Idiopaattinen epilepsia suomenpystykorvilla : Epidemiologinen, kliininen ja diagnostinen näkökulma

Epilepsy, a common neurologic disorder in dogs, has also been recognized in the Finnish Spitz dog (FSD) since the 1980s, but scientifically verified data has been lacking. In this thesis, epilepsy in FSDs was characterized. Diagnostic investigations, using tools such as magnetic resonance imaging (MRI) and electroencephalography (EEG), have not been used consistently in veterinary medicine to diagnose epilepsy in dogs. The usefulness of these modalities to diagnose different forms of canine epilepsy needs to be proven. Thus, FSDs with and without focal epilepsy were studied by MRI and EEG. In addition, the novel functional method to investigate epileptic dogs, 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET), was described and results were compared with EEG. Epidemiological information was based on 2141 FSDs, of which 143 were epileptic, and prevalence on 2069 living FSDs, of which 111 had epilepsy. The prevalence of idiopathic epilepsy (IE) in FSDs was found to be 5.3%; males were more predisposed to epilepsy. The median age at seizure onset was 3 years, seizure frequency was 3 per year, and duration of seizure episode was 12 min. Focal onset seizures, characterized by frequent behavioral and autonomic signs were the main phenotype of epilepsy in FSDs. Although epilepsy in FSDs follows a generally benign course, generalization of seizure indicate a progressive course of epilepsy. The heritability estimate of IE in FSDs (0.22) was best explained by polygenic traits. Although characterized with focal seizures, FSDs have non-lesional epilepsy based on 1.5T MRI examinations. Infrequent reversible brain changes can be found, as a consequence of seizures. Visual evaluation of EEG in epileptic FSDs showed interictal epileptiform paroxysmal activity (20%) less frequently than had been described previously. This activity was expressed by spikes, polyspikes, and spike slow-wave complexes in the posterior-occipital derivation. Epileptiform activity, consisting of midline spikes, was recognized in healthy FSDs. Sleep transients, which were frequently found in FSDs from both groups, could be easily misinterpreted as epileptiform activity. Quantitative EEG showed significant difference in various frequency bands related to diseased status or medication. Cerebral glucose utilization was examined by FDG-PET in 11 epileptic and 8 healthy FSDs. Glucose uptake abnormalities/asymmetries were detected in various brain regions of 82% of epileptic and in 50% of control FSDs; findings in the occipital cortex specifically associated with epilepsy. The epileptic dogs had significantly lower standardized uptake values in numerous cortical regions, cerebellum, and hippocampus compared to the control dogs. The low cortical glucose uptake values found in the occipital lobe in both groups of FSDs is an unique finding and may indirectly reflect the lowered seizure threshold in that region characteristic for this dog breed. Inability to reveal significant difference of white matter normalized uptake values and left-right asymmetry indexes between epileptic and control groups might be related to the method used to define regions of interest. Based on these results, epilepsy in FSDs is defined as idiopathic epilepsy, as FSDs lack changes on the brain MRI and epilepsy is genetically determined. EEG and FDG-PET suggest involvement of the occipital region, although also wider posterior cortical areas could be related to epileptogenesis in FSDs. Visual evaluation of both EEG and FDG-PET can support the diagnosis of IE in dogs. Although diagnostic yield of EEG to diagnose epilepsy seems to be lower than suggested for dogs, it is a method of choice for everyday clinical settings. FDG-PET is a useful research modality for examining epileptic dogs, where visual detection of hypometabolic areas provides the highest sensitivity. Quantitative assessment methods of EEG and FDG-PET can be beneficial, but should be used alongside visual evaluation in epileptic dogs.Epilepsia on yleinen neurologinen sairaus