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Antiepileptic drug; Antiseizure medication; Tolerability Fármaco antiepiléptico; Medicamento anticonvulsivo; Tolerabilidad Medicament antiepilèptic; Medicament anticonvulsiu; Tolerabilitat Objective To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. Methods The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic–clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. Results In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: −5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). Significance In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.

Objective To examine serologic markers of vascular risk under treatment with commonly used antiepileptic drugs (AEDs) in the elderly in a randomized setting, and to determine whether the reduced exposure to hydroxymethylglutaryl-CoA reductase inhibitors ("statins") caused by carbamazepine reduces the effectiveness of the drugs as lipid-lowering agents. Methods Standard lipid fractions, lipoprotein(a), and C-reactive protein (CRP) were examined in a subset of those participating in the STEP-ONE trial, in which elderly patients with new epilepsy were randomized to treatment with carbamazepine, lamotrigine, or levetiracetam. Separate comparisons were made by individual AED, among those treated with statins, and, for CRP, among those treated with anti-inflammatory drugs. Results One hundred ninety-four patients had the aforementioned serologic measurements. In patients not taking statins, those treated with carbamazepine had higher total cholesterol than those treated with levetiracetam (+16.6 mg/dL, P = 0.053), with values from patients on lamotrigine intermediate, whereas cholesterol fractions were subject to drug-gender interactions which did not show a consistent pattern. Lipoprotein(a) was significantly lower in lamotrigine patients than in the carbamazepine and levetiracetam groups. After accounting for the effects of steroids, CRP was higher in carbamazepine patients than in other patients. Patients taking a statin had lower lipid levels than those not taking a statin regardless of AED, but the differences between statin-treated and non-statin-treated patients were much larger (50%-100% or more) in the lamotrigine and levetiracetam groups than in the carbamazepine group (P = 0.035 for interaction effect of statin use and AED on total cholesterol). Significance Here, we demonstrate that carbamazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Native AED effects on lipids were inconsistent and subject to drug-gender interaction, in contrast with other studies; further investigation is necessary to determine if these latter findings are genuine or spurious.

SummaryObjective To assess the safety profile of lacosamide monotherapy in elderly (≥65 years) subjects with diabetic neuropathic pain (DNP). Methods Of 1,863 DNP subjects in double-blind, randomized, placebo-controlled trials of lacosamide monotherapy (NCT00861445, NCT00235469, NCT00238524, NCT00135109, NCT00350103), 502 were elderly. Safety data from elderly subjects were compared with that of younger subjects (

Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10–15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18–60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy., Guided by results of two human PET imaging studies, a single 400 mg bid dose of the antiepileptic drug candidate, padsevonil, was evaluated for patients with treatment-resistant epilepsy. At the end of a 3-week double-blind inpatient period, padsevonil displayed a favourable safety profile and conferred clinically meaningful benefit over placebo., Graphical Abstract Graphical Abstract

Objectives Cognitive comorbidity at epilepsy onset reflects disease severity and provides a baseline estimate of reserve capacities with regard to the effects of epilepsy and its treatment. Given the high incidence of epilepsy at an older age, this study analyzed objective and subjective cognition as well as quality of life in elderly patients with new-onset focal epilepsy before initiation of anti-epileptic treatment. Materials and methods A total of 257 untreated patients (60–95 years of age) with new-onset epilepsy underwent objective assessment of executive function (EpiTrack) and performed subjective ratings of cognition (Portland Neurotoxicity Scale) and quality of life (QoL; QOLIE-31). Results According to age-corrected norms, 58% of patients (N = 257) demonstrated deficits in executive function; major determinants were cerebrovascular etiology, neurological comorbidity, and higher body mass index. Subjective ratings indicated deficits in up to 27% of patients. Self-perceived deficits were associated with neurological, cardiovascular, and/or psychiatric comorbidity, whereas poorer QoL was related to neurological comorbidity and female gender. Objectively assessed executive functions correlated with subjective social functioning, energy, motor function, and vigilance. Conclusions We found a relatively high QoL, a low rate of subjective impairment, but a high incidence of objective executive deficits in untreated elderly patients with new-onset epilepsy. Neurological status and body mass index, rather than seizure frequency or severity, were risk factors for cognitive impairment. Given the relevance of cognition in the course of epilepsy and its treatment, routine screening before treatment initiation is highly recommended.

