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| 2. |
- Chioza, Barry A., et al.
(författare)
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Genome wide high density SNP-based linkage analysis of childhood absence epilepsy identifies a susceptibility locus on chromosome 3p23-p14
- 2009
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 87:2-3, s. 247-255
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Tidskriftsartikel (refereegranskat)abstract
- Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by typical absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to the aetiology is well recognised but the mechanism of inheritance and the genes involved are yet to be fully established. A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Z(mean)=3.9, p<0.0001; HLOD=3.3, alpha=0.7). The linked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1.
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| 3. |
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| 4. |
- Danielsson, Bengt R, et al.
(författare)
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Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents
- 2005
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 63:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (I(Kr)) can be proarrhythmic and their clinical use has been associated with sudden unexpected death (SUD) due to cardiac arrhythmia. SUD is 20-40 times more common among people with epilepsy than in the general population and case-control studies have identified polytherapy with antiepileptic drugs (AEDs) as a risk factor. In a previous study, it was described that the old AEDs phenytoin and phenobarbital had the potential to inhibit the I(Kr) channel and it was suggested that this could contribute to the increased risk for SUD in patients with epilepsy. In this study, we have investigated the I(Kr) blocking potential of some more recently introduced AEDs, lamotrigine (LTG), topiramate (TPM) and gapapentin (GBP). The whole cell patch-clamp recording technique was used to study the effects on I(Kr) channels expressed by the human ether-a-go-go related gene (hERG) stably expressed in human embryo kidney (HEK) 293 cells. Tail currents, which are purely related to hERG currents, were blocked with IC50 and IC20 (the concentrations when 50% and 20% inhibition was obtained compared to control values) of 229 and 21 microM, respectively, for LTG. A 40% inhibition of tail currents was obtained at GBP concentrations of 100 mM and a 20% inhibition at 54 mM. A 35% inhibition of tail currents was obtained at TPM concentrations of 1000 microM and a 20% inhibition at 87 microM, respectively. Collective data show that drugs with the same margins (ratio hERG IC50/unbound therapeutic concentration) as LTG, may have arrhythmogenic potential. The risk for arrhythmia may be clinically significant in the presence of predisposing factors such as seizure-induced acidosis and in the case of concurrent treatment with other I(Kr) blocking drugs, or in case of pharmacokinetic drug-drug interactions resulting in excessively high concentrations of LTG.
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| 5. |
- Davidsson, Josef, et al.
(författare)
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Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: An array-based genotype-phenotype correlation and a comprehensive review of previously published cases.
- 2008
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Ingår i: Epilepsy Research. - : Elsevier BV. - 1872-6844 .- 0920-1211. ; Jun 6, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterize a deletion of chromosome 2q at the molecular level in a patient suffering from severe epilepsy resembling severe myoclonic epilepsy of infancy/Dravet's syndrome (SMEI/DS) and to correlate other cases harboring deletions in the same region to morphological and clinical data. METHODS: Array-based comparative genomic hybridization (array CGH) was performed on DNA from the patient. Forty-three previously published cases reporting deletions within region 2q21-q31 were collected and analyzed regarding their cytogenetic and clinical data. RESULTS: A del(2)(q24.3q31.1) was detected in the patient, spanning a 10.4-megabase (Mb) region between 165.18 and 175.58Mb, harboring 47 genes. FISH analysis was performed, confirming this deletion. Twenty-two of the 43 previously published cases were seizure-positive. The most common dysmorphic features were ear abnormalities, microcephaly, micrognathia and brachysyndactyly for all patients as well as for solely the seizure-positive and -negative ones. For the 22 seizure-positive cases chromosome subband 2q24.3 constituted the smallest commonly deleted region among the majority of the cases, where subbands 2q22.1 and 2q33.3 represented the most proximal and distal breakpoint, respectively. CONCLUSIONS: Based on the early age of presentation and the severity of the epilepsy reported for the majority of the seizure-positive cases it was concluded that SMEI/DS could be the epileptic encephalopathy associated with deletions within the 2q22.1-q33.3 region, due to haploinsuffiency of SCN1A and/or complete or partial deletion of other voltage-gated sodium channel genes caused by the aberration. Furthermore, our study supports that array CGH is a competent technique for screening SCN1A mutation-negative patients diagnosed with SMEI/DS-like epilepsies and dysmorphic features, generating rapid and high-resolution data of genomic imbalances present in the patients.
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| 6. |
- Everett, Kate, et al.
(författare)
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Linkage and mutational analysis of CLCN2 in childhood absence epilepsy
- 2007
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 75:2-3, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, α=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent–child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT , p<0.03. Case–control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: , p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.
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| 7. |
- Hallböök, Tove, et al.