koirilla. Sitä on tavattu suomenpystykorvilla jo 1980-luvulta lähtien, mutta tieteellisesti varmennettua tietoa ei ole aiemmin ollut saatavilla kyseisen rodun epilepsiasta. Tässä väitöskirjassa kuvataan suomenpystykorvien epilepsian esiintyvyyttä, kliinisia oireita ja diagnostiikka. Koiria tutkitiin magneettikuvauksen (MRI) ja aivosähkökäyrätutkimuksen (EEG) avulla. Uutena toiminnallisen-kuvantamisen menetelmänä koirien epilepsian tutkimisissa käytetiin positroniemissiotomografia (PET). ----- Epidemiologinen tieto perustui 2141 suomenpystykorvan tietoihin ja esiintyvyys 2069 elossa olevan Suomenpystykorvan tietoihin. Epilepsian esiintyvyys suomenpystykorvilla todettiin olevan 5,3% urosten ollessa alttiimpia sairastumaan epilepsiaan. Kohtaukset alkavat pystykorvilla keskimäärin 3 vuoden iässä, niitä on keskimäärin kolmesti vuodessa, ja kohtauksen tyypillinen kesto on 12 minuuttia. Rodulle tyypillisiä olivat paikallisalkuiset kohtaukset, joihin liittyi tavallisesti käytösmuutoksia ja autonomisia oireita, kuten oksentelua ja kuolaamista. Kohtausten yleistyminen voi viitata epilepsian etenemiseen, vaikka pystykorvien epilepsian kulku on yleensä hyvänlaatuinen. Suomenpystykorvien idiopaattisen epilepsian perinnöllisyysasteen arvio (0.22) selittyy parhaiten usean geenin mallin avulla. Vaikkakin suomenpystykorvien epilepsialle tyypillisiä ovat paikalliset kohtaukset, korkeakenttämagneetilla tehtyjen tutkimuksien perusteella kyseessä on epilepsia, jossa ei havaita aivoissa rakenteellisia muutoksia. Harvakseltaan voidaan kuitenkin havaita palautuvia, kohtausten seurauksena syntyneitä muutoksia aivoissa. Epilepsiaa sairastavien suomenpystykorvien aivosähkökäyrässä havaittiin kohtausten välillä epileptistä aktiivisuutta harvemmin (20%) kuin on raportoitu aiemmin. Tietyntyyppistä epänormaalia aktiivisuutta havaittiin myös terveillä pystykorvilla, mutta löydöksen kliininen merkitys on tuntematon. Uneen liittyvää aktiivisuutta, joka voidaan helposti tulkita virheellisesti epileptiseksi aktiivisuudeksi, todettiin sekä terveillä että sairailla koirilla. Aivosähkökäyrän kvantitatiivisessa tulkinnassa havaittiin merkittäviä eroja riippuen terveysstatuksesta tai lääkityksestä. ------ Aivojen glukoosinkäyttöä tutkittiin 2-deoksi-2-[18F]fluoro-D-glukoosi (FDG)-PET avulla 11 epileptisellä ja 8 terveellä suomenpystykorvalla. Glukoosinkäytössä todettiin epänormaaliutta tai epäsymmetrisyyttä eri aivoalueilla 82%:lla epileptisistä ja 50%:lla terveistä koirista; muutokset erityisesti isoaivojen takaraivonlohkon kuorikerroksen alueella liittyivät epilepsiaan. Epileptisillä koirilla todettiin merkittävästi alhaisemmat glukoosinkäyttöarvot useilla aivoalueilla verrattuna kontrollikoiriin. Isoaivojen kuorikerroksen takaraivonlohkon alhaiset glukoosinkäyttöarvot molemmissa koiraryhmissä ovat aiemmin havaitsematon löydös ja tämä saattaa epäsuorasti viitata alentuneeseen kohtauskynnykseen kyseisellä alueella luonteenomaisena tutkitulle rodulle. Kyvyttömyys havaita merkittäviä eroja epileptisten ja kontrolliryhmien välillä valkeaan ainekseen suhteutetuissa glukoosinkäyttöarvoissa ja vasen-oikea epäsymmetria-indekseissä voi liittyä käytettyihin menetelmiin. Näihin tuloksiin perustuen suomenpystykorvien epilepsia luokitellaan idiopaattiseksi epilepsiaksi, koska aivojen magneettikuvauksessa ei havaita muutoksia ja epilepsia on perinnöllinen kyseessä olevalla rodulla. EEG ja FDG-PET viittaavat takaraivonlohkon osallisuuteen, vaikkakin myös laajempi taaimmaisten aivoalueiden mukanaolo on mahdollinen pystykorvien epilepsian synnyssä. EEG ja FDG-PET visuaalinen analyysi voivat tukea idiopaattisen epilepsian diagnoosin tekemistä koirilla. Vaikkakin EEG:n tuoma diagnostinen apu koirilla näyttää olevan alhaisempi kuin aiemmin on ehdotettu, se on ensisijainen menetelmä jokapäiväisessä kliinisessä työssä. FDG-PET on hyödyllinen menetelmä tutkimusmielessä arvioitaessa epileptisiä koiria, ja siinä hypometabolisten alueiden visuaalinen havaitseminen antaa parhaimman herkkyyden. EEG ja FDG-PET tulosten kvantitatiivinen arviointi voi olla hyödyllistä, mutta niitä tulisi käyttää rinnakkain visuaalisen analyysin kanssa

