[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.RESULTS 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.INTERPRETATION 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.
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række. 07/2014; 134(12-13):1239-42.
[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.
Tidsskrift for den Norske laegeforening 01/2014; 134(1):37-41.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND. There are currently around 25 antiepileptic drugs in use in Norway, of which 15 have entered the market in the last 20 years. All have somewhat different effect- and adverse effect profiles and mechanisms of action. Here we present a brief overview of current knowledge regarding the basic mechanisms of action of these drugs.METHOD. The review is based on a discretionary selection of relevant articles found through a literature search in PubMed and our own clinical and research experience.RESULTS. There are, roughly speaking, four main mechanisms; 1) modulation of ion channels (sodium and calcium channel blockers, potassium channel openers), 2) potentiation of GABAergic inhibition, 3) reduction of glutamatergic excitation and 4) modulation of presynaptic neurotransmitter release. Some of the drugs have several mechanisms of action, and for some of them it is unclear which mechanism is clinically most important. To some extent, the drugs' mechanisms of action predict their effect against different types of epilepsy and seizures. For instance, sodium channel blockers work best against focal seizures, while calcium channel blockers work best against absences, a type of generalised seizure.INTERPRETATION. Optimal treatment of patients with epilepsy requires not only thorough knowledge of seizure- and epilepsy classification, but also insight into the mechanisms of action of antiepileptic drugs.
Tidsskrift for den Norske laegeforening 01/2014; 134(1):42-6.
[Show abstract][Hide abstract] ABSTRACT: Histone deacetylases (HDACs) are often overexpressed in cancer cells, leading to altered expression and activity of numerous proteins involved in carcinogenesis. Recent evidence suggests that expression of class I HDACs is increased in ovarian carcinomas and plays a significant role in carcinogenesis and resistance to chemotherapeutic agents. Two compounds, valproic acid (VPA) and levetiracetam (LEV), exhibit HDAC inhibitor (HDACI) activity in various cell types, but data concerning their activity in ovarian cancer are lacking. Here we compared the effects of VPA and LEV as HDACIs, using a human ovarian cancer cell line, OVCAR-3. Cells were cultured with VPA or LEV at concentrations between 1 and 10mM for 1 to 24h. HDAC activity was determined by fluorometric assay and confirmed by western blotting. Expression of HDAC genes was determined by real-time PCR and HDAC proteins expression was evaluated by western blotting. Additionally, we used high-performance liquid chromatography to determine whether OVCAR-3 cells can metabolize LEV to its major metabolite, 2-pyrrolidinone-n-butyric acid (PBA), which might exert HDACI activity. LEV, however, had no apparent effect on HDAC activity, or gene and protein expression. The OVCAR-3 cell line was able to metabolize LEV to PBA, but the effect was small. Our observations suggest that VPA should be considered as a possible adjunctive drug in ovarian cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: The long QT syndrome (LQTS) is an inherited cardiac channelopathy associated with syncope and sudden cardiac death due to ventricular arrhythmias and most frequently caused by potassium channel mutations. Potassium channels are also expressed in brain tissue and play an important role in idiopathic epilepsies. Recent reports have indicated that LQTS-related potassium channel mutations may co-express as concomitant epilepsy and LQTS.
To explore cerebral activity by means of EEG recordings in individuals with LQTS related to potassium channel mutations.
Seventeen individuals with confirmed LQTS related to potassium channel mutations (11 LQT1 and 6 LQT2) were prospectively studied with 21-channel electroencephalography (EEG). LQTS-related symptoms, co-morbidity, medication and QTc (12-lead ECG) were recorded. Sixteen healthy individuals previously studied with EEG served as a control group. All EEGs were reviewed by 2 independent Neurophysiologists.
EEG recordings were abnormal in 12/17 (71%) in the LQTS group, while abnormalities were present in only 2/16 (13%) of healthy controls (p<0.01). In the LQTS group, all abnormal EEGs showed a combination of theta activity and sharp waves. Two patients showed additional delta activity. None of the patients had definite epileptic activity (spikes, spike-waves).
