Eslicarbazepine acetate: its effectiveness as adjunctive therapy in clinical trials and open studies.

Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug that is approved as adjunctive therapy in adults with focal-onset seizures. Following oral administration, ESL is rapidly metabolized to its active metabolite, eslicarbazepine, which acts primarily by enhancing slow inactivation of voltage-gated sodium channels. The efficacy and safety/tolerability of ESL in the adjunctive setting were established in a comprehensive Phase III program (n = 1702 randomized patients) and this evidence has been supported by several open studies (n = 864). ESL treatment has demonstrated improvements in health-related quality of life, in both randomized clinical trials and open studies. ESL has also been shown to be usually well tolerated and efficacious when used in the adjunctive setting in elderly patients. The effectiveness of ESL as the only add-on to antiepileptic drug monotherapy has been demonstrated in a multinational study (n = 219), subgroup analyses of which have also shown it to be efficacious and generally well tolerated in patients who had previously not responded to carbamazepine therapy. Open studies have also demonstrated improvements in tolerability in patients switched overnight from oxcarbazepine to ESL. Due to differences in pharmacokinetics, pharmacodynamics, and metabolism, there may be clinical situations in which it is appropriate to consider switching patients from oxcarbazepine or carbamazepine to ESL.

Changes in interleukin-6 levels during electroconvulsive therapy may reflect the therapeutic response in major depression.

OBJECTIVE: Interleukin-6 (IL-6) has been reported to be elevated in major depressive disorder (MDD) but decreased by antidepressive medication. IL-6 levels are markedly elevated both after epileptic seizures and single electroconvulsive therapy (ECT) session, but long-term changes in IL-6 levels after ECT have not been studied. The correlation between immediate and long-term changes in proinflammatory cytokines and outcome after ECT was investigated. METHOD: Thirty patients suffering from MDD participated in the study. IL-6, interleukin-1ß (IL-1ß) and interleukin-1 receptor antagonist (IL-1RA) levels were examined at baseline and at 2 and 4 h after the first, fifth and the last ECT sessions. The response to ECT was measured with Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: ECT repeatedly caused an increase in IL-6 levels at the 4-h time point. However, the baseline IL-6 levels decreased among remitters, but not among non-remitters, towards the end of ECT. IL-1ß levels were mostly below detectable level, and IL-1Ra levels did not change during and after ECT. CONCLUSION: ECT has distinct acute and long-term effects on IL-6 levels. Interestingly, the long-term effect of ECT on IL-6 seems to correlate with outcome, providing further evidence of the mechanism of action of ECT and supporting the inflammation theory in MDD.

Outcome based definition of the anterior thalamic deep brain stimulation target in refractory epilepsy.

BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT) is an emerging therapy for refractory focal epilepsy. However, the most optimal target for stimulation has not been unambiguously described. OBJECTIVE: In the present study, we investigated the correlation between the stimulation site and outcome in order to define the optimal target for deep brain stimulation in refractory epilepsy. METHODS: The locations of 62 contacts used in 30 treatment attempts in 15 prospectively followed patients during a 5 year period were assessed. Treatment attempts were classified into responding and non-responding trials using seizure reduction and side effect profile as criteria. The locations of active contacts were calculated with respect to mid-commissural point and visible borders of ANT in 3T MRI (ANT-normalized coordinate system) aiming to minimize the confounding effect of individual variation in the location and size of the ANT. RESULTS: Contacts in successful treatment trials were located significantly more anterior and superior both in AC-PC and ANT-normalized coordinate systems. Favourable outcome was observed at 3T MRI based location of ANT but not at location predicted by Schaltenbrandt atlas sagittal data. Contacts used in successful trials were at anterior aspect of the ANT complex evidenced by the ANT-normalized coordinate system. CONCLUSION: The anti-epileptic effect of anterior thalamic DBS may be dependent on stimulation site especially in the anterior to posterior axis. Extensive anatomical variation confounds severely the targeting of ANT. Therefore, direct visualization of the desired target for stimulation is essential for favourable outcome in refractory epilepsy.

Defining the anterior nucleus of the thalamus (ANT) as a deep brain stimulation target in refractory epilepsy: Delineation using 3 T MRI and intraoperative microelectrode recording.

