 1 had serum T4 concentrations less than the reference range, compared with 4 (8%) dogs in group 2. All dogs in group 2 with low serum T4 concentrations had recently had seizure activity. Five (7%) dogs in group 1, but none of the dogs in group 2, had serum TSH concentrations greater than the reference range. Associations were not detected between serum T4 concentration and TSH concentration, age, phenobarbital dosage, duration of treatment, serum phenobarbital concentration, or degree of seizure control. Signs of overt hypothyroidism were not evident in dogs with low T4 concentrations. Addition of phenobarbital in vitro to serum did not affect determination of T4 concentration and only minimally affected fT4 concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Clinicians should be aware of the potential for phenobarbital treatment to decrease serum T4 and increase TSH concentrations and should use caution when interpreting results of thyroid tests in dogs receiving phenobarbital.     

Serum triglyceride concentration in dogs with epilepsy treated with phenobarbital or with phenobarbital and bromide

OBJECTIVE: To compare serum triglyceride concentrations obtained after food had been withheld (i.e., fasting concentrations) in dogs with epilepsy that had been treated long term (> or = 3 months) with phenobarbital or with phenobarbital and potassium bromide with concentrations in healthy control dogs. DESIGN: Cross-sectional study. ANIMALS: 57 epileptic dogs that had been treated with phenobarbital (n=28) or with phenobarbital and bromide (29) and 57 healthy, untreated control dogs matched on the basis of age, breed, sex, neuter status, and body condition score. PROCEDURES: Blood samples were collected after food had been withheld for at least 12 hours, and serum biochemical and lipid concentrations were determined. Oral fat tolerance tests were performed in 15 control dogs and 9 dogs with epilepsy treated with phenobarbital alone. RESULTS: 19 of the 57 (33%) epileptic dogs had fasting serum triglyceride concentrations greater than the upper reference limit. Nine (16%) dogs had a history of pancreatitis, and 5 of the 9 had high fasting serum triglyceride concentrations at the time of the study. A significant relationship was found between body condition score and fasting serum triglyceride concentration in all dogs, but serum triglyceride concentration was not significantly associated with phenobarbital dosage or serum phenobarbital concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that dogs treated long term with phenobarbital or with phenobarbital and bromide may develop hypertriglyceridemia. Fasting serum triglyceride concentration should be periodically monitored in dogs treated with phenobarbital because hypertriglyceridemia is a risk factor for pancreatitis.     

The Use of Diazepam Per Rectum at Home for the Acute Management of Cluster Seizures in Dogs

The use of diazepam per rectum (RDZ) in the home to control generalized cluster seizures in 11 dogs diagnosed with idiopathic epilepsy was evaluated over a 16-month period. All dogs had a prior history of clusters of generalized seizures and were treated with multiple antiepileptic drugs. Owners were instructed to administer diazepam injectable solution (5 mg/mL) per rectum to their dogs at a dose of 0.5 mg/kg when an initial generalized seizure occurred and when a second or third generalized seizure occurred within 24 hours of the first seizure. Seizure activity was recorded by owners in a daily log before the onset of RDZ use and for the duration of RDZ use, which ranged from 57 to 464 days (median = 157 days). The median age at which the first seizure occurred and the median age at the time of enrollment in the study were 19 and 42 months, respectively. All 11 dogs were treated with phenobarbital, with 10 dogs receiving concomitant bromide therapy. No significant correlation between the duration of the first, second, or third antiepileptic drug therapy and the change in the number of cluster seizure events before or after use of RDZ was found. Comparisons of seizure activity were done for the same time interval before and after the onset of RDZ availability. A significant decrease in the total number of seizure events and the total number of cluster seizures events was found after RDZ availability. Similarly, a significant difference in the average number of seizures per cluster seizure event and the total number of isolated seizure events occurred before and after RDZ therapy. Eight of the 11 dogs (73%) that received RDZ for 1 or more times after the first or second seizure had a 100% success rate in prevention of further seizure activity after the first dose. In 3 dogs, success and compliance rates were both equal at 100%, thus suggesting 100% efficacy of RDZ in blocking further seizure activity over the next 24 hours in these dogs. Owners had a large cost-savings because of the decrease in emergency clinic visits after initiating treatment with RDZ. Before RDZ use, the average number of emergency clinic visits was 3, with an average cost of $308 per dog. After RDZ use, the average number of emergency clinic visits was 1, with an average cost of $81 per dog. The results of this study suggest that RDZ may be an effective method of home treatment of generalized cluster seizures in dogs with idiopathic epilepsy, regardless of prior antiepileptic drug history.     

