The evidence behind the diagnostic investigation of canine idiopathic epilepsy

Clinical bottom line There remains until recently an overall lack of clarity for the practical criteria for the diagnosis of canine idiopathic epilepsy. Signalment and an interictal neurological examination are vital for the diagnosis of idiopathic epilepsy. Despite the current insufficient evidence, the emerge of new diagnostic methods, such as cerebrospinal fluid and/or serum biomarkers, advanced functional neuroimaging techniques and electroencephalography, is likely to change the diagnostic approach in canine epilepsy in the near future.

Outcome studied: Objective: To investigate whether dogs with seizures have higher cerebrospinal interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) concentrations compared to dogs with no seizures

Main findings: (relevant to PICO question):
Higher TNF-α and IL-6 concentration in the CSF of dogs with naturally occurring seizures were detected.

Limitations:
 Unclear number of dogs with seizures.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases

Sample size: 17 dogs, n=17
Intervention details: Outcome studied: Objective: To investigate differences in cerebrospinal fluid (CSF) concentrations of excitatory and inhibitory neurotransmitters in dogs with idiopathic epilepsy with and without T2-weighted (T2W) MRI hyperintense areas in the limbic system

Main findings: (relevant to PICO question):
 No significant difference was evident between glutamate concentrations in CSF of dogs with idiopathic epilepsy and with and without hyperintense areas detected by means of T2W MRI, but glutamate, though, concentrations typically were higher in CSF of dogs with idiopathic epilepsy and MRI hyperintense areas. Concentrations of GABA in CSF were higher in dogs idiopathic epilepsy with MRI hyperintense areas than in dogs with idiopathic epilepsy and normal MRI and in latter dogs than in healthy dogs.
seizures/year) The majority (85%) of the seizures had a focal onset, and 54% were characterized as generalized secondary.

Limitations:
 Non-blinded, non-randomised and uncontrolled. Insufficient confidence level for diagnosing idiopathic epilepsy for some cases. Potential subjective assessment mainly by owners and secondary by investigators.

Akos (2012)
Population: Dogs with idiopathic (Tier II) and structural epilepsy Sample size: 40 dogs, n=40 Intervention details:  Dogs with structural and idiopathic epilepsy. Propofol was used for chemical restraint in all dogs and electroencephalogram (EEG) was performed Study design: Open-labeled, non-randomised, controlled experimental animal study Outcome studied: Objective: To identify interictal epileptiform discharges via EEG in a group of dogs with seizures of known aetiology and in dogs with idiopathic epilepsy.

Main findings: (relevant to PICO question):
 Interictal EEG examinations of propofol-anaesthetised dogs suffering from idiopathic and structural epilepsy rarely show epileptic discharges. This, the diagnostic value of such EEGs in the work-up for epilepsy seems to be low as epileptic discharges were unlikely to be detected.rocuronium bromide in epileptic dogs.

Main findings: (relevant to PICO question):
 Interictal paroxysmal epileptiform activity was found in 25% of idiopathic and in 29% of symptomatic epileptic dogs. Despite the use of activation techniques, the results showed that short time EEG recordings in epileptic dogs can detect interictal epileptic activity in less than one third of all seizuring dogs. Therefore, it was not a useful diagnostic method when used during the interictal periods of epileptic dogs Limitations: Non-blinded and non-randomised.

Calvo (2012)
Population: Dogs with idiopathic epilepsy (insufficient level of evidence) Outcome studied: Objective: To evaluate C-reactive protein concentration in blood of patients with idiopathic epilepsy and verify if the protein can be considered a biomarker to help its diagnose.

Main findings: (relevant to PICO question):
 Seizures associated with idiopathic epilepsy promote an acute phase response characterized by an increase of blood C reactive protein concentrations within 24 hours, and after this period C reactive protein concentrations declined due to the liberation of inflammatory mediators by the brain and muscle contractions. Therefore blood and C reactive protein concentrations can be used as a biomarker to differentiate idiopathic epilepsy from other seizures causes.

Limitations:
 Non-blinded and non-randomised. The ELISA technique for C reactive protein liquor analysis needs to be validated. Insufficient confidence level for diagnosing idiopathic epilepsy for some cases.

Study design: Epidemiological study-questionnaires
Outcome studied: Objective: To study the clinical and genetic background of epilepsy in Belgian Shepherds.

Main findings: (relevant to PICO question):
Genetic predispose of Belgian Shepherd dogs.