BACKGROUND: Deep brain stimulation (DBS) is a minimally invasive and reversible method to treat an increasing number of neurological and psychiatric disorders, including epilepsy. Targeting poorly defined deep structures is based in large degree on stereotactic atlas information, which may be a major source of inconsistent treatment effects. AIM OF THE STUDY: In the present study, we aimed to study whether a recently approved target for epilepsy (anterior nucleus of thalamus, ANT) is visualized in clinically established 3 T MRI and whether ANT is delineated using intraoperative microelectrode recording (MER). We have especially focused on individual variation in the location of ANT in stereotactic space. We also aimed to demonstrate the role of individual variation in interpretation of MER data by projecting samples onto AC-PC (anterior and posterior commissure) and ANT-normalized coordinate systems. METHODS: Detailed analysis of ANT delineations in 3 T MRI short tau inversion recovery (STIR) images from eight patients undergoing DBS for refractory epilepsy was performed. Coronal and sagittal cross-sectional models of ANT were plotted in the AC-PC coordinate system to study individual variation. A total of 186 MER samples collected from 10 DBS trajectories and 5 patients were analyzed, and the location of each sample was calculated and corrected accordingly to the location of the final DBS electrode and projected to the AC-PC or coordinate system normalized to ANT. RESULTS: Most of the key structures in the anatomic atlas around ANT (mammillothalamic tract and external medullary lamina) were identified in STIR images allowing visual delineation of ANT. We observed a high degree of anatomical variation in the location of ANT, and the cross-sectional areas overlapped by study patients decreased in a linear fashion with an increasing number of patients. MER information from 10 individual trajectories correlated with STIR signal characteristics by demonstrating a spike-negative zone, presumably white matter layer, at the lateral aspect of ANT in ANT-normalized coordinate system as predicted by STIR images. However, MER information projected to the AC-PC coordinate system was not able to delineate ANT. CONCLUSIONS: ANT is delineated in 3 T MRI by visualization of a thin white matter lamina between ANT and other nuclear groups that lack spiking activity. Direct targeting in the anterior thalamic area is superior to indirect targeting due to extensive individual variation in the location of ANT. Without detailed imaging information, however, a single trajectory MER has little localizing value.

Cardiolipin and ß2-Glycoprotein I antibodies associate with cognitive impairment and seizure frequency in developmental disorders.

Cardiolipin (CL) and ß(2)-Glycoprotein I (ß(2)-GpI) antibodies have been shown to associate with various neurological symptoms including seizures and cognitive dysfunction. Here we studied the prevalence of CL, ß(2)-GpI and antinuclear (ANA) antibodies in 74 patients with various developmental disorders with epilepsy and 70 healthy controls. Developmental disorders were classified into genetic syndromes and diseases, genetic and/or acquired conditions, cortical dysgenesias and acquired encephalopathias. IgM-CL and ß(2)-GpI antibodies were significantly more common in patients (46% vs. 20%, p<0.001 and 10% vs. 0%, p<0.05). Patients with most frequent seizures were more likely to have IgM-CL antibodies. The risk for positive IgM-CL, IgG-CL and ß(2)-GpI antibodies increased concomitantly with increasing intellectual disability. Present data demonstrates that epilepsy with frequently recurring seizures may be associated with secondary immune system activation.

Boar spermatozoa as a biosensor for detecting toxic substances in indoor dust and aerosols.

The presence, quantity and origins of potentially toxic airborne substances were searched in moisture damaged indoor environments, where building related ill health symptoms were suspected and reference sites with no health complaints. Boar spermatozoa were used as the toxicity sensor. Indoor aerosols and dusts were collected from kindergartens, schools, offices and residences (n=25) by electrostatic filtering, vacuuming, wiping from elevated surfaces and from the interior of personal computers. Toxicity was measured from the ethanol or methanol extracts of the dusts and aerosols. EC(50) was expressed as the lowest concentration of the airborne substance that inhibited motility of >50% of the exposed sperm cells compared to vehicle control, within 30 min, 1 day or 3-4 days of exposure. Remarkably toxic aerosols (EC(50)

Idiopathic generalized epilepsies: a follow-up study in a single-center.

OBJECTIVE: To characterize adult patients with idiopathic generalized epilepsies (IGEs) with precise evaluation and to assess factors related to refractoriness. MATERIALS AND METHODS: Hospital records of all our patients with IGEs (n = 128) were evaluated in 2005 and followed-up until 2008. RESULTS: In 2005, 76% of patients were 1-year seizure-free. Seizure freedom increased to 82% during the 3-year follow-up. Seizure freedom was not significantly associated with age, age at diagnosis, epilepsy duration, exposure to inappropriate initial antiepileptic drug (AED), or delay time between starting initial AED and appropriate AED. Women constituted 78% of patients with merely provoked seizures. In 58% of women with recent seizure, one to two avoidable precipitating factors, such as lack of sleep, alcohol, and forgetting to take AED, were observed. In 2008, all patients with no medication, 91% of monotherapy patients, 60% of patients on two AED, and 14% of patients on three AED were seizure-free. CONCLUSIONS: Most of patients with IGEs can be successfully treated with monotherapy. Refractory seizures in some patients may be because of avoidable factors, especially in young women.