Risk factors associated with development of seizures after use of iohexol for myelography in dogs: 182 cases (1998)

OBJECTIVE: To determine prevalence of seizures after use of iohexol for myelography and identify associated risk factors in dogs. DESIGN: Retrospective study. ANIMALS: 182 dogs that received iohexol for myelography in 1998. PROCEDURE: Medical records were reviewed for age, breed, sex, weight, dose and total volume of iohexol, injection site, number of injections, lesion type and location, total duration of anesthesia, duration from time of iohexol injection to recovery, presence and number of seizures, and whether surgery followed the myelogram. RESULTS: 39 (21.4%) dogs had at least 1 generalized seizure during or after myelography. Injection site was strongly associated with prevalence of seizures, and risk of seizure was significantly higher after cerebellomedullary injections, compared with lumbar injections. Mean total volume of iohexol administered to dogs that had seizures was significantly higher, compared with that administered to dogs that did not have seizures, although dosage did not differ between groups. Weight was significantly correlated with risk of seizure, and dogs that weighed > 20 kg (44 lb) had higher prevalence of seizures than dogs that weighed < 20 kg. CONCLUSIONS AND CLINICAL RELEVANCE: It is preferential to administer iohexol via the L5-6 intervertebral space to minimize the risk of seizures. Higher prevalence of seizures in large dogs, compared with smaller dogs, may be caused by administration of larger total volumes of contrast agent per volume of CSF.     

Owner perception of the care of long-term phenobarbital-treated epileptic dogs

A study was undertaken to evaluate owners' perception of the effect that epilepsy and long-term phenobarbital therapy had on the quality of pet and owner lifestyle. Selected owners who participated in a prospective, longitudinal clinical epilepsy study were sent a questionnaire at the end of the two-year study. Inclusion criteria were dogs with a history of seizures without previous medical attention or therapy by any veterinarian before enrolment, subsequent determination of seizure aetiology using a standardised diagnostic protocol and treatment with phenobarbital for a minimum period of six months. A relatively equal distribution of the respondents' dogs had a determined (secondary, 47 per cent) or undetermined (primary, 53 per cent) seizure aetiology, and the vast majority of owners agreed that they would choose to treat their epileptic pet again rather than opt for other alternatives. Most owners disagreed that their pet was leading a poor quality of life after the start of phenobarbital therapy. A significant negative correlation existed between an owner's perception of the pet's quality of life and the amount of work required to care for the pet during the two-year study period. This study demonstrates that many owners are willing to care for epileptic dogs on long-term phenobarbital treatment, regardless of the underlying cause.     

Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy

Eleven dogs diagnosed with refractory idiopathic epilepsy were treated orally with gabapentin for a minimum of three months at an initial dose of 10 mg/kg every eight hours. They were all experiencing episodes of generalised tonic-clonic seizures and had been treated chronically with a combination of phenobarbital and potassium bromide at doses sufficient to reach acceptable therapeutic serum levels without causing significant side effects. In each dog, the number of seizures per week, the average duration of the seizures and the number of days on which seizures occurred were compared for the three months before and after they were treated with gabapentin. A minimum 50 per cent reduction in the number of seizures per week was interpreted as a positive response to gabapentin, and six of the dogs showed a positive response. After the addition of gabapentin, both the number of seizures per week (P= 0.005) and the number of days with any seizures in a one-week period (P=0.03) were significantly reduced. Mild side effects of ataxia and sedation were observed in five of the dogs, but they were not severe enough to warrant the treatment being discontinued during the trial.     

CT-GUIDED BRAIN BIOPSY USING A MODIFIED PELORUS MARK III STEREOTACTIC SYSTEM: EXPERIENCE WITH 50 DOGS

This report describes the results of CT-guided stereotactic brain biopsies performed on 50 consecutive dogs using a modified Pelorus Mark III Stereotactic System. Based on available histopathologic samples (stereotactic biopsy [n = 50], surgery [n = 17], necropsy [n = 9]) the patient population consisted of 34 dogs with primary brain tumors, 2 with invasive nasal adenocarcinomas, and 13 with non-neoplastic brain lesions. Brain tissue was not obtained from one dog. In 22 dogs a final diagnosis was made from tissue subsequently obtained from surgical resection or at necropsy. The final diagnosis was in agreement with the stereotactic biopsy diagnosis in 20 of these 22 dogs. In 17 other dogs without follow-up, stereotactic biopsy provided a diagnosis of a specific primary brain tumor subtype. Postoperative complications associated with the biopsy procedure were assessed in 41 dogs. The other 9 dogs either went directly to surgery (n = 7) or were killed (n = 2) immediately after the biopsy procedure. Thirty-six dogs recovered without apparent clinical complications. Postoperative clinical complications in the remaining 5 dogs included transient epistaxis (1 dog), transient exacerbation of cerebellar signs (1 dog), obtundation progressing to coma (1 dog), and medically uncontrollable seizures (2 dogs). The latter 3 dogs with severe neurologic complications all had large primary brain tumors and had been receiving high doses of phenobarbital and glucocorticoids to control seizures at the time of biopsy. These results suggest that this CT-guided biopsy procedure can provide an accurate pathologic diagnosis of brain lesions detected by CT and MR neuroimaging. Further refinement of both technique and case selection is expected to reduce the rate of clinical complications and to improve the accuracy of the procedure.     

Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy

OBJECTIVE: To determine whether there are therapeutically relevant changes in serum phenobarbital concentrations throughout a daily dosing interval in epileptic dogs receiving phenobarbital for > or = 3 weeks. DESIGN: Prospective study. ANIMALS: 33 epileptic dogs receiving phenobarbital. PROCEDURE: Serum phenobarbital concentrations were measured at 0 hour (trough), 3 hours, and 6 hours after oral administration of phenobarbital in epileptic dogs that had received phenobarbital twice daily for a minimum of 3 weeks. For each dog, trough, 3-hour, and 6-hour serum phenobarbital concentrations were evaluated to determine whether they were within the same therapeutic category (lower, middle, or upper end of the therapeutic range of 15 to 45 micrograms/ml), or whether there was a > 30% change in serum concentrations throughout the day. RESULTS: Ninety-one percent (30/33) of dogs had trough, 3-hour, and 6-hour serum phenobarbital concentrations in the same therapeutic category. Only 9% (3/33) of dogs had trough, 3-hour, and 6-hour serum concentrations in different therapeutic categories with a > 30% change in concentrations throughout the day. Significant differences were not detected among mean serum phenobarbital concentrations when comparing the trough, 3-hour, and 6-hour samples for all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: There is no therapeutically relevant change in serum phenobarbital concentrations throughout a daily dosing interval in most epileptic dogs. Therefore, timing is not important when collecting blood samples to measure serum phenobarbital concentrations in most epileptic dogs treated long-term with phenobarbital.     

Outcome from status epilepticus after portosystemic shunt attenuation in 3 dogs treated with propofol and phenobarbital

Objective – To describe outcome of treatment with propofol and phenobarbital for status epilepticus (SE) after portosystemic shunt (PSS) attenuation. Case or Series Summary – Three dogs without preceding seizure activity, were diagnosed with a single extrahepatic PSS. Following standard preoperative medical therapy, an ameroid constrictor was placed surgically. Recovery was uneventful until spontaneous SE developed 46–96 hours after surgery. After unsuccessful seizure control with benzodiazepines, dogs were treated with a bolus of propofol followed by a propofol constant rate infusion. Phenobarbital was concurrently administered and supportive care was optimized. All dogs recovered uneventfully over the next 7–9 days. Over the following months phenobarbital was slowly tapered. All dogs have been free from antiepileptic drugs for several months, without recurrence of neurologic signs. New or Unique Information Provided – In this case series, we describe the treatment of 3 dogs with propofol and phenobarbital for refractory SE following attenuation of a single congenital PSS. After weaning of the propofol constant rate infusion, and tapering and discontinuation of phenobarbital over the following months, all dogs experienced a complete recovery. This study provides evidence that use of propofol in combination with phenobarbital may be efficacious for management of SE in dogs after PSS surgery.     

Case Series: Continuous electroencephalographic monitoring of status epilepticus in dogs and cats: 10 patients (2004–2005)

Objective – To describe the use of continuous electroencephalographic (EEG) monitoring for management of status epilepticus (SE) in dogs and cats. Design – Retrospective study. Setting – University teaching hospital. Animals – Ten patients (7 dogs, 3 cats) with SE of differing etiology (idiopathic epilepsy, n=3; toxicity, n=4; meningoencephalitis, n=2; undefined, n=1). Interventions – The EEG was recorded continuously from 5 stainless‐steel needle electrodes inserted SC. Animals were treated with diazepam and phenobarbital followed by either propofol (n=3) or pentobarbital (n=7) as a continuous rate of infusion. Measurements and Main Results – Clinical seizures stopped after induction of anesthesia in each animal. The EEG, however, still showed distinct epileptiform patterns (spikes, polyspikes) in all animals. Paroxysms were suppressed by increasing the infusion rate of either pentobarbital or propofol. A burst‐suppression pattern was achieved in 5 animals. EEG epileptiform activity reappeared in 4 animals when attempting to taper the dose after >6 hours of anesthesia. This was interpreted as ongoing EEG seizure activity and an increased risk for clinical seizures, and the anesthetic dosage was adjusted accordingly. Conclusion – Continuous EEG monitoring appears to be a useful tool for therapeutic monitoring of SE in dogs and cats. It allows the detection of EEG seizures without the appearance of clinical seizures. Further investigations with blinded investigators and homogeneous animal groups to define therapeutic endpoints are warranted.     

