Epilepsy in Cavalier King Charles Spaniels
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Epilepsy refers to repeated seizures. A form of epilepsy, called "idiopathic epilepsy', is inheritable and is prevalent in cavalier King Charles spaniels.* It is caused by a mutation in a specific gene which the dogs have inherited from their parents.
It is to be distinguished from Flycather's Syndrome, which is a separate disorder of the CKCS.
According to a report in the June 2004 issue of the Journal of Veterinary Internal Medicine, idiopathic epilepsy has been found to occur more frequently in descendants from bloodlines originating from whole-colored CKCS ancestors from the late 1960s, especially from matings of blood relatives, such as half-siblings. See also a follow up report in July 2005.
In a 2012 report, UK neurology researchers C.J. Driver, K. Chandler, G. Walmsley, N. Shihab, and H.A. Volk examined the MRIs of 85 cavalier King Charles spaniels, looking for a relationship between Chiari-like malformation (CM), ventriculomegaly, and seizures in the dogs. The 85 CKCSs all had CM; 27 of them also had had seizures. They found no association between CM, ventriculomegaly, and the seizures. The seizures were classified as having partial onset -- meaning that they occur in in one area of the brain, unlike generalized seizures which typically affect nerve cells throughout the brain -- in 61% of the dogs. They also stated that "Another cause of recurrent seizures in CKCS (such as familial epilepsy) is suspected, as previously reported."
There are many different types of seizures in dogs. The most common is the generalized major motor seizure, characterized by paddling of the limbs. The dog may cry, bark or whine during the seizure, and it may snap or bite, not quite fully aware of its surroundings. Urination and defecation are common during a generalized seizure. Post seizural signs may last from a few minutes to an hour.
The onset of epilepsy in cavaliers is most common between the ages of six months and five years.
Diagnosing epilepsy in dogs is difficult. It begins by attempting to rule out other causes for the seizures. The electroencephalogram (EEG) is a frequently used device in diagnosing epilepsy, but has serious drawbacks in animals. Advanced imaging, such as magnetic resonance imaging (MRI) or CT scans, is necessary to be able to actually see the brain. By imaging the brain, veterinarians are able to diagnose diseases such as brain tumors or hydrocephalus (water on the brain) which can cause seizures. Apart from the EEG or MRI or CT scans, there is no health test for epilepsy.
Immediately after a seizure, the dog should be handled with caution. The dog likely will pant after a seizure, due to heat generated by the intense brain activity and seizure. Cool, wet compresses place at the base of the skull and in the groin area will help decrease the body temperature. The dog should be offered a drink of water, but should not be left unattended with a water bowl.
In a 2004 article, Dr. H. C. Gurney of Colorado reports success in treating dogs during epileptic seizures by applying ice directly to the dogs' backs at T10 to L4 of the spine. See the article citation for details and a diagram.
All dogs should be examined by a veterinarian after their first seizure for determination of the cause. Anti-convulsant therapy (usually oral phenobarbital [Solfoton, Luminal, Phenoleptil] and/or potassium bromide) may be started once the seizures recur frequently. The owner should keep a calendar noting the frequency of the seizures, and the dog that seizures more than once a month should treated long term with anti-convulsants. In an April 2014 report, a cavalier suffered loss of muscle control and repetitive leg twitching due to an overdose of potassium bromide.
The anti-convulsant gabapentin (Neurontin, Gabarone) is being prescribed, following a study which has shown that between 41% and 55% of dogs have responded to it. Gabapentin works through a receptor on the membranes of brain and peripheral nerve cells. It binds to calcium channels and modulates calcium influx as well as influences GABergic neurotransmission. In humans, gabapentin reportedly does not interact with any other medications, and it is not metabolized, so it is fully excreted in the urine and has no affect upon the liver. However, in dogs, gabapentin is partially metabolized in the liver, and therefore the prescribing neurologist may be expected to order periodic blood tests to check the liver enzymes.
A newer anti-convulsant, pregabalin (Lyrica), is being prescribed by some neurologists. Dr. Curtis Dewey, board certified veterinary neurologist at Cornell University's college of veterinary medicine, has reported that 78% of dogs responded to pregabalin, and that there was a 57% mean reduction in seizures for the participants who finished the study; all had been diagnosed with difficult-to-control seizures. For more details, go here.
Pregabalin is closely related to gabapentin and was developed by Pfizer, which also developed gabapentin. Pfizer reports that pregabalin is more potent than gabapentin and achieves its effect at lower doses. Doses of pregabalin also reportedly have a longer lasting effect than gabapentin. No generic version is available, and as an exclusive brand, Lyrica is quite expensive in comparison to generic gabapentin.
