Canine versus human epilepsy: are we up to date?

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1 ttp:// REVIEW Canine versus human epilepsy: are we up to date? A. Uriarte *,1 and I. Maestro Saiz * North Down Specialist Referrals, Surrey, RH1 4QP Clinical Neurophysiology Department, Cruces University Hospital, Barakaldo, Biscay, 48903, Spain 1 Corresponding author auriarte@ndsr.co.uk In this paper we analyse and compare features of canine and human epilepsy and we suggest new tools for better future understanding of canine epilepsy. The prevalence of epileptic seizures in dogs ranges between 0.5% and 5.7% and between 1% and 3% in the human population. Studies on human epilepsy provide a ready-made format for classification, diagnosis and treatment in veterinary epilepsy. Human studies highlight the value of a thorough seizure classification. Nevertheless, a matter of concern in canine epilepsy is the limited information regarding seizure description and classification because of the lack of EEG-video recording. Establishment of a consensus protocol for ambulatory home video-recording in dogs who suffer from epilepsy, mainly considering indications, duration of monitoring, the sufficient essential training for an optimal interpretation of ictal semiology and the methodology of recordings is needed. The ultimate goal is that the information gathered by these videos will be analysed to describe the epileptic seizures thoroughly, recognize patterns and move towards a better understanding and therefore classification of canine epileptic seizures. Journal of Small Animal Practice (2016) 57, DOI: /jsap Accepted: 13 August 2015 INTRODUCTION Epilepsy is a common neurological disorder. The prevalence of epileptic seizures in dogs ranges between 0 5% and 5 7% (Podell et al. 1995, Kearsley-Fleet et al. 2013, Heske et al ) and between 1 and 3% in the human population (Engel et al ). A seizure is the appearance of signs and symptoms because of abnormal excessive or synchronous neuronal activity of the brain, and epilepsy is considered to be a disorder of the brain in which patients suffer from an enduring predisposition to have seizures. The definition of epilepsy in humans also includes other aspects such as neurobiological, cognitive, psychological and social consequences of this disease (Fisher et al ). There are striking similarities between human and canine epilepsy (Potschka et al ), and the published literature is extensive. The objective of this article, written by a veterinary neurologist and a human epileptologist, is to analyse and compare features of canine and human epilepsy and to suggest new tools for the better understanding of canine epilepsy. CANINE EPILEPSY AS A TRANSLATIONAL MODEL The domestic dog not only provides companionship and working activities cultivated through domestication and selective breeding but is also a model for biomedical research (Nowend et al ). Many studies have revealed similarities between human and canine epileptic syndromes (Jokinen et al. 2007, Berendt et al. 2009, Hülsmeyer et al. 2010, Weissl et al ), including status epilepticus (Leppik et al ), and the identification of genetic abnormalities in dogs has been useful in elucidating novel genes in human epilepsies (Potschka et al ). Multidrug refractory epilepsy is also comparable between dogs and humans (Potschka et al ) and provides opportunities for anti-epileptic drug development (Löscher et al ). Moreover, dogs are also an interesting natural model for studies on human posttraumatic epilepsy because head trauma is associated with a significant risk of developing epilepsy in both species (D Ambrosio & Perucca 2004, Pitkänen et al. 2009, Steinmetz et al ). Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association 115

2 I. Maestro Saiz & A. Uriarte Several limitations need to be considered when comparing human and veterinary epilepsy; for instance, an owner-based record will differ from a self-assessed seizure record. There are species differences in pharmacokinetics, and there are clearly different social implications related to a dog or a human having a seizure. EPILEPSY AND SEIZURE CLASSIFICATION Since 1981, the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) has periodically updated seizure and epilepsy classification, which were initially based on semiology, interictal electroencephalographic (EEG) findings and EEG ictal patterns. Compared to the previous task report (Engel 2006 ), the latest review in 2010 (Berg et al ) did not include major changes in terms of epileptic syndromes other than changes in nomenclature. The dichotomous classification of seizures into generalised and focal types was maintained although terms such as simplex and complex for partial or focal seizures were considered imprecise, and authors recommended classifying focal seizures according to the most useful key aspects in each patient in order to establish the diagnostic prognosis and anti-epileptic drug or surgery (Berg et al ). The Semiological Seizure Classification (Lüders et al ) provided common terms for ictal symptoms independent of EEG findings or other laboratory information. Therefore, this classification is exclusively based on ictal seizure semiology that can be reported by the patients or observers or recorded by video- EEG. Ictal symptoms result from the interference of seizures in the sensorial, consciousness, autonomic or motor sphere. On the other hand, in the latest revision, the ILAE Commission stated that previously used terms such as idiopathic, symptomatic