Changes in serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs receiving phenobarbital for one year

A multicentric prospective study was conducted to monitor the effect of phenobarbital on serum total thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations in epileptic dogs. Serum T4 concentrations were determined for 22 epileptic dogs prior to initiation of phenobarbital therapy (time 0), and 3 weeks, 6 months, and 12 months after the start of phenobarbital. Median T4 concentration was significantly lower at 3 weeks and 6 months compared to time 0. Thirty-two percent of dogs had T4 concentrations below the reference range at 6 and 12 months. Nineteen of the 22 dogs had serum TSH concentrations determined at all sampling times. A significant upward trend in median TSH concentration was found. No associations were found between T4 concentration, dose of phenobarbital, or serum phenobarbital concentration. No signs of overt hypothyroidism were evident in dogs with low T4, with one exception. TSH stimulation tests were performed on six of seven dogs with low T4 concentrations at 12 months, and all but one had normal responses. In conclusion, phenobarbital therapy decreased serum T4 concentration but did not appear to cause clinical signs of hypothyroidism. Serum TSH concentrations and TSH stimulation tests suggest that the hypothalamic-pituitary-thyroid axis is functioning appropriately.     

Effects of long-term primidone and phenytoin administration on canine hepatic function and morphology

Primidone, phenytoin, or phenytoin and primidone in combination were given to healthy Beagle dogs for 6 months. Serum biochemical changes in dogs given primidone alone or phenytoin and primidone in combination for the entire 6-month test period included increased activities of alanine aminotransferase, alkaline phosphatase (AP), and gamma-glutamyltransferase, and decreased concentrations of albumin and cholesterol. Changes in dogs given phenytoin alone were limited to increased AP activity and decreased albumin concentration. Sulfobromophthalein excretion and conjugated bile acid concentration were within normal limits. All dogs given primidone alone or phenytoin alone remained clinically healthy throughout the treatment period. Three of 8 dogs given both drugs in combination became clinically ill after 9, 14, and 15 weeks of treatment, and were euthanatized. Two of the dogs developed clinical jaundice. In addition to the serum biochemical abnormalities observed in clinically healthy dogs, these dogs developed hyperbilirubinemia, delayed sulfobromophthalein excretion, and increased conjugated bile acid concentrations. Histologic examination of the liver showed intracanalicular casts of bile pigment typical of intrahepatic cholestasis in all 3 dogs. Histologic findings characteristic of treated dogs included hepatocellular hypertrophy attributable to hyperplasia of the smooth endoplasmic reticulum. Single-cell necrosis and multifocal lipidosis were observed in individuals of all treatment groups. Electron microscopy of the liver showed dilated bile canaliculi and damaged sinusoidal epithelium in dogs given both drugs. The elevated serum AP activity, associated with anticonvulsant drug therapy, was found to be exclusively the liver isoenzyme by cellulose acetate electrophoresis. The hepatic AP was localized to primarily the canalicular membranes by enzyme histochemistry. There was a statistically significant positive correlation between the AP activities of liver and serum. The results of this study indicate that long-term administration of anticonvulsant drugs to dogs is associated with clinical, serum biochemical, and histologic evidence of hepatic dysfunction. High drug dosage contributed most to abnormal serum biochemical test results, and combining phenytoin with primidone was responsible for more severe electron microscopic lesions of the liver of surviving dogs and for the death of 3 dogs.     

Bromide toxicosis (bromism) in a dog treated with potassium bromide for refractory seizures.

A 4-year-old German Shepherd Dog was evaluated because of chronic hind limb lameness and recurrent seizures. Diagnostic evaluation of the dog confirmed rheumatoid arthritis and idiopathic epilepsy. The rheumatoid arthritis was treated with prednisone and piroxicam. The seizures were treated with phenobarbital plus clonazepam. The seizures were refractory and potassium bromide was substituted for clonazepam. The dog was reevaluated 4 months after initiation of potassium bromide treatment because of recurrence of arthritis signs. During hospitalization, the dog had neurologic signs, which progressed from depression to recumbency and stupor. Anisocoria, muscle pain, and hyporeflexia were noticed. Bromide toxicosis was diagnosed on the basis of toxic serum bromide concentration (2.7 mg/ml; therapeutic range, 1.0 to 2.0 mg/ml). Following cessation of potassium bromide treatment, the neurologic signs resolved. The seizures recurred 6 weeks after potassium bromide was discontinued. Bromide treatment was reinitiated at half the initial dosage. After 6 weeks, the serum bromide concentration was 1.9 mg/ml, and no seizures had been reported by the dog's owners. Therapeutic serum bromide concentrations in dogs has been reported to be 0.5 to 2.3 mg/ml. The serum bromide concentration at which toxic signs are expected is variable in human beings because individuals differ in their tolerance of the drug. Clinical trials are necessary to determine the toxic serum bromide concentrations in dogs. This case of bromism in a dog suggests that the dosage of potassium bromide should be based on serial measurement of serum bromide concentrations.