Takayuki Kuwabara

A familial spontaneous epileptic feline strain: A novel model of idiopathic/genetic epilepsy

A spontaneous epileptic model of cats has not been described previously. Recently, we identified familial epileptic cats and investigated their clinical features. These epileptic cats are healthy except for the presence of recurrent seizures that are typically a focal limbic seizure with secondary generalization. Furthermore, generalized seizures were induced by vestibular stimulation in some cats. This spontaneous epileptic cat strain may be a valuable model for idiopathic/genetic epilepsy.

Pharmacokinetics and toxicity of zonisamide in cats

With the eventual goal of making zonisamide (ZNS), a relatively new antiepileptic drug, available for the treatment of epilepsy in cats, the pharmacokinetics after a single oral administration at 10 mg/kg and the toxicity after 9-week daily administration of 20 mg/kg/day of ZNS were studied in healthy cats. Pharmacokinetic parameters obtained with a single administration of ZNS at 10 mg/day were as follows: Cmax=13.1 μg/ml; Tmax=4.0 h; T1/2=33.0 h; areas under the curves (AUCs)=720.3 μg/mlh (values represent the medians). The study with daily administrations revealed that the toxicity of ZNS was comparatively low in cats, suggesting that it may be an available drug for cats. However, half of the cats that were administered 20 mg/kg/day daily showed adverse reactions such as anorexia, diarrhoea, vomiting, somnolence and locomotor ataxia.

Magnetic resonance volumetry of the hippocampus in familial spontaneous epileptic cats

A strain of familial spontaneous epileptic cats (FSECs) with typical limbic seizures was identified in 2010. The electroencephalographic features suggested that an epileptogenic zone is present in the mesial temporal structures (i.e., amygdala and/or hippocampus). In this study, visual evaluations and quantitative analyses were performed by using 3D MR hippocampal volumetry in comparing FSECs with age-matched controls. Visual hippocampal asymmetries were seen in 8 of 14 (57.1%) FSECs. The FSEC group showed a significantly higher asymmetric ratio (4.15%) than the control group (0.99%). The smaller side of hippocampal volume (HV) (0.206 cm(3)) in FSECs was significantly smaller than the mean HV in controls (0.227 cm(3)). However, the means of left and right HVs and total HVs in FSECs showed no differences because the laterality of hippocampal atrophy was different in each individual. Therefore, since FSECs represent a true model of spontaneous epilepsy, hippocampal volumetry should be evaluated in each individual as well as in human patients. The significant asymmetry of HV suggests the potential for hippocampal atrophy in FSECs.

Electroencephalographic features of familial spontaneous epileptic cats

A feline strain of familial spontaneous epileptic cats (FSECs) with typical limbic seizures was identified in 2010, and have been maintained as a novel animal model of genetic epilepsy. In this study, we characterized the electroencephalographic (EEG) features of FSECs. On scalp EEG under sedation, FSECs showed sporadic, but comparatively frequent interictal discharges dominantly in the uni- or bilateral temporal region. Bemegride activation was performed in order to evaluate the predisposition of epileptogenicity of FSECs. The threshold doses of the first paroxysmal discharge, clinical myoclonus and generalized convulsion in FSECs were significantly lower than those in control cats. Chronic video-intracranial EEG monitoring revealed subclinical or clinical focal seizures with secondarily generalization onset from the unilateral amygdala and/or hippocampus. Clinical generalized seizures were also recorded, but we were unable to detect the onset site. The results of the present study show that FSECs resemble not only feline kindling or the kainic acid model and El mouse, but also human familial or sporadic mesial temporal lobe epilepsy. In addition, our results indicate that FSECs are a natural and valuable model of mesial temporal lobe epilepsy.

Feline anaplastic oligodendroglioma: long-term remission through radiation therapy and chemotherapy

A 10-year-old spayed female Abyssinian cat was presented with cluster limbic focal seizures with secondary generalisation. From magnetic resonance imaging (MRI) findings, the cat was diagnosed clinically as having a glioma in the left piriform lobe, and hypofractionated radiation therapy (RT) was performed using a linear accelerator. Although the tumour size had reduced significantly at 4 months after RT, recurrence was observed at 11 months after RT. Additional RT was performed and was effective; however, recurrence was observed at 11 months after the additional RT. Chemotherapy was started using nimustine (ACNU; 30 mg/m2, every 6 weeks). Tumour regression was confirmed by follow-up MRIs from 2 to 5 months after starting chemotherapy. Four years and 2 months after the first presentation the cat died as a result of tumour lysis syndrome following treatment of a high-grade lymphoma. Histopathological diagnosis of the brain tumour confirmed anaplastic oligodendroglioma.