and cryptogenic epilepsy should be modified and suggested the new terms genetic, structural-metabolic and unknown-origin epilepsy (Berg et al ). Veterinary publications based on terminology and classification of seizures have generally adapted the basis of ILAE classifications to fit small animal patients (Berendt & Gram 1999 ), but a formally endorsed system to classify seizures and epilepsy has not been developed yet for veterinary patients. Mariani ( 2013 ) recently proposed a broad and very useful glossary of terms for describing ictal manifestations in veterinary patients also based on human classification systems. This classified canine seizures as motor (elementary motor and motor with automatisms), non-motor and autonomic. Elementary motor seizures include tonic, myoclonic, tonic clonic and atonic with special attention to synchrony. Automatisms included oroalimentary, mimetic, hyperkinetic, hypokinetic, vocal, spontaneous and interactive automatisms. Non-motor seizures were mainly auras, sensory and dyscognitive (Mariani 2013 ) or, as proposed here, hypomotor. In seizure terminology, the dichotomy between simplex and complex for partial or focal seizures also makes no sense in small animals. For example, it is almost impossible to evaluate a dog s memory during seizures, which is a frequently useful tool in humans to evaluate ictal loss of consciousness (complex partial seizures). Therefore, in the absence of EEG recordings, the correct choice for animal seizure classification should be to use generalised and focal or partial seizures, depending on the extent of motor manifestations during the seizure. Mariani ( 2013 ) described the range of seizure semiology that could be observed in small animals: motor, non-motor and autonomic aspects. Mariani ( 2013 ) also proposed the term dyscognitive seizure to define some non-motor seizures that are characterised by the disturbance of cognition, but this would be difficult to determine in animals. Human epileptologists have the same problem when dealing with patients in whom consciousness cannot be evaluated, such as infants or patients with severe impairment of basal mental state (Lüders et al ). In these particular cases, when patients present with a decrease or total absence of motor activity as the main sign, the term hypomotor seizures is used, which could be also useful in animals, avoiding cognitionrelated terms. In humans, the term idiopathic has been changed to of unknown cause. Canine epilepsy could benefit from this corrected epilepsy classification to avoid terminology misunderstandings. Epileptic dogs with normal interictal neurological examinations, no structural or metabolic disorders and possible genetic predisposition, with both focal and/or generalised seizures, should be included in this classification. The structural metabolic epilepsy term highlights the existence of a separate disorder, in some cases, not directly related to epilepsy. This term should be used in animals with concurrent structural, metabolical or neurological impairment suggesting lesion or diseases that could induce epilepsy (Berg et al ). CLINICAL MANIFESTATIONS DURING SEIZURES In humans, the cortical area that generates the initial ictal symptomatology is called the symptomatogenic zone (Lüders 2008 ). The location of this zone provides information about the location of the epileptogenic zone, which is the cortical region or network that generates epileptic seizures. It is well known that certain brain functions are located in specific cortical areas, and a detailed analysis of signs and symptoms during seizures is considered crucial in determining the potential location of the symptomatogenic zone. The symptomatogenic zone and the epileptogenic zone usually do not overlap perfectly but are in close proximity. Several symptomatogenic zones can be activated simultaneously during a seizure. In humans, historical information is supplemented by data obtained from video recordings selected from video-eeg recordings acquired in hospital and from videos recorded at home by family members. The videos allow repeated analysis, if necessary, by more than one independent observer. Video analysis of seizures is ideally complemented by EEG recordings. Electrographic patterns help in distinguishing the beginning and the end of seizures, non-ictal behaviours such as daydreaming and non-epileptic seizures from true seizures. Since smartphones became popular a few years ago, many owners record their dog 116 Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association

3 Canine versus human epilepsy while it has a seizure. However, it is unlikely that EEG recordings in epileptic dogs can be used to document seizure foci unless novel implantable EEG devices and continuous EEG monitoring become available (Poma et al ). The initial symptom or sign during a seizure is the most interesting point, but information is also gained from the nature of the progression of these manifestations. During the last few decades, many signs and symptoms in human epilepsy have been analysed and related to the location of epileptogenic zone in terms of location and lateralisation. Certain symptoms allow confidence in the lateralisation of the origin of seizures in humans (Lüders 2008 ), and the utility of these symptoms could be analysed in dogs. Some symptoms, such as somatosensory focal or visual auras, preserved consciousness or speech impairment, are almost impossible to detect in dogs, but other signs could provide invaluable information about the