A recent study of the use of acepromazine maleate (i.e., acetylpromazine), which is a common sedative administered to dogs, involved administered it for tranquilization during hospitalization to 36 dogs with a prior history of seizures and to 11 other dogs to decrease seizure activity. No seizures were observed within 16 hours of its administration in the 36 dogs that received the drug for tranquilization, and seizures abated for from 1.5 to 8 hours or did not recur in 8 of 10 of the 11 dogs that had been actively seizing. Also, excitement-induced seizure frequency was reduced for 2 months in one dog.
Imepitoin (Pexion) became available in the UK and Europe in 2012. Imepitoin is a centrally acting antiepileptic substance which inhibits seizures by acting on a specific receptor in the brain cells to reduce the amount of excessive electrical activity present, in order to reduce the number of seizures the dog experiences. In addition, imepitoin has a weak calcium-channel-blocking effect.
Zonisamide (Zonegram) is an anticonvulsant which in clinical trials appears to be effective for generalized seizures in dogs. It’s anti-seizure effect is believed to work through sodium and calcium channels. Dr. Curtis Dewey has conducted studies of this drug.
Levetiracetam (Keppra) is an anticonvulsant which can also be used in conjunction with phenobarbital and/or potassium bromide. it appears to be relatively safe for dogs, and reportedly rarely has any adverse side effects and does not appear to affect the liver or liver enzymes. In a July 2014 study, researchers found that the adding phenobarbital to a dosage of Levetiracetam significantly altered the disposition of the levetiracetam.
Other anti-convulsants, such as topiramate (Topamax), lamotrigine (Lamictal), oxcarbazepine (Trileptal), tiagabine (Gabitril), primidone, sodium valproate, felbamate, and topiramate may be prescribed.
Medication will usually eliminate seizures entirely, and is considered effective if a seizure occurs no more than every four to six weeks. Any time the dog exhibits a cluster of seizures, the veterinarian should be consulted, and may require immediate emergency treatment by the veterinarian, due to the possibility of permanent brain damage.
In an October 2014 report, UK researchers UK researchers Marios Charalambous, David Brodbelt, and Holger A. Volk found evidence to support the efficacy of oral phenobarbital and imepitoin and a "fair level of evidence" to support the efficacy of oral potassium bromide and levetiracetam. However, for zonisamide, primidone, gabapentin, pregabalin, sodium valproate, felbamate, and topiramate, they found "insufficient evidence to support their use due to lack of bRCTs [blinded randomized clinical trials]". They concluded that "there is a need for greater numbers of adequately sized bRCTs evaluating the efficacy of AEDs [antiepileptic drugs] for IE."
The Canine Inherited Disorders Database (www.upei.ca/~cidd/intro.htm) recommends that cavaliers which have had seizures should not be bred, nor should their parents and siblings.
February 2015: NC State researchers find adding phenobarbital and bromide increases Levetiracetam's movement through epileptic dogs. In a February 2015 study, a team of researchers at North Carolina State University report that the concurrent administration of phenobarbital alone or with bromide increased the clearance of Levetiracetam in epileptic dogs.
February 2015: UK's Royal Veterinary College's research team finds levetiracetam to effectively reduce seizures. In a February 2015 report by UK's Royal Veterinary College's canine epilepsy research team, it found that in a study of 52 affected dogs, the epilepsy drug levetiracetam was effective and well-tolerated for reducing seizures -- 69% of the dogs had a 50% or greater reduction in seizure frequency while 15% of all the dogs were completely free from seizures.
UK's Royal Veterinary College's new Epilepsy & Stress study needs
affected dogs. The Royal Veterinary College's Canine
Epilepsy Research team (Rowena Packer, Holger Volk, and Rob Fowkes) is
seeking saliva samples from dogs affected with idiopathy epilepsy and
information from their owners about the dogs' quality of life, including
their seizure frequency, type, severity, and how well their seizures are
controlled by medication. They assure that all information will be kept
secure and anonymous. No visit to RVC will be necessary, as all samples
and data will be collected remotely.
If you live in the UK and have an eligible dog (must not be affected by any known endocrine disorder, such as Cushing's, hypothyroidism or hyperthyroidism and not taking any steroids), contact Dr. Packer at firstname.lastname@example.org with this information: (a) name, age, breed, sex, and neuter status of the dog; (b) whether you and your dog meet the inclusion criteria; (c) how often your dog has seizures per month; and (d) where in the UK you are located.