Changes in the interictal and early postictal diffusion and perfusion magnetic resonance parameters in familial spontaneous epileptic cats

OBJECTIVE The familial spontaneous epileptic cat (FSEC) is thought to be a good genetic model of mesial temporal lobe epilepsy. In the current study, cerebral diffusion and perfusion magnetic resonance imaging (MRI) were used to confirm the functional deficit zone in the FSEC and evaluate the effect of a single seizure on different brain regions. METHODS Six FSECs and six healthy control cats were used in this study. MRI was performed in the interictal state (resting state for control) and postictal state immediately after the vestibular stimulation-induced generalized epileptic seizure (control cats received the same stimulation as the FSECs). The apparent diffusion coefficient (ADC), fractional anisotropy and perfusion parameters (i.e., relative regional cerebral blood volume (rCBV), relative regional cerebral blood flow (rCBF), and relative regional mean transit time (rMTT)) were measured in the hippocampus, amygdala, thalamus, and gray and white matter. RESULTS In the interictal state, the rCBV and rMTT in the hippocampus was significantly decreased in FSECs, compared to the control. In the postictal state, FSECs had a significantly decreased ADC and an increased rCBV, rCBF, and rMTT in the hippocampus, and an increased rMTT in the amygdala, compared to the interictal state. CONCLUSION This study showed that FSECs had interictal hypoperfusion in the hippocampus, and postictal hypodiffusion and hyperperfusion in the hippocampus and/or amygdala. These findings suggested that the hippocampus and/or amygdala act as the functional deficit and expanded seizure-onset zones in FSECs.

Additional file 11 of Molecular cloning and characterization of the family of feline leucine-rich glioma-inactivated (LGI) genes, and mutational analysis in familial spontaneous epileptic cats

Allelic and genotypic distribution of synonymous and intronic polymorphisms other than non-synonymous mutation found in LGI1â 4 genes in familial spontaneous epileptic cats (FPSCs) and controls (DOCX 86 kb)

Molecular cloning and characterization of the family of feline leucine-rich glioma-inactivated (LGI) genes, and mutational analysis in familial spontaneous epileptic cats

BackgroundLeucine-rich glioma-inactivated (LGI) proteins play a critical role in synaptic transmission. Dysfunction of these genes and encoded proteins is associated with neurological disorders such as genetic epilepsy or autoimmune limbic encephalitis in animals and human. Familial spontaneous epileptic cats (FSECs) are the only feline strain and animal model of familial temporal lobe epilepsy. The seizure semiology of FSECs comprises recurrent limbic seizures with or without evolution into generalized epileptic seizures, while cats with antibodies against voltage-gated potassium channel complexed/LGI1 show limbic encephalitis and recurrent limbic seizures. However, it remains unclear whether the genetics underlying FSECs are associated with LGI family genes. In the present study, we cloned and characterized the feline LGI1–4 genes and examined their association with FSECs. Conventional PCR techniques were performed for cloning and mutational analysis. Characterization was predicted using bioinformatics software.ResultsThe cDNAs of feline LGI1–4 contained 1674-bp, 1650-bp, 1647-bp, and 1617-bp open reading frames, respectively, and encoded proteins comprising 557, 549, 548, and 538 amino acid residues, respectively. The feline LGI1–4 putative protein sequences showed high homology with Homo sapiens, Canis familiaris, Bos taurus, Sus scrofa, and Equus caballus (92%–100%). Mutational analysis in 8 FSECs and 8 controls for LGI family genes revealed 3 non-synonymous and 14 synonymous single nucleotide polymorphisms in the coding region. Only one non-synonymous single nucleotide polymorphism in LGI4 was found in 3 out of 8 FSECs. Using three separate computational tools, this mutation was not predicted to be disease causing. No co-segregation of the disease was found with any variant.ConclusionsWe cloned the cDNAs of the four feline LGI genes, analyzed the amino acid sequences, and revealed that epilepsy in FSEC is not a monogenic disorder associated with LGI genes.