Weber (2012)
Population: Dogs with various neurological disorders, included idiopathic epilepsy (insufficient level of confidence)

Main findings: (relevant to PICO question):
 The median of the CSF-glucose level (mmol/l) and the median of the glucose ratio in the SRMA group displayed the lowest values and differed significantly from the CSF-glucose levels of dogs in the groups IVDD, N, idiopathic epilepsy and healthy dogs (CSF-glucose level: p<0.01; glucose ratio: p<0.05). Therefore, the CSF-glucose level and glucose ratio was not useful for supporting the diagnoses idiopathic epilepsy according to the findings of this study

Limitations:
 Retrospective case series  Subjective assessment  Insufficient confidence level for diagnosing idiopathic epilepsy for some cases.

Sample size: 211 dogs and cats, n=211
Intervention details:  Epileptic seizures in 211 canine and feline patients diagnosed with idiopathic epilepsy were evaluated for temporal significance in relation to the lunar cycle. Seizure counts were compared among each of the eight individual lunar phases, among each of eight exact lunar phase dates, and by percent of lunar illumination using generalized estimating equations.

Study design: Retrospective case series
Outcome studied: Objective: To investigate the potential connection between canine and feline epileptic seizures and the lunar cycle.

Main findings: (relevant to PICO question):
No statistical significance was found in any of these comparisons excluding a relationship between the onset of epileptic seizures and the phases of the moon.

Limitations:
 Only abstract was retrieved. Retrospective case series.

Main findings: (relevant to PICO question):
 Most of these candidate genes were not significantly associated with idiopathic epilepsy in these four dog breeds, while a few genes remained inconclusive. Other genes not included in this study may still be causing monogenic idiopathic epilepsy in these breeds or, like many cases of human idiopathic epilepsy, the disease in dogs may be likewise polygenic

Limitations:
 Only abstract was available. Insufficient confidence level for diagnosing idiopathic epilepsy for some cases

Goncalves (2010)
Population: Dogs with idiopathic epilepsy (Tier I-II) Sample size: 124 dogs, n= 124 Intervention details: 3 investigation groups in comparison Dogs were divided into three groups depending on the time interval between their last seizure and the cerebrospinal fluid (CSF) collection:  up to two days (group 1)  between three and seven days (group 2)  >seven days (group 3).
The dogs were also divided into two groups based on whether or not cluster seizures occurred before CSF collection.

Study design:
Open-labeled, non-randomised experimental animal study.
Outcome studied: Objective: To determine the effect of seizures on CSF composition of dogs with idiopathic epilepsy.Main findings: (relevant to PICO question):  A significant association was observed between the total nucleated cell count (TNCC) and the time interval between the last seizure and the collection of the CSF, the longer the time interval, the lower the TNCC. There was no association observed between time interval and CSF protein concentration; and no association was also found between the current of cluster seizures and either TNCC CSF or protein concentration. It was suggested that alterations in the CSF TNCC can be induced by seizures in dogs.

Limitations:
 Non-blinded and non-randomized  Tier I confidence level for diagnosing idiopathic epilepsy for some cases

Sample size: 359 dogs, n=359
Intervention details: The frequency of surface epithelial cells in 359 canine CSF samples was analyzed for 5 disease groups: central nervous system (CNS) neoplasia, CNS compression, CNS inflammation, idiopathic epilepsy, and miscellaneous diseases.Groups were also combined into those with and without expected meningeal involvement.

Study design: Retrospective case series
Outcome studied: Objective: To identify the frequency of surface epithelial cells in CSF from dogs with neurologic disease was investigated along with the potential association with age, specific type of CNS disease, and CSF total nucleated cell count (TNCC) and protein concentration.

Main findings: (relevant to PICO question):
 Surface epithelial cells were found in idiopathic epilepsy in 8/124 (6.5%)  Significant associations between surface epithelial cell presence in CSF and age, disease type, CSF TNCC, and CSF protein concentration were not found. The presence of surface epithelial cells was not related to a specific disease group or CSF changes in the studied population.Thus, the presence of surface epithelial cells should be interpreted carefully, as it could represent an incidental finding in CSF specimens.

Limitations:
 Retrospective case series.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Main findings: (relevant to PICO question):
 Dogs with Chari malformation and idiopathic epilepsy, prostate cancer, insulinoma, malignant lymphoma, pituitarydependent hyperadrenocorticism, myasthenia gravis and polyarthritis also exhibited high values. Thus, serum GFAP autoantibodies might be non-specific and not of use for diagnosing NME or any of the diseases mentioned (including idiopathic epilepsy)

Limitations:
 Non-blinded  Insufficient confidence level for diagnosing idiopathic epilepsy

Sample size: 365 dogs, n=365
Intervention details: Questionnaires and metabolic screening tests were used.Dogs were also included in a large pedigree, which was subdivided into ten smaller subsets

Study design: Prospective study-epidimiological -pedigree analysis
Outcome studied: Objective: To identify a genetic basis for the condition in Border Terrier dogs.