(författare)
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Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy
- 2007
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Ingår i: Epilepsy Research. - : Elsevier BV. - 1872-6844 .- 0920-1211. ; 77:2-3, s. 134-140
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose was to quantify changes of epileptiform activity during ketogenic diet (KD) treatment in children with therapy resistant epilepsy, and evaluate how these changes are related to activity stage and to clinical effects on seizure frequency, seizure severity, attentional behaviour, quality of life (QOL), and beta-hydroxybutyrate (betaOHb). METHODS: Eighteen children were investigated with 24h ambulatory EEG monitoring 1 week prior to KD initiation and, after 3 months of KD treatment. Epileptiform activity was evaluated by automated spike detection. This data was compared with data presented in a previous study published in Epilepsia 2006, on sleep structure and different activity stages, clinical data on seizure frequency, seizure severity, QOL and attentional behaviour on the same children [Hallbook, T., Lundgren, J., Rosen, I., 2007. Ketogenic diet improves sleep quality in children with therapy resistant epilepsy. Epilepsia 48, 59-65]. RESULTS: After 3 months of KD treatment the number of interictal epileptiform discharges (IEDs) was significantly reduced (p<0.001). When considering the four activity stages separately, the reduction was significant during non-rapid eye movement sleep stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep (p=0.001, 0.001, 0.002), and not significantly so during awake (p=0.07). Beta-hydroxybutyrate was significantly increased (p<0.001). There was a significant correlation between the reduction in IEDs and clinical seizures (Spearman r=0.6, p=0.005) and between improvement in attentional behaviour and the increase in betaOHb (Spearman r=0.5, p=0.03). There was no significant correlation between changes in attentional behaviour and IEDs or clinical seizures. CONCLUSION: This study shows that KD reduces the number of IEDs, especially during sleep. It shows a correlation between reduction in epileptiform activity and clinical seizures. There were no correlations between reduction in epileptiform activity and clinical seizures and improvement in QOL or attention. The increase in betaOHb correlated with improvement in attention.
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| 8. |
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| 9. |
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| 10. |
- Persson, H., et al.
(författare)
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No apparent effect of surgery for temporal lobe epilepsy in heart rate variability
- 2006
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 70:2-3, s. 127-132
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Tidskriftsartikel (refereegranskat)abstract
- Background: Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Clinical observations indicate that successful epilepsy surgery is associated with a reduced risk of SUDEP. However, in a previous study we found impaired cardiac control pre-surgically in patients with poor outcome of surgery, indicating an a priori lower risk in responders to epilepsy surgery. We have now examined the effect of surgery on cardiac autonomic control in the same patients. Methods: We used 24 h EKG recordings to assess heart rate variability (HRV) by spectral analysis in 21 consecutive patients after temporal lobe epilepsy surgery. The HRV was compared with healthy controls, with pre-surgical HRV in the same patients, and analyzed in relation to seizure control 1 year after surgery. Results: The patients with poor outcome after surgery had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. The patients with favorable outcome did not differ from the controls, and the postoperative HRV was not different from HRV before surgery in any of the patient groups. Conclusion: We could not demonstrate any effect on HRV of temporal lobe epilepsy surgery in these patients. The observed lower HRV in the poor outcome group was present already before epilepsy surgery as previously reported. Although our results need confirmation in a larger study, the observations suggest that the increased risk of SUDEP in patients failing epilepsy surgery may be due to a common factor predisposing to surgical failure, impaired HRV as well as to an increased risk of SUDEP.
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| 11. |
- Qu, Mingqi, et al.
(författare)
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DLG3/SAP102 protein expression in malformations of cortical development : A study of human epileptic cortex by tissue microarray
- 2009
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 84:1, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- The human DLG3 gene encodes the synapse-associated protein 102 (SAP102), which is concentrated in the postsynaptic densities of excitatory synapses and involved in receptor-mediated synaptic transmission via binding to the NR2B subunit of the NMDA receptor. In this study, we investigated the expression and cellular distribution of the DLG3/SAP102 protein in human epileptic cortex. Tissue microarrays of a large number of specimens from patients operated for medically intractable epilepsy were used for immunohistochemical screening with anti-DLG3 antibody. The cellular distribution of the protein was further investigated in samples of malformations of cortical development, and the amount of DLG3 protein in the total homogenate and in the postsynaptic membrane fraction of these samples was quantified by Western blot. We found a strictly neuronal expression of DLG3/SAP102 in epileptogenic cortex as well as in non-epileptic human cortex used for control. In focal cortical dysplasia and tuberous sclerosis complex, the protein was expressed in most neurons including dysplastic neurons, but not in giant cells. Increased expression of DLG3 protein was observed in the postsynaptic membrane fraction of patients with focal cortical dysplasia. Double-labeling experiments confirmed the exclusive neuronal character of the DLG3 expressing cells and the co-localization of the DLG3 protein with the NR2B subunit. Our results suggest a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development.
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| 12. |
- Xu, Xianping, 2000-, et al.
(författare)
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Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel : A putative mechanism of antiseizure action
- 2008
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 80:1, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. Methods: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (β-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. Results: We found that PUFAs at concentrations down to 21 μM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5 mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. Conclusions: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels. © 2008 Elsevier B.V. All rights reserved.
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| 13. |
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| 14. |
- Broberg, Marita, 1973, et al.
(författare)
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Cell swelling precedes seizures induced by inhibition of astrocytic metabolism.
