Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies

Background: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. Hypothesis/Objectives: Variation in the ABCB1 gene encoding the permeability‐glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs). Animals: Two hundred and thirty‐six client‐owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment. Methods: Prospective and retrospective case‐control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base‐pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case‐control studies: idiopathic epileptic and control BCs and PB‐responsive and resistant idiopathic epileptic BCs. Results: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G‐allele of the c.‐6‐180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P_raw= .0025). Conclusions and Clinical Importance: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.     

Clinical Characterization of Epilepsy of Unknown Cause in Cats

Background

The diagnosis of feline epilepsy of unknown cause (EUC) requires a thorough diagnostic evaluation, otherwise the prevalence of EUC could be overestimated.

Hypothesis

Feline EUC is a clinically defined disease entity, which differs from feline hippocampal necrosis by the absence of magnetic resonance imaging (MRI) signal alteration of the hippocampus. The objectives of this study were (1) to evaluate the prevalence of EUC in a hospital population of cats by applying well‐defined inclusion criteria, and (2) to describe the clinical course of EUC.

Animals

Eighty‐one cats with recurrent seizures.

Methods

Retrospective study—medical records were reviewed for cats presented for evaluation of recurrent seizures (2005–2010). Inclusion criteria were a defined diagnosis based on laboratory data, and either MRI or histopathology. Final outcome was confirmed by telephone interview with the owner. Magnetic resonance images were reviewed to evaluate hippocampal morphology and signal alterations.

Results

Epilepsy of unknown cause was diagnosed in 22% of cats with epilepsy. Physical, neurologic, and laboratory examinations, and either 1.5 T MRI and cerebrospinal fluid analysis or postmortem examination failed to identify an underlying cause. Cats with EUC had a higher survival rate (P < .05) and seizure remission occurred frequently (44.4%).

Conclusion and Clinical Importance

A detailed clinical evaluation and diagnostic imaging with MRI is recommended in any cat with recurrent seizures. The prognosis of cats with normal MRI findings and a clinical diagnosis of EUC are good. Standardized imaging guidelines should be established to assess the hippocampus in cats.     

Epilepsy in Cats: Theory and Practice

The veterinary literature on epilepsy in cats is less extensive than that for dogs. The present review summarizes the most important human definitions related to epilepsy and discusses the difficulties in applying them in daily veterinary practice. Epileptic seizures can have a wide range of clinical signs and are not necessarily typical in all cases. Whether a seizure event is epileptic can only be suspected based on clinical, laboratory, and neuroimaging findings as electroencephalography diagnostic techniques have not yet been developed to a sufficiently accurate level in veterinary medicine. In addition, the present review aims to describe other diagnoses and nonepileptic conditions that might be mistaken for epileptic seizures. Seizures associated with hippocampal lesions are described and discussed extensively, as they seem to be a special entity only recognized in the past few years. Furthermore, we focus on clinical work‐up and on treatment that can be recommended based on the literature and summarize the limited data available relating to the outcome. Critical commentary is provided as most studies are based on very weak evidence.     

Serum cobalamin, urine methylmalonic acid, and plasma total homocysteine concentrations in Border Collies and dogs of other breeds

Objective-To determine reference ranges for serum cobalamin (Cbl), urine methylmalonic acid (uMMA), and plasma total homocysteine (tHcys) concentrations and to compare values for healthy control dogs with values for Border Collies (BCs), a breed in which hereditary cobalamin deficiency has been identified. Animals-113 BCs, 35 healthy control dogs fed a typical diet, and 12 healthy dogs fed a bone and raw food diet exclusively. Procedures-Urine and blood samples were obtained from each dog and Cbl, uMMA, and tHcys concentrations were determined. Results-Reference ranges for Cbl (261 to 1,001 ng/L), uMMA (0 to 4.2 mmol/mol of creatinine), and tHcys (4.3 to 18.4 μmol/L) concentrations were determined. Four BCs had a Cbl concentration lower than the assay detection limit (150 ng/L); median uMMA and tHcys concentrations in these dogs were 4,064 mmol/mol of creatinine and 51.5 μmol/L, respectively. Clinical abnormalities included stunted growth, lethargy, anemia, and proteinuria. Abnormalities improved after administration of cobalamin. Of the 109 healthy BCs with Cbl and tHcys concentrations within reference ranges, 41 (37.6%) had a high uMMA concentration (range, 5 to 360 mmol/mol). Results for dogs fed raw food were similar to those for control dogs. Conclusions and Clinical Relevance-Hereditary cobalamin deficiency is a rare disease with various clinical signs. The finding of methylmalonic aciduria in healthy eucobalaminemic BCs and BCs with clinical signs of Cbl deficiency was surprising and indicated these dogs may have defects in intracellular processing of Cbl or intestinal Cbl malabsorption, respectively. Studies investigating Cbl absorption and metabolic pathways are warranted.     