seizure source. Ninety percent of patients who present with focal clonic/tonic activity have a seizure origin in the contralateral hemisphere, and this sign may appear in over 45% of patients with frontal lobe epilepsy (Lüders 2008 ). The specificity of lateralisation depends on the signs. For example, the specificity of a contralateral origin for forced head version less than 10 seconds before secondary generalisation is higher than 90% and for unilateral dystonic posturing or for postictal palsy, is higher than 99%. The specificity for ipsilaterality to a unilateral last clonic movement in a secondary generalised seizure is about 80%. The work of Armas u et al. (2014 ) also established the relevance of the analysis of clinical signs in dogs in order to state a rational and useful clinical reasoning approach. Some factors such as age of seizure onset, severity of the seizures and an abnormal neurological examination should be considered as good predictors for intracranial structural lesions and epilepsy of unknown origin (Armas u et al ). Video recordings of seizures in dogs will make it possible to analyse canine seizure presentation and manifestations. Most of the episodes are only observed by the owners, and a veterinary neurologist s diagnosis is based most of the time on owner observation and description, which can be very limited. A recent research study was performed to investigate the level of agreement between veterinarians (both neurologist specialists and non-specialists) on the description and classification of the videos depicting paroxysmal events, without knowing any results of diagnostics workup ( Packer et al ). This study highlighted the need for ongoing debate regarding the descriptive terminology used for seizure semiology in veterinary medicine and the need for further training in focused areas. It is crucial to remark that home video-recordings and interpretations should follow a consensus protocol; sufficient training for an optimal interpretation of these recordings is required. Canine epilepsy video recording is an accessible and nondeveloped tool that we would like to introduce. The purpose of our website, named canineseizures.org, is to build up an international database of canine epilepsy videos recorded by owners and uploaded by American or European neurology diplomats. This pool of information will be accessible for research and will help spread knowledge of the disease amongst academics, veterinarians and dog owners. The detailed description of ictal semiology in dogs could be useful not only in establishing the brain areas involved in seizure origin or suspicion of structural lesion location but also in determining main seizure types in the most prevalent epileptic syndromes in order to facilitate the diagnosis, especially if neuroimaging or other complementary tests are not available. Preston et al. ( 2013 ) published a very interesting study about public perception of epilepsy comparing dogs and humans. They analysed a 150-video sample from YouTube and classified the comments of viewers in sympathetic/empathetic, derogatory and neutral categories. They observed that viewers generally considered videos of canine seizures in a more positive way than videos showing human seizures. This group s work also stated a high value of comments about the videos for dog owners that required advice. The authors finally remarked on the potential relevance of the Internet to epilepsy in terms of providing information and reducing the stigma associated with the lack of information about this disease. AETIOLOGY OF EPILEPSY Canine classification of epilepsy is mainly based on aetiology: primary or genetic epilepsy (often termed idiopathic), structural epilepsy, reactive seizures and epilepsy of unknown origin (Chandler 2006 ). Genetic/primary or idopathic epilepsy Canine epilepsy researchers share the view that idiopathic epilepsy might be the most common form of epilepsy in dogs from five months up to six years of age at the onset of epilepsy, with a prevalence of up to 75% of the epileptic dogs (Podell et al. 1995, Bush et al. 2002, Chandler 2006, Thomas 2010, Arrol et al ). However, there is still a debate about how to define idiopathic epilepsy in veterinary medicine. In humans, idiopathic epilepsy is stated as a disorder not preceded or occasioned by another, without an underlying cause other than a possible hereditary predisposition and defined by age of onset, clinical and electroencephalographic characteristics and a presumed genetic aetiology (Commission on Classification and Terminology of the International League Against Epilepsy 1989 ). In veterinary medicine, idiopathic epilepsy, also called primary epilepsy, is defined as chronic recurring seizures with no underlying structural brain lesion or other neurological signs (Berendt & Gram 1999, Engel 2006 ). There is continued confusion regarding the use of the term idiopathic, and this term is variably used by different veterinarians (March 1998, Thomas 2010 ). The term idiopathic means a disorder by itself and not cause unknown. The term idiopathic epilepsy is not simply applied to any patient in whom the cause of the seizures is unknown. It needs to be emphasised that the lack of diagnostic equipment probably results in an overestimation of idiopathic epilepsy (Berendt & Gram 1999 ). Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association 117