Main findings: (relevant to PICO question):
 About 70% of the affected dogs showed generalised seizures, and in about 45% of the cases the seizures had a tonic character. About 80% of the animals did not lose consciousness during the seizures. The median age of the Border Terriers included in the study was 3.73 years and the median age at seizure onset was 3.15 years. The inspection of the pedigrees showed that the majority of affected Border Terriers were descended from unaffected

Study design: Retrospective case series
Outcome studied: Objective: To examine the underlying aetiology and to compare idiopathic epilepsy with symptomatic epilepsy concerning signalment, history, ictal pattern, clinical and neurological findings.

Main findings: (relevant to PICO question):
 Status epilepticus, cluster seizures, partial seizures, vocalisation during seizure and impaired neurological status were more readily seen with symptomatic epilepsy. If the first seizure occurred between one and five years of age or the seizures occurred during resting condition, the diagnosis was more likely idiopathic epilepsy than structural epilepsy. No correlation of seizures with oestrus, full moon and stress or excitement could be found. Golden Retrievers and Beagles were the most common reported pure breeds suffering from idiopathic epilepsy.

Smith (2008)
Population: Dogs with seizures and idiopathic epilepsy (Tier II level of confidence)

Sample size: 76 dogs, n=76
Intervention details: In this study the prevalence of clinically significant magnetic resonance imaging (MRI) abnormalities was determined in two groups of interictally normal dogs, those younger than 6 years and those older than 6 years of age

Main findings: (relevant to PICO question):
 Seizures in puppies began at 5 to 9 weeks of age and usually resolved spontaneously by 8 to 13 weeks.Those with the most severe seizures also had signs of neurologic disease between these seizures, including generalized ataxia and hypermetria. There were no abnormalities in routine laboratory screenings of blood, urine, and cerebrospinal fluid.Electromyography, brainstem auditory-evoked potentials, and magnetic resonance imaging revealed no specific and consistent abnormalities. Pedigree analysis suggests an autosomal recessive mode of inheritance. For the cases that had simple or complex focal seizures and cerebellar lesions, it represents a newly recognized epileptic syndrome in dogs Limitations: Non-blinded, uncontrolled study

Licht (2007)
Population: Dogs with idiopathic epilepsy (Tier I level of confidence).

Sample size: 90 dogs, n=90
Intervention details: Researchers contacted owners to determine whether dogs had ever had any seizures and, if so, the nature of any such seizures and any potential underlying causes.
To determine the mode of inheritance, segregation analyses were designed to allow the family to be analyzed as a whole, as opposed to as nuclear families.Competing models of inheritance were compared statistically for their ability to explain the data.total pages: 36 Patterson (2005) Population: Dogs with idiopathic epilepsy (Tier I-II).

Sample size: 119 dogs, n=119
Intervention details: Forty-five dogs with idiopathic epilepsy and 74 siblings and their respective parents were included in the analysis

Study design: Prospective case series study
Outcome studied: Objective: To determine clinical characteristics and mode of inheritance of idiopathic epilepsy in English Springer Spaniels

Main findings: (relevant to PICO question):
 Median age at the onset of seizures was 3 years; however, 9 (20%) dogs were between 5 and 6 years old at the time of the onset of seizures.Twenty-one dogs (47%) had generalized seizures, and 24 (53%) had focal onset seizures  In English Springer Spaniels, idiopathic epilepsy segregated in a manner that is consistent with partially penetrant autosomal recessive inheritance (ie, a single major locus with modifying genes) or polygenic inheritance Limitations: Tier I confidence level for diagnosing idiopathic epilepsy in many cases

Ellenberger (2004)
Population: Dogs with idiopathic epilepsy (insufficient level of confidence). CSF concentrations of GLU and ASP were significantly lower when all dogs with epilepsy were compared with controlgroup dogs

Limitations:
 Non-blinded and non-randomized  Insufficient confidence level for diagnosing idiopathic epilepsy

Rusbridge (2004)
Population: Dogs with secondary syringomyelia and seizures Sample size: 120 dogs, n=120 Intervention details: A worldwide family tree of more than 5,500 CKCSs spanning a maximum of 24 generations wasestablished by obtaining pedigree information from 120 dogs diagnosed with secondary syringomyelia secondary to occipital bone hypoplasia Study design: Retrospective case series-pedigree analysis.
Outcome studied: Objective: To identify the inheritance character of occipital bone hypoplasia (Chiari type I malformation) in CavalierKing Charles Spaniels.

Main findings: (relevant to PICO question):
Idiopathic epilepsy is more frequent in lines originating from wholecolor dogs.Selection for coat color is believed to have influenced the development of both occipital hypoplasia with secondary SM and IE Limitations: Not identified but retrospective case series-pedigree analysis study

Main findings: (relevant to PICO question):
 Idiopathic epilepsy has a polygenic, recessive mode of inheritance in the Bernese mountain dog. A clear predisposition for males was also noted.The majority (62 per cent) of the epileptic dogs had had their first seizures at between one and three years of age

Limitations:
 Only abstract was retrieved. Insufficient confidence level for diagnosing idiopathic epilepsy.