The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs

Twenty-two dogs with idiopathic epilepsy which were pharmacoresistant to phenobarbitone and bromide were treated with levetiracetam as an add-on medication. Records of eight dogs were used retrospectively to determine a safe, efficient levetiracetam dosage. Fourteen dogs were entered into a prospective, open label, non-comparative study. After 2 months of levetiracetam oral treatment (10 mg/kg TID), 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by 50%. In dogs that remained refractory, the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment. Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure frequency and seizure days after 4-8 months continuing with the levetiracetam treatment at the last effective dosage. Levetiracetam was well tolerated by all dogs and sedation was the only side-effect reported in just one of the 14 dogs.     

Epilepsy and seizure classification in 63 dogs: a reappraisal of veterinary epilepsy terminology

The human definitions of epilepsy and seizure classification were applied rigidly to epileptic dogs to investigate whether the distribution of the seizure types and epilepsies of dogs is comparable to that of human beings. Sixty-three dogs were referred because of recurrent (> 2) epileptic seizures. Only dogs without previous or ongoing antiepileptic treatment were included. All dogs had a physical and neurologic examination and blood work that included a CBC and a biochemical profile. All owners were asked to complete a questionnaire, focusing on seizure development. In addition, video recordings of suspected seizure episodes were analyzed if available. In the majority of dogs where an intracranial lesion was suspected, a computerized tomography scan was performed. Sixty-five percent of the dogs experienced partial seizures with or without secondary generalization and 32% exhibited primary generalized seizures; in 3% of the dogs the seizures could not be classified. Twenty-five percent of these cases were classified as idiopathic, 16% as symptomatic, and 45% as cryptogenic epilepsy; in 14% of these a classification was not possible. Applying human definitions, the distribution of seizure types and epilepsy classifications in these dogs differed widely from those in previous reports of canine epilepsy, where generalized seizures and idiopathic epilepsy were most frequently reported. However, our findings are consistent with the results of several large studies of human epilepsy patients. In dogs with epilepsy, closer attention must be given to the detection of a partial onset of seizures. In this study, detailed questioning of the owners and when possible analysis of video recorded seizures, proved to be sufficient for diagnosing seizures with a partial onset in a significant number of dogs. Partial onset of seizures may be an indication of underlying cerebral pathology. Some adjustments of veterinary epilepsy terminology are suggested.     

Steroid Responsive Meningitis-Arteritis: A Prospective Study of Potential Disease Markers, Prednisolone Treatment, and Long-Term Outcome in 20 Dogs (2006–2008)

Background: Previous multidrug studies have identified the value of prednisolone in treating steroid responsive meningitis-arteritis (SRMA) and the potential value of acute phase proteins (APPs) and immunoglobulin A (IgA) in diagnosis and monitoring.
Hypothesis: (1) Prednisolone monotherapy is a successful immunosuppressive modality in the treatment of SRMA; (2) protein markers are useful in identifying the potential for relapse.
Animals: Twenty client-owned dogs with SRMA presented to the University of Glasgow Small Animal Hospital between May 2006 and May 2008.
Methods: A prospective, observational study: CBC, biochemistry, and cerebrospinal fluid (CSF) analyses were performed. C-reactive protein (CRP), serum amyloid-A, α-1-acid glycoprotein, and haptoglobin (Hp) were assessed in the serum. IgA concentrations were determined in the serum and CSF.
Results: Clinical resolution of SRMA was achieved in all 20 dogs. Serum CRP concentration remained increased at remission in 16/20 dogs whereas CSF cytology was within normal limits in 20/20 dogs. Serum APPs decreased significantly on treatment ( P < .05) except Hp, which remained unaltered. Serum and CSF IgA concentrations remained increased for the duration of treatment.
Conclusions and Clinical Importance: The prednisolone regimen presented was successful in treating SRMA without the need for additional drugs. Serum APPs are of use in the diagnosis and management of SRMA, particularly in relation to identifying relapse. Serum and CSF IgA concentrations remain increased throughout disease, aiding in diagnosis but not contributing to the management of SRMA.     

Epidemiology and Inheritance of Mitral Valve Prolapse in Dachshunds

One hundred ninety consecutive Dachshunds >2 years of age, including 18 families consisting of both parents and 4 or more offspring, were examined clinically and echocardiographically to study the epidemiology and inheritance of mitral valve prolapse (MVP) and other signs of myxomatous mitral valve disease in the dog. From video-recorded echocardiograms, MVP severity, jet size (color Doppler), and leaflet thickness were assessed. With regard to murmur intensity and each of these 3 echocardiographic measurements. the inheritance and the influence of age, gender, coat type, body weight, degree of obesity, heart rate, and thorax dimensions were evaluated. MVP severity correlated positively with age (P < .0001) and heart rate (P = .002), negatively with thorax circumference (P = .0005), and was related to coat type (P = .006). MVP severity progressed faster in males than in females (P = .0002). The other measures of disease severity (jet size, leaflet thickness, and murmur intensity) also correlated positively with age (all P < .0001). When compared in pairs, all 4 measures of disease severity correlated significantly with one other. Pedigree analyses did not disclose agreement with simple Mendelian models, but high disease prevalence made interpretation difficult. Mean parental MVP severity correlated significantly with MVP severity in the offspring (P = .03). The epidemiology of MVP in Dachshunds resembles that of MVP in humans, MVP severity correlates significantly with other measures of the degree of myxomatous mitral valve disease, and MVP is an inherited condition in Dachshunds. A polygenic mode of inheritance is suggested.     

