Edward E. Patterson

International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals

Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, “a common language”, for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.

Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )

BackgroundMalignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date. MethodsTo determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane–succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large. ResultsPedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a &thgr; = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at &thgr; = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele. ConclusionsThese results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.

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.

A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse

Labrador retrievers are the most common dog breed in the world, with over 200,000 new kennel club registrations per year. The syndrome of exercise-induced collapse (EIC) in this breed is manifested by muscle weakness, incoordination and life-threatening collapse after intense exercise. Using a genome-wide microsatellite marker scan for linkage in pedigrees, we mapped the EIC locus to canine chromosome 9. We then used SNP association and haplotype analysis to fine map the locus, and identified a mutation in the dynamin 1 gene (DNM1) that causes an R256L substitution in a highly conserved region of the protein. This first documented mammalian DNM1 mutation is present at a high frequency in the breed and is a compelling candidate causal mutation for EIC, as the dynamin 1 protein has an essential role in neurotransmission and synaptic vesicle endocytosis.

Double-masked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs.

BACKGROUND Status epilepticus (SE) and acute repetitive seizures (ARS) are common canine neurologic emergencies. No evidence-based studies are available to guide treatment in veterinary patients. Parenteral levetiracetam (LEV) has many favorable properties for the emergency treatment of seizures, but its safety and efficacy in dogs for SE and ARS are unknown. HYPOTHESIS Intravenous LEV is superior to placebo in controlling seizures in dogs with SE or ARS after treatment with IV diazepam. ANIMALS Nineteen client-owned dogs admitted for SE or ARS. METHODS Randomized, placebo-controlled, double-masked study. Dogs with SE or ARS were randomized to receive IV LEV (30 or 60 mg/kg using an adaptive dose-escalation approach) or placebo, in addition to standard of care treatment. They were monitored for at least 24 hours after admission for additional seizures. RESULTS The responder rate (defined as dogs with no additional seizures after administration of the study medication) after LEV was 56% compared with 10% for placebo (P = .06). Dogs in the placebo group required significantly more boluses of diazepam compared with the LEV group (P < .03). Seizure etiologies identified were idiopathic epilepsy (n = 10), inflammatory central nervous system disease (n = 4), intracranial neoplasia (n = 2), hepatic encephalopathy (n = 1), and 2 dogs had no cause determined. No serious adverse effects were attributable to LEV administration. CONCLUSIONS AND CLINICAL IMPORTANCE LEV was safe and potentially effective for the treatment of SE and ARS in these client-owned dogs. Larger, controlled clinical trials are needed to confirm this preliminary observation.

Forecasting seizures in dogs with naturally occurring epilepsy.

Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), low-gamma (30–70 Hz), and high-gamma (70–180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.

Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics

Intravenous (IV) levetiracetam (LEV) is available for humans for bridge therapy when the oral route is unavailable. We investigated the safety and pharmacokinetics of LEV administered intramuscularly (IM), IV, and orally to dogs. Six Hound dogs received 19.5-22.6 mg/kg of LEV IM, IV and orally with a wash-out period in between. All dogs received 500 mg LEV orally and 5 mL of 100 mg/mL LEV IM. Three dogs received 500 mg of LEV IV and three dogs received 250 mg LEV IV with 250 mg given perivascularly to approximate extravasation. Safety was assessed using a pain scale at time of IM administration and histopathological examination 24 h to 5 days after injection. Intravenous LEV half-life was 180 +/- 18 min. Bioavailability of IM LEV was 100%. Mean time to T(max) after IM was 40 +/- 16 min. The mean C(max) IM was 30.3 +/- 3 mug/mL compared to the C(0) of 37 +/- 5 mug/mL for IV. Mean inflammation score (0-4 scale) for IM LEV was 0.28 and for saline 0.62. Extravasation did not cause tissue damage. Parenteral LEV is well tolerated and appears safe following IM and IV injections in dogs. Parenteral LEV should be evaluated for use in dogs with epilepsy.

Crowdsourcing reproducible seizure forecasting in human and canine epilepsy

See Mormann and Andrzejak (doi:10.1093/brain/aww091) for a scientific commentary on this article.   Seizures are thought to arise from an identifiable pre-ictal state. Brinkmann et al. report the results of an online, open-access seizure forecasting competition using intracranial EEG recordings from canines with naturally occurring epilepsy and human patients undergoing presurgical monitoring. The winning algorithms forecast seizures at rates significantly greater than chance.

Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high‐steppage pelvic‐limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size–frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X‐linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants. Muscle Nerve 27: 471–477, 2003

International Veterinary Epilepsy Task Force consensus proposal: medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.