The evidence behind the diagnostic investigation of canine idiopathic epilepsy
a Knowledge Summary by
Marios Charalambous DVM GPCert(Neuro) RSci MRSB MRCVS 1 *
1University College London
2Royal Veterinary College
*Corresponding Author (marios.charalambous.15@ucl.ac.uk)
Vol 1, Issue 1 (2016)
Published: 9 Feb 2016
Next Review date: 23 Nov 2017
DOI: 10.18849/VE.V1I1.8
Question
In dogs, are biomarker and advanced imaging methods superior to signalment and an interictal neurological examination for the diagnosis of epilepsy?
Clinical scenario
A 5 years old 17 kg German Shepherd intact male dog manifested generalized tonic-clonic seizures one year ago. In the last two months the dog manifested five episodes. The dog is normal between the episodes, idiopathic epilepsy is suspected. You wonder what the best diagnostic investigation to confirm the presumed idiopathic epilepsy would be.
Summary of the evidence
Population: | Dogs with idiopathic (Tier II) and structural epilepsy. |
Sample size: | 99 dogs, n=99 |
Intervention details: | Dogs ≥ 5 years of age with a diagnosis of idiopathic or structural epilepsy were retrieved from medical files. Classification of dogs based on age was performed. The prevalence of idiopathic and structural epilepsy and the proportion of subjects with secondary epilepsy due to neoplasia and other disorder was assessed. The sensitivity and specificity of abnormal neurological signs in cases with structural epilepsy were also evaluated |
Study design: | Retrospective case series |
Outcome Studied: | Objective: To classify the origin of epilepsy and assess the neurological defects during clinical examination as a predictor of structural epilepsy in dogs ≥ 5 years of age |
Main Findings (relevant to PICO question): |
It was shown that lack of deficits on neurologic examination does not exclude the possibility of intracranial lesions. Neurologic deficits found during clinical examination had 74 % sensitivity and 62 % specificity to predict structural epilepsy. |
Limitations: | Retrospective case series. |
Population: | Dogs with idiopathic epilepsy (Tier I confidence level). |
Sample size: | 45 dogs (intact females only), n=45 |
Intervention details: | Medical records of intact female dogs diagnosed with epilepsy. The stage of the estrous cycle as reported either by the owner or the veterinarian at the time of the first seizure was noted. Unclear diagnostic procedures for idiopathic epilepsy. |
Study design: | Retrospective case series. |
Outcome Studied: | Objective: To evaluate whether there is an association between onset of seizures and the estrous cycle in intact bitches with idiopathic epilepsy and whether a pattern to the onset of seizures could be recognized. |
Main Findings (relevant to PICO question): |
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Limitations: | Retrospective case series.Tier I confidence level for diagnosing idiopathic epilepsy for some cases. |
Population: | Dogs with idiopathic (Tier II) and structural epilepsy. |
Sample size: | 258 dogs, n=258 |
Intervention details: | Data including age, sex, neuter status, time until diagnosis, age of seizure onset in years, type of seizure, seizure symmetry, seizure severity, interictal neurological deficits, MRI changes and side effects associated with antiepileptic drugs were extracted from medical files |
Study design: | Retrospective case series. |
Outcome Studied: | Objective: To assess the influence of the aforementioned factors, such as age, sex, interictal neuro exam, seizure type etc. on the likelihood of structural or functional brain disease, via a thorough history taking process and interictal neurological examination. |
Main Findings (relevant to PICO question): |
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Limitations: | Retrospective case series study. However, multinomial statistics were used which were good in filtering out the non-significant. |
Population: | Dogs with SRMA, MUO, IVDD, idiopathic epilepsy (Tier I) and healthy dogs. |
Sample size: | 141 dogs, n=141 |
Intervention details: | 3 investigation groups, 1 Control group. 1 group with healthy dogs
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Study design: | Open-labeled, non-randomised,controlledexperimental animal study. |
Outcome Studied: | Objective: Chemokines such as MIP-3β/CCL19 are important factors in the mechanism of cell migration and pathogenesis of central nervous system (CNS) inflammatory reactions. The hypothesis of this study is that CCL19, also known as MIP-3β, is involved in the pathogenesis of inflammatory and non-inflammatory CNS diseases of dogs. |
Main Findings (relevant to PICO question): |