Dosimetry and image quality of four dental cone beam computed tomography scanners compared with multislice computed tomography scanners.

OBJECTIVES: The aim of this study was to evaluate the radiation dose and image quality of four dental cone beam CT (CBCT) scanners, and to compare them with those of two multislice CT (MSCT) scanners. METHODS: Tissue doses were measured using a tissue-equivalent anthropomorphic RANDO Head Phantom((R)) with thermoluminescence dosemeters (TLD). An RSVP Head Phantom(TM) with a specially designed cylindrical insert was used for comparison of image quality and absorbed dose. Image quality was evaluated in the form of contrast-to-noise ratio (CNR) and modulation transfer function (MTF). RESULTS: Using standard imaging parameters, the effective doses varied between 14 microSv and 269 microSv (International Commission on Radiation Protection (ICRP) 1990) and 27 microSv and 674 microSv (ICRP 2008) with the CBCT scanners, and between 350 microSv and 742 microSv (ICRP 1990) and 685 microSv and 1410 microSv (ICRP 2008) with the MSCT scanners. The CNR of the CBCT and MSCT scanners were 8.2-18.8 and 13.6-20.7, respectively. Low-dose MSCT protocols provided CNRs comparable with those from CBCT scanners. The 10% MTF of the CBCT scanners varied between 0.1 mm(-1) and 0.8 mm(-1), and was 0.5 mm(-1) for all the MSCT protocols examined. CONCLUSIONS: CBCT scanners provide adequate image quality for dentomaxillofacial examinations while delivering considerably smaller effective doses to the patient. Large variations in patient dose and image quality emphasize the importance of optimizing imaging parameters in both CBCT and MSCT examinations.

Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: A video-EEG study.

UNLABELLED: Experimental and clinical studies have shown that prolonged seizures result in increased cytokine production in the central nervous system. The purpose of this study was to examine plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-1 beta (IL-1beta) in 20 patients with epilepsy undergoing a video-EEG study. Plasma samples were obtained at the onset of the recordings and 3, 6, 12 and 24 h after the index seizure. Localization of the seizure focus and classification of epilepsy was based on concordant electroclinical findings in the video-EEG study, and on MRI examination. Patients were divided into two groups: temporal lobe epilepsy (TLE) (n=11), and extratemporal lobe epilepsy (XLE) (n=9). RESULTS: Only the TLE group showed significant increase in plasma levels of IL-6 peaking at 6 h postictally. Postictal plasma levels of IL-1RA and IL-1beta did not significantly differ from baseline levels in either of the patient groups. IL-1RA showed a decreasing trend (p>0.059) in TLE patients during 12 to 24 postictal hours. CONCLUSIONS: This study further supports the role of focal seizures in regulation of cytokine responses.

Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity.

BACKGROUND: Previous studies have associated coeliac disease (CD) and gluten sensitivity (defined as the presence of anti-gliadin antibodies and positive immunogenetics) with cerebellar degeneration and epilepsy with occipital calcifications. Hippocampal sclerosis (HS) in temporal lobe epilepsy (TLE) is a potentially progressive disorder with unknown aetiology; however, autoimmunity has been implicated as one of the possible mechanisms leading to HS. The purpose of this study is to analyze CD-associated antibodies and gluten sensitivity in a well-characterised group of patients with refractory focal epilepsy. METHODS: We measured anti-gliadin, anti-tissue-transglutaminase and anti-endomysium antibodies, and coeliac-type human leukocyte antigen (DQ2 and DQ8), in 48 consecutive patients with therapy-resistant, localisation-related epilepsy. The patients were categorised into the following three groups on the basis of ictal electro-clinical characteristics and the findings of high resolution MRI: TLE with HS (n = 16), TLE without HS (n = 16) and extratemporal epilepsy (n = 16). Patients with suspected CD or gluten sensitivity underwent duodenal biopsies. RESULTS: Seven patients in total were gluten sensitive; all of these patients fell in the TLE with HS group. On the other hand, none of the TLE without HS patients or those with extratemporal epilepsy were gluten sensitive (p<0.0002). The results of duodenal biopsies showed that three of the seven gluten-sensitive patients had histological evidence of CD and four had inflammatory changes consistent with early CD without villous atrophy. Four of the patients with gluten sensitivity had evidence of dual pathology (HS+another brain lesion), whereas none of the remaining patients did (p<0.0002). CONCLUSIONS: The present study demonstrates a previously unrecognised link between gluten sensitivity and TLE with HS. This association was very robust in this well-characterised group of patients; thus gluten sensitivity should be added to the list of potential mechanisms leading to intractable epilepsy and HS.