Background Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. Methods This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged ≥ 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. Results Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2–89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28–0.67); LEV vs. VPA-ER: 0.46 (0.16–1.33); LEV vs. CBZ-CR: 0.45 (0.28–0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63–1.35), LEV and VPA-ER (0.77, 0.38–1.56), and LEV and CBZ-CR (1.02, 0.64–1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively. Conclusions Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV may be a suitable option for initial monotherapy for patients aged ≥ 60 years with newly diagnosed epilepsy. Trial registration ClinicalTrials.gov: NCT00175903; September 9, 2005. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0663-7) contains supplementary material, which is available to authorized users.

Summary Background Further options for monotherapy are needed to treat newly diagnosed epilepsy in adults. We assessed the efficacy, safety, and tolerability of lacosamide as a first-line monotherapy option for these patients. Methods In this phase 3, randomised, double-blind, non-inferiority trial, patients from 185 epilepsy or general neurology centres in Europe, North America, and the Asia Pacific region, aged 16 years or older and with newly diagnosed epilepsy were randomly assigned in a 1:1 ratio, via a computer-generated code, to receive lacosamide monotherapy or controlled-release carbamazepine (carbamazepine-CR) twice daily. Patients, investigators, and trial personnel were masked to treatment allocation. From starting doses of 100 mg/day lacosamide or 200 mg/day carbamazepine-CR, uptitration to the first target level of 200 mg/day and 400 mg/day, respectively, took place over 2 weeks. After a 1-week stabilisation period, patients entered a 6-month assessment period. If a seizure occurred, the dose was titrated to the next target level (400 or 600 mg/day for lacosamide and 800 or 1200 mg/day for carbamazepine-CR) over 2 weeks with a 1-week stabilisation period, and the 6-month assessment period began again. Patients who completed 6 months of treatment and remained seizure-free entered a 6-month maintenance period on the same dose. The primary efficacy outcome was the proportion of patients remaining free from seizures for 6 consecutive months after stabilisation at the last assessed dose. The predefined non-inferiority criteria were −12% absolute and −20% relative difference between treatment groups. This trial is registered with ClinicalTrials.gov, number NCT01243177. Findings The trial was done between April 27, 2011, and Aug 7, 2015. 888 patients were randomly assigned treatment. 444 patients taking lacosamide and 442 taking carbamazepine-CR were included in the full analysis set (took at least one dose of study treatment), and 408 and 397, respectively, were included in the per-protocol set. In the full analysis set, 327 (74%) patients in the lacosamide group and 308 (70%) in the carbamazepine-CR group completed 6 months of treatment without seizures. The proportion of patients in the full analysis set predicted by the Kaplan-Meier method to be seizure-free at 6 months was 90% taking lacosamide and 91% taking carbamazepine-CR (absolute treatment-difference: −1·3%, 95% CI −5·5 to 2·8 relative treatment difference: −6·0%). Kaplan-Meier estimates results were similar in the per-protocol set (92% and 93%; −1·3%, −5·3 to 2·7; −5·7%). Treatment-emergent adverse events were reported in 328 (74%) patients receiving lacosamide and 332 (75%) receiving carbamazepine-CR. 32 (7%) patients taking lacosamide and 43 (10%) taking carbamazepine-CR had serious treatment-emergent adverse events, and 47 (11%) and 69 (16%), respectively, had treatment-emergent adverse events that led to withdrawal. Interpretation Treatment with lacosamide met the predefined non-inferiority criteria when compared with carbamazepine-CR. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed epilepsy. Funding UCB Pharma.

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine ( 3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.

Epilepsies frequently only start in old age and given the current demographic trend the prevalence of epilepsy in the elderly population will increase. This article summarizes the most relevant aspects of diagnosis and therapy in elderly patients with epilepsy. Guidelines, systematic reviews or meta-analyses are lacking and there are only three randomized controlled trials of epilepsy in the elderly. Clinically, seizures in the elderly may be missed since warning signs (auras) and seizure evolution into generalized tonic-clonic seizures are rarer in older people. Sudden loss of consciousness occurs more frequently with increasing age and poses a challenge for the differential diagnosis. Therapy is more complex due to frequent comorbidity and multiple drug therapy necessitating a cautious approach. Therapy is hampered by side effects and drug interactions making a definite diagnosis indispensable and requiring the use of newer generation antiepileptic drugs. In case of doubt, to ensure a safe diagnosis long-term video EEG should be considered even in the elderly before hazarding the negative consequences of a misdiagnosis for years.