4 I. Maestro Saiz & A. Uriarte Due to high prevalence of idiopathic (or primary) epilepsy in certain breeds, familial predisposition and genetic components of disease origin are suspected for many purebred dogs. However, identification of a causative gene mutation in canine epilepsy has only been successful in familial juvenile epilepsy in Lagotto Romagnolo dogs (Lohi & Nicholas 2009, Seppälä et al ) and in cases of autosomal recessive progressive myoclonus epilepsy in miniature, wire-haired Dachshunds (Lohi et al ). A risk-conferring locus has also been identified in idiopathic epilepsy in Belgian Shepherd dogs ( Seppälä et al ). Between 30 and 40% of all epilepsies in humans are considered to be idiopathic epilepsies. Most idiopathic generalised epilepsies (IGE) present oligogenic or polygenic patterns of inheritance, but there is also a rare monogenic group of partial or generalised idiopathic epilepsies. The seizure recurrence risk in first-degree relatives of patients who suffer from IGE is lower than in monogenic disorders (Steinlein et al ). The group of IGE includes some well-known and highly prevalent syndromes such as juvenile myoclonic epilepsy, childhood absence epilepsy and awakening grand mal seizures. There is plenty of genetic and phenotypic heterogeneity in human epilepsies. Nowadays, the most useful diagnostic tests for epilepsy of suspected genetic origin are genetic panels, array comparative genomic hybridisation and gene panel testing and, in some selected cases, whole exome sequencing. Some disadvantages of these studies are the high cost of tests and that genes must be known and suspected by the clinician (Sisodiya 2015 ). Although a hereditary basis is suspected in a large population of idiopathic epileptic dogs, genetic studies are currently expensive and of modest help in clinical practice. Even so, research in human genetic epilepsies is focused on treating the underlying cause and not just the symptomatic manifestations of epilepsy (Weckhuysen & Korff 2014 ), which will certainly develop pharmacotherapy in human and canine species. Structural epilepsy About 20% of symptomatic epilepsy in humans can be considered of posttraumatic origin (Agrawal et al ), and recent studies showed that 15 5% of dogs presenting with seizures had a previous history of head injury (Steinmetz et al ). There is some possibility that traumatic epilepsy in dogs could form a translational model of posttraumatic epilepsy (PTE) in humans (Steinmetz et al ). The increased risk of PTE related to the severity of head injuries, as previously demonstrated in humans by Lowenstein ( 2009 ), and the incidence of seizures during the first week after trauma were also correlated, as in humans, with the severity of the head injury. The latency between head trauma (~2 years) and the increased risk of epilepsy in dogs and humans (3 4-fold versus 3 1-fold, respectively) were also equivalent. Many other structural conditions are related to an increased risk of developing epilepsy in both humans and dogs, including stroke, intracranial infections (encephalitis and meningitis), brain tumours, neurosurgery and congenital disorders such as malformations of cortical development. Cryptogenic epilepsy This term was used by the Commission on Classification and Terminology in 1989 for designating probably symptomatic epilepsies. Cryptogenic epilepsy was used for epilepsies that did not fit the criteria of an idiopathic condition, and there was no evidence of a symptomatic cause. Plenty of syndromes previously classified as cryptogenic are considered idiopathic these days. Thus, the term cryptogenic should be used for identifying epilepsies with a truly unknown underlying cause. Epilepsy in dogs who have not been adequately studied and when a symptomatic cause has not been excluded should not be classified as cryptogenic. Fewer types of epilepsy are included in idiopathic or cryptogenic groups nowadays mainly due to modern structural and functional brain imaging in humans (Engel et al ). The immense progress in imaging techniques, especially the increasing application of magnetic resonance scanning in veterinary practice, has disclosed an increasing number of structural causes for epilepsy that were not previously recognised. TREATMENT OF EPILEPSY The most active aspect of translational studies in epilepsy between dogs and humans is the development of epilepsy treatments (Löscher et al ). In human medicine, the best improvement in quality of life (QoL) for epilepsy patients is achieved when treatment leads to remission; therefore, seizure freedom should always be the main goal (Poochikian-Sarkissian et al. 2008, Kwan et al ). The National Institute for Health and Care Excellence (NICE) states that the objective of treatment includes not only total remission of seizures but also minimisation of side effects of therapy so that patients can lead as normal a life as possible (Lee 2014 ). The majority of human patients respond to their first antiepileptic drug. Selection of the first treatment is mainly based on the risk of side effects because they significantly impact QoL. Drugs that are considered first line treatment for epilepsy in humans include carbamazepine, oxcarbazepine, lamotrigine, levetirazetam, phenytoine, valproic acid, topiramate, ethosuximide and phenobarbital. However, there are other drugs such as gabapentin, tiagabine, pregabalin, vigabatrin, zonisamide or benzodiazepines that can be used, sometimes alone or mostly in combination. Combined therapy is considered only for patients that do not respond adequately to the first drug. The efficacy of new anti-epileptic drugs is not higher, but they do often have lower rate of interactions, varying mechanisms of action and open the possibility to synergistic drug combinations. In veterinary medicine, most epilepsy trials have primarily focused on reducing seizure frequency rather than achieving seizure freedom; up to 80% of dogs in referral hospital populations will continue to have seizures despite anti-epileptic treatment (Hülsmeyer et al. 2010, Arrol et al ). Nevertheless, remission with or without medication is still possible in canine epilepsy cases, and rates vary from 24 (Berendt et al ) to 15% of dogs (Berendt et al ). In these studies, remission was classified as being seizure-free for two or three years. 118 Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association