The high prevalence of antiphospholipid antibodies in refractory focal epilepsy is related to recurrent seizures.

BACKGROUND: Previous studies have shown the association between antiphospholipid antibodies with epilepsy but there are no studies addressing the effect of seizure frequency, duration of epilepsy, epilepsy type and aetiology on the prevalence of these antibodies in well-evaluated refractory epilepsy. METHODS: Anticardiolipin, anti-beta2-glycoprotein I and antinuclear antibody levels were measured in 105 well-evaluated patients with refractory focal epilepsy. Clinical determinants included the patient history, electroclinical classification and high resolution brain magnetic resonance imaging. RESULTS: Patients with seizures during the month prior to sampling (recent seizures) had increased prevalence of immunoglobulin (Ig) G class anticardiolipin antibodies (29%) compared with healthy controls [13%; age-adjusted odds ratio (OR): 3.09, 95% confidence interval (CI): 1.30-7.34] and patients with no recent seizures (11%; age-adjusted OR: 4.00, CI: 0.84-19.02). The patients with recent seizures had increased prevalence of moderate positive IgG class anticardiolipin antibodies (12%) compared with the controls (4%) and the patients with no recent seizures (0%; age-adjusted OR: 4.45, CI: 1.14-17.36). The prevalence of IgG class anticardiolipin antibodies was not associated with epilepsy type, duration or aetiology. CONCLUSION: The presence of antiphospholipid antibodies is associated with recurrent seizures in patients with refractory focal epilepsy. The measurement of these antibodies may be useful in evaluating the outcome of epilepsy.

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study.

OBJECTIVES: We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively. METHODS: We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital. RESULTS: There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. CONCLUSIONS: Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

Accuracy of linear measurements using dental cone beam and conventional multislice computed tomography.

OBJECTIVES: The aim of this study was to evaluate the accuracy of linear measurements obtained with dental cone beam CT (CBCT) and multislice CT (MSCT) by altering radiation doses using pre-operative planning of the placement of oral implants as a model. METHODS: A human cadaver mandible was examined in two edentulous areas and one dentate area using CBCT and MSCT. The mandible was examined both dry and immersed in sucrose solution isointense with soft tissue. Two readers measured four linear distances twice from each section. The mandible was cut into 4 mm thick slices at three marked places. These slices were microradiographed and used as the gold standard for measurements from each section. RESULTS: The intraclass correlations between the intra- and interobserver readings obtained with the different methods showed almost perfect matches. The measurement error (ME) showed significant differences between the methods studied (P = 0.022): the mean ME was 4.7% for CBCT and 8.8% for MSCT of the dry mandible, 2.3% and 6.6%, respectively, for the mandible immersed in sucrose solution and 5.4% for low-dose MSCT. Lowering the MSCT radiation dose to less than a quarter of its conventional original value did not significantly affect the ME. CONCLUSIONS: CBCT is a reliable tool for implant-planning measurements when compared with MSCT. In this study, a considerable radiation dose reduction could be achieved with low-dose MSCT examinations without a major loss of measurement accuracy.

Clinical predictors in patients with refractory epilepsy exposed to levetiracetam: a single-center study.

OBJECTIVES: This aim of the study was to ascertain the importance of clinical parameters on the response to treatment in refractory epilepsy patients on levetiracetam (LEV). MATERIALS AND METHODS: We retrospectively evaluated medical records of 132 patients aged 17-78 years with refractory epilepsy (defined as a failure of at least two antiepileptic drugs due to the lack of efficacy) exposed to LEV. We analyzed the response (seizure freedom or continuing LEV) using logistic regression. RESULTS: Of 132 patients exposed to LEV, 103 cases continued the drug. Of the discontinuations (29/132), 75% were for lack of efficacy and 25% for tolerability problems. Twenty-three percent of the previously refractory patients achieved seizure freedom for at least 1 year with LEV in combination therapy. The dose of LEV in 80% of seizure-free patients was 1000 mg/day or less. The duration of epilepsy, age and sex were not associated with response to LEV. Seizure freedom was associated with epileptic syndrome or etiology. If no specific syndrome was recognized, there was a significantly greater chance for response compared with temporal lobe epilepsy (OR 20.76; 95% CI 2.12-203.61). CONCLUSIONS: Our study was based on the careful clinical evaluation of the patients with extensive use of video EEG (50%) and MRI scans (95%). These clinical predictors were evasive in previous studies. This study showed that they are worth pursuing but significantly larger groups of patients need to be investigated to reach significant findings.