October 2014: UK researchers find oral phenobarbital, imepitoin, potassium bromide, and levetiracetam likely are effective to treat idiopathic epilepsy, with a big BUT. UK researchers Marios Charalambous, David Brodbelt, and Holger A. Volk (right) examined various antiepileptic drugs (AEDs) used for the management of canine idiopathic epilepsy (IE). In an October 2014 report, they found evidence to support the efficacy of oral phenobarbital and imepitoin and a "fair level of evidence" to support the efficacy of oral potassium bromide and levetiracetam. However, for the remaining AEDs (zonisamide, primidone, gabapentin, pregabalin, sodium valproate, felbamate, and topiramate), they found "insufficient evidence to support their use due to lack of bRCTs [blinded randomized clinical trials]". They concluded that "there is a need for greater numbers of adequately sized bRCTs evaluating the efficacy of AEDs for IE."
April 2014: Epileptic CKCS has leg twitching and loss of muscle control reactions to potassium bromide treatment. In an April 2014 report, a spayed female cavalier diagnosed with idiopathic epilepsy was treated with potassium bromide and phenobarbital. Eight days later, the veterinarians found her suffering from a lack of muscle control and repetitive twitching of the limbs. They concluded she was overdosed with the bromide solution. She had no similar episodes following a reduction in the dosing.
May 2013: UK's Royal Veterinary College needs dogs with idiopathic epilepsy for study. The Royal Veterinary College of the University of London still is seeking dogs suspected of suffering idiopathic epilepsy for a study of the influence of a diet on improving seizure control. Details are available here. See our June 2012 item below for more information.
July 2012: UK researchers find no connection between Chiari-like malformation and epilepsy in cavaliers. In a 2012 report in the Veterinary Journal, UK neurology researchers C.J. Driver, K. Chandler, G. Walmsley, N. Shihab, and H.A. Volk examined the MRIs of 85 cavalier King Charles spaniels, looking for a relationship between Chiari-like malformation (CM), ventriculomegaly, and seizures in the dogs. The 85 CKCSs all had CM; 27 of them also had had seizures. They found no association between CM, ventriculomegaly, and the seizures. The seizures were classified as having partial onset -- meaning that they occur in in one area of the brain, unlike generalized seizures which typically affect nerve cells throughout the brain -- in 61% of the dogs. They also stated that "Another cause of recurrent seizures in CKCS (such as familial epilepsy) is suspected, as previously reported."
June 2012: Royal Veterinary College (RVC) conducts study of the influence of diet on improving seizure control. The RVC is working with a small animal health and wellness company to confirm the efficacy and safety of a novel diet in the management of dogs with idiopathic epilepsy being treated with phenobarbitone and/or potassium bromide. To confirm the efficacy of this new diet, RVC seeks to recruit dogs which are suspected of having idiopathic epilepsy, with these qualifications: (a) dogs which have a seizure frequency of at least three seizures in the last three months; and (b) dogs receiving phenobarbitone and/or potassium bromide treatment. For more information, contact RVC by clicking here, and/or downloading this brochure.
March 2012: Intravenous levetiracetam is reported to be safe and potentially effective for treatment of epileptic dogs. University of Minnesota veterinary researchers report in a March 2012 article that intravenous levetiracetam. in addition to IV diazepam treatment, showed a trend toward superiority over placebo and IV diazepam for the treatment of epilepsy and acute repetitive seizures in dogs.
December 2009: Pregabalin (Lyrica) is being studied to treat epileptic dogs. Dr. Curtis Dewey, board certified veterinary neurologist at Cornell University's college of veterinary medicine, reports that 78% of dogs respond to pregabalin (Lyrica) and that there was a 57% mean reduction in seizures for the participants who finished the study; all had been diagnosed with difficult-to-control seizures. For more details, go here.
The Canine Epilepsy Project, led by Dr. Ned Patterson, of the University of Minnesota's College of Veterinary Medicine, and by Dr. Gary Johnson, of the University of Missouri's College of Veterinary Medicine, is a collaborative study into the causes of epilepsy in dogs. Its goal is to find the genes responsible for epilepsy in dogs so that wise breeding can decrease the incidence of the disease in dogs, and that, knowing what genes regulate epilepsy in dogs may help better tailor therapy to the specific cause. Participation by owners of affected dogs and their relatives is essential to the success of this project. Researchers need DNA samples from dogs who have experienced seizures, and immediate relatives, both normal and affected. Specifically, they need samples from all available siblings, parents, and grandparents. If the affected dog has been bred, all offspring and mates should be sampled as well. Useful research families are explained in more detail here. Participation in this research project is confidential - the names of individual owners or dogs will not be revealed. Data and DNA sample collection instructions and sample submission forms are available on www.canine-epilepsy.net, or the packet will be mailed or faxed upon request. Contact Liz Hansen, at the Animal Molecular Genetics Laboratory, University of Missouri - College of Veterinary Medicine, email email@example.com Go to the Canine Epilepsy Network website for more information.