Summary Purpose: To quantify extrastriatal and striatal D2/D3 receptor binding in patients with juvenile myoclonic epilepsy (JME) using the high-affinity dopamine D2/D3 receptor positron emission tomography (PET) ligand 18F-Fallypride ([18F]FP). Methods: Twelve patients with JME and 21 age-matched control subjects were studied. Dynamic images (180 min) were acquired after injection of [18F]FP. Patients had been seizure-free of all seizure types for at least 10 days before scanning. Parametric images of binding potential (BP) were created using the simplified reference tissue model. The images were stereotactically normalized using a ligand-specific template. We performed a voxel-based analysis with statistical parametric mapping (SPM2). Region of interest (ROI) analysis was done comparing the BP of the thalamus, caudate nucleus, anterior (ventral) and posterior (dorsal) putamen, ventral striatum, and temporal lobe. Results: Compared to controls, patients with JME showed a significant decrease in [18F]FP BP (SPM analysis corr. p

Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy.Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5).Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p0.05), but binding was unaffected in other striatal or extrastriatal regions.The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.

Resective epilepsy surgery is an elective therapy indicated in focal epilepsy patients who are resistant to pharmacotherapy. Every effort should be undertaken to perform the procedures as safe and less traumatic as possible. Neuronavigation could represent a suitable tool to reduce surgical morbidity and increase surgical radicality. Here, we present a series of 41 patients who were operated on for medically intractable epilepsy using neuronavigation. Overall, complication rate was 17% with a favourable seizure outcome of 88% (Engel’s class I/II). Our data suggest that neuronavigation is a valuable surgical technique to accomplish a favourable outcome in epilepsy surgery.

The level of excitability within the motor cortex can be described as a balance between excitation and inhibition, but it is unknown how well both processes correlate. To address this question, the authors measured motor cortical excitability and inhibition in healthy human subjects, comparing the recruitment of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) after transcranial magnetic stimulation (TMS). Single-pulse "focal" TMS was applied at intensities varying between 90% and 200% of motor thresholds to the right motor cortex of 15 healthy volunteers. The peak-to peak size of MEP responses and the duration of the CSP were measured in small hand muscles. Stimulus-response (S-R) curves were constructed by plotting the MEP size and CSP duration against stimulus intensities. The absolute duration of CSP and the size MEPs correlated significantly and to a similar extent with stimulus intensity (r = 0.60 and 0.53, respectively). The slope of the MEP-S-R was steeper compared with CSP-S-R, particularly at low stimulation intensities. CSP duration saturated earlier and CSP-S-Rs were shifted upwards at a given stimulus intensity compared with MEP-S-Rs. The findings suggest that recruitment of inhibition and excitation within the sensorimotor cortex correlate. However, inhibitory effects are recruited at lower intensities and saturate earlier than excitation.

Contrary to former views, the incidence rate of epilepsy after the age of 65 years is higher than in childhood and adolescence, and epileptic seizures are one of the most common neurological problems in the elderly. Given that the incidence of epilepsy increases with advancing age and is not accompanied by an increase in mortality and given that elderly people now live longer, the prevalence of epilepsy is increasing with older age. Antiepileptic drugs (AEDs) are the primary treatment for epilepsy, although they are prescribed for other conditions too. Among nursing home residents the prevalence of seizures or epilepsy is between 5 and 8%, while AEDs are taken by approximately 5–10%. It is unclear why AED use is inversely related to age in nursing home residents. AEDs may be of considerable risk for the elderly due to falls, cognitive side effects, other adverse events and drug interactions. In addition, inappropriate use of all medication (up to 40% of prescriptions) has a significant impact on public-health costs leading to increased hospitalization and mortality. Despite evidence from controlled clinical trials and expert recommendations, most AEDs used in nursing home residents are outdated. Efforts should therefore be made to improve the medical management of nursing facility residents receiving AEDs.