5 Canine versus human epilepsy Despite major disadvantages regarding drug interactions and adverse effects, phenobarbital remains a popular choice in the treatment of focal and generalised seizures in dogs (Boothe et al ). In dogs with phenobarbital-refractory epilepsy, the oldest anti-epileptic drug, potassium bromide, is often tried as an addon medication (Kluger et al ). However, the combination of both drugs also fails to result in seizure freedom in a considerable subgroup of dogs (Schwartz-Porsche & Jürgens 1991, Hülsmeyer et al. 2010, Boothe et al. 2012, Weissl et al ). Anti-epileptic drugs used so far in polytherapy in dogs include levetiracetam, zonisamide, felbamate, topiramate, gabapentin and pregabalin as well as the new drug imepitoin (ELB ) (Löscher et al. 2004, Platt et al. 2006, Von Klopmann et al. 2007, Volk et al. 2008, Dewey et al ). Moreover, the fact that dogs tend to metabolise and excrete drugs more rapidly than humans needs to be considered (Frey & Löscher 1985, Potschka et al ). Similar to human epilepsy, multidrug resistance is considered to be a major problem in canine epilepsy (Potschka et al ). It is well known that an early response to anti-epileptic treatment is a powerful predictor of the long-term outcome in newly diagnosed human epilepsies (Mohanraj & Brodie 2013 ). Seizure type (MacDonald et al ), age at onset of epilepsy and EEG patterns (Berg 2001 ) are considered to be limited guidance factors in prognosis. On the other hand, epileptic patients presenting structural abnormalities in neuroimaging have shown a poorer outcome than patients without lesions (Sillanpää 1993 ). Presentation with convulsive seizures in infancy is also clearly related to a poorer response to treatment in newly diagnosed epilepsy, such as cases with positive familiar history of epilepsy, mainly in generalised syndromes and probably related to underlying genetic mechanisms (Berg 2001 ). Some groups have shown a relationship between high initial seizure frequency and poor outcome, but this finding has only been demonstrated in patients suffering from complex partial seizures (Shinnar & Berg 1996 ). Dietary treatment is another useful therapy for refractory epilepsy in humans; an adjunctive ketogenic diet and a modified Atkins diet appear to be very quickly effective, with only a few benign side effects. However, high rates of diet discontinuation, mainly because of culinary and social restrictions, have been reported. A seizure reduction 50% was observed in ketogenic diet-treated patients and 29% within the Atkins diet, with 9 and 5% of patients, respectively, showing seizure reduction of more than 90% (Klein et al ). Although nutritional approaches in general, and ketogenic diets in particular, play an important role in the management of epilepsy in humans, similar guidelines for dogs currently lack strong scientific support (Larsen et al ) and may be problematical because of differences in fat metabolism between the species. Studies in dogs demonstrated that the stimulation of the cervical vagus trunk could prevent experimentally induced seizures (Zabara 1992 ). This finding led to the development of a vagal nerve stimulator device (VNS) approved by Food and Drug Administration (FDA) for the treatment of refractory epilepsy in humans in VNS appears to be a safe treatment option in dogs (Muñana et al ). This device has already been implanted in about 100,000 human patients (De Herdt et al ). THE FUTURE DIAGNOSTIC APPROACH In humans, when a seizure disorder or epilepsy is suspected, EEG is considered the most useful diagnostic test (Engel et al ), after history and physical examination, in classifying the seizure type or epileptic syndrome. Sometimes, this test also provides information about prognosis or need for antiepileptic treatment. Polygraphic studies including electrocardiogram (EKG) and electromyogram (EMG) recordings also aid in distinguishing seizures from non-epileptic ictal events, such as episodes of syncope and pseudo-seizures. EEG long-term monitoring (LTM) has several advantages compared with routine or short EEG recordings. For example, nocturnal seizures and seizures occurring on awakening in the morning are more frequently observed in 24-hour recordings. Most studies report yields of successfully captured seizures during LTM of between 60 and 96%. Findings during this kind of recording confirm the diagnosis of epilepsy in 50 90% of cases and lead to changes in treatment in 45 80% of patients (Engel et al ). Therefore, LTM has been related to an improvement of outcome in 30 74% of cases. The main benefit of ambulatory recordings (AEEG), beyond inexpensiveness, is based on the fact that patients are in their usual environment with their usual habits. When AEEG includes video recording, the subject should desirably be