Lengweiler (1999)
Population: Dogs with idiopathic epilepsy (insufficient level of confidence).Intervention details: Seven hundred and ninety-two pedigree certificates from a population of healthy and epileptic dogs from 11 generations were evaluated.Forty-four different families (giving a total of 55 epileptic dogs) were included and analysed

Study design: Pedigree analysis
Outcome studied: Subjective: To investigate genetic aspects of idiopathic epilepsy in Labrador retrievers.

Main findings: (relevant to PICO question):
Results of pedigree analysis and from use of the binomial test support the hypothesis of a polygenic, recessive mode of inheritance in Labrador retrievers Limitations: Insufficient confidence level for diagnosing idiopathic epilepsy

Sample size: 37 dogs, n=37
Intervention details: Interictal electroencephalographic recordings of 37 anaesthetised dogs were statistically analysed.characteristics of the sample population and of the seizures.

Main findings: (relevant to PICO question):
Altered GABA and GLU values in CSF might be indicative of a state of chronic over excitation in the brain of dogs with idiopathic epilepsy

Hall (1996)
Population: Dogs with idiopathic epilepsy(insufficient level of confidence) and healthy animals

Sample size: Unclear
Intervention details: Pedigrees of 15 litters which included animals diagnosed as epileptic ('fitters') were compared with those of 34 contemporary, normal animals

Study design: Prospective case series
Outcome studied: Objective: To investigate a genetic counselling programme for Keeshonds

Main findings: (relevant to PICO question):
The predisposition of Keeshonds (Dutch barge dogs) to idiopathic epilepsy appears to be determined by a single autosomal recessive gene

Limitations:
 Only abstract was retrieved. Insufficient confidence level for diagnosing idiopathic epilepsy.

Sample size: 15 dogs, n=15
Intervention details: Main findings: (relevant to PICO question):  Despite deep anaesthesia, the EEG abnormalities were consistent and extremely important for the confirmation of idiopathic epilepsy in the dog. EEG combined with pedigree analysis may be very helpful in risk assessment of IE in the dog

Limitations:
 Non-blinded and non-randomised  Low study population  Only one breed was included

Sample size: 50 dogs, n=50
Intervention details: Fifty dogs were classified on the basis of antemortem and postmortem test results and history.

Study design: Retrospective case series study
Outcome studied: Objective: To investigate the seizure classification in dogs from a non referral-based population.

Main findings: (relevant to PICO question):
A diagnosis of idiopathic epilepsy was more probable when the dog was between 1 and 5 years of age at the first seizure, when the dog was a large breed (>15 kg), when the seizure occurred between 8 am and midnight, or when the interval between the first and second seizure was long (>4 weeks).
Limitations: Retrospective case series.

Sample size: 14 dogs, n=14
Intervention details: Clinical and clinicopathological description of 14 epileptic dogs.

Study design: Retrospective case series
Outcome studied: Objective: To investigate the clinical and clinicopathological findings as well as response to treatment in epileptic dogs.

Main findings: (relevant to PICO question):
 Between seizures, neurological and funduscopic examinations were normal, and no important biochemical, haematological or cerebrospinal fluid abnormalities were observed  Of 8 dogs treated with phenobarbital, seizures were controlled completely in 6 and partially in 2 Limitations:  Retrospective case series  Low study population  Tier I level of confidence for diagnosing idiopathic epilepsy total pages: 36 Srenk (1994) Population: Dogs with idiopathic epilepsy (insufficient level of confidence).

Sample size: 336 dogs, n=336
Intervention details: Analysis of the pedigrees of 336 Swiss-bred Golden Retrievers over five generations.

Study design: Retrospective case series study
Outcome studied: Objective: To investigate the genetic background for idiopathic epilepsy in Golden Retrievers.

Main findings: (relevant to PICO question):
 Males were particularly at risk. There was evidence of an autosomal multifactorial recessive mode of inheritance

Limitations:
 Retrospective case series  Insufficient confidence level for diagnosing idiopathic epilepsy The level of confidence for diagnosing idiopathic epilepsy (Tier I-III) used in this knowledge summary was based on the international veterinary epilepsy task force (IVETF) consensus statement on the diagnosis of idiopathic epilepsy (De Risio, L. et al. 2015).Any paper that included dogs with idiopathic epilepsy for which diagnostic investigations were below this Tier level of evidence or unclear was considered to provide insufficient level of confidence for diagnosing idiopathic epilepsy.Tier I was listed in the limitations of the papers as this could indicate that a few dogs might have suffered from structured epilepsy and as a result have not responded adequately or at all to the treatment.In addition, the terminology used was based on the IVETF consensus statement on the definition, classification and terminology of seizures in companion animals (Berendt, M. et al. 2015).