Objective Dopamine is an endogenous neuromodulator in cortical circuits and the basal ganglia. In animal models of temporal lobe epilepsy (TLE), seizure threshold is modulated to some extent by dopamine, with D1-receptors having a pro- and D2-receptors an anticonvulsant effect. We aimed to extend our previously reported results on decreased D2/D3 receptor binding in the lateral epileptogenic temporal lobe and to correlate them with demographic and seizure variables to gain a more comprehensive understanding of the underlying involvement of the dopaminergic system in the epileptogenesis of TLE. Methods To quantify D2/D3 receptor binding, we studied 21 patients with TLE and hippocampal sclerosis (13 left- and eight right-sided) and 18 controls using PET with the high-affinity dopamine D2/D3-receptor ligand 18F-Fallypride to image striatal and extrastriatal binding. TLE was defined by interictal and ictal video-EEG, MRI and 18F-Fluorodeoxyglucose PET. Voxel-based statistical and regions-of-interest analyses were performed. Results 18F-Fallypride binding potential was significantly reduced in the affected temporal lobe and bilateral putamen. A positive correlation between age at onset of epilepsy and [18F]FP BPnd (binding potential non-displaceable) in temporal regions on the epileptogenic side was found, as well as a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole on the epileptogenic side and a positive correlation between the estimated number of lifetime GTCS and [18F]FP BPnd in the hippocampus on the epileptogenic side. Significance The areas of reduced D2/D3 receptor availability correspond to “the irritative zone” surrounding the epileptogenic area. Moreover, reduced D2/D3 receptor availability was detectable in the basal ganglia, which are suspected to be involved in a control circuit for epileptic seizures. The correlational analysis additionally suggests that increased epilepsy duration leads to increasing impairment of the dopaminergic system.

Der kurzlich erschienene Vorschlag der ILAE-Taskforce zur Epilepsieklassifikation ist ein multiaxialer, syndromorientierter Ansatz. Hierbei werden die Patienten unterschiedlichen und oftmals unzureichend definierten Kriterien zugeordnet. Die resultierenden Syndrome haben haufig keine atiologische oder pathophysiologische Relevanz, uberlappen und wechseln je nach Alter des Patienten. Wir schlagen einen 5-dimensionalen, patientenorientierten Ansatz zur Klassifikation der Epilepsien vor. Dieser Ansatz wendet sich von der Orientierung an Syndromen ab und basiert stattdessen auf dem methodologischen Ansatz der allgemeinen Neurologie, in dem einerseits das klinische Bild des einzelnen Patienten im Mittelpunkt steht und andererseits in jeder Dimension voneinander unabhangige und moglichst operationalisierbare Kriterien angewandt und schlieslich zusammengefuhrt werden. Die Dimension dieser Klassifikation sind: (1) Lokalisation der epileptogenen Zone, (2) Semiologie der epileptischen Anfalle, (3) Atiologie, (4) Anfallshaufigkeit und (5) sonstige relevante medizinische Faktoren. Diese Dimensionen enthalten alle fur das Management eines Patienten notwendige Information und sind voneinander unabhangige Parameter. Alle Patienten konnen selbst beim initialen Patientenkontakt sinnvoll in das System eingeordnet werden, auch wenn noch keine apparativen Untersuchungen durchgefuhrt wurden. Die Information aller Untersuchungen (z. B. MRT, EEG) fliest zum jeweiligen Zeitpunkt der Klassifikation in die Zuordnung des Patienten ein und erlaubt mit jeder neu verfugbaren Information eine Zunahme der Prazision und Validitat der Klassifikation.

Listeriosis is a bacterial infection with Listeria monocytogenes mostly affecting immunocompromised patients. In every fourth case, the CNS is involved, usually as meningoencephalitis. This case report of an immunocompetent woman represents the first one of neurolisteriosis initially presenting as cervical myelitis and progressing to supratentorial areas of the brain. Diagnosis was based on universal polymerase chain reaction from a cortical brain biopsy, followed by sequencing of the amplified rDNA gene. Under antibiotic treatment with gentamycin and ampicillin, the patient slowly recovered and has been improving ever since.