Evaluation of the traditional way of euthanasia of farmed foxes from an animal welfare point of view

v2009o

Electroencephalography Findings in Healthy and Finnish Spitz Dogs with Epilepsy : Visual and Background Quantitative Analysis

Background: Qualitative and quantitative electroencephalography (EEG) parameters of healthy and Finnish Spitz dogs with epilepsy have not been determined. Objective: To determine if EEG can provide specific characteristics to distinguish between healthy dogs and dogs with epilepsy. Animals: Sixteen healthy and 15 Finnish Spitz dogs with epilepsy. Methods: A prospective clinical EEG study performed under medetomidine sedation. Blinded visual and quantitative EEG analyses were performed and results were compared between study groups. Results: Benign epileptiform transients of sleep and sleep spindles were a frequent finding in a majority of animals from both groups. The EEG analysis detected epileptiform activity in 3 Finnish Spitz dogs with epilepsy and in 1 healthy Finnish Spitz dog. Epileptiform activity was characterized by spikes, polyspikes, and spike slow wave complexes in posterior-occipital derivation in dogs with epilepsy and with midline spikes in control dog. The healthy dogs showed significantly less theta and beta activity than did the dogs with epilepsy (P < .01), but the only significant difference between healthy dogs and dogs with untreated epilepsy was in the alpha band (P < .001). Phenobarbital treatment increased alpha, beta (P < .001), and theta (P < .01), and decreased delta (P < .001) frequency bands compared with dogs with untreated epilepsy. Conclusions and Clinical Importance: Benign epileptiform transients of sleep could be easily misinterpreted as epileptiform activity. Epileptiform activity in Finnish Spitz dogs with epilepsy seems to originate from a posterior-occipital location. The EEG of dogs with epilepsy exhibited a significant difference in background frequency bands compared with the control dogs. Phenobarbital treatment markedly influenced all background activity bands. Quantitative EEG analysis, in addition to visual analysis, seems to be a useful tool in the examination of patients with epilepsy

Prevalence of radiographic detectable intervertebral disc calcifications in Dachshunds surgically treated for disc extrusion

<p>Abstract</p> <p>Background</p> <p>An association between the occurrence of calcified discs, visible on radiographic examination (CDVR), and disc extrusions has been suggested in published literature over the past 10-20 years, mainly from Nordic countries. It has also been postulated that dogs without CDVR would not develop disc extrusions. Furthermore, inheritance of CDVR has been calculated and it has been postulated that, by selecting dogs for breeding with few, or no CDVR, the prevalence of disc extrusions in the Dachshund population may be reduced.</p> <p>Methods</p> <p>The prevalence of radiographic detectable intervertebral disc calcifications was calculated from one hundred surgeries for disc extrusion, performed in 95 Dachshunds, in order to determine if the disc causing clinically significant IVDD, had radiographic signs of calcification at the time of confirmed disc extrusion. Inclusion criteria, for each dog, included a complete physical, orthopedic and neurologic examination, radiographs of the entire vertebral column, a myelogram or magnetic resonance imaging examination indicating extradural spinal cord compression, and finally a surgical procedure confirming the diagnosis of a disc extrusion. In addition to descriptive statistics, age correlation with number of calcifications visible at radiographic examination and with CDVR at the surgery site was examined.</p> <p>Results</p> <p>We found that disc extrusions occur as frequently in discs that are found to have radiographic evidence of calcification as those discs that do not have signs of radiographic calcification, and that IVDD (intervertebral disc disease) requiring surgery does occur in the absence of any calcified discs on radiographic examination. We found that calcified discs were more frequent in our Dachshund population compared to previous studies suggesting that disc calcification might be a serious risk factor for developing disc extrusion. Further studies are needed to show, conclusively, if selection of breeding dogs based on CDVR in the Dachshund will reduce the incidence of IVDD. The presence of the calcifications of intervertebral disc should be evaluated with caution, as only part of the calcifications will be detected and the real extent of the disc degeneration may be underestimated.</p