Appraisal, application and reflection
Idiopathic epilepsy is a diagnosis of exclusion.The studies included in this summary supportthe fact that a thorough investigation of history and dog's signalment are vital "starting points" for excluding other potential underlying causes of seizures.In all the studies the vast majority of dogs with confirmed or, at least, presumptive idiopathic epilepsy had an age onset less than 6-7 years.Apart from the signalment and history, the cornerstone for diagnosing idiopathic epilepsy is a normal interictal neurological examination.Prior to the neurological examination, though, a general clinical examination should be performed to detect possible signs that could be related to or even be confused with seizures.In all the studies the dogs with confirmed or presumptive idiopathic epilepsy had normal inter-ictal neurological status (only a few dogs had neurological signs but these were considered as postictal).Indeed, Armasu et al. (2007) reported that there are further risk factors, besides signalment, that increase or decrease the risk of intracranial pathology or provide one with a diagnosis of idiopathic epilepsy.Precisely, the seizure severity (e.g.cluster seizures) and abnormal neurological examination findings (which was considered one of the most important) were highly associated withstructural epilepsy.The same authors reported that 84% of dogs with idiopathic epilepsy had a normal neurological examination.

Limitation of the summary:
The main limitation of this summary is that we could not obtain full access to a few papers included in the summary of evidence.

de la Fuente ( 2012 Population:
Dogs with various neurological disorders, included idiopathic epilepsy (Tier I and insufficient level of confidence) Limitations:  Non-blinded and non-randomised. Tier I and insufficient confidence level for diagnosing idiopathic epilepsy for some cases Seppälä (2012) Population: Dogs with idiopathic epilepsy (Tier III) Sample size: 307 dogs, n= 307 Intervention details: Investigators collected 159 cases and 148 controls and confirmed the presence of idiopathic epilepsy through epilepsy questionnaires and clinical examinations via advance imaging (MRI) and electroencephalograms(EEGs).
parents.Matings among two unaffected animals or affected and unaffected animals resulted always in affected and unaffected offspringLimitations: Tier I confidence level for diagnosing idiopathic epilepsy  Risk of subjective assessmentPákozdy (2008)Population: Dogs with idiopathic (Tier II level of confidence) and structural epilepsy Sample size: 240 dogs, n=240Intervention details: Data search was performed.Seizure aetiologies were classified as idiopathic epilepsy (n = 115) and structural epilepsy (n = 125).


Non-blinded and non-randomized. Insufficient confidence level for diagnosing idiopathic epilepsy Oberbauer (2003) Population: Dogs with idiopathic epilepsy (insufficient level of confidence) Sample size: Unclear Intervention details: Genomic DNA from families of affected tervuren and sheepdogs was screened with 100widely dispersed, polymorphic canine microsatellite markers Study design: Unclear Outcome studied: Objective: To investigate the genetics of epilepsy in the Belgian tervuren and sheepdog Main findings: (relevant to PICO question): Although not significant (LOD scores <3.0), three genomic regions have shown nominal linkage between markers and the epileptic phenotype Limitations:  Only abstract was retrieved  Insufficient confidence level for diagnosing idiopathic epilepsy Patterson (2003) Population: Dogs with idiopathic epilepsy (Tier I-II) Sample size: 11 dogs, n=11 Intervention details: Medical record, seizure survey, and telephone interview information was obtained for 29 Vizslas with idiopathic epilepsy (IE), 74 unaffected siblings, and 41 parents to determine the common clinical characteristics and most likely mode of inheritance.Study design: Retrospective case series.Questionnaire.Survey Outcome studied: Objective: To identify clinical characteristics and inheritance of idiopathic epilepsy in Vizslas Main findings: (relevant to PICO question): Idiopathic epilepsy in Vizslas appears to be primarily a partial onset seizure disorder that may be inherited as an autosomal recessive trait Limitations: Overall high risk of bias related to the study design.Tier I confidence level for diagnosing idiopathic epilepsy in some cases Morita (2002) Population: Dogs with idiopathic epilepsy (Tier II) Sample size: 11 dogs, n=11

p a g e | 14 total pages: 36
Blood serum samples were randomly collected from 310 dogs  The dogs were divided into three groups: NME cases (group 1), non-NME CNS disease cases (group 2) and non-CNS disease cases (group 3)  Twenty-six (26) serum samples from clinically healthy dogs were also included for comparison (control group) DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 15 total pages: 36 epilepsy (insufficient level of confidence).Sample size: 310 dogs, n=310Intervention details: 

36 Main findings: (relevant to PICO question):
A low likelihood of revealing an underlying lesion by MRI, in seizuring dogs <6 years of age with an unremarkable interictal neurological examination was found Limitations: Non-blinded and non-randomised Study design: Open-labeled, non-randomised controlled clinical study Outcome studied: Objective: To determine the prevalence of positive MR findings in dogs with no evidence of forebrain dysfunction on interictal neurological examination and to determine whether it is affected by patient age Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 17 total pages: Study design: Uncontrolled experimental animal study-prospective case series study Outcome studied: Objective: To identify idiopathic juvenile epilepsies with benign outcomes in Lagotto Romagnolo dogs.