October 2004: New anti-epileptic drug ELB138. Profs. Chris Rundfeldt, Andrea Tipold, Wolfgang Loscher, and others, of the Department of Small Animal Medicine and Surgery, University of Veterinary Medicine, and Center for Systems Neuroscience, Hannover, Germany, have researched, developed, and have been studying the efficacy of a new antiepileptic and anxiolytic drug, ELB138, which is a low-affinity partial BZD-receptor agonist, formerly called AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one. They and others hold a U.S.patent (20050070537) for this drug. They report in their October 2004 veterinary journal article that "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" with reportedly rare side effects.
June 2004: Clare Rusbridge finds epilepsy is inheritable in CKCSs, especially whole-colors. UK's Clare Rusbridge reports that idiopathic epilepsy is an inheritable disease in the cavalier King Charles spaniel and is seen imore frequently in lines originating from whole-colored ancestors from the late 1960s, especially where there were half-brother/sister matings.
Extramedullary Hematopoiesis in the Choroid Plexus of Five Dogs. D. Bienzle, J. M. Kwiecien, J. M. Parent. Vet.Pathol. 1995;32:437-440. Quote: "Five dogs euthanatized because of refractory seizures were found to have hematopoietic elements in the interstitium of the choroid plexus at the level of the fourth ventricle. None of the dogs had significant hematologic or cerebrospinal fluid abnormalities. Dog No. 4 was a 3-year-old male Cavalier King Charles Spaniel with seizures since the age of 7 months. Five months of phenobarbital therapy had not affected the clinical status, and addition of KBr and dexamethasone yielded no improvement. Relevant laboratory findings consisted of mild hyperglycemia and a mild leukocytosis due to a mature neutrophilia (Table 1). CSF analysis disclosed blood contamination and several small clumps of meningeal cells (Table 2). Based on clinical examination and magnetic resonance imaging, a diagnosis of genetic epilepsy was established, and euthanasia was elected. Dog No. 4 had swollen, vacuolated hepatocytes attributed to recent glucocorticoid and barbiturate therapy and a cystic craniopharyngeal duct considered an incidental finding. Individual small foci of gliosis were present throughout the white matter of the frontal cortex, the internal capsule, and the substantia nigra. The temporal cortex had several ectopic islands of gray matter. Immature myelocytic cells, ranging from myeloblasts to band neutrophils, and scattered rubricytes were present in the stroma of the choroid plexus of the fourth ventricle. The xtramedullary hematopoiesis was confined to the central nervous system and consisted of megakaryocytes, immature granulocytes, and rubricytes in two dogs and of one predominant cell population in each of the other three dogs. These findings are unique, and factors possibly contributing to the formation of a hematopoietic inductive microenvironment in the choroid plexus are cytokine neurokine homologies, locally altered vascular supply, and aberrant functioning of bone marrow-derived central nervous system macrophages."
Control of Canine Genetic Diseases. Padgett, G.A., Howell Book House 1998, pp. 198-199, 235.
A Simple, Effective Technique for Arresting Canine Epileptic Seizures. H. C. Gurney, Janice Gurney. J. Amer. Holistic Vet. Med. Assn. Jan 2004; 22(4):17-18. Quote: "Fifty-one epileptic canine patients were successfully treated during an epileptic seizure with a technique involving the application of ice on the back (T10 to L4). This technique was found to be effective in aborting or shortening the duration of ictus. ... Ice is applied as soon as the seizure is observed. The application itself is either a block of ice (i.e., water frozen in a metal ice tray, with the tray applied directly to the seizing patient), or ice (cubes or crushed ice in a plastic bag). The ice is held firmly to the dog’s back, on the area superior to the spinal process from T10 (palpable at the 'low spot' on the canine spine) to L4 (Figure at right). The size of a given ice application is sufficient to cover the described area. Maintain firm pressure in that location until the patient spontaneously recovers sternal recumbency and makes efforts to rise and walk. If the patient is prone to 'chain' episodes or displays evidence of returning to ictus after removal of the ice, the ice should once again be applied until the patient regains sternal recumbence (when chain seizures occur, aggressive medical intervention is necessary). Clients have used bags or boxes of frozen vegetables, but such applications are reported to be less effective. ... The sooner ice was applied during an epileptic event, the more effective the intervention was in stopping or abbreviating the seizure. Also of note was the observation that the canines’ post-ictus recovery time was shorter, and recovery appeared to be augmented."
