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.

[1]  J. Steiss,et al.  Electroencephalographic and histopathologic correlations in eight dogs with intracranial mass lesions. , 1990, American journal of veterinary research.

[2]  D. Montgomery,et al.  Brain Damage in the Epileptic Beagle Dog , 1983, Veterinary pathology.

[3]  W. Hauser,et al.  Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features , 2002, Nature Genetics.

[4]  A. Draguhn,et al.  Sodium bromide: effects on different patterns of epileptiform activity, extracellular pH changes and GABAergic inhibition , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[5]  A. Jaggy,et al.  Idiopathic epilepsy in 125 dogs: a long-term study. Clinical and electroencephalographic findings. , 1998, The Journal of small animal practice.

[6]  L. Gram,et al.  Epilepsy and seizure classification in 63 dogs: a reappraisal of veterinary epilepsy terminology. , 1999, Journal of veterinary internal medicine.

[7]  Ernst Fernando Lopes Da Silva Niedermeyer,et al.  Electroencephalography, basic principles, clinical applications, and related fields , 1982 .

[8]  E. Becker,et al.  Panniculitis due to potassium bromide , 1998, Brain and Development.

[9]  D. Kullmann,et al.  Plasticity of GABAB Receptor-Mediated Heterosynaptic Interactions at Mossy Fibers After Status Epilepticus , 2003, The Journal of Neuroscience.

[10]  M. Gutnick,et al.  Comparative Clinical and Electroencephalographic Studies of Canine Epilepsy , 1970, Epilepsia.

[11]  Redman Hc,et al.  Sire- and sex-related differences in rates of epileptiform seizures in a purebred beagle dog colony. , 1971 .

[12]  Wagner Jl,et al.  Clinical use of the electroencephalogram in canine encephalitis. , 1966 .

[13]  J. Mattoon,et al.  Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995-2002). , 2004, Journal of veterinary internal medicine.

[14]  J. Zabara Inhibition of Experimental Seizures in Canines by Repetitive Vagal Stimulation , 1992, Epilepsia.

[15]  L. Trepanier,et al.  Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996). , 1998, Journal of the American Veterinary Medical Association.

[16]  Farnbach Gc,et al.  Serum concentrations and efficacy of phenytoin, phenobarbital, and primidone in canine epilepsy. , 1984 .

[17]  K. Braund Clinical Syndromes in Veterinary Neurology , 1994 .

[18]  P. Dickinson,et al.  Reversible magnetic resonance imaging abnormalities in dogs following seizures. , 1999, Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association.

[19]  S. Berkovic,et al.  A potassium channel mutation in neonatal human epilepsy. , 1998, Science.

[20]  M. Brodie,et al.  Update on the mechanisms of action of antiepileptic drugs. , 2001, Epileptic disorders : international epilepsy journal with videotape.

[21]  M. Baulac,et al.  Monogenic idiopathic epilepsies , 2004, The Lancet Neurology.

[22]  J. Jefferys,et al.  Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions. , 1995, Physiological reviews.

[23]  C. Elger,et al.  Anticonvulsant pharmacology of voltage‐gated Na+ channels in hippocampal neurons of control and chronically epileptic rats , 2003, The European journal of neuroscience.

[24]  S. A. Steinberg,et al.  Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989). , 1991, Journal of the American Veterinary Medical Association.

[25]  M. Doherr,et al.  Inhibitory and excitatory neurotransmitters in the cerebrospinal fluid of epileptic dogs. , 2004, American journal of veterinary research.

[26]  A. Jaggy,et al.  Clinical, epidemiological and treatment results of idiopathic epilepsy in 54 labrador retrievers: a long-term study. , 1997, The Journal of small animal practice.

[27]  H. Brunengraber,et al.  Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. , 2000, The Journal of nutritional biochemistry.

[28]  R. Sica,et al.  Canine electroencephalographic recording technique: findings in normal and epileptic dogs , 2004, Clinical Neurophysiology.

[29]  K. Goa,et al.  Topiramate: as monotherapy in newly diagnosed epilepsy. , 2003, CNS drugs.

[30]  F. Dudek,et al.  Absence of temporal lobe epilepsy pathology in dogs with medically intractable epilepsy. , 2002, Journal of veterinary internal medicine.

[31]  H. Lüders,et al.  Semiological Seizure Classification * , 1998, Epilepsia.

[32]  B. Abou-Khalil,et al.  Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions , 1998, Neurology.

[33]  S. Budsberg,et al.  Zonisamide therapy for refractory idiopathic epilepsy in dogs. , 2004, Journal of the American Animal Hospital Association.

[34]  G. Jacobs,et al.  Neutropenia and thrombocytopenia in three dogs treated with anticonvulsants. , 1998, Journal of the American Veterinary Medical Association.