Main findings: (relevant to PICO question):
Prospective case series study Dogs with seizures in general and idiopathic epilepsy (Tier II level of confidence).
Limitations: Tier I confidence level for diagnosing idiopathic epilepsy  Part of the assessment of the study was subjectiveCasal (2006)Population: Dogs with idiopathic epilepsy (insufficient level of confidence).Sample size: 796 dogs, n=796 Intervention details: Clinical data and pedigrees from closely related Irish Wolfhounds were collected retrospectively and analysed Study design: Retrospective case series study.Pedigree analysis Outcome studied: Objective: The aim of this study was to identify inheritance characteristics in Irish Wolfhounds. Insufficient confidence level for diagnosing idiopathic epilepsy Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 19 total pages: 36 Pákozdy (2006) Population: Population: Dogs with seizures Sample size: 14 dogs, n=14 Intervention details: 1 investigation group, 1 control group  Investigation group: Finnish Spitz dogs with focal seizures n=11  Control group: Healthy dogs.n=3 Study design: Open-labelled, non-randomized controlled experimental animal study Outcome studied: Objective: To investigate the magnetic resonance imaging findings in Finnish spitz dogs with focal epilepsy Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 20 2 Investigation groups, 1 Control group.
Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 22 total pages: 36 Questionnaire survey of the owners of 25 Golden Retrievers in Switzerland [date not given], in which data were obtained on signs, clinical history, feeding and housing Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 24 total pages: 36 Intervention details: Population: Dogs with idiopathic epilepsy (Tier II) Sample size: Unclear Intervention details: Inter-ictal electroencephalograms (EEGs) were performed in sedated epileptic dogs Study design: Open-labeled, non-randomised, uncontrolled experimental animal study Outcome studied: Objective: To investigate interictal paroxysmal discharges in the EEG of epileptic dogs Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | 25 total pages: 36 Fredsø, N. et al. (2014)d that 89% of dogs with idiopathic epilepsy had an age of seizure onset <6 years.Similarly,Smith et al. (2008)reported that only 2.2% of dogs <6 years old with unremarkable inter-ictal neurological examination had significant lesion (identifiable on MRI), compared to 26.7% of dogs >6 years old.Pákozdy et al. (2008)provided a more limited scale for the age of seizures onset (<5 years).Podell et al. (1995)reported that the diagnosis of idiopathic epilepsy was more probable when the dog experienced the first seizure(s) between 1 and 5 years of age and was a large breed (>15 kg).Viitmaaet al. (2013), Kloene et al. (2008), Casal et al. (2006) and Patterson et al. (2005) found that the median age of seizure onset in their study population was 3 years.De Risio et al. (2015) combined and analyzed the data from Pákozdy et al. (2008) and Armaşu et al. (2014) and found that there was a significant association between age of onset and cause of epilepsy for dogs under 6 years of age at epileptic seizure onset (Chi-squared = 5.136, n = 431, p = 0.023) when the cut-off was set at 6 months.Dogs aged between 6 months and 6 years were significantly more likely to be affected by idiopathic than structural epilepsy in comparison to the dogs aged beyond this range.Various breeds have been considered to be prone to idiopathic epilepsy.Multiple genes and recessive modes of inheritance have been investigated.Seppäläet al. (2012), Ekenstedt, K. et al. (2011), Kloene, J. et al. (2008), Pákozdy et al. (2008), Licht et al. (2007), Casal, M. et al. (2006), Patterson et al. (2005), Patterson et al. (2003), Kathmann et al. (1999), Jaggy et al. (1998a) and Hall et al. (1996) reported various breeds.Also, the consensus statement byHülsmeyer et al. (2015), reviewed all the current evidence available for breeds that have been identified as being predisposed to idiopathic epilepsy with a proven or suspected genetic background.Specifically, breeds include German shepherds, Australian Shepherds, Belgian Shepherds, Bernese mountain dogs, Beagles, Border Collies, Border Terriers, Cavalier King Charles Spaniels, Dachshunds, Dalmatians, English Springer Spaniels, Finnish Spitz, Golden Retrievers, Hungarian Vizslas, Lagotto Romagnolo, Labrador Retrievers, Irish Wolfhounds, Italian Spinone, Petit Basset Griffon Vendeen, Shetland Sheepdogs, Standard Poodles and Keeshonds.Jokinen et al. (2007)reported juvenile epilepsy in Lagotto Romagnolo with mainly focal seizures and seizure onset of5 to 9 weeks.Rusbridge et al. (2004)reported that idiopathic epilepsy in Cavalier King Charles spaniels is more frequent in lines originating from whole-colour dogs.The latter characteristic was also considered to influence the development of occipital hypoplasia.Distribution of epilepsy has been considered to be affected by Most reports suggest males have an increased likelihood to develop seizures compared to females.Viitmaa et al. (2013),Jaggy and Bernadini  (2008),Pákozdy et al. (2008)andCasal et al. (2006)found that males were predisposed to idiopathic epilepsy.Fredsø, N. et al. (2014)reported that neutered male dogs with idiopathic epilepsy had a significant shorter survival (median: 38.5 months) compared to intact male dogs (median: 71 months).Van Meervenne et al. (2014) also reported and that there was an over-representation of male dogs with idiopathic epilepsy but no conclusions could be drawn as far as the effect of sterilisation status in seizures is concerned.In a retrospective case series study byVanMeervenne et al. (2014), it was suggested an association between oestrus and seizures onset in intact female dogs with presumptive idiopathic epilepsy.However, Pákozdy et al. (2008) found no correlation of seizures with oestrus as well as stress or excitement.In addition, the relation between lunar cycle and seizures has been investigated by Browand-Stainback et al. (2011) and Pákozdy et al. (2008) who showed no relationship between the two.