Magnetic Resonance Imaging Findings in Finnish Spitz Dogs with Focal Epilepsy

Eleven Finnish Spitz dogs with focal seizures and 3 healthy controls were evaluated. General clinical and neurological examinations, blood examination, urinalysis, cerebrospinal fluid examination, electroencephalography (EEG), and magnetic resonance imaging (MRI) of the brain were performed on all dogs. On EEG examination, focal epileptic activity was found in 7 of 11 dogs (64%), and generalized epileptic activity was observed in 4 of 11 dogs (36%). MRI (performed with 1.5 T equipment) detected changes in 1 epileptic dog. Mild contrast enhancement after gadolinium injection was identified in this dog's right parietal cortex. However, no such changes were observed in repeated magnetic resonance images. Special emphasis was given to seizure history to determine any correlations between seizure intervals and MRI findings. Our results indicate that Finnish Spitz dogs with focal seizures suffer from focal idiopathic epilepsy and have nondetectable findings on MRI or pathology. MRI showed poor sensitivity in detecting epileptogenic areas in our patients with focal seizures. Reversible MRI changes in 1 dog could have been caused by seizures

A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia

Inherited skeletal disorders affect both humans and animals. In the current study, we have performed series of clinical, pathological and genetic examinations to characterize a previously unreported skeletal disease in the Karelian Bear Dog (KBD) breed. The disease was recognized in seven KBD puppies with a variable presentation of skeletal hypomineralization, growth retardation, seizures and movement difficulties. Exome sequencing of one affected dog revealed a homozygous missense variant (c. 1301T > G; p. V434G) in the tissue non-specific alkaline phosphatase gene, ALPL. The identified recessive variant showed full segregation with the disease in a cohort of 509 KBDs with a carrier frequency of 0.17 and was absent from 303 dogs from control breeds. In humans, recessive and dominant ALPL mutations cause hypophosphatasia (HPP), a metabolic bone disease with highly heterogeneous clinical manifestations, ranging from lethal perinatal hypomineralization to a relatively mild dental disease. Our study reports the first naturally occurring HPP in animals, resembling the human infantile form. The canine HPP model may serve as a preclinical model while a genetic test will assist in breeding programs.Peer reviewe

ADAM23 is a common risk gene for canine idiopathic epilepsy

Background: Idiopathic or genetic adult-onset epilepsy is a common neurological disorder in domestic dogs. Genetic association has been reported only with ADAM23 on CFA 37 in few breeds. To identify novel epilepsy genes, we performed genome-wide association (GWA) analyses in four new breeds, and investigated the association of the previously reported ADAM23 haplotype with the epilepsy phenotype in eight breeds. Results: GWA analysis did not reveal new epilepsy loci. ADAM23 association (p < 0.05) was identified in five breeds. Combined analysis of all eight breeds showed significant association (p = 4.6e(-6), OR 1.9). Conclusions: Our results further support the role of ADAM23 in multiple breeds as a common risk gene for epilepsy with low penetrance. The lack of findings in the GWA analyses points towards inefficient capture of genetic variation by the current SNP arrays, causal variant(s) with low penetrance and possible phenocopies. Future work will include studies on ADAM23 function and expression in canine neurons, as well as whole-genome sequencing in order to identify additional IE genes

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene

Background: Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results: We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions: These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.Peer reviewe

Electrocution in farmed foxes : evaluation from an animal welfare point of view

Abstract The aim was to evaluate at what point consciousness is lost and brain activity ceases in electrically stunned blue foxes (Alopex lagopus), and to establish whether or not there is any return to consciousness after stunning before death. The study was conducted on 15 female blue foxes. All animals were sedated with an intramuscular injection of medetomidine. The results showed that the animal was unconscious immediately after stunning as documented by the absence of all reflexes. The EEG recording showed a status epilepticus pattern in all foxes immediately after stunning, and in none of the animals was a return to normal brain pattern observed. Such a generalised status epilepticus is connected with state of total unconsciousness and leads to ultimately to brain death. All the foxes in our experiment had respiratory arrest and heart fibrillation after stunning. The heart changes were irreversible in all cases and most probably contributed heavily to the death of the brain after stunning, as the fibrillating heart is not able to provide the necessary blood flow to the brain and other organs. This leads to failure of multiple organ systems and inevitable death. Rapid disappearance of the BAER after stunning indicates brainstem affection and death. Magnetic resonance imaging examination and histopathological examination of the brain revealed no severe changes to the brains of any of the foxes, indicating that stunning mainly affects the function of the brain without distorting the anatomy of the brain. In conclusion, electrical stunning produces an immediate and irreversible state of unconsciousness and therefore is a humane way of euthanasia of farmed foxes.vo

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene.

BackgroundIdiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37.ResultsWe have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy.ConclusionsThese results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies