Euthyroid sick syndrome in dogs with idiopathic epilepsy before treatment with anticonvulsant drugs

Euthyroid sick syndrome is a common finding in dogs and is attributable to nonthyroidal illness or treatment with any of a variety of drugs such as phenobarbital. In dogs with epilepsy, treatment with anticonvulsant drugs can lead to subnormal plasma thyroid hormone concentrations despite normal thyroid function. One-hundred thirteen dogs with seizure activity were retrospectively evaluated to determine the influence of idiopathic epilepsy (IE) on thyroid hormone concentrations. Blood samples were taken from 60 dogs with IE before initiation of anticonvulsant therapy. Control groups consisted of 34 dogs with IE and receiving anticonvulsants and 19 dogs with secondary epilepsy. Thyroid concentrations consistent with euthyroid sick syndrome were diagnosed in 38% of dogs with untreated IE without clinical signs of hypothyroidism or concomitant diseases. There was a significant correlation (r = 0.363, P = .01) between seizure frequency and plasma thyroid hormone concentrations: the longer the interval between 2 seizure events, the higher the serum total thyroxine concentration. There was no correlation between the degree of alteration of thyroid hormone concentrations and the time span between the most recent seizure event and blood collection, the type of the most recent seizure event, the duration of the complete seizure history, or the predominant seizure type. These results suggest that IE can be a reason for euthyroid sick syndrome in dogs. The effect of phenobarbital on plasma thyroid hormone concentrations must be investigated in future studies, as it might be less pronounced than expected.     

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.     

Idiopathic epilepsy in dogs: owners' perspectives on management with phenobarbitone and/or potassium bromide

OBJECTIVES: To explore seizure management from the perspective of the owners of dogs with idiopathic epilepsy. METHODS: Questionnaires were mailed to owners of 29 dogs under management for suspected or diagnosed idiopathic epilepsy through the clinics of the Small Animal Hospital of the University of Glasgow Veterinary School, using either phenobarbitone or potassium bromide alone or in combination. RESULTS: The postal survey had an 86 per cent response rate. Analysis of the responses demonstrated that "the dog's quality of life", "adequate seizure frequency" and "acceptable side effects of antiepileptic drugs" were the three greatest concerns for owners; 52 per cent of owners strongly agreed that the seizure management for their dog was adequate, though the seizure frequency reported varied within this group; the majority of owners did not consider the administration of medication a nuisance. However, approximately 60 per cent of owners reported that caring for an epileptic dog had an effect on the organisation of their free time, though this was not dependent on perception of seizure control. Opinions as to the value of further diagnostic procedures, in particular intracranial imaging, were significantly affected by having pet health insurance. CLINICAL SIGNIFICANCE: From the owners' perspective, adequacy of seizure control is determined by the balance between "the dog's quality of life", "adequate seizure frequency" and "acceptable side effects of antiepileptic drugs". A frequency of less than one seizure every three months is associated with the perception by owners of adequate seizure control.     

Plasma levels of valproic acid and its metabolites during continued treatment in dogs

Dogs were treated with the anti-epileptic drug valproic acid (VPA) for 2 weeks in order to determine whedier therapeutic plasma levels could be maintained. VPA (as the sodium salt) was administered in a dosage of 170–180 mg/kg/day divided into three equal doses in the form of enteric-coated tablets. Due to the rapid elimination of this drug in dogs, therapeutic plasma levels were reached only intermittently. However, the concentrations maintained may be sufficient for anti-epileptic therapy in dogs because the lower plasma protein binding of VPA in this species gives rise to higher central concentrations compared with man. Furthermore, some VPA metabolites previously shown to exert anticonvulsant activity (2-en-VPA and 3-keto-VPA) were found in relatively high concentrations in dog plasma.
We would recommend the dosages used in this study as a basis for assessment of VPA in the treatment of canine epilepsy.     

Clinical evaluation of gamma-vinyl-gamma-aminobutyric acid for control of epilepsy in dogs

Gamma-vinyl-gamma-aminobutyric acid is a novel antiepileptic drug that exerts its effects by increasing the concentration of gamma-aminobutyric acid in the brain. The mechanism of action involves irreversible inhibition of the metabolic pathway of gamma-aminobutyric acid. The drug was administered to 14 dogs in conjunction with other anticonvulsants, in an attempt to control refractory epilepsy. Four of these dogs had clinically relevant evidence of decreased seizure frequency. In 4 dogs, response to the drug was no better than response to phenobarbital alone. In 2 dogs, seizure control improved, but gamma-vinyl-gamma-aminobutyric acid was withdrawn because of development of hemolytic anemia. For various reasons, the therapeutic effect in the remaining 4 dogs could not be evaluated. This study of only 14 dogs illustrates some of the problems that confound our ability to judge the efficacy of anticonvulsant treatment.     

Placebo Effect in Canine Epilepsy Trials

Background: The placebo effect is a well-recognized phenomenon in human medicine; in contrast, little information exists on the effect of placebo administration in veterinary patients.
Hypothesis: Nonpharmacologic therapeutic effects play a role in response rates identified in canine epilepsy trials.
Animals: Thirty-four dogs with epilepsy.
Methods: Meta-analysis of the 3 known prospective, placebo-controlled canine epilepsy trials. The number of seizures per week was compiled for each dog throughout their participation in the trial. Log-linear models were developed to evaluate seizure frequency during treatment and placebo relative to baseline.
Results: Twenty-two of 28 (79%) dogs in the study that received placebo demonstrated a decrease in seizure frequency compared with baseline, and 8 (29%) could be considered responders, with a 50% or greater reduction in seizures. For the 3 trials evaluated, the average reduction in seizures during placebo administration relative to baseline was 26% ( P = .0018), 29% ( P = .17), and 46% ( P = .01).
Conclusions and Clinical Importance: A positive response to placebo administration, manifesting as a decrease in seizure frequency, can be observed in epileptic dogs. This is of importance when evaluating open label studies in dogs that aim to assess efficacy of antiepileptic drugs, as the reported results might be overstated. Findings from this study highlight the need for more placebo-controlled trials in veterinary medicine.     

Alternative therapeutic options for medical management of epilepsy in apes

Phenobarbital has been the primary antiepileptic drug used in primates, but the dosage required for seizure control is frequently associated with significant side effects. Newer antiepileptic drugs and adjunctive therapies currently being used in human medicine provide additional options for treatment of nonhuman primates. This report describes different drug regimes used for control of epileptic seizures in apes at the Milwaukee County Zoo (Milwaukee, Wisconsin, U.S.A.), including the addition of acetazolamide to phenobarbital, levetiracetam, carbamazepine, and the use of extended cycle oral contraceptives to assist seizure control in female apes with catamenial epilepsy.     

Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs

OBJECTIVE: To evaluate safety and efficacy of vagal nerve stimulation in dogs with refractory epilepsy. DESIGN: Placebo-controlled, double-masked, crossover study. ANIMALS: 10 dogs with poorly controlled seizures. PROCEDURE: A programmable pacemaker-like device designed to deliver intermittent stimulation to the left cervical trunk of the vagus was surgically implanted in each dog. Dogs were assigned randomly to two 13-week test periods, 1 with nerve stimulation and 1 without nerve stimulation. Owners recorded data on seizure frequency, duration, and intensity, as well as adverse effects. RESULTS: No significant difference in seizure frequency, duration, or severity was detected between overall 13-week treatment and control periods. During the final 4 weeks of the treatment period, a significant decrease in mean seizure frequency (34.4%) was detected, compared with the control period. Complications included transient bradycardia, asystole, and apnea during intraoperative device testing, and seroma formation, subcutaneous migration of the generator, and transient Horner's syndrome during the 14-day period between surgery and suture removal. No adverse effects of stimulation were detected, and most owners were satisfied with the treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Vagal nerve stimulation is a potentially safe approach to seizure control that appears to be efficacious in certain dogs and should be considered a possible treatment option when antiepileptic medications are ineffective.     

Erythema multiforme associated with zonisamide in a dog

This report describes a dog that developed erythema multiforme in temporal association with administration of the sulphonamide‐based anticonvulsant drug zonisamide. Similar adverse drug reactions have been associated with sulphonamide antimicrobial drugs. Caution should be exercised when prescribing this medication for dogs with known hypersensitivity to sulphonamides.     

Treatment of partial seizures and seizure-like activity with felbamate in six dogs

Six dogs with partial seizures or partial seizure-like activity were treated with the antiepileptic drug felbamate between 1993 and 1998. All dogs had a history and results of diagnostic testing suggestive of either primary (idiopathic) or occult secondary epilepsy. Dogs ranged between four months and eight years of age at the onset of seizure activity. The median time period between onset of the first seizure and the start of felbamate therapy was 3.8 months (range 0.75 to 36 months). Median duration of therapy was nine months (range two to 22 months). All dogs experienced a reduction in seizure frequency after felbamate administration. Median total number of seizures post-treatment was two (range 0 to 9). Two dogs had an immediate and prolonged cessation of seizure activity. Steady-state trough serum felbamate concentrations measured at two weeks, and one, 12 and 22 months after the commencement of therapy in four dogs ranged between 13 and 55 mg/litre (median 35 mg/litre). Reversible haematological adverse effects were detected in two dogs, with one dog developing concurrent keratoconjunctivitis sicca. These results suggest that felbamate can be an effective antiepileptic drug without life-threatening complications when used as monotherapy for partial seizures in the dog.     

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.     

Epilepsy in Border Collies: Clinical Manifestation, Outcome, and Mode of Inheritance

Background: There is a lack of data on idiopathic epilepsy (IE) in Border Collies (BCs) in the veterinary literature.
Hypothesis: Genetic epilepsy occurs in BCs and is frequently characterized by a severe clinical course and poor response to medical treatment.
Animals: Forty-nine BCs diagnosed with IE.
Methods: Medical records, seizure data, treatment data, and pedigree information of affected dogs were collected. Cases were classified phenotypically as affected or not affected; mild, moderate, or severe clinical course; active epilepsy (AE) or remission; and drug resistant or not drug resistant.
Results: Clinical manifestations were classified as having a moderate (33%) or severe clinical course (49%), characterized by a high prevalence of cluster seizures and status epilepticus. Survival time was significantly decreased in dogs <2 years of age at seizure onset, and in dogs with a severe clinical course. Drug resistance was apparent in 71% of 24 dogs treated with ≥2 antiepileptic drugs. The epilepsy remission rate was 18%. Median age at onset was significantly higher and initial seizure frequency was significantly lower in dogs with remission compared with dogs with AE. Pedigree analyses indicated a strong genetic founder effect in the appearance of epilepsy, resembling autosomal recessive inheritance.
Conclusion and Clinical Importance: The present study confirms the occurrence of genetically mediated epilepsy with a frequent severe clinical course and drug resistance in BCs. The results provide information about the long-term prognosis of IE in BCs for veterinarians and concerned owners, and may benefit breeders as well.     

Successful long term treatment of a dog with psychomotor seizures using carbamazepine

Psychomotor seizures (temporal lobe epilepsy) were diagnosed in a dog based on history, clinical findings and electroencephalography. Long-term seizure control was achieved with carbamazepine, despite serum drug concentrations which were low to unmeasurable. It is suggested that serum levels of carbamazepine are not a useful guide to clinical efficacy in the dog, that an unmeasured metabolite of carbamazepine may account for the anti-convulsant activity and that carbamazepine may be potentially useful in treating certain canine seizure disorders.     

Influence of anesthetic regimen on the frequency of seizures after cervical myelography in the dog

We examined the influence of various anesthetic drug combinations on the frequency of seizures in dogs after cervical myelography with metrizamide. Over a 12-month period, 78 dogs admitted to the teaching hospital for cervical myelography were assigned randomly to 1 of 6 anesthetic protocols. Myelography was performed, and the dogs were observed for signs of seizure activity after recovery from anesthesia. The person making the decision as to whether or not a dog had had a seizure was unaware of the anesthetic protocol that had been used. Preanesthetic treatment with pentobarbital (5.0 mg/kg) and maintenance of anesthesia with methoxyflurane significantly reduced the frequency of seizures (P less than 0.05). No reduction in seizure frequency was seen with any anesthetic protocol using halothane as the maintenance agent.     

Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs

O bjectives : Investigation of the efficacy of zonisamide as an add-on therapy in dogs with refractory epilepsy.
M ethods : Thirteen dogs fulfilled the inclusion criteria of poor seizure control despite adequate serum levels of phenobarbital, potassium bromide or both. One further dog was treated with zonisamide as monotherapy because of severe blood dyscrasia due to phenobarbital treatment. Various seizure parameters were evaluated retrospectively for a four month period without zonisamide and prospectively for the same time period under zonisamide add-on therapy. The study time period was extended by up to 17 months to evaluate long-term outcome.
R esults : Data of 11 dogs could be evaluated: nine of them were responders. The median reduction of seizure frequency of all dogs on zonisamide add-on therapy was 70 per cent (range 14 to 100 per cent). Only transient central nervous system side effects were reported. No further increase of liver enzymes occurred. In three of the responder dogs, seizure control subsided after individual time periods (between 69 days and seven months).
C linical S ignificance : In dogs with refractory epilepsy, zonisamide may have a beneficial effect on seizure control. In three responder dogs, seizure activity relapsed possibly because of an induction of tolerance. Limiting factors are the high costs.     

Medical Management of Recurrent Seizures in Dogs and Cats

The problem of recurrent seizures is a common and challenging one in veterinary medical practice. The pathophysiology and pharmacologic suppression of focal seizure activity have been studied extensively in basic research settings, yet little is known of the genesis, modulation, and termination of generalized seizures, the most common form of seizures noted to occur in companion animals. Knowledge concerning the pharmacokinetic fate of anticonvulsant drugs currently used in veterinary medicine is adequate, though prospective clinical studies of the efficacy of these drugs in the treatment of various types of seizures are lacking. This study will review the available literature regarding the pharmacology, use, and side effects of anticonvulsant drugs currently available for control of recurrent seizures in companion animals. Alternative anticonvulsant drugs will also be described.     

Absence of temporal lobe epilepsy pathology in dogs with medically intractable epilepsy

Epilepsy is a common neurological problem in dogs. In some dogs, seizures cannot be controlled adequately with anticonvulsant medication. Temporal lobe epilepsy is the most common type of epilepsy in adult humans, it is frequently resistant to anticonvulsant therapy, and it is commonly associated with characteristic neuropathological abnormalities in the hippocampal dentate gyrus. We sought to test the hypothesis that dogs with medically intractable epilepsy have temporal lobe epilepsy. The hippocampi of 6 dogs that were euthanized because of chronic, recurrent seizures were compared with those of 8 nonepileptic controls. In control and epileptic dogs, stereological cell counting showed similar numbers of neurons in the hilus of the dentate gyrus, somatostatin immunoreactivity identified numerous immunopositive neurons in the hilus, and Timm staining showed the normal pattern of granule cell axon projections. These findings demonstrate a lack of hilar neuron loss and granule cell axon reorganization, suggesting that temporal lobe epilepsy is not a common cause of medically intractable epilepsy in dogs.     

Canine epilepsy: what can we learn from human seizure disorders?

Epilepsy is a common neurological disorder in both dogs and humans. It is refractory to therapy in approximately one-third of canine patients, and even with the advent of new antiepileptic drugs for humans, appropriate treatment options in dogs remain limited. The pathogenesis and pathophysiology of epilepsy is being studied extensively in both human patients and rodent models of experimental epilepsy at the cellular and molecular level, but very little is known about the aetiologies of epilepsies in dogs. In this review, canine epilepsy will be discussed with reference to the human epilepsies and experimental epilepsy research. There is much work to be done in order to classify canine seizure types and breed-specific epileptic syndromes, particularly with reference to electroencephalographic abnormalities and possible genetic abnormalities. The review considers the appropriate use of antiepileptic drugs: phenobarbitone and potassium bromide are effective in most canine patients, although dosing regimes need to be carefully tailored to the individual, with serum concentration measurement. However, a significant proportion of patients remains refractory to these drugs. Work is currently underway to test the efficacy of newer antiepileptic drugs in the treatment of canine epilepsy, and preliminary data suggest that human drugs such as levetiracetam and gabapentin are of benefit in dogs with refractory epilepsy.     

The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs

Twenty-two dogs with idiopathic epilepsy which were pharmacoresistant to phenobarbitone and bromide were treated with levetiracetam as an add-on medication. Records of eight dogs were used retrospectively to determine a safe, efficient levetiracetam dosage. Fourteen dogs were entered into a prospective, open label, non-comparative study. After 2 months of levetiracetam oral treatment (10 mg/kg TID), 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by 50%. In dogs that remained refractory, the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment. Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure frequency and seizure days after 4-8 months continuing with the levetiracetam treatment at the last effective dosage. Levetiracetam was well tolerated by all dogs and sedation was the only side-effect reported in just one of the 14 dogs.