Inheritance of occipital bone hypoplasia (Chiari type I malformation) in Cavalier King Charles spaniels. Rusbridge C., Knowler S. P. J Vet Intern Med 2004;18:673–678. Quote: "Occipital bone hypoplasia with foramen magnum obstruction and secondary syringomyelia (SM) is a common condition in the Cavalier King Charles Spaniel (CKCS) that is similar to human Chiari type I malformation. A worldwide family tree of more than 5,500 CKCSs spanning a maximum of 24 generations was established by obtaining pedigree information from 120 dogs diagnosed with SM secondary to occipital bone hypoplasia. The ongoing study showed 6 of 8 great grandparents of all affected dogs could be traced back to 2 female ancestors so that all 8 were descended from one or the other or both. The disease appears to be more severe and have an earlier onset with increased inbreeding, especially when breeding from affected dogs. The family tree of idiopathic epilepsy (IE) appears to be a different subset of the CKCS population, although some overlap was observed. Idiopathic epilepsy is more frequent in lines originating from whole-color dogs. Selection for coat color is believed to have influenced the development of both occipital hypoplasia with secondary SM and IE. In addition, breeding guidelines to reduce the incidence of mitral valve disease have placed further pressures on the gene pool."
"Seizures" (Podell, M.) in: Manual of Small Animal Neurology, 3d ed. Editors Olby N., Platt S., British Small Animal Vety Assn (2004). pp 97-112.
Alternative anticonvulsant drugs for dogs with seizure disorders. Curtis W. Dewey, Georgina Barone, Kerry Smith, Gregg D. Kortz. DVM360.com. Sept. 2004.
Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Loscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Epilepsia. 2004 Oct;45(10):1228-39. Quote: "Results: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138. Conclusions: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures."
Neurological diseases of the Cavalier King Charles spaniel. Rusbridge, C. J Small Animal Practice, June 2005, 46(6): 265-272(8). "Idiopathic epilepsy is a inheritable disease in the CKCS and is seen in all colour varieties but is more frequent in lines originating from whole-coloured ancestors from the late 1960s, especially where there were half-brother/sister matings (Rusbridge and Knowler 2004). Diagnosis is by ruling out other causes of seizures; for example, using haematology and biochemistry to rule out reactive causes such as hepatic encephalopathy, and MRI and CSF analysis to rule out structural and inflammatory disease such as GME. The author’s firstline therapy is phenobarbital or bromide monotherapy, progressing to a combination of both drugs if the seizures are not adequately controlled. Some cases of CKCS epilepsy are difficult to control and novel anticonvulsants such as levetiracetam (Keppra; UCB Pharma) or topiramate (Topamax; Janssen-Cilag) may be useful. For a more extensive review of the management of epilepsy see Podell (2004)."
Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: A clinical pilot study. Rieck S, Rundfeldt C, Tipold A. Vet J. 2005 May 16.
From Gold Beads to Keppra: Update on Anticonvulsant Therapy. Gregg Kortz. 2d Ann. Vet. Neurology Symposium. Univ. Calif.-Davis. 2005.
A Retrospective Study on the Use of Acepromazine Maleate in Dogs With Seizures. Karen M. Tobias, Katia Marioni-Henry, and Rebecca Wagner. J. Am.An. Hosp. Assn. (2006) 42:283-289.
Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. Curtis W. Dewey, Sofia Cerda-Gonzalez, Jonathan M. Levine, Britton L. Badgley, Julie M. Ducoté, Gena M. Silver, Jocelyn J. Cooper, Rebecca A. Packer, and James A. Lavely. JAVMA, Dec 2009; 235(12):1442-1449, Quote: "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. ... 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. ... 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 μg/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."
Breed Predispositions to Disease in Dogs & Cats (2d Ed.). Alex Gough, Alison Thomas. 2010; Wiley-Blackwell Publ. 53.