30 total pages: 36 profile
Brauer et al. (2012)))Pákozdy et al. (2008)also supported that unremarkable inter-ictal neurological findings in combination with the age of seizure onset are important factors for diagnosing idiopathic epilepsy.Specifically,Pákozdy et al. (2008)reported that status epilepticus, cluster seizures, partial seizures, vocalisation during seizure and impaired neurological status were more readily seen with structural epilepsy.Ghormie et al. (2015)found that in 99 dogs ≥ 5 years of age at seizure onset, an abnormal neurologic examination had 74 % sensitivity and 62 % specificity to predict structural epilepsy.Armaşu et al. (2014)found that dogs with neurological abnormalities interictally were 16.5 and 12.5 times more likely to have an asymmetrical structural cerebral lesion and a symmetrical structural cerebral lesion, respectively, rather than idiopathic epilepsy.andurinalysisaswellascerebrospinalfluid(CSF)analysiscanbeconsideredanimportantpart in the diagnostic investigation of idiopathic epilepsy.De Risio et al.(2015)suggested that clinicians should perform brain MRI and CSF analysis, after exclusion of reactive seizures, in dogs with age at epileptic seizure onset <6 months or >6 years, inter-ictal neurological abnormalities as a result of intracranial lesion, status epilepticus or cluster seizure at epileptic seizure onset, or a previous presumptive diagnosis of IE and in refractory cases.The findings from these results are expected to be unremarkable and non-indicative of any known underlying cause of seizures.In the plasma and CSF, in particular, various studies have been performed to reveal potential biomarkers that would help to identify epilepsy in dogs, either in earlier or later stages of the disease.Bartels et al. (2014)showed that chemokines (e.g.CCL19) were increased in dogs with idiopathic epileptic compared to healthy individuals; but compared to dogs with other neuro-inflammatory diseases, chemokines were markedly decreased.Hasegawa et al. (2014)showed that metabolites including glutamic acid and ascorbic acid in CSF might be useful for the diagnosis of canine epilepsy.Merblet al. (2014) found higher CSF concetrations of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in dogs with naturally occurring seizures compared to a control group of healthy dogs.Wessmann et al. (2010) found epithelial cells in 6.5% of dogs of the study population affected by idiopathic epilepsy, although it was considered as a non-specific incidental finding.Goncalves et al. (2010) reported that seizures could initially result in a mild increase oftotal nucleated cell count; thus, this fact should be considered when taking CSF straight after a seizure (false positive elevation).Podell, M. et al. (1997) reported that altered gamma-aminobutyric acid and glutamate values in CSF might be indicative of a state of chronic overexcitation in the brain of dogs with idiopathic epilepsy.Similarly, Ellenberger et al. (2004), reported that CSF concentrations of gamma-aminobutyric acid and glutamate were significantly lower in Labrador Retrievers with genetic epilepsy compared to control group dogs or in non-Labrador Retrievers with idiopathic epilepsy; the same study showed that CSF concentration of aspartate was significantly lower in all the epileptic dogs.Creevy et al. (2013)andGesell et al. (2013)found that glutamate and endocannabinoids anandamide (AEA) concentrations, respectively, were higher in CSF of dogs with idiopathic epilepsy compared to a control group of healthy dogs.Calvo (2012) measured the C-reactive protein in the blood of dogs with idiopathic epilepsy and, contrary to dogs suffering from other causes of seizures as well as healthy dogs, detected increased concentrations within 24 hours but a decline after that period.Further CSF and/or plasma indicators that were investigated failed to contribute towards the diagnosis of idiopathic epilepsy.Specifically, Weber et al. (2012), Fuente et al. (2012), Fujiwara et al. (2008) and Lobert, V. et al.(2003)showed that CSF glucose level/glucose ratio, D-dimers, glial fibrillary acidic protein autoantibodies and pyruvate/lactate levels respectively were not useful for supporting the diagnoses of idiopathic epilepsy.In all, based on these results, researchers succeeded or failed to establish certain plasma and/or CSF biomarkers associated with seizures in epileptic dogs.However, there is still research that could be performed in the future, either for the above or new biomarkers for epilepsy.Electroencephalogram (EEG) is regularly used as one of the diagnostic procedures in humans and its utility in dogs has been assessed in a few studies.Jaggy et al. (1998b)andSrenk et al. (1996)reported that, despite anaesthesia, interictal EEG features were consistent and unique in dogs with idiopathic epilepsy.Holliday and Williams (1998) reported that interictal EEG might be useful diagnostic technique in dogs with idiopathic epilepsy.Viitmaa et al. (2014)supported the use of fluoro-d-glucose positron emission tomography (FDG-PET) and to less extend, EEG in epileptic dogs as diagnostic tool.However,Akos et al. (2012)revealed that interictal EEG rarely showed epileptic discharges and therefore the diagnostic value of the EEG in the diagnosis of epilepsy appeared to be low.Brauer et al. (2012)found that interictal EEG was not a useful diagnostic method because it could detect epileptic activity in less than one third of all seizuring dogs (including symptomatic Magnetic resonance imaging (MRI) of the brain, clinicopathological tests, i.e. haematological, biochemistry Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e | Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e |