Purpose: To examine the influence of cardiac activity-related head movements and varying blood pulse frequencies on the shape of electroencephalography (EEG) recordings in a high magnetic field, and to implement a post-processing technique to eliminate cardiac activity-related artifacts. Material and Methods: Respiratory thoracic movements, changes of blood pulse frequency and passive head movements of 20 healthy subjects were examined outside and inside an MR magnet at rest in a simultaneously recorded 21-channel surface EEG. An electrocardiogram (ECG) was recorded simultaneously. On the basis of the correlation of the left ventricular ejection time (LVET) with the heart-rate, a post-processing heart-rate dependent subtraction of the cardiac activity-related artifacts of the EEG was developed. The quality of the post-processed EEG was tested by detecting alpha-activity in the pre- and post-processed EEGs. Results: Inside the magnet, passive head motion but not respiratory thoracic movements resulted in EEG artifacts that correlated strongly with cardiac activity-related artifacts of the EEG. The blood pulse frequency influenced the appearance of the cardiac activity-related artifacts of the EEG. The removal of the cardiac activity-related artifacts of the EEG by the implemented post-processing algorithm resulted in an EEG of diagnostic quality with detected alpha-activity. Conclusion: When recording an EEG in MR environment, heart rate-dependent subtraction of EEG artifacts caused by ballistocardiogram contamination is essential to obtain EEG recordings of diagnostic quality and reliability.

Ein Grosteil der Bevolkerung in Deutschland wird in der nahen Zukunft zu den sog. „Alteren“, das heist uber 65–Jahrigen, gehoren, wobei der Anteil der uber 85–Jahrigen am schnellsten wachsen wird. Die Inzidenz einzelner unprovozierter epileptischer Anfalle liegt im Alter von 80 Jahren hoher als im Kindesalter und die Pravalenz von Epilepsien wird auf 1–1,5% geschatzt. Trotzt dieser Entwicklung ist das Wissen uber Epilepsien im Alter gering. Altere Patienten haben haufig neurodegenerative und zerebrovaskulare Begleiterkrankungen, fur die sie in der Regel in Vielzahl von Medikamenten einnehmen. Die Klinik der Anfalle kann sich im Alter von der in jungen Erwachsenenjahren unterscheiden, was die Diagnose erschwert, zumal das EEG im Alter weniger sensitiv fur epilepsie–typische Veranderungen ist. Auch die Haufigkeit von nicht–epileptischen Anfallen in dieser Altersgruppe wird vermutlich unterschatzt. Mit fortschreitendem Alter treten drastische Veranderungen, der Medikamenten–Absorption, –Disposition und –Bindung zusatzlich zu einer erhohten pharmakodynamischen Empfindlichkeit auf, die eine medikamentose Behandlung erschweren. In diesem Ubersichtsartikel werden der aktuelle Stand der Epidemiologie, Klinik, Fallstricke der Diagnosestellung und Aspekte der medikamentosen Behandlung von alten Patienten mit Epilepsie beschrieben.

The purpose of this study was to develop a spike-related functional magnetic resonance (MR) imaging method to detect epileptic brain activity. Correlations between simultaneous spike-related functional MR imaging and electroencephalographic (EEG) recordings were performed in 10 patients with focal epilepsy. Postprocessing techniques were implemented to eliminate contamination of the EEG recording from ballistocardiography and the echo-planar MR imaging sequence. A diagnostic EEG recording was achieved during functional MR imaging. Spike location correlated with the site of blood oxygen level-dependent signal increase. Spike-related functional MR imaging is a promising technique for detecting focal epileptic brain activity.