The association between Chiari-like malformation, ventriculomegaly and seizures in cavalier King Charles spaniels. C.J. Driver, K. Chandler, G. Walmsley, N. Shihab, H.A. Volk. Vety.J. Feb. 2013;195(2):235-237. Quote: "Cavalier King Charles spaniels (CKCSs) with Chiari-like malformation (CM) and associated seizures are frequently diagnosed with idiopathic epilepsy. There could be an association between ventriculomegaly (V) or caudal fossa overcrowding (CCFP) and seizures. A retrospective case-control study was performed using MRI to investigate the possible association between these morphological abnormalities and seizures. Seizure semiology and, where possible, electroencephalographic (EEG) abnormalities were documented. Eighty-five CKCS with CM were included, 27 with seizures. There was no association between V or CCFP and seizures (P = 0.10 and 0.71, respectively). Seizures were classified as having partial onset [meaning that they occur in in one area of the brain, unlike generalized seizures which typically affect nerve cells throughout the brain] in 61% of individuals in the study population (95% CI 42.41–76.43%). Another cause of recurrent seizures in CKCS (such as familial epilepsy) is suspected, as previously reported."
Double-Masked, Placebo-Controlled Study of Intravenous Levetiracetam for the Treatment of Status Epilepticus and Acute Repetitive Seizures in Dogs. B.T. Hardy, E. E. Patterson, J.M. Cloyd, R.M. Hardy, I.E. Leppik. J.Vet.Inter.Med. March 2012;26(2):334-340. Quote: "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."
Prevalence of Lateral Ventricle Asymmetry in Brain MRI Studies of Neurologically Normal Dogs and Dogs with Idiopathic Epilepsy. Mauro Pivetta, Luisa De Risio, Richard Newton, Ruth Dennis. Vet.Radiology&Ultrasound. Sept. 2013;54(5):516-521. Quote: "Asymmetry of the cerebral lateral ventricles is a common finding in cross-sectional imaging of otherwise normal canine brains and has been assumed to be incidental. The purpose of this retrospective study was to compare the prevalence of ventricular asymmetry in brain MRI studies of normal dogs and dogs with idiopathic epilepsy. Brain MRI archives were searched for 100 neurologically normal dogs (Group 1) and 100 dogs with idiopathic epilepsy (Group 2). For each dog, asymmetry of the lateral ventricles was subjectively classified as absent, mild, moderate, and severe based on a consensus of two observers who were unaware of group status. ... The prevalence of asymmetry was 38% in Group 1 dogs and 44% in Group 2 dogs. Asymmetry was scored as mild in the majority of Group 2 dogs. There was no significant association between presence/absence and degree of ventricular asymmetry vs. dog group, age, gender, or skull conformation. Findings from the current study supported previously published assumptions that asymmetry of the lateral cerebral ventricles is an incidental finding in MRI studies of the canine brain."
Pediatric Seizure Disorders in Dogs and Cats. James A. Lavely. Vet. Clinics of No. America: Small Animal Prac. Dec. 2013. Quote: "Seizure disorders in young animals pose different considerations as to cause and therapeutic decisions compared with adult animals. Infectious diseases of the nervous system are more likely in puppies and kittens compared with adults. The diagnosis of canine distemper is often based on clinical signs. Idiopathic epilepsy typically occurs in dogs between 1 and 5 years of age; however, inflammatory brain diseases such as necrotizing encephalitis and granulomatous meningoencephalomyelitis also commonly occur in young to middle-aged small-breed dogs. The choice of which anticonvulsant to administer for maintenance therapy is tailored to each individual patient. ... A 6-month-old Cavalier King Charles spaniel was reported to have seizures secondary to a hexanoylglycine aciduria."
Unusual manifestation of bromide toxicity (bromism) in an idiopathic epileptic dog already treated with phenobarbital. Fabio Stabile, Alberta de Stefani, and Luisa De Risio. Veterinary Record Case Report. April 2014;2(1). Quote: "A three-year seven-month-old female spayed Cavalier King Charles spaniel was diagnosed with idiopathic epilepsy. Because of poor seizure control, the dog was started on oral treatment with potassium bromide as adjunctive treatment to phenobarbital. The dog presented eight days following bromide loading, having developed sedation, general proprioceptive ataxia and generalised appendicular repetitive myoclonus [twitching of the limbs]. The serum bromide concentration was 15.9 mg/ml (target range 1 mg/ml to 2.5 mg/ml), which was suggestive of a bromide overdose. The dog improved after reduction of bromide dosing and no similar episodes were reported by the owners at a follow up of 26 months. To the authors’ knowledge this is the first report describing generalised repetitive myoclonus related to bromide toxicity."