always in the field of view of the camera. Nowadays, portable devices have enough memory to easily allow 24-hour recording of 20 channel EEGs, and their combination with video systems will render LTM redundant in many cases (Engel et al ). However, in cases where drug withdrawal is necessary or seizures must be induced anyway, AEEG is not recommended. EEG in canine epilepsy is almost entirely confined to research mainly because of the anatomy of the dog skull, which is largely covered by thick muscle. The optimisation of EEG procedures face specific challenges related to muscle artefacts: the frequent need for sedation and muscle relaxants, the short recording protocols and the limited number of electrodes without routine use of temporalis electrodes (Brauer et al ). Therefore, scalp EEG is not practical for clinical studies in dogs because of the need for behavioural training or sedation to minimise these recording artefacts (Pellegrino & Sica 2004, Jeserevics et al ). Intracranial EEG (ieeg) has been used in research and highlights the need for long continuous ieeg recordings to capture an adequate number of seizures and to solve some of the anatomical limitations related to non-invasive EEG (Coles et al. 2013, Howbert et al ). A major concern regarding ambulatory EEG studies in canine patients is that the assessment of seizure frequency has to rely on owner-based seizure reporting. Therefore, it is critical to consider owner compliance and the percentage of time spent with the dog during day and night as an inclusion/exclusion criterion during patient recruitment. Moreover, it should be considered that owners might not recognise or report all seizures even during times of close observation. Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association 119

6 I. Maestro Saiz & A. Uriarte However, simultaneous video-eeg monitoring of two dogs has been performed for intermittent periods to capture and categorise ictal events. Clinical seizures were identified by consensus review of synchronised video recordings by two expert EEG readers ( Brauer et al ). In daily clinical practice, the most used method of analysis for EEG data interpretation in humans is still qualitative. However, new mathematical quantitative methods of analysis for EEG signals are being introduced that allow the clinician to distinguish high frequency electromyographic activity from cerebral activity. This is a complex method considering that fast frequencies such as EMG are usually mixed with cerebral fast frequencies during seizures. Methods based on independent component analysis (ICA) (Engel et al ), applied in order to remove noise signals mixed with cerebral activity, could be a good alternative for removing EEG artefact from canine-eeg recordings. Reflecting the still necessary improvement in EEG signal analysis in dogs, we consider that a consensus protocol-based ambulatory video recording could be very useful for veterinary neurologists to better evaluate real seizure frequency, type and severity of seizures. This method could also promote a more accurate syndrome diagnosis in epilepsy and facilitate the choice of a more specific complementary test or drug treatment in each case. In any case, specific training is necessary for an optimal interpretation of canine seizure semiology and signs progression during seizures. CONCLUSIONS Epilepsy is not a single disease but a group of disorders characterised by a broad array of clinical signs, age of onset and underlying causes. The ILAE periodically revises their classification aiming for a thorough description, and veterinary classifications usually follow their recommendation. Nevertheless, some epilepsies bridge these categories, and human and veterinary neurologists have acknowledged the suboptimal classification schemes regarding seizures and the need for them to evolve over time mainly based on new scientific and clinical evidence. A matter of concern in canine epilepsy is the limited information regarding seizure description and classification, mainly limited due to the lack of EEG-video recording. Establishing a consensus protocol for ambulatory home videorecording in dogs who suffer from epilepsy, mainly considering indications, duration of monitoring, the sufficient essential training for an optimal interpretation of ictal semiology and the methodology of recordings is needed. Future steps will probably lead, as in humans, to the common use of mathematical methods of EEG recordings analysis in order to facilitate signal interpretation despite huge EMG artefacts. References Agrawal, A., Timothy, J., Pandit, L., et al. ( 2006 ) Post-traumatic epilepsy: an overview. Clinical Neurology and Neurosurgery 108, Armaşu, M., Packer, R. M. A., Cook, S., et al. ( 2014 ) An exploratory study using a statistical approach as a platform for clinical reasoning in canine epilepsy. The Veterinary Journal 202, Arrol, L., Penderis, J., Garosi, L., et al. ( 2012 ) Aetiology and long-term outcome of juvenile epilepsy in 136 dogs. Veterinary Record 170, Berendt, M. & Gram, L. ( 1999 ) Epilepsy and seizure classification in 63 dogs: a reappraisal of veterinary epilepsy terminology. Journal of Veterinary Internal Medicine 13, Berendt, M., Gredal, H., Pedersen, L., et al. ( 2002 ) A cross-sectional study of epilepsy in Danish Labrador retrievers: prevalence and selected risk factors. Journal of Veterinary Internal Medicine 16, Berendt, M., Gredal, H., Alving, J. ( 2004 ) Characteristics and phenomenology of epileptic partial seizures in dogs: Similarities