Abnormal electrical cerebral activity was identified more frequently in subjects with LQTS secondary to a potassium channel mutation compared to healthy controls. This result indicates a possible link between cardiac and cerebral channelopathy.
Heart rhythm: the official journal of the Heart Rhythm Society 09/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to investigate immunoglobulin levels in patients with epilepsy using the antiepileptic drugs (AED) levetiracetam (LEV), carbamazepine (CBZ), or lamotrigine (LTG).
A total of 211 patients and 80 controls (age: 18-45 years) of both genders were included. The patients had been treated with either LEV (n = 47), CBZ (n = 90), or LTG (n = 74) monotherapy for at least 6 months. Total concentrations of immunoglobulin G (IgG), IgG subclasses (IgG1, IgG2, IgG3, and IgG4), immunoglobulin A (IgA), and immunoglobulin M (IgM) were measured. Smoking, drinking habits, and physical activity were recorded, and body mass index (BMI) was calculated.
A significantly lower total IgG and IgG1 was found in both men and women treated with LTG and in men on CBZ. IgG2 and IgG4 were also lower in LTG-treated women, and IgA and IgM were lower in LTG-treated men. Patients treated with LEV did not differ from the control group.
Low levels of immunoglobulins were found in patients with epilepsy treated with LTG or CBZ. As our group of patients consisted of otherwise healthy young adults, one should be especially aware of a possible effect of AEDs on immunoglobulin levels when treating selected patient groups, for example immunocompromised patients. Immunoglobulin concentrations should be measured in patients treated with LTG or CBZ who experience recurrent infections, and a change in medication should be considered.
[Show abstract][Hide abstract] ABSTRACT: Antiepileptic drugs (AEDs) have been associated with cardiac conduction abnormalities and arrhythmias, predominantly in patients with predisposing cardiac conditions. Ventricular late potentials (VLPs) detected in the signal-averaged electrocardiogram (SAECG) may imply an increased risk of ventricular tachycardia or fibrillation. Twenty-six AED-naïve patients with newly diagnosed epilepsy and no clinical evidence of heart disease were examined with SAECG and standard ECG. Fifteen patients were treated with lamotrigine and ten with carbamazepine. No significant abnormality was found in the standard ECG or SAECG three to nine months after initiation of AED therapy. In one patient, a VLP was detected at baseline and subsequent MRI demonstrated significant right ventricular pathology; therefore, this patient was excluded from the rest of the study. This exclusion along with only newly diagnosed patients with a low total seizure count being included in the study may explain the lack of AED-induced electrocardiographic abnormalities in this patient cohort.
[Show abstract][Hide abstract] ABSTRACT: Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of β-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.
Journal of Neuropathology and Experimental Neurology 08/2012; 71(9):814-25. · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The reasons why the mortality of patients with epilepsy is significantly increased, even many years after seizure onset, are not fully understood. The aim of this study was to compare the distribution of the causes of death (COD) in an epilepsy population with that in the general population and with previous findings in other epilepsy populations. In addition, we investigated the chronological relationship between the onset of epilepsy and the onset of the diseases leading to death.
The COD for patients who were registered with a diagnosis of epilepsy at Stavanger University Hospital from August 1 1995-July 31 2005 and died during the same period were obtained from the Norwegian Cause of Death Registry and the hospital records were reviewed. The distribution of the corresponding COD in the general population was obtained from Statistics Norway.
At least 6.8% (18/266) of the deaths of epilepsy patients were directly related to seizures. Epilepsy patients who had died from brain tumors (n=46) were excluded from further analysis. Of the remaining 220 deceased epilepsy patients, 39 (17.7%) had died from heart disease, compared with 27.8% in the general population (p<0.001). No other significant differences in the distribution of COD in the epilepsy population and the general population were identified. The majority of the epilepsy patients who died from heart disease (71.8%) and cerebrovascular disease (72%) had cardiovascular disease prior to seizure onset and in at least 43% of those who died from neoplasms the onset of malignancy occurred before the first seizure.
Comorbid diseases and underlying conditions were the major determinants of mortality in this population of epilepsy patients. Conditions that are not caused by epilepsy or its treatment may represent an important explanation for the previously documented excess mortality in people with epilepsy.