Short-term deprivation of sensory input by ischaemic nerve block (INB) leads to functional reorganization in the deafferented motor cortex. Here, we show that INB also elicits functional changes in homotopic regions of the cortex contralateral to the deafferented one. We measured motor evoked potential (MEP) amplitudes elicited by transcranial magnetic stimulation (TMS) in small hand and biceps brachii muscles before, during and after INB of the right hand. INB increased excitability of the cortical representation of (i) the intact hand and (ii) body parts proximal to the deafferented hand (upper arm), in the absence of excitability changes in other body part representations such as thorax or leg muscles. This effect persisted throughout the entire period of deafferentation and returned to baseline values afterward. Motor responses to brainstem electrical stimulation remained unchanged during INB, indicating that the effect is probably of cortical origin. Lorazepam, a GABA(A) receptor agonist, blocked this increased excitability. Interhemispheric inhibition between hand muscles decreased during INB. After chronic deafferentation in amputees, MEP amplitudes and motor output curves in small hand muscles were depressed and motor thresholds were elevated compared with aged-matched controls. These results indicate that acute hand deafferentation can elicit a focal increase in excitability in the hand motor representation contralateral to the deafferented cortex that is influenced by transcallosal interactions and GABAergic transmission, and is balanced in the setting of chronic deafferentation.

Objective: To compare the effectiveness of controlled-released carbamazepine (CR-CBZ) to levetiracetam (LEV) and to lamotrigine (LTG) in elderly patients with newlydiagnosedfocalepilepsy.Methods: Randomized, double-blind, parallel-group trial conducted between January2007andAugust2011,in47ambulatoryorhospitalsitesinGermany,Austria,orSwit-zerland. Eligible participants were aged ≥60, had new-onset epilepsy, had no acute ill-nessasthecauseoftheirseizures,andhadnocontraindicationtothedrugsinthetrial.Patients were randomized 1:1:1 to CR-CBZ, LTG, or LEV. Doses were up-titrated for6 weeks and could be maintained or adjusted depending on seizure relapse or tolera-bility over an additional period of 52 weeks. Primary outcome was the retention totreatment at week 58; secondary measures related to seizure and adverse event fre-quency.Results: Of 361 randomized patients, 359 were included (CR-CBZ n = 121, LTGn = 117, LEV n = 122) in the modified intent-to-treat population (mean age [range]71.4 [60–95] years). At week 58, the retention rate for LEV was significantly higherthan for CR-CBZ (61.5% vs. 45.8%, p = 0.02), and similar to LTG (55.6%). Seizure free-dom rates at weeks 30 and 58 were not different across the groups. Twice as manypatients receiving CR-CBZ discontinued due to adverse events or death compared tothose in the LEV group (32.2% vs. 17.2%; odds ratio 2.28, 95% confidence interval [CI]1.25–4.19, p = 0.007), whereas discontinuation was intermediate for LTG (26.3%).Mediandailydosesofcompleters(n = 195)wereCR-CBZ380.0 mg/day(333.0–384.0),LTG95 mg/day(94.0–97.0),andLEV950 mg/day(940.0–985.0).Significance: In the initial monotherapy of focal epilepsy in the elderly, 1-year reten-tion to LEV was higher compared to CR-CBZ due to better tolerability. Retention ofLTG was intermediate and close to LEV, but did not differ significantly from eithercomparators.NCT00438451,www.clinicaltrials.gov.KEY WORDS: Elderly, Monotherapy, Antiepileptic drugs, Levetiracetam, Carbamaz-epine.

PurposeTo assess the latency of interictal epileptiform discharges (IED) and seizures in long-term EEG recordings of patients with epilepsy.MethodIED latency was measured in 210 consecutive patients (mean (SD) age 38.6±13.9 years) with active epilepsy and the relationship to clinical variables was analyzed retrospectively. Median duration of EEG recording was 101.5h (95% confidence interval [CI] 92 to 117h).ResultsIEDs were absent in 45 (21.4%) and present in 165 (78.6%) patients who had a longer duration (p

We studied the excitability of the motor cortex using, transcranial magnetic stimulation (TMS) in patients with temporal and extratemporal epilepsy. We applied single and paired-pulse TMS to 15 patients with temporal (n = 7), extratemporal (n = 6) and focal epilepsy lateralised to one hemisphere (n = 2). Patients had no antiepileptic drugs in the last 48 h and were seizure free for 4 h prior to testing. We determined the threshold for EMG responses at rest (RMT), the cortically evoked silent period (CSSP) and intracortical inhibition (ICI, intervals of 2-4 ms) and facilitation (ICF, 7-15 ms) and compared the results to those obtained in 17 normal controls. ICI and ICF was reduced in both hemispheres (P < 0.01. ANOVA) compared to the controls. In the hemisphere of seizure origin ('abnormal') there was a reduction of ICF (P < 0.01) and normal ICI, in the 'normal' hemisphere there was a reduced ICI (P < 0.01) and a slight reduction of ICF (P < 0.05). ICF on the 'abnormal' side was reduced (P < 0.05) compared to the 'normal' hemisphere. RMT was increased in two patients, but group comparison of RMT and CSSP showed no significant differences between patients and controls. The results suggest a remote effect of epileptic activity onto the motor cortex leading to an alteration of activity in local inhibitory circuits.