with human seizure semiology. Epilepsy Research 61, Berendt, M., Gredal, H., Ersbøll, A. K., et al. ( 2007 ) Premature death, risk factors, and life patterns in dogs with epilepsy. Journal of Veterinary Internal Medicine 21, Berendt, M., Gulløv, C. H., Fredholm, M. ( 2009 ) Focal epilepsy in the Belgian shepherd: evidence for simple Mendelian inheritance. Journal of Small Animal Practice 50, Berg, A. T. ( 2001 ) Epidemiology in epilepsy. Epilepsy Currents 1, Berg, A. T., Berkovic, S. F., Brodie, M. J., et al. ( 2010 ) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, Epilepsia 51, Boothe, D. M., Dewey, C., Carpenter, D. M. ( 2012 ) Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. Journal of the American Veterinary Medical Association 240, Brauer, C., Kästner, S. B., Rohn, K., et al. ( 2012 ) Electroencephalographic recordings in dogs suffering from idiopathic and symptomatic epilepsy: diagnostic value of interictal short time EEG protocols supplemented by two activation techniques. The Veterinary Journal 193, Bush, W. W., Barr, C. S., Darrin, E. W., et al. ( 2002 ) Results of cerebrospinal fluid analysis, neurologic examination findings, and age at the onset of seizures as predictors for results of magnetic resonance imaging of the brain in dogs examined because of seizures: 115 cases ( ). Journal of the American Veterinary Medical Association 220, Chandler, K. ( 2006 ) Canine epilepsy: what can we learn from human seizure disorders? The Veterinary Journal 172, Coles, L. D., Patterson, E. E., Sheffield, W. D., et al. ( 2013 ) Feasibility study of a caregiver seizure alert system in canine epilepsy. Epilepsy Research 106, Commission on Classification and Terminology of the International League Against Epilepsy. ( 1989 ) Epilepsia 30, D Ambrosio, R. & Perucca, E. ( 2004 ) Epilepsy after head injury. Current Opinion in Neurology 17, De Herdt, V., Boon, P., Ceulemans, B., et al. ( 2007 ) Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. European Journal of Paediatric Neurology 11, Dewey, C. W., Cerda-Gonzalez, S., Levine, J. M., et al. ( 2009 ) Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. Journal of the American Veterinary Medical Association 235, Engel, J. Jr. ( 2006 ) Report of the ILAE classification core group. Epilepsia 47, Engel, J. Jr., Pedley, T. A., Aicardi, J. ( 2008 ) Chapter I. Epidemiology, Pathology, and Genetics of Epilepsy. In: Epilepsy a Comprehensive Textbook. 2nd edn. W. Allen Hauser, H. V. Vinters and T. A. Pedley. Lippincott Williams & Wilkins. A Wolters Kluwer Business, Philadelphia, PA, USA Fisher, R. S., Acevedo, C., Arzimanoglou, A., et al. ( 2014 ) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, Frey, H. H. & Löscher, W. ( 1985 ) Pharmacokinetics of anti-epileptic drugs in the dog: a review. Journal of Veterinary Pharmacology and Therapeutics 8, Heske, L., Nødtvedt, A., Hultin Jäderlund, K., et al. ( 2014 ) A cohort study of epilepsy among 665,000 insured dogs: incidence, mortality and survival after diagnosis. The Veterinary Journal 202, Howbert, J. J., Patterson, E. E., Stead, S. M., et al. ( 2014 ) Forecasting seizures in dogs with naturally occurring epilepsy. PLoS One 9, e81920 Hülsmeyer, V., Zimmermann, R., Brauer, C., et al. ( 2010 ) Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. Journal of Veterinary Internal Medicine 24, Jeserevics, J., Viitmaa, R., Cizinauskas, S., et al. ( 2007 ) Electroencephalography findings in healthy and Finnish Spitz dogs with epilepsy: visual and background quantitative analysis. Journal of Veterinary Internal Medicine 21, Jokinen, T. S., Metsähonkala, L., Bergamasco, L., et al. ( 2007 ) Benign familial juvenile epilepsy in Lagotto Romagnolo dogs. Journal of Veterinary Internal Medicine 21, Kearsley-Fleet, L., O Neill, D. G., Volk, H. A., et al. ( 2013 ) Prevalence and risk factors for canine epilepsy of unknown origin in the UK. Veterinary Record 172, 338 Klein, P., Tyrlikova, I., Mathews, G. C. ( 2014 ) Dietary treatment in adults with refractory epilepsy: a review. Neurology 83, Kluger, E. K., Malik, R., Govendir, M. ( 2009 ) Veterinarians preferences for anticonvulsant drugs for treating seizure disorders in dogs and cats. Australian Veterinary Journal 87, Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association

7 Canine versus human epilepsy Kossoff, E. H., Zupec-Kania, B. A., Rho, J. M. ( 2009 ) Ketogenic diets: an update for child neurologists. Journal of Child Neurology 24, Kwan, P., Arzimanoglou, A., Berg, A. T., et al. ( 2010 ) Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, Lane, S. B. & Bunch, S. E. ( 1990 ) Medical management of recurrent seizures in dogs and cats. Journal of Veterinary Internal Medicine 4, Larsen, J. A., Owens, T. J., Fascetti, A. J. ( 2014 ) Nutritional management of idiopathic epilepsy in dogs. Journal of the American Veterinary Medical Association 245, Lee, S. K. ( 2014 ) Old versus new: why do we need new antiepileptic drugs? Journal of Epilepsy Research 4, Leppik, I. E., Patterson, E. N., Coles, L. D., et al. ( 2011 ) Canine status epilepticus: a translational platform for human therapeutic trials. Epilepsia 52 ( S8 ), Lohi, H. & Nicholas, F. W. ( 2009 ) Unlocking the genetic make-up of canine hip dysplasia: we can work it out. The Veterinary Journal 181, Lohi, H., Young, E. J., Fitzmaurice, S. N., et al. ( 2005 ) Expanded repeat in canine epilepsy. Science 307, 81 Löscher, W., Schwartz-Porsche, D., Frey, H. H., et al. ( 1985 ) Evaluation of epileptic dogs as an animal model of human epilepsy. Arzneimittel-Forschung 35, Löscher, W., Potschka, H., Rieck, S., et al. ( 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. Epilepsia 45, Lowenstein, D. H. ( 2009 ) Epilepsy after head injury: an overview. Epilepsia 50 ( S2 ), 4-9 Lüders, H. O. ( 2008 ) Textbook of Epilepsy Surgery. 