The benefit of active drug trials is dependent on aetiology in refractory focal epilepsy.

BACKGROUND: Earlier studies have shown that aetiology makes a difference in the outcome of epilepsy, but there is a paucity of follow-up studies to evaluate the possibilities of achieving seizure freedom in initially refractory epilepsy. METHODS: We evaluated the cause of epilepsy based on high-resolution brain MRI and patient history in 119 consecutive thoroughly examined adult patients with refractory focal epilepsy followed up in our centre. We also evaluated the influence of aetiology and duration of epilepsy in this patient cohort on the chances of achieving 12-month remission in a 2-year follow-up. RESULTS: The major finding was that a substantial group of patients achieved remission; 30 (25%) initially refractory patients achieved at least 12 months remission during follow-up. A total of 40.0% of the patients with cryptogenic aetiology had achieved 12-month remission compared with the 16.2% patients with symptomatic aetiologies (age-adjusted OR 3.74, 95% CI 1.54 to 9.07, p = 0.004). Aetiologies often considered for surgical treatment (hippocampal sclerosis, cortical dysplasia, vascular malformation, tumour and dual pathology) carried an almost six-fold risk of persistent seizures compared with cryptogenic epilepsy (age-adjusted OR 5.85, 95% CI 2.00 to 17.11, p = 0.001). CONCLUSIONS: Patients with vascular malformation and dual pathology as aetiology were most refractory, none being in remission for 12 months. There were also patients achieving 12-month remission after a long period of active epilepsy. These results encourage physicians to continue with new drug trials, especially on patients with no possibilities of epilepsy surgery, as well as on those still having seizures after epilepsy surgery.

Increased plasma levels of cytokines after seizures in localization-related epilepsy.

OBJECTIVES: Experimental studies suggest increased cerebral production of inflammatory cytokines after prolonged seizures. Whether a single non-prolonged seizure in human patients is associated with activation of cytokine network is still unknown. MATERIALS AND METHODS: We studied the levels of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1ra), interlukin-6 (IL-6) and soluble IL-6 receptors (sIL-6R and Gp130) in plasma after single seizures during video-EEG recordings in patients with chronic localization-related epilepsy. RESULTS: The levels of IL-1ra and IL-6 were increased after seizures, whereas IL-1beta and IL-6 cytokine receptors remained unchanged. CONCLUSIONS: These results show that only single seizures cause activation of cytokine cascade and associated inflammatory signals. In the case of recurrent seizures, these signals may result in structural changes in the nervous tissue, which are generally associated with drug refractory epilepsy.

The 3DX multi image micro-CT device in clinical dental practice.

OBJECTIVES: To evaluate the usefulness of 3DX multi-image micro-CT device in clinical dental practice. METHODS: Images of 198 examinations performed with a 3DX device during a 6 month period in a private dental practice were evaluated retrospectively for the benefit of additional information compared with panoramic or intraoral radiographs. RESULTS: The main indication for the use of 3DX micro-CT was planning of dental implant placement in 49% of the examinations. Diagnosis or exclusion of dental infection or peri-implantitis represented 28% of the examinations and tooth, root or foreign body localization represented 13%. Temporomandibular joint (TMJ) imaging and cyst or tumour diagnosis represented 7.5% and 2.5% of the examinations, respectively. In implant planning and tooth, root or foreign body localization examinations, the required information was obtained in every case except three implant planning examinations, in which the exact measurements were hampered by artefacts caused by root fillings and retrograde fillings or metal posts. When compared with conventional radiography, additional radiographic information was obtained in 51% of the micro-CT examinations performed to confirm or exclude dental infection or peri-implantitis. Micro-CT also showed the bone structure of TMJs precisely. CONCLUSIONS: The 3DX micro-CT device visualizes bony anatomical structures precisely, which makes it a reliable tool for, for example, planning of implant treatment. The device is highly suitable for diagnosing dental infections. Dental restorations may cause disturbing artefacts and in 4.5% of the examinations the small imaging area resulted in re-examination.