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that due to its cytotoxic and cytostatic activities, valproic acid (VPA), but not levetiracetam (LEV), may have potential as a drug for treating human ovarian cancer. In the present study, we compare apoptotic mechanisms including gene and protein expression in the human ovarian cancer cell line, OVCAR-3, following exposure to VPA and LEV.
Cells were cultured with VPA or LEV at concentrations between 0.1 mM and 10 mM. Apoptosis was assessed by DNA fragmentation assay and expression of apoptosis-regulatory genes determined by real-time PCR and confirmed by western blotting. Time-dependent effects of VPA and LEV on activity of caspases (-3, -8 and -9) activity were evaluated by fluorescent assay and western blotting.
Exposure to VPA at concentrations above 5 mM resulted in an increase in DNA fragmentation, modulated expression of genes and proteins associated with apoptosis and activated caspases cascade. Exposure to LEV, however, did not affect DNA fragmentation and modulation of the mechanisms of apoptosis was not observed in LEV-treated cells at all doses used.
Exposure to high concentrations of VPA significantly stimulated apoptosis, by modulating the expression of genes and proteins responsible for cell death and also by activation of caspases cascade. Such effects were not observed with LEV. These data suggest that VPA should be seriously evaluated as an anti-cancer drug for ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: Concentration- and time-dependent effects of two antiepileptic drugs (AEDs), levetiracetam (LEV) and valproic acid (VPA), on proliferation, cytotoxicity and expression of cell cycle regulatory genes were investigated in a human ovarian cancer cell line, OVCAR-3. Cells were cultured with VPA or LEV, at concentrations between 100 μM and 10 mM. Cell proliferation was determined by alamarBlue and BrdU incorporation assays; cytotoxic effects by tetrazolium hydroxide (XTT), acid phosphatase (AP) and lactate dehydrogenase (LDH) assays. Expression of cell cycle regulatory genes was determined by real-time PCR. Exposure to VPA caused a concentration- and time-dependent decrease in cell proliferation (alamarBlue and BrdU incorporation assays), cytotoxic effects above 2.5 mM (XTT and AP assays) and modulated expression of genes primarily responsible for cell cycle arrest in G(1) phase. Cell proliferation was unaffected by exposure to LEV for 24 h and 120 h (alamarBlue assay), but increased when exposed to LEV for 72 h and 168 h, at concentrations from 250 μM to 1 mM. The BrdU incorporation assay showed no effect of LEV on cell proliferation. LEV was cytotoxic at higher concentrations (AP assay), but modulation in expression of cell cycle regulatory genes was not observed. Changes in LDH release were not observed with either AED. In summary, VPA apparently decreased cell proliferation by down-regulating genes responsible for transition from G(1) to S phase and up-regulating genes responsible for G(1) phase arrest, which suggest its potential as an anticancer drug. LEV does not exhibit such action.
[Show abstract][Hide abstract] ABSTRACT: To estimate the incidence of sudden unexpected death in epilepsy (SUDEP) in Rogaland County, Norway, in the period August 1 1995-July 31 2005, and to investigate whether use of lamotrigine (LTG) was associated with increased risk in female patients or other subgroups.
SUDEP victims were identified from autopsy reports and data from the Norwegian Cause of Death Registry. In all cases where SUDEP was considered as a possible cause of death, the hospital records were also reviewed. For each deceased, at least three living patients with epilepsy were randomly selected as controls. The market share in defined daily doses was collected for each year to estimate the number of patient-years at risk on each antiepileptic drug.
We identified 26 cases of SUDEP: 16 definite, 3 probable, and 7 possible; 15 patients were female and 11 were male. Of these, 10 patients (38.5%) were treated with LTG: 9 of these patients were female. The incidence of SUDEP was estimated as 1.0 per 1,000 patient-years when all cases were included, and 0.7 per 1,000 patient-years for definite and probable SUDEP. Seven of 12 (58.3%) of female patients with definite and probable SUDEP and 10 of 41 (24.4%) of controls matched on age and gender were on LTG (p = 0.038). The incidence of definite and probable SUDEP in women on LTG, was estimated as 2.5 per 1,000 patient-years and 0.5 per 1,000 patient-years in female who were not taking LTG (p = 0.007).
The incidence of SUDEP was significantly higher among female patients with epilepsy who were being treated with LTG than among female patients with epilepsy who were not taking LTG, and a significantly higher proportion of female SUDEP cases than controls were taking LTG. Our findings may have implications for treatment of epilepsy in female patients.
[Show abstract][Hide abstract] ABSTRACT: Pharmacoresistance continues to be a major challenge in Temporal Lobe Epilepsies (TLE). A key to overcome pharmacoresistance is to identify subgroups among the TLE and disclose their specific molecular pathways. This will facilitate a tailored pharmacological treatment and improve outcome. There is growing evidence in favor of the theory that TLE with childhood febrile seizures (TLE-FS) may represent one distinctive subgroup among the TLE.
We compared clinical features from 102 TLE-FS patients with 105 TLE patients without FS. We also conducted a logistic regression analysis to adjust for possible confounders caused by overrepresentation of patients with Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) in the TLE-FS group.
MTLE-HS was overrepresented in patients with TLE-FS (p=0.043). Age at epilepsy onset was lower in patients with TLE-FS (p<0.001). TLE-FS patients had a higher frequency of first grade family members with FS (p=0.003, adjusted for MTLE-HS: p=0.002). They were more frequently plagued with simple partial seizures (p=0.015, adjusted: p=0.038), and especially with vertiginous symptoms (p=0.004 adjusted: p=0.006). They also had the higher frequency of autonomic symptoms (p=0.003; adjusted: p=0.012), and more generalized tonic-clonic seizures (0.034; adjusted p=0.038).
We identified TLE-FS as a phenotype that can be delineated from other TLE. None of the characteristics are specific, but we disclosed a set of features also when adjusted for MTLE-HS.
[Show abstract][Hide abstract] ABSTRACT: Little is known about the haematological side effects of the newer antiepileptic drugs (AEDs), but recent case reports have raised concerns regarding the possibility of altered thrombocyte counts or function in some patients during levetiracetam (LEV) treatment. The aim of our study was to investigate haematological changes in patients treated with the newer AEDs, LEV and lamotrigine (LTG), compared with the older AEDs, valproate (VPA) and carbamazepine (CBZ).
This cross-sectional study included 251 patients with epilepsy of both genders, aged 18-45 years, using AED monotherapy: 52 patients on LEV (31 men, 21 women), 80 on LTG (37 men, 43 women), 90 on CBZ (61 men, 29 women), 29 on VPA (15 men, 14 women), and 79 healthy controls (36 men, 43 women). Haemoglobin (Hb), white blood cells (WBC) and platelet (thrombocyte) counts were estimated. The subjects were recruited from hospitals in south-eastern Norway and Innsbruck, Austria.
Significantly lower platelet counts were recorded in both men and women on LEV monotherapy. In the LEV group, platelets were 14% lower (40.68 × 10(9) /l lower) than in the control group. There was no difference according to sex or age of the patients. Only minor changes in haematological parameters were observed for the other drugs investigated.
Both men and women treated with LEV monotherapy have lower blood platelet counts than healthy controls, with no difference in Hb or WBC. Haematological changes observed with the other AEDs were minor.
[Show abstract][Hide abstract] ABSTRACT: Patients with epilepsy have a 2-6 times greater risk of bone fractures compared with the general population. There are several potential explanations. Some fractures are caused by seizure-related injuries, or they may be associated with the osteopenic effect of reduced physical activity in patients with epilepsy. Antiepileptic drugs (AEDs), especially those that affect the liver enzymes, e.g., phenytoin, carbamazepine, phenobarbital, as well as valproate, are also associated with increased fracture rate and low bone mineral density. Many patients with epilepsy and general practitioners seem unaware of this problem. Measurements of bone density should be taken regularly in patients at risk of developing osteoporosis. Non-pharmaceutical initiatives, such as partaking in regular physical activity and eating a well-balanced diet, should be recommended. The risk of developing osteoporosis should be taken into consideration in the selection of an AED for treating a newly diagnosed patient with epilepsy.