1st edn. Informa Healthcare, London Lüders, H., Acharya, J., Baumgartner, C., et al. ( 1998 ) Semiological seizure classification. Epilepsia 39, MacDonald, B. K., Johnson, A. L., Goodridge, D. M., et al. ( 2000 ) Factors predicting prognosis of epilepsy after presentation with seizures. Annals of Neurology 48, March, P. A. ( 1998 ) Seizures: classification, etiologies, and pathophysiology. Clinical Techniques in Small Animal Practice 13, Mariani, C. L. ( 2013 ) Terminology and classification of seizures and epilepsy in veterinary patients. Topics in Companion Animal Medicine 28, Mohanraj, R. & Brodie, M. J. ( 2013 ) Early predictors of outcome in newly diagnosed epilepsy. Seizure 22, Muñana, K. R., Vitek, S. M., Tarver, W. B., et al. ( 2002 ) Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs. Journal of the American Veterinary Medical Association 221, Nowend, K. L., Starr-Moss, A. N., Murphy, K. E. ( 2011 ) The function of dog models in developing gene therapy strategies for human health. Mammalian Genome 22, Packer, R. M., Shihab, N. K., Torres, B. B., et al. ( 2014 ) Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy. Plos One 9, e Packer, R. M. A., Berendt, M., Bhatti, S., et al. ( 2015 ) Inter-observer agreement of canine and feline paroxysmal event semiology and classification by veterinary neurology specialists and non-specialists. BMC Veterinary Research 11, 39 Pellegrino, F. C. & Sica, R. E. ( 2004 ) Canine electroencephalographic recording technique: findings in normal and epileptic dogs. Clinical Neurophysiology 115, Pitkänen, A., Immonen, R. J., Grohn, O. H., et al. ( 2009 ) From traumatic brain injury to posttraumatic epilepsy: what animal models tell us about the process and treatment options. Epilepsia 50 ( S2 ), Platt, S. R., Adams, V., Garosi, L. S., et al. ( 2006 ) Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. The Veterinary Record 159, Podell, M., Fenner, W. R., Powers, J. D. ( 1995 ) Seizure classification in dogs from a non referral-based population. Journal of the American Veterinary Medical Association 206, Poma, R., Ochi, A., Cortez, M. A. ( 2010 ) Absence seizures with myoclonic features in a juvenile Chihuahua dog. Epileptic Disorders 12, Poochikian-Sarkissian, S., Sidani, S., Wennberg, R., et al. ( 2008 ) Seizure freedom reduces illness intrusiveness and improves quality of life in epilepsy. The Canadian Journal of Neurological Sciences 35, Potschka, H., Volk, H. A. & Pekcec, A. ( 2009 ) Aktueller Stand und Trends in der Epilepsietherapie bei Hund und Katze. Tieraerztl Prax 37, Potschka, H., Fischer, A., von Rüden, E. L., et al. ( 2013 ) Canine epilepsy as a translational model? Epilepsia 54, Preston, S. M., Shihab, N., Volk, H. A. ( 2013 ) Public perception of epilepsy in dogs is more favorable than in humans. Epilepsy & Behavior 27, von Rüden, E. L., Avemary, J., Zellinger, C., et al. ( 2012 ) Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis. Neuropathology and Applied Neurobiology 38, Schwartz-Porsche, D. & Jürgens, U. ( 1991 ) Effectiveness of bromide in therapy resistant epilepsy of dogs. Tierärztliche Praxis 19, Seppälä, E. H., Jokinen, T. S., Fukata, M., et al. ( 2011 ) LGI2 truncation causes a remitting focal epilepsy in dogs. PLoS Genetics 7, e Shihab, N., Bowen, J., Volk, H. A. ( 2011 ) Behavioral changes in dogs associated with the development of idiopathic epilepsy. Epilepsy & Behavior 21, Shinnar, S. & Berg, A. T. ( 1996 ) Does antiepileptic drug therapy prevent the development of chronic epilepsy? Epilepsia 37, Sillanpää, M. ( 1993 ) Remission of seizures and predictors of intractability in longterm follow-up. Epilepsia 34, Sisodiya, S. M. ( 2015 ) Genetic screening and diagnosis in epilepsy? Current Opinion in Neurology 28, Sloviter, R. S., Zappone, C. A., Bumanglag, A. V., et al. ( 2007 ) On the relevance of prolonged convulsive status epilepticus in animals to the etiology and neurobiology of human temporal lobe epilepsy. Epilepsia 48, 6-10 Smith, P. M., Talbot, C. E., Jeffery, N. D. ( 2008 ) Findings on low-field cranial MR images in epileptic dogs that lack interictal neurological deficits. The Veterinary Journal 176, Steinlein, O. K., Mulley, J. C., Propping, P., et al. ( 1995 ) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics 11, Steinmetz, S., Tipold, A., Löscher, W. ( 2013 ) Epilepsy after head injury in dogs: a natural model of posttraumatic epilepsy. Epilepsia 54, Thomas, W. B. ( 2010 ) Idiopathic epilepsy in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 40, Volk, H. A., Matiasek, L. A., Luján Feliu-Pascual, A., et al. ( 2008 ) The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. The Veterinary Journal 176, Von Klopmann, T., Rambeck, B., Tipold, A. ( 2007 ) Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of Small Animal Practice 48, Weckhuysen, S. & Korff, C. M. ( 2014 ) Epilepsy: old syndromes, new genes. Current Neurology and Neuroscience Reports 14, 447 Weissl, J., Hülsmeyer, V., Brauer, C., et al. ( 2012 ) Disease progression and treatment response of idiopathic epilepsy in Australian Shepherd dogs. Journal of Veterinary Internal Medicine 26, Zabara, J. ( 1992 ) Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33, Journal of Small Animal Practice Vol 57 March British Small Animal Veterinary Association 121