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Limitations: | Non-blinded and non-randomised. Tier I confidence level for diagnosing idiopathic epilepsy for some cases.Since only a small number of neurologically normal dogs were available for evaluation, further studies with a larger cohort of dogs focusing on idiopathic epilepsy in comparison to healthy dogs are indicated before definite recommendations. |
Population: | Dogs with idiopathic (Tier I or insufficient level of confidence) and structural epilepsy |
Sample size: | 102 dogs, n=102 |
Intervention details: |
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Study design: | Retrospective case series, questionnaire. |
Outcome Studied: | Objective: To investigate risk factors for survival and duration of survival in a population of dogs with idiopathic or structural epilepsy. |
Main Findings (relevant to PICO question): |
Neutered male dogs with idiopathic epilepsy had a significant shorter survival (median: 38.5 months) compared to intact male dogs (median: 71 months). |
Limitations: | Retrospective case series. Tier I or insufficient or confidence level for diagnosing idiopathic epilepsy. |
Population: | Dogs with idiopathic (insufficient level of confidence) and structural epilepsy and healthy dogs |
Sample size: | N/A |
Intervention details: |
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Study design: | Open-labeled, non-randomised, controlled experimental animal study. |
Outcome Studied: | Objective: To explore canine epilepsy diagnostic biomarkers in the cerebrospinal fluid (CSF). |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (Tier I level of confidence) and healthy dogs. |
Sample size: | Unclear number of dogs with seizures. Number of healthy dogs was 12. |
Intervention details: |
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Study design: | Blinded, randomized, controlled experimental animal study. |
Outcome Studied: | Objective: To investigate whether dogs with seizures have higher cerebrospinal interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) 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. r |
Population: | Dogs with idiopathic epilepsy (Tier III). |
Sample size: | 17 dogs, n=17 |
Intervention details: |
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Study design: | Blinded, non-randomised controlled experimental animal study. |
Outcome Studied: | Objective: In human epileptic patients, changes in cerebral glucose utilization can be detected 2-deoxy-2-[18F] fluoro-d-glucose positron emission tomography (FDG-PET). The purpose of this prospective study was to determine whether epileptic dogs might show similar findings. Electroencephalography (EEG) was also performed. |
Main Findings (relevant to PICO question): |
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Limitations: | Non-randomised Low number of dogs.Breed specific changes found might not be applicable for other breeds.The test was not evaluated in dogs with generalized seizures. |
Population: | Dogs with idiopathic epilepsy (Tier II) |
Sample size: | 17 dogs, n=17 |
Intervention details: |
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Study design: | Open-labelled, non-randomised, controlled experimentalanimal study |
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): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (Tier II). |
Sample size: | 56 dogs, n=56 |
Intervention details: |
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Study design: | Retrospective case series |
Outcome Studied: | Objective: The hypothesis was that cerebrospinal fluid (CSF) concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2AG) are altered in epileptic dogs. Concentrations of AEA and total AG (sum of 2AG and 1AG) were measured in dogs with idiopathic epilepsy and healthy control dogs using liquid chromatography combined with tandem mass spectrometry. |
Main Findings (relevant to PICO question): |
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Limitations: | Retrospective case series |
Population: | Dogs with idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 2069 dogs, n=2069 |
Intervention details: | From 2003 to 2004, questionnaires (n=5,960) were sent to all owners of 1- to 10-year-old Finnish Spitz dogs (FSDs) in Finland. Phone interviews were performed 1 to 2 years later. |
Study design: | Prospective epidemiological study-questionnaires |
Outcome Studied: | Objective: To determine the phenotype, inheritance characteristics, and risk factors for idiopathic epilepsy in FSDs. |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic (Tier II) and structural epilepsy. |
Sample size: | 40 dogs, n=40 |
Intervention details: |
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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): |
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Limitations: | Non-blinded and non-randomised |
Population: | Dogs with idiopathic (Tier III) and structural epilepsy |
Sample size: | 89 dogs, n=89 |
Intervention details: |
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Study design: | Open-labeled, non-randomised, controlled experimental animal study |
Outcome Studied: | Objective: To investigate the diagnostic value of interictal short time electroencephalographic (EEG) recordings in epileptic dogs under general anaesthesia with propofol and the muscle relaxant rocuronium bromide in epileptic dogs. |
Main Findings (relevant to PICO question): |
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Limitations: | Non-blinded and non-randomised |
Population: | Dogs with idiopathic epilepsy |
Sample size: | 56 dogs, n=56 |
Intervention details: |
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Study design: | Open-labeled, non-randomised, controlled experimental animal study |
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): |
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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. |
Population: | Dogs with various neurological disorders, included idiopathic epilepsy (Tier I and insufficient level of confidence) |
Sample size: | 169 dogs, n=169 |
Intervention details: |
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Study design: | Prospective observational study |
Outcome Studied: | Objective: To investigate fibrinolytic activity in the CSF of dogs with neurological disorders by measuring cerebrospinal fluid (CSF) D-dimer concentration. |
Main Findings (relevant to PICO question): |
All dogs with idiopathic epilepsy as well as dogs with systematic non-neurological inflammatory diseases and controls had undetectable concentrations of D-dimers in the CSF. |
Limitations: |
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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 throughepilepsy questionnaires and clinical examinations via advance imaging (MRI) and electroencephalograms(EEGs) |
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 |
Limitations: | Non-blinded and non-randomised |
Population: | Dogs with various neurological disorders, included idiopathic epilepsy (insufficient level of confidence) |
Sample size: | 328 dogs, n=328 |
Intervention details: | The dogs were assigned to seven different groups:
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Study design: | Retrospective case series study |
Outcome Studied: | Objective: To evaluate the glucose ratio (glucose level in the cerebrospinal fluid [CSF]/blood glucose level) as a quickly available marker for detecting bacterialmeningoencephalomyelitis and compared to other diseases |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (insufficient level of confidence) |
Sample size: | 211 dogs and cats, n=211 |
Intervention details: |
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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: |
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Population: | Dogs with idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 34 dogs, n=34 |
Intervention details: |
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Study design: | Experimental study/genetic analysis |
Outcome Studied: | Objective: To investigate if there are simple genetic bases for IE in some purebred dog breeds, specifically in Vizslas, English Springer Spaniels (ESS), Greater Swiss Mountain Dogs (GSMD), and Beagles, and that the gene(s) responsible may, in some cases, be the same as those already discovered in humans |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (Tier I-II) |
Sample size: | 124 dogs, n=124 |
Intervention details: |
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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): |
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Limitations: |
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Population: | Dogs with various neurological conditions, included idiopathic epilepsy (Tier I-II). |
Sample size: | 359 dogs, n=359 |
Intervention details: |
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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 thepotential association with age, specific type of CNS disease, and CSF totalnucleated cell count (TNCC) and protein concentration. |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with various neurological disorders, including idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 310 dogs, n=310 |
Intervention details: |
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Study design: | Open-labeled, randomised controlled experimental animal study |
Outcome Studied: | Objective: To determine whether serum autoantibodies against glial fibrillary acidic protein (GFAP) can be used for diagnosing canine necrotizing meningoencephalitis (NME) and secondarily, other diseases. |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (Tier I) |
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): |
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Limitations: |
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Population: | Dogs with idiopathic (Tier II level of confidence) and structural epilepsy |
Sample size: | 240 dogs, n=240 |
Intervention details: | Data search was performed. Seizure aetiologies were classified as idiopathic epilepsy (n = 115) and structural epilepsy (n = 125). |
Study design: | Retrospective case seriesr |
Outcome Studied: | Objective: To examine the underlying aetiology and to compareidiopathic epilepsy with symptomatic epilepsy concerningsignalment, history, ictal pattern, clinical and neurological findings |
Main Findings (relevant to PICO question): |
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Limitations: | Retrospective case series |
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 determinedin two groups of interictally normal dogs, those younger than 6 years and those older than 6 years of age |
Study design: | Open-labeled, non-randomised controlled clinical study |
Outcome Studied: | Objective: To determine the prevalence of positive MR findingsin dogs with no evidence of forebrain dysfunction on interictal neurological examination and to determine whether it isaffected by patient age |
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 |
Population: | Dogs with seizures and idiopathic epilepsy (Tier II). |
Sample size: | 25 dogs, n=25 |
Intervention details: |
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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): |
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Limitations: | Non-blinded, uncontrolled study |
Population: | Dogs with idiopathic epilepsy (Tier I level of confidence). |
Sample size: | 90 dogs, n=90 |
Intervention details: |
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Study design: | Prospective case series study. |
Outcome Studied: | Objective: To determine clinical characteristics and mode of inheritance of seizures in a family of Standard Poodles. |
Main Findings (relevant to PICO question): |
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Limitations: |
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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 |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with seizures in general and idiopathic epilepsy (Tier II level of confidence). |
Sample size: | 13 dogs, n=13 |
Intervention details: | All boxers with seizures within the last 7 years were included in this retrospective study |
Study design: | Retrospective case series study |
Outcome Studied: | Objective: The aim of this study was to evaluate the aetiology of seizures in Boxers of our patient-index and to compare it with literature data |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with seizures |
Sample size: | 14 dogs, n=14 |
Intervention details: | 1 investigation group, 1 control group
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Study design: | Open-labelled, non-randomized controlled experimentalanimal study |
Outcome Studied: | Objective: To investigate the magnetic resonance imaging findings in Finnish spitz dogs with focal epilepsy |
Main Findings (relevant to PICO question): |
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Limitations: |
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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): |
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Limitations: | Tier I confidence level for diagnosing idiopathic epilepsy in many cases |
Population: | Dogs with idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 149 dogs, n=149 |
Intervention details: |
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Study design: | Open-labelled, non-randomized, controlled experimental animal study |
Outcome Studied: | Objective: To determine concentrations of excitatory and inhibitory amino acids in CSF of a large number of dogs with idiopathic epilepsy and to evaluate changes in CSF amino acid concentration with regard to drug treatment and sex |
Main Findings (relevant to PICO question): |
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Limitations: |
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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 Cavalier King Charles Spaniels |
Main Findings (relevant to PICO question): |
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 |
Limitations: | Not identified but retrospective case series-pedigree analysis study |
Population: | Dogs with various neurological disorders, including idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 130 dogs, n=130 |
Intervention details: | 2 Investigation groups, 1 Control group.