Purpose: Comparison of regional reduction of GABA receptor binding and seizure onset zone in patients with extratemporal epilepsy due to focal cortical dysplasia.Methods: Two patients with frontal lobe epilepsy who remained seizure free after partial frontal lobe resection were investigated with magnetic resonance imaging, positron emission tomography (PET) with F-18-fluoro-deoxy-glucose (FDG) and C-11-flumazenil, subdural EEG-video recordings, and postoperative benzodiazepine (BDZ)-receptor autoradiography.Results: The area of reduced BDZ-receptor binding as documented by preoperative flumazenil-PET and postoperative BDZ-receptor autoradiography corresponded to the seizure on-set zone and was smaller than the interictal hypometabolism documented by FDG-PET.Conclusion: Flumazenil-PET is a useful tool for localization of the epileptogenic zone in patients with extratemporal epilepsy caused by focal cortical dysplasia. Neuronal distribution of BDZ-receptor density confirms in vivo flumazenil-PET findings. The regional reduction of BDZ-receptor binding in focal cortical dysplasia seems to be confined to the seizure onset zone and not to the extent of dysplastic cortex.

The extent and function of synchronization of oscillatory elements in the human sensorimotor cortex during movement remains unclear. Here we determine whether synchronization is distributed in both the spatial and frequency domains and whether it changes according to task. Electrocorticographic (ECoG) signals were recorded from presumed nonpathological areas simultaneously with electromyographic (EMG) signals from upper limb muscles during isometric and phasic movement tasks in humans with subdural electrodesin situfor investigation of epilepsy. Functional mapping of the sensorimotor cortex was performed by previous electrical stimulation through the same ECoG electrodes used for recording. Significant coherence between ECoG and EMG was seen at discrete frequencies in the range of 7–100 Hz. There was no predilection for coherence within a given frequency band to be associated with cortical sites that had been functionally defined as producing contralateral arm motor responses on stimulation. However, coherence with muscle in the 7–14 and 15–30 Hz band tended to be associated with ECoG sites that lay close to or within the central sulcus as determined intraoperatively. The spatial pattern and frequency of coherence changed with different tasks, although similarities in the coherence pattern remained for tasks that shared common features. These findings provide support for the hypothesis that that synchronization at specific frequencies links cortical activities into a functional ensemble during voluntary movement.

EEG has been used to trigger functional MRI of patients with focal epilepsy, but EEG can be obscured by artifacts during MR data acquisition, and no continuous correlation of EEG and MRI has been possible without limiting the image time. Artifacts caused by an MRI sequence were investigated in five healthy subjects, and an EEG of five patients with epileptic discharges was recorded during echo-planar imaging. All interfering frequencies in the EEG were discrete and defined by loop structures in the MRI sequence. In post-processing of the EEG interfering frequencies were automatically detected by comparing the frequency spectra of the EEG recorded before and during imaging. After elimination of interfering frequencies by filters in the time domain or by Fourier transform, reliable spike detection in the EEG recorded during MR data acquisition became feasible, without loss of EEG quality.