[35]  P. J. Armstrong,et al.  Clinical description and mode of inheritance of idiopathic epilepsy in English springer spaniels. , 2005, Journal of the American Veterinary Medical Association.

[36]  A. Oberbauer,et al.  Segregation analysis of epilepsy in the Belgian tervueren dog , 2000, Veterinary Record.

[37]  A. Cribb,et al.  Pancreatitis associated with potassium bromide/phenobarbital combination therapy in epileptic dogs. , 2000, The Canadian veterinary journal = La revue veterinaire canadienne.

[38]  P. Kwan,et al.  The mechanisms of action of commonly used antiepileptic drugs. , 2001, Pharmacology & therapeutics.

[39]  M. Podell The use of diazepam per rectum at home for the acute management of cluster seizures in dogs. , 1995, Journal of veterinary internal medicine.

[40]  J. Huguenard Neuronal circuitry of thalamocortical epilepsy and mechanisms of antiabsence drug action. , 1999, Advances in neurology.

[41]  R. Dingledine,et al.  Reduced Excitatory Drive onto Interneurons in the Dentate Gyrus after Status Epilepticus , 2001, The Journal of Neuroscience.

[42]  S. Tasker,et al.  Idiopathic phenobarbital-responsive hypersialosis in the dog: an unusual form of limbic epilepsy? , 2000, The Journal of small animal practice.

[43]  O. Steinlein Genes and mutations in human idiopathic epilepsy , 2004, Brain and Development.

[44]  O. Steinlein,et al.  LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures , 2002, Annals of neurology.

[45]  W. Löscher,et al.  Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. , 1985, Journal of veterinary pharmacology and therapeutics.

[46]  E. Thiele,et al.  Assessing the Efficacy of Antiepileptic Treatments: The Ketogenic Diet , 2003, Epilepsia.

[47]  N. Fountain,et al.  Functional anatomy of limbic epilepsy: a proposal for central synchronization of a diffusely hyperexcitable network , 1998, Epilepsy Research.

[48]  J. Velazquez,et al.  Synchronization of GABAergic interneuronal networks during seizure‐like activity in the rat horizontal hippocampal slice , 1999, The European journal of neuroscience.

[49]  R. C. Collins,et al.  Functional anatomy of limbic seizures: Focal discharges from medial entorhinal cortex in rat , 1983, Brain Research.

[50]  A. Busato,et al.  Clinical and genetic investigations of idiopathic epilepsy in the Bernese mountain dog. , 1999, The Journal of small animal practice.

[51]  W. Löscher,et al.  Low Levels of γ‐Aminobutyric Acid in Cerebrospinal Fluid of Dogs with Epilepsy , 1986 .

[52]  P. G. Croft Electroencephalography in canine encephalitis. , 1970, The Journal of small animal practice.

[53]  L. Trepanier,et al.  Effect of dietary chloride content on the elimination of bromide by dogs. , 1995, Research in veterinary science.

[54]  W. Tarver,et al.  Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs. , 2002, Journal of the American Veterinary Medical Association.

[55]  G. Holmes,et al.  Synchronization of Kainate-Induced Epileptic Activity via GABAergic Inhibition in the Superfused Rat Hippocampus In Vivo , 2003, The Journal of Neuroscience.

[56]  H. Beck,et al.  “Epileptic Neurons” in Temporal Lobe Epilepsy , 2002, Brain pathology.

[57]  Asla Pitkänen,et al.  Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy , 2002, The Lancet Neurology.

[58]  M. Wallace,et al.  Canine epilepsy: a genetic counselling programme for keeshonds , 1996, Veterinary Record.

[59]  D. Coulter,et al.  Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. , 1997, Journal of neurophysiology.

[60]  I. Módy,et al.  Properties of single NMDA receptor channels in human dentate gyrus granule cells. , 1999, The Journal of physiology.

[61]  M. Podell,et al.  Bromide therapy in refractory canine idiopathic epilepsy. , 1993, Journal of veterinary internal medicine.

[62]  L. Garosi,et al.  Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy , 2006, Veterinary Record.

[63]  L. Trepanier,et al.  Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in epileptic dogs treated with anticonvulsants. , 1999, Journal of the American Veterinary Medical Association.

[64]  Jerome Engel,et al.  A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force on Classification and Terminology , 2001, Epilepsia.

[65]  I. Scheffer,et al.  A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy , 1995, Nature Genetics.

[66]  S L Moshé,et al.  Kainic Acid-Induced Seizures Enhance Dentate Gyrus Inhibition by Downregulation of GABAB Receptors , 1996, The Journal of Neuroscience.

[67]  Robert S. Fisher,et al.  Animal models of the epilepsies , 1989, Brain Research Reviews.

