[Show abstract][Hide abstract] ABSTRACT: For children with pharmacoresistant epilepsy, the ketogenic diet is an established treatment option worldwide. However, for adults, this treatment is less frequently offered, and its efficacy less well-documented. The aim of this study was to examine efficacy and tolerability of such a diet as an adjuvant therapy to antiepileptic drugs for adult patients with pharmacoresistant generalized epilepsy. Thirteen patients (12 women) aged 16-57years were included prospectively. They were treated with a modified Atkins diet for 12weeks. Nine of the 13 participants had juvenile myoclonic epilepsy (JME), two had childhood absence epilepsy, one had Jeavons syndrome, and one had generalized epilepsy of unknown type. Six participants, all with JME, completed the 12-week study period. Among these six, four had >50% seizure reduction. Their seizure severity, using the revised Liverpool Seizure Severity Scale, was reduced by 1, 5, 57.5, and 70 points, respectively (scale: 1-100 points). In three of these four responders, quality of life, assessed by QOLIE-89, increased more than 20 points (scale: 0-100 points). Mean reduction of body weight after 12weeks on diet was 6.5 (range: 4.3-8.1) kg. Lack of motivation, poor compliance, and seizure aggravation were the main reasons for premature termination of the diet. Apart from one patient who developed gallstones when ending the treatment after 10months, no adverse effects were noted. In conclusion, using a modified Atkins diet for 12weeks led to a clinically relevant reduction of seizure frequency in four of thirteen adult patients with pharmacoresistant generalized epilepsy. All responders were diagnosed with JME. In three of the four, the benefits of diet were so considerable that they chose to continue the treatment.
No preview · Article · Dec 2015 · Epilepsy & Behavior
[Show abstract][Hide abstract] ABSTRACT: Objective:
Patients treated with carbamazepine (CBZ) have increased serum levels of total cholesterol (TC), high-density lipoproteins (HDL), and low-density lipoproteins (LDL). We aimed to investigate whether these changes of serum lipids are reversible after CBZ withdrawal.
Material and methods:
We used a prospective, randomized double-blinded design. A total of 160 patients who had been seizure free on anti-epileptic drug monotherapy for more than 2 years were included and randomized to withdrawal or not. The intervention was completed by 150 (80 females, 53%) patients. Serum samples from before and 4 months after completed withdrawal or no withdrawal were obtained from 130 patients (63 females, 48%). Of these, 84 were treated with CBZ, 28 with valproate, nine with phenytoin, four with phenobarbital, and five with lamotrigine. Of the patients who had been treated with CBZ, 47 were randomized to the withdrawal group, and 37 were randomized to the non-withdrawal group.
Among the CBZ-treated patients, a significant decrease in serum levels of TC, LDL, and apolipoprotein B (ApoB) were found in the withdrawal group compared with the non-withdrawal group. Mean differences in change were as follows: TC 0.68 mmol/l (P = 0.005, CL - 1.15 to -0.21); LDL - 0.67 mmol/l (P = 0.001, CL - 1.03 to -0.29); ApoB - 0.13 g/l (P = 0.02, CL - 0.23 to -0.03). No significant changes in HDL, apolipoprotein A, and C-reactive protein were detected.
Our results indicate that CBZ may have unfavorable effects on serum levels of TC, LDL, and ApoB. However, these changes seem to be reversible even after years of treatment.
No preview · Article · Nov 2015 · Acta Neurologica Scandinavica
[Show abstract][Hide abstract] ABSTRACT: Reproductive endocrine dysfunction is common among both women and men with epilepsy. The reasons for this are multifactorial and bidirectional; epilepsy can affect hormones, and hormones can affect seizures. Furthermore, several antiepileptic drugs (AEDs) can have endocrine side-effects, while psychosocial factors and co-morbidity add further complexity. Animal models and experimental models using human tissue or cell lines provide new approaches to investigating the independent effects of the epilepsy itself, hormonal effects, and the effects of AEDs, in isolation and without confounding factors. This paper reviews the literature regarding animal studies and selected experiments using human cell lines related to reproductive endocrine function in epilepsy. By comparing results from clinical and experimental studies and by developing appropriate animal models, several mechanistic questions regarding the complex interplay between epilepsy, hormones, and AEDs can be explored. Animal experiments should be an integral tool in the study of reproductive endocrine disorders in epilepsy.