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Study design: | Open-labeled, non-randomised, controlled experimental animal study |
Outcome Studied: | Objective: To determine reference values for pyruvate, lactate and the pyruvate/lactate ratio in the blood and cerebrospinal fluid |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (insufficient level of confidence) |
Sample size: | |
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 haveshown nominal linkage between markers and the epileptic phenotype |
Limitations: |
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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: |
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Population: | Dogs with idiopathic epilepsy (Tier II). |
Sample size: | 11 dogs, n=11 |
Intervention details: |
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Study design: | Open-labeled, non-randomised, uncontrolled experimental animal study |
Outcome Studied: | Objective: To investigate the clinicopathologic findings of familial frontal lobe epilepsy in Shetland sheepdogs |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (insufficient confidence level |
Sample size: | 50 dogs, n=50 |
Intervention details: | Pedigree analysis was carried out on an open, non-preselected population of 4005 dogs. Five different subpopulations with 50 epileptic dogs from 13 generations were included |
Study design: | Pedigree Analysis |
Outcome Studied: | Objective: To investigate clinical and genetic icharacteristics of idiopathic epilepsy in the Bernesemountain dog |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (insufficient level of confidence). |
Sample size: | 25 dogs, n=25 |
Intervention details: | 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 |
Study design: | Questionnaire. Survey |
Outcome Studied: | Subjective: To investigate clinical, epidemiological and treatment aspects of idiopathic epilepsy in 25 Golden Retrievers |
Main Findings (relevant to PICO question): |
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Limitations: |
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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 |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with idiopathic epilepsy (insufficient confidence level). |
Sample size: | 792 dogs, n=792 |
Intervention details: |
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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 |
Population: | Dogs with idiopathic epilepsy (Tier II) |
Sample size: | 37 dogs, n=37 |
Intervention details: | Interictal electroencephalographic recordings of 37 anaesthetised dogs were statistically analysed |
Study design: | Retrospective case series study |
Outcome Studied: | Subjective: To investigate the clinical andelectroencephalographic findings in dogs. |
Main Findings (relevant to PICO question): |
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Limitations: | Retrospective case series |
Population: | Dogs with idiopathic epilepsy (insufficient confidence level). |
Sample size: | 29 dogs, n=29 |
Intervention details: |
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Study design: | Open-labeled, non-randomised, controlled, experimental trial |
Outcome Studied: | Objectives: To investigate changes in CSF concentrations of inhibitory and excitatory neurotransmitters in dogs with confirmed idiopathic epilepsy, and to evaluate them with regard to the clinical characteristics of the samplepopulation and of the seizures |
Main Findings (relevant to PICO question): |
Altered GABA and GLU values in CSF might be indicative of a state ofchronic overexcitation in the brain of dogs with idiopathic epilepsy |
Limitations: |
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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: |
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Population: | Dogs with idiopathic epilepsy (Tier II), exercise induced weakness and healthy dogs |
Sample size: | 15 dogs, n=15 |
Intervention details: |
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Study design: | Open-labeled, non-randomised, controlled experimental animal study |
Outcome Studied: | Objective: To investigate interictal electroencephalographic findings in a family of Golden Retrievers with idiopathic epilepsy |
Main Findings (relevant to PICO question): |
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Limitations: |
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Population: | Dogs with seizures |
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 nonreferral-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. |
Population: | Dogs with idiopathic epilepsy (Tier I level of confidence). |
Sample size: | 14 dogs, n=14 |
Intervention details: | |
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): |
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Limitations: |
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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: |
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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. Armaşu et al. (2014) found 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). Viitmaa et 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. Seppälä et 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 by Hülsmeyer 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 gender. 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) and Casal 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 by Van Meervenne 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.
Apart from the signalment and history, the cornerstone for diagnosing idiopathic epilepsy is a normal inter-ictal 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. Smith et al. (2008) and 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.
Magnetic resonance imaging (MRI) of the brain, clinicopathological tests, i.e. haematological, biochemistry profile and urinalysis as well as cerebrospinal fluid (CSF) analysis can be considered an important part 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. Merbl et 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) and Gesell 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) and Srenk 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 epilepsy) of the study population. 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 by Rusbridge et al. (2015) and Matiasek 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.
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. These included: Hasegawa, T. et al. (2014), Browand-Stainback, L. et al. (2011), Ekenstedt, K. et al. (2011), Oberbauer, A. et al. (2003), Kathmann, I. et al. (1999), Holliday, T. and Williams, D. (1998) and Hall, S. et al. (1996)
Methodology Section
Search Strategy | |
Databases searched and dates covered: | 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*) |
Dates searches performed: | 23 November 2015 |
Exclusion / Inclusion Criteria | |
Exclusion: | 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. (2014) 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)
Search Outcome | ||||||
Database |
Number of results |
Excluded – study design |
Excluded – did not answer PICO question | Excluded – duplicates |
Total relevant papers |
|
NCBI PubMed and CAB Abstracts |
260 | 28 | 22 | 162 | 48 | |
Total relevant papers when duplicates removed |
48 |
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