[68]  R. Sams,et al.  Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy Beagles. , 2002, Journal of veterinary pharmacology and therapeutics.

[69]  F. Mormann,et al.  Epileptic seizures are preceded by a decrease in synchronization , 2003, Epilepsy Research.

[70]  D. Türck,et al.  Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[71]  M. Baulac,et al.  Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25‐q31 , 2001, Annals of neurology.

[72]  Makiko Takahashi,et al.  Cliniconeuropathologic findings of familial frontal lobe epilepsy in Shetland sheepdogs. , 2002, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[73]  M. Podell,et al.  Cerebrospinal fluid gamma-aminobutyric acid and glutamate values in dogs with epilepsy. , 1997, American journal of veterinary research.

[74]  L. Lagae,et al.  De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. , 2001, American journal of human genetics.

[75]  Ravis Wr,et al.  Pharmacokinetics of phenobarbital in dogs given multiple doses. , 1989 .

[76]  R. Miles,et al.  On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy in Vitro , 2002, Science.

[77]  J. Mattoon,et al.  Liver Histopathology and Liver and Serum Alanine Aminotransferase and Alkaline Phosphatase Activities in Epileptic Dogs Receiving Phenobarbital , 2005, Veterinary pathology.

[78]  M. Falco,et al.  The genetics of epilepsy in the British Alsatian. , 1974, The Journal of small animal practice.

[79]  I. Módy,et al.  Zinc-Induced Collapse of Augmented Inhibition by GABA in a Temporal Lobe Epilepsy Model , 1996, Science.

[80]  Shili Lin,et al.  Clinical presentations of naturally occurring canine seizures: similarities to human seizures , 2002, Epilepsy & Behavior.

[81]  A. Jaggy,et al.  Genetic aspects of idiopathic epilepsy in Labrador retrievers. , 1998, The Journal of small animal practice.

[82]  P. G. Croft Electroencephalography in canine head injury. , 1970, The Journal of small animal practice.

[83]  U. Jürgens,et al.  [Effectiveness of bromide in therapy resistant epilepsy of dogs]. , 1991, Tierarztliche Praxis.

[84]  Carlos E. M. Tassinari,et al.  Glossary of Descriptive Terminology for Ictal Semiology: Report of the ILAE Task Force on Classification and Terminology , 2001, Epilepsia.

[85]  P. J. Armstrong,et al.  Clinical characteristics and inheritance of idiopathic epilepsy in Vizslas. , 2003, Journal of veterinary internal medicine.

[86]  Zhong Chen,et al.  Spatiotemporal changes of the N-methyl-d-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures , 2004, Neuroscience Letters.

[87]  Jw Sander,et al.  Epilepsy: Questions and Answers , 1997 .

[88]  B. Söderpalm Anticonvulsants: aspects of their mechanisms of action , 2002, European journal of pain.

[89]  P. G. Croft Electroencephalography in cerebrovascular disease in small animals. , 1971, Journal of Small Animal Practice.

[90]  R. Nicoll,et al.  GABA Generates Excitement , 2003, Neuron.

[91]  A. Jaggy,et al.  Interictal electroencephalographic findings in a family of golden retrievers with idiopathic epilepsy. , 1996, The Journal of small animal practice.

[92]  M. Cortez,et al.  Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet , 2003, Annals of neurology.

[93]  Jerome Engel,et al.  Introduction to temporal lobe epilepsy , 1996, Epilepsy Research.

[94]  Catherine André,et al.  Expanded Repeat in Canine Epilepsy , 2005, Science.

[95]  M. Baulac,et al.  Fever, genes, and epilepsy , 2004, The Lancet Neurology.

[96]  I. Scheffer,et al.  Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. , 2001, American journal of human genetics.

[97]  Josemir W. Sander,et al.  Epidemiology of the epilepsies. , 1996, Handbook of clinical neurology.

[98]  M. Podell,et al.  Treatment of partial seizures and seizure-like activity with felbamate in six dogs. , 2001, The Journal of small animal practice.

[99]  J. Speciale,et al.  Use of ocular compression to induce vagal stimulation and aid in controlling seizures in seven dogs. , 1999, Journal of the American Veterinary Medical Association.

[100]  P. G. Croft Electroencephalography and space-occupying lesions in small animals. , 1972, The Journal of small animal practice.

[101]  M. Fujita,et al.  Complex partial status epilepticus induced by a microinjection of kainic acid into unilateral amygdala in dogs and its brain damage , 2002, Brain Research.

[102]  M. Podell Epilepsy and seizure classification: a lesson from Leonardo. , 1999, Journal of veterinary internal medicine.

[103]  H. Høgenhaven,et al.  Electroencephalography in dogs with epilepsy: similarities between human and canine findings , 1999, Acta neurologica Scandinavica.