Preview · Article · Jun 2015 · Zeitschrift für Epileptologie
[Show abstract][Hide abstract] ABSTRACT: Astrocytic endfeet are specialized cell compartments whose important homeostatic roles depend on their enrichment of water and ion channels anchored by the dystrophin associated protein complex (DAPC). This protein complex is known to disassemble in patients with mesial temporal lobe epilepsy and in the latent phase of experimental epilepsies. The mechanistic underpinning of this disassembly is an obvious target of future therapies, but remains unresolved. Here we show in a kainate model of temporal lobe epilepsy that astrocytic endfeet display an enhanced stimulation-evoked Ca(2+) signal that outlast the Ca(2+) signal in the cell bodies. While the amplitude of this Ca(2+) signal is reduced following group I/II metabotropic receptor (mGluR) blockade, the duration is sustained. Based on previous studies it has been hypothesized that the molecular disassembly in astrocytic endfeet is caused by dystrophin cleavage mediated by Ca(2+) dependent proteases. Using a newly developed genetically encoded Ca(2+) sensor, the present study bolsters this hypothesis by demonstrating long-lasting, enhanced stimulation-evoked Ca(2+) signals in astrocytic endfeet.
Full-text · Article · Feb 2015 · Frontiers in Cellular Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of Hexokinase 1, which channels fructose into glycolysis, and whose activity was similar to fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Feb 2015 · Journal of Neurochemistry
[Show abstract][Hide abstract] ABSTRACT: Background
Modified Atkins diet is a treatment option for patients with pharmacoresistant epilepsy that is not suitable for surgery. In the last few years, we have tried dietary treatment added to antiepileptic drugs (AEDs) in adult patients with severe epilepsy.Aim of the studyTo examine a possible pharmacokinetic interaction between the modified Atkins diet and AEDs.Methods
In four patients, AED serum concentrations were measured before onset and after 4 and 12 weeks on the diet. The patients used combinations of two or three AEDs, including carbamazepine, clobazam, lamotrigine, nitrazepam, oxcarbazepine, valproate, zonisamide, and topiramate. The patients did not change the type or dose of their AEDs during the diet period.ResultsAfter 12 weeks on the diet, the average serum concentrations of the respective AEDs were reduced by 35% (range 6–46%) compared to prediet values.Conclusions
Modified Atkins diet used as add-on therapy to AEDs in four patients with drug resistant seizures caused a considerable decrease in AED serum concentrations. In individual patients, this could be of clinical relevance, and we recommend that AED serum concentrations should be closely monitored when offering this diet to adults with epilepsy.
No preview · Article · Oct 2014 · Acta Neurologica Scandinavica
[Show abstract][Hide abstract] ABSTRACT: Background:
In pregnant women with epilepsy the use of antiepileptic drugs may increase the risk of harming the foetus. For the treating neurologist it may be challenging to find a balance between optimal seizure control and the lowest possible drug dosage. The aim of this study was to assess the prevalence and type of congenital malformations in children exposed to antiepileptic drugs during pregnancy.
Material and method:
In Norway we have prospectively followed 813 pregnancies in women with epilepsy as part of an international cohort study. The women had three check-ups during the pregnancy, and the children were followed up twice during their first year of life.
We found a total of 34 congenital malformations in the children, of which 12 were heart defects, yielding a malformation rate of 4.5%. Six of the malformations (18%) were detected prenatally, 20 (59%) were reported immediately after birth, and eight (24%) were discovered during the child's first year of life.
Our study shows that 95.5%.of the women included who used antiepileptic drugs during pregnancy gave birth to a healthy child. This Norwegian cohort is too small to evaluate the teratogenic risk associated with the individual drugs.
Preview · Article · Jul 2014 · Tidsskrift for den Norske laegeforening
[Show abstract][Hide abstract] ABSTRACT: Objective:
Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans.
We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients.
Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE.
Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND Brain research in the last century was mainly directed at neurons, with the role of glia assumed to be limited to repair, supplying nutrients and above all acting as a packing material between neurons. In recent years, the importance of glial cells for normal brain function has been recognised. This article summarizes knowledge of glial cells of relevance to epilepsy.METHOD The article is based on a literature search in PubMed as well as the authors' clinical and research experience.RESULTS Astrocytes are the largest subgroup of glial cells and, in common with neurons, have diverse membrane transporters, ion channels and receptors. Among the most important roles of astrocytes are the uptake and redistribution of ions and water, glucose metabolism and communication with nerve cells. Disturbances in all of these functions have been associated with epilepsy.INTERPRETATION Epilepsy has previously been regarded as exclusively a disturbance in the functioning of neurons and especially of their contact points, the synapses. The mechanisms of action of today's anti-epileptic drugs are therefore primarily directed at neuronal channels and receptors. New knowledge of the role played by glial cells could increase our understanding of how epilepsy arises and could lead to new treatment strategies.
No preview · Article · Jan 2014 · Tidsskrift for den Norske laegeforening