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Matiasek et al. (2015))on.All in all, there are quite a few challenges of using EEG routinely in animals and further work need to be performed.In conclusion, diagnosis should be based on history, signalment (age of onset (>6months and <6years), breed, sex), normal interictal neurological examination, seizure type, unremarkable complete blood count, biochemistry profile and urinalysis in the first instance.This can be supported by excluding structural lesions with advanced brain imaging techniques (i.e.MRI) and an unremarkable CSF analysis and cytology.EEG for identification of the characteristic patterns of epileptic seizures is highly recommended as a confirmation of the diagnosis.Based on the recent consensus statement by De Risio et al.(2015), all these diagnostic features and tests were categorized based on their value in criteria for the diagnosis of idiopathic epilepsy are described in a three-tier system.Precisely, Tier I is based on signalment, history, general and neurological examination as well as minimum data base blood tests and urinalysis.Tier II is based on tier I, plus unremarkable fasting plus post-prandial bile acids as well as brain MRI and CSF analysis.Tier III is based on tier I and II, plus identification of electroencephalographic abnormalities characteristic for seizure disorders.Implications for the future: Advance diagnostic procedures, such as MRI and EEG willbecome more widely available in order to improve the quality of diagnosis of canine epilepsy.Recently, the consensus statements byRusbridge et al. (2015)andMatiasek et al. (2015)recommended specific MRI and diagnostic pathology protocol, respectively, for investigating idiopathic epilepsy.Lastly, further studies with a high quality design (i.e.blinded randomised controlled studies), low overall risk of bias and greater number of dogs investigating established or new diagnostic methods (e.g.CSF or serum biomarkers) for idiopathic epilepsy are needed because the current evidence in veterinary medicine is relatively weak.

32 total pages: 36 Exclusion / Inclusion Criteria Exclusion
Strategy PubMed and CAB Abstracts 1973 to 2015 combined search on OVID platform Search terms: (dog or dogs or puppy or puppies or canis or canine) AND (idiopath*) AND (epilep* or seizur* or convuls*) AND (diagnos* or identif* or assess* or test* or exam* or history or compaint* or symptom* or risk* or aetiolog* or etiolog*) : Summary updates, Non-systematic reviews* Inclusion: Studies evaluating or reporting the diagnosis of canine idiopathic epilepsy *There was a non-systematic review Van Meervenne, et al. (2014a) that was included because it made important conclusions and valuable up-to-date points for our summary.This paper was not included in the table but in the text.The same applies for the IVETF consensus statements by Berendt et al. (2015), De Risio et al. (2015), Hülsmeyer et al. (2015), Matiasek et al. (2015) and Rusbridge et al. (2015) Veterinary Evidence ISSN: 2396-9776 Vol 1, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v1i1..8 next review date: 23 Nov 2017 p a g e |