昆明地区鸡源沙门氏菌的分离鉴定及耐药性分析

为了解昆明周边养鸡场的沙门氏菌耐药状况,采集昆明周边5家养殖场的50只疑似沙门氏菌病的发病鸡的肝脏和脾脏进行细菌分离,通过常规生化特性鉴定和PCR分子鉴定,然后通过药敏试验检测分离株耐药性,通过PCR技术对分离株的耐药基因进行检测。结果表明:共分离出8株沙门氏菌,8株菌的靛基质试验、尿素酶试验和VP试验结果均呈阴性,S3、S4菌株不产H2S,柠檬酸试验也呈阴性,针对沙门氏菌设计特异性引物进行扩增,得到目的条带495 bp,与预期一致;在药敏试验中,分离株对氨苄西林和头孢氨苄有较强的耐药性,对四环素中介耐药,对恩诺沙星、加替沙星、卡那霉素、庆大霉素以及氧氟沙星敏感,说明分离株已出现耐药性;在所检测的6种耐药基因中,β-内酰胺类的bla TEM-1和喹诺酮类的GyrA基因检出率为100%,四环素类的tetA基因未被检出,其他三种耐药基因aadA1、tetB和strB检出率均在50%以上,说明分离株耐药基因的携带率较高,需要引起养殖业的重视。     

Risk Factors for Survival in a University Hospital Population of Dogs with Epilepsy

Background

Although a common neurological disorder in dogs, long‐term outcome of epilepsy is sparsely documented.

Objectives

To investigate risk factors for survival and duration of survival in a population of dogs with idiopathic epilepsy or epilepsy associated with a known intracranial cause.

Animals

One hundred and two client owned dogs; 78 dogs with idiopathic epilepsy and 24 dogs with epilepsy associated with a known intracranial cause.

Methods

A retrospective hospital based study with follow‐up. Dogs diagnosed with epilepsy between 2002 and 2008 were enrolled in the study. Owners were interviewed by telephone using a structured questionnaire addressing epilepsy status, treatment, death/alive, and cause of death.

Results

Median life span was 7.6 years, 9.2 years, and 5.8 years for all dogs, and dogs with idiopathic epilepsy or dogs with epilepsy associated with a known intracranial cause (P < .001), respectively. Survival time for dogs with idiopathic epilepsy was significantly (P = .0030) decreased for dogs euthanized because of epilepsy (median: 35 months) compared to dogs euthanized for other reasons (median: 67.5 months). Neutered male dogs with idiopathic epilepsy had a significant (P = .031) shorter survival (median: 38.5 months) after index seizure compared to intact male dogs (median: 71 months). Treatment with two antiepileptic drugs (AED′s) did not negatively influence survival (P = .056).

Conclusion and Clinical Importance

Dogs with idiopathic epilepsy can in many cases expect a life span close to what is reported for dogs in general. In dogs where mono‐therapy is not sufficient, the need for treatment with two AED′s is not linked to a poor prognosis.     

Effect of Chronic Administration of Phenobarbital,or Bromide,on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy

Background

Levetiracetam (LEV) is a common add‐on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs.

Hypothesis/Objectives

To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs.

Animals

Eighteen client‐owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB–BR group, n = 6).

Methods

Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high‐pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area‐under‐the‐curve (AUC) calculated to the last measured time point.

Results

Compared to the PB and PB–BR groups, the BR group had significantly higher peak concentration (C _max) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028).

Conclusions and Clinical Importance

Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add‐on treatment with phenobarbital in dogs.     

旋毛虫各隔离种对猪的感染性和低温耐受性的研究

用消化法所得的猪旋毛虫、犬旋毛虫、旋毛形线虫（Trichinella spiralis）和本地毛形线虫（Trichinella nati-va）分别感染猪和小鼠,以观察其感染性,同时在-22℃和-32℃条件下对其进行冷冻试验。结果表明:4个旋毛虫隔离种对猪的感染性存在着明显差异,猪旋毛虫和T.spiralis对猪易感,其繁殖力指数（RCI）分别为385.68±41.51和300.55±12.45;而犬旋毛虫和T.nativa对猪不易感,RCI分别是0.064±0.031和0.033±0.033。猪旋毛虫和旋毛形线虫不耐低温,在猪体内-32℃、24 h,-22℃、72 h;在小鼠体内-32℃、12 h即全部死亡。而犬旋毛虫和本地毛形线虫对低温抵抗力较强,在猪体内-32℃、72h,-22℃、192 h;在小鼠体内-32℃、48 h才失去感染性。结果揭示:黑龙江省猪旋毛虫相当于旋毛形线虫,犬旋毛虫相当于本地毛形线虫;犬旋毛虫和T.nativa很难通过猪的感染而对人体健康构成威胁。