Validation of the diagnosis canine epilepsy in a Swedish animal insurance database against practice records. Linda Heske, Mette Berendt, Karin Hultin Jäderlund, Agneta Egenvall, Ane Nødtvedt. Preventive Vet. Med. June 2014;114(3-4):145-150. Quote: "Canine epilepsy is one of the most common neurological conditions in dogs but the actual incidence of the disease remains unknown. A Swedish animal insurance database has previously been shown useful for the study of disease occurrence in companion animals. The dogs insured by this company represent a unique population for epidemiological studies, because they are representative of the general dog population in Sweden and are followed throughout their life allowing studies of disease incidence to be performed. The database covers 50% of all insured dogs (in the year 2012) which represents 40% of the national dog population. Most commonly, dogs are covered by both veterinary care insurance and life insurance. Previous studies have shown that the general data quality is good, but the validity of a specific diagnosis should be examined carefully before using the database for incidence calculations. The aim of the current study was therefore to validate the information contained in the insurance database regarding canine epilepsy. The validation focused on the positive predictive value and the data-transfer from the veterinary practice records to the insurance database. The positive predictive value was defined as the proportion of recorded cases that actually had the disease in question. The quality of the data-transfer was assessed by comparing the diagnostic codes in practice records to the codes in the insurance database. The positive predictive value of the diagnostic codes for canine epilepsy (combining “epileptic convulsions” and “idiopathic epilepsy”) in the insurance database was validated in a cross-sectional study where insurance claims for canine epilepsy were compared to diagnostic information in practice records. A random sample of dogs with a reimbursed insurance claim during 2006 was included in the study sample (n = 235). Practice records were requested by mail from attending veterinarians. Two independent examiners scrutinized all the records. All 235 dogs were coded correctly in the database as they really had suffered seizures with or without convulsions, and the quality of the data-transfer was therefore excellent. In total, 167 dogs (71%) were classified as cases of canine epilepsy according to pre-defined criteria, and the positive predictive value was therefore considered relatively high. The most common breeds were mongrel (n = 26), Labrador retriever (n = 26), Cavalier King Charles spaniel (n = 11), Golden retriever (n = 10) and and German shepherd (n = 10). Based on these results, it was concluded that the data regarding canine epilepsy in the insurance database can be used for further population studies."
Pharmacokinetics of levetiracetam in epileptic dogs when administered concurrently with phenobarbital, bromide, or phenobarbital and bromide in combination. K.R. Muñana, J.A. Nettifee-Osborne, M.G. Papich. J.Vet.Int.Med. July 2014;28(4):1358. Quote: "Levetiracetam (LEV) is a common add-on antiepileptic medication (AED) for dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs. The objective of this study was to evaluate the pharmacokinetics of LEV in epileptic dogs when administered concurrently with conventional AEDs. Eighteen client-owned dogs on maintenance therapy with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB-BR group, n = 6) were enrolled. All AEDs had attained steady state concentrations. Blood samples were collected at 0, 1, 2, 4 and 6 hours after a morning dose of LEV. Plasma LEV concentrations were determined by high-pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations using a noncompartmental method, and AUC calculated using the trapezoidal method. Compared to the PB and PB-BR groups, the BR group had significantly higher Cmax (70.6 ± 24.0 μg/mL, versus 35.5 ± 13.7 μg/mL and 25.3 ± 9.0 μg/mL, respectively) and AUC0-Cn (314.2 ± 114.3 h*μg/mL versus 127.0 ± 64.7 h*μg/mL and 91.0 ± 42.2 h*μg/mL, respectively), and significantly lower CL/F (68.9 ± 22.1 mL/h/kg versus 172.1 ± 81.9 mL/h/kg and 247.6 ± 126.9 mL/h/kg, respectively). Concurrent administration of phenobarbital alone or in combination with bromide significantly alters the disposition of LEV in epileptic dogs compared to concurrent administration of bromide alone. These findings warrant consideration when utilizing LEV for add-on therapy in dogs with epilepsy."
A cohort study of epilepsy among 665,000 insured dogs: Incidence, mortality and survival after diagnosis. L. Heske, A. Nødtvedt, K. Hultin Jäderlund, M. Berendt, A. Egenvall. Vet.J. October 2014. Quote: "The main objective of this study was to estimate the incidence and mortality rates of epilepsy in a large population of insured dogs and to evaluate the importance of a variety of risk factors. Survival time after a diagnosis of epilepsy was also investigated. The Swedish animal insurance database used in this study has previously been helpful in canine epidemiological investigations. More than 2,000,000 dog-years at-risk (DYAR) were available in the insurance database. In total, 5013 dogs had at least one veterinary care claim for epilepsy [including 173 cavalier King Charles spaniels], and 2327 dogs were euthanased or died because of epilepsy. Based on veterinary care claims the incidence rate of epilepsy (including both idiopathic and symptomatic cases) was estimated to be 18 per 10,000 DYAR. Dogs were followed up until they were 10 (for life insurance claims) or 12 years of age (veterinary care claims). Among the 35 most common breeds in Sweden, the Boxer was at the highest risk of epilepsy with 60.3 cases per 10,000 DYAR, and also had the highest mortality rate of 46.7 per 10,000 DYAR (based on life insurance claims). Overall, males were at a higher risk than females (1.4:1). Median survival time (including euthanasia and death) after diagnosis was 1.5 years. In general, breeds kept solely for companionship lived longer after diagnosis than those kept for dual-purposes, such as hunting and shepherd and working breeds. The study demonstrates marked breed differences in incidence and mortality rates, which are assumed to reflect genetic predisposition to epilepsy."
Treatment in canine epilepsy - a systematic review. Marios Charalambous, David Brodbelt, Holger A Volk. BMC Vet. Research. Oct. 2014;10:257. Quote: "Background: Various antiepileptic drugs (AEDs) are used for the management of canine idiopathic epilepsy (IE). Information on their clinical efficacy remains limited. A systematic review was designed to evaluate existing evidence for the effectiveness of AEDs for presumptive canine IE. Electronic searches of PubMed and CAB Direct were carried out without date or language restrictions. Conference proceedings were also searched. Peer-reviewed full-length studies describing objectively the efficacy of AEDs in dogs with IE were included. Studies were allocated in two groups, i.e. blinded randomized clinical trials (bRCTs), non-blinded randomized clinical trials (nbRCTs) and non-randomized clinical trials (NRCTs) (group A) and uncontrolled clinical trials (UCTs) and case series (group B). Individual studies were evaluated based on the quality of evidence (study design, study group sizes, subject enrolment quality and overall risk of bias) and the outcome measures reported (in particular the proportion of dogs with ≥50% reduction in seizure frequency). Results: Twenty-six studies, including two conference proceedings, reporting clinical outcomes of AEDs used for management of IE were identified. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. Only four bRCTs were identified in group A and were considered to offer higher quality of evidence mong the studies. A good level of evidence supported the efficacy of oral phenobarbital and imepitoin and fair level of evidence supported the efficacy of oral potassium bromide and levetiracetam. For the remaining AEDs, favorable results were reported regarding their efficacy, but there was insufficient evidence to support their use due to lack of bRCTs. Conclusions: Oral phenobarbital and imepitoin in particular, as well as potassium bromide and levetiracetam are likely to be effective for the treatment of IE. However, variations in baseline characteristics of the dogs involved, significant differences between study designs and several potential sources of bias preclude definitive recommendations. There is a need for greater numbers of adequately sized bRCTs evaluating the efficacy of AEDs for IE."
Assessment into the usage of levetiracetam in a canine epilepsy clinic. Rowena MA Packer, George Nye, Sian Elizabeth Porter, holger A Volk. BMC Vet. Research. February 2015. Quote: "Background: The purpose of this retrospective study was to describe the use of LEV in a canine epilepsy clinic and determine the long-term efficacy and tolerability of LEV in veterinary clinical practice. The electronic database of a UK based referral hospital was searched for LEV usage in dogs with seizures. Information and data necessary for the evaluation were obtained from a combination of electronic and written hospital records, the referring veterinary surgeons? records and telephone interviews with dog owners. Only dogs that were reportedly diagnosed with idiopathic epilepsy were included in the study. Results: Fifty-two dogs [including one cavalier King Charles spaniel] were included in this retrospective study. Two treatment protocols were recognised; 29 dogs were treated continuously with LEV and 23 dogs received interval or pulse treatment for cluster seizures. LEV treatment resulted in 69% of dogs having a 50% or greater reduction of seizure frequency whilst 15% of all the dogs were completely free from seizures. Seizure frequency reduced significantly in the whole population. No dog was reported to experience life-threatening side effects. Mild side effects were experienced by 46% of dogs and a significantly higher number of these dogs were in the pulse treatment group. The most common side-effects reported were sedation and ataxia. Conclusions: LEV appears to be effective and well tolerated for reduction of seizures."
Effect of Chronic Administration of Phenobarbital, or Bromide, on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy. K.R. Muñana1, J.A. Nettifee-Osborne, M.G. Papich. J.Vet. Int. Med. February 2015. Quote: "Background: Levetiracetam (LEV) is a common add-on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs. Hypothesis/Objectives: To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs. Animals: Eighteen client-owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB–BR group, n = 6). Methods: Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high-pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area-under-the-curve (AUC) calculated to the last measured time point. Results: Compared to the PB and PB–BR groups, the BR group had significantly higher peak concentration (Cmax) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028). Conclusions and Clinical Importance: Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add-on treatment with phenobarbital in dogs."