- 2008
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Ingår i: Epilepsy Res.. - : Elsevier BV. - 0920-1211. ; 80:2-3, s. 132-41
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Tidskriftsartikel (refereegranskat)abstract
- It is currently unknown what processes take place at the interface between non-ictal and ictal activity during seizure initiation. In this study, using paralysed awake rats, we focally inhibited astrocytic metabolism with fluorocitrate (FC), causing seizures. We measured changes in electroencephalogram (EEG) (0-300 Hz), and extracellular ion-concentrations during ictal onsets defining possible relationships with impedance-determined cell swelling. In animals showing ictal activity (69%) there were spike-wave discharges, spike-wave discharges followed by spreading depression and spreading depression without any discharges. In a high proportion of spike-wave discharges (>95%), just prior to the first spike-wave discharge, there was a decrease in the volume of the extracellular space. Following the initiation of cell swelling and prior to discharges, there were increases in high-frequency (150-300 Hz) EEG activity, increases in extracellular potassium- and decreases in extracellular calcium-concentrations. We suggest that EEG and ionic changes are not causative of cell swelling. Cell swelling due to metabolic failure in astrocytes at the injected site may release excitatory amino acids. At the same time, our results suggest ion homeostasis is not maintained and increased neuronal excitability and synchronisation occur. These could be the drivers changing normal brain activity into ictal activity.
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| 15. |
- Chioza, B., et al.
(författare)
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Evaluation of CACNA1H in European patients with childhood absence epilepsy
- 2006
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Ingår i: Epilepsy Res. - : Elsevier BV. - 0920-1211. ; 69:2, s. 177-81
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Tidskriftsartikel (refereegranskat)abstract
- CACNA1H was evaluated in a resource of Caucasian European patients with childhood absence epilepsy by linkage analysis and typing of sequence variants previously identified in Chinese patients. Linkage analysis of 44 pedigrees provided no evidence for a locus in the CACNA1H region and none of the Chinese variants were found in 220 unrelated patients.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Nilsson, Daniel, 1973, et al.
(författare)
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Bilateral diffusion tensor abnormalities of temporal lobe and cingulate gyrus white matter in children with temporal lobe epilepsy.
- 2008
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Ingår i: Epilepsy research. - : Elsevier BV. - 0920-1211. ; 81:2-3, s. 128-35
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Bilateral diffusion tensor imaging (DTI) abnormalities have been reported in the white matter associated to the hippocampus in adults with mesial temporal lobe epilepsy (TLE). In children with a shorter duration of epilepsy, such changes may not have yet emerged. The aim of this study was to investigate interictal changes in the temporal lobe white matter (TLWM) and cingulate gyrus white matter (CGWM) of children with TLE using DTI. METHODS: DTI was performed in eight children with TLE and 10 healthy, age-matched controls. Fractional anisotropy (FA), trace, parallel (lambda(||)) and perpendicular (lambda( perpendicular)) diffusivity were calculated for a volume of interest in the TLWM and CGWM on the seizure focus side and the contralateral side. Data were compared for differences between sides for patients and between patients and controls. RESULTS: There was no significant difference in FA, trace, lambda(||) and lambda( perpendicular) between TLWM and CGWM on the seizure focus side versus the contralateral side in TLE patients. Increased diffusivity, lambda(||) and lambda( perpendicular) within the TLWM and CGWM were found in TLE patients compared to controls, but no significant difference in FA was seen. CONCLUSIONS: Bilaterally increased diffusivity, lambda(||) and lambda( perpendicular) in the white matter in children with TLE may be related to seizure induced functional or structural changes. The preserved FA in our pediatric cohort is in contrast to the reduced FA in the white matter of adults with TLE and may relate to differences in the duration of epilepsy or in the vulnerability of white matter to seizures.
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| 20. |
- Nilsson, Daniel, 1973, et al.
(författare)
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Intersubject variability in the anterior extent of the optic radiation assessed by tractography
- 2007
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Ingår i: Epilepsy Res. - : Elsevier BV. - 0920-1211. ; 77:1, s. 11-6
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Temporal lobe resection for epilepsy involves a risk of damaging the anterior part of the optic radiation, Meyer's loop, causing a contralateral upper quadrant visual field defect. This study aims to assess the intersubject variability in the course of Meyer's loop in vivo by diffusion tensor imaging and tractography. METHODS: Seven healthy volunteers and two patients with previous temporal lobe resection were recruited. Diffusion tensor imaging and tractography were used to visualize the optic radiation. The distances from the anterior edge of Meyer's loop to landmarks in the temporal lobe were calculated. RESULTS: In the healthy subjects, the mean distance between the most anterior part of Meyer's loop and the temporal pole was 44mm (range 34-51mm). Meyer's loop did not reach the tip of the temporal horn in any subject. A disruption in Meyer's loop could be demonstrated in the patient with quadrantanopia after temporal lobe resection. CONCLUSIONS: Meyer's loop has a considerable variability in its anterior extent. Tractography may be a useful method to visualize Meyer's loop, and assess the risk of a visual field defect, prior to temporal lobe resection.
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