Wir stellen ein nichtinvasives Protokoll fur die epilepiechirurgische Diagnostik vor, demzufolge bei 50 von 173 Patienten mit pharmakoresistenten fokalen Epilepsien ein resektiver epilepsiechirurgischer Eingriff durchgefuhrt wurde. Die lokalisatorische Ubereinstimmung von Befunden des nichtinvasiven EEG-Video-Monitorings, der Magnet-Resonanz-Tomographie (MRT), der interiktalen Positronen-Emissions-Tomographie (PET) und der iktalen SPECT (Single-Photon-Emissions-Computer-Tomographie) bildete die Grundlage der Fokuslokalisation. Bei 46 (92%) der Patienten lagen temporale und bei 4 (8%) extratemporale Epilepsien vor. 78% (n=39) aller 50 Patienten wurden anfallsfrei oder hatten nur noch sehr selten Anfalle. Extratemporale Resektionen konnten ohne invasive EEG-Untersuchungen erfolgen, wenn umschriebene MRT-Lasionen vorlagen und die Resektionen in ausreichendem Abstand vom eloquenten Kortex durchgefuhrt werden konnten. Anfallsfreiheit konnte so bei insgesamt 3 der 4 extratemporalen Patienten erreicht werden. Wir folgern aus unseren Ergebnissen, das bei einer Reihe von ausgewahlten Patienten mit pharmakoresistenten fokalen, insbesondere temporalen Epilepsien nichtinvasive EEG-Ableitungen in der prachirurgischen Diagnostik ausreichen und so das Risiko invasiver EEG-Untersuchungen vermieden werden kann.

1. Non-invasive mapping by focal transcranial magnetic stimulation (TMS) is frequently used to investigate cortical motor function in the intact and injured human brain. We examined how TMS-derived maps relate to the underlying cortical anatomy and to cortical maps generated by functional imaging studies. 2. The centres of gravity (COGs) of TMS maps of the first dorsal intersosseus muscle (FDI) were integrated into 3-D magnetic resonance imaging (MRI) data sets in eleven subjects. In seven of these subjects the TMS-derived COGs were compared with the COG of regional cerebral blood flow increases using positron emission tomography (PET) in an index finger flexion protocol. 3. Mean TMS-derived COG projections were located on the posterior lip of the precentral gyrus and TMS-derived COG projections were in close proximity to the mean PET-derived COG, suggesting that the two methods reflect activity of similar cortical elements. 4. Criteria for a reliable assessment of the COG and the number of positions with a minimum amplitude of two-thirds of the maximum motor-evoked potential (T3Ps) were determined as a function of the number of stimuli and extension of the stimulation field. COGs and T3Ps were compared with an estimate of the size of the human motor cortex targeting alpha-motoneurons of forearm muscles. This comparison suggests that TMS can retrieve spatial information on cortical organization below the macroanatomic scale of cortical regions. 5. Finally, we studied the cortical representation of hand muscles in relation to facial and foot muscle representations and investigated hemispherical asymmetries. We did not find any evidence for a different ipsi- or contralateral representation of the mentalis muscle. Also, no difference was found between FDI representations on the dominant versus the non-dominant hemisphere.

Although ictal single-photon emission tomography (SPET) with technetium-99m ethyl cysteinate dimer (ECD) has a well-established role in the diagnostic evaluation of patients with temporal lobe epilepsy who are being considered for epilepsy surgery, its use in cases of extratemporal epilepsy is still limited. We investigated the influence of the propagation of extratemporal epileptic seizure activity on the regional increase in cerebral blood flow, which is usually associated with epileptic seizure activity. Forty-two consecutive patients with extratemporal epilepsies were prospectively evaluated. All patients underwent ictal SPET studies with simultaneous electroencephalography (EEG) and video recordings of habitual seizures and imaging studies including cranial magnetic resonance imaging and positron emission tomography with 2-[18F]-fluoro-2 deoxy-d-glucose. Propagation of epilptic seizure activity (PESA) was defined as the absence of hyperperfusion on ictal ECD SPET in the lobe of seizure onset, but its presence in another ipsilateral or contralateral lobe. Observers analysing the SPET images were not informed of the other results. PESA was observed in 8 of the 42 patients (19%) and was ipsilateral to the seizure onset in five (63%) of these eight patients. The time between clinical seizure onset and injection of the ECD tracer ranged from 14 to 61 s (mean 34 s). Seven patients (88%) with PESA had parieto-occipital epilepsy and one patient had a frontal epilepsy. PESA was statistically more frequent in patients with parieto-occipital lobe epilepsies (58%) than in the remaining extratemporal epilepsy syndromes (3%) (P

Recent advances in epileptology and epilepsy surgery require revision of the currently used International Classification of Epileptic Seizures, which was published 1981. We present a classification of epileptic seizures which is based purely on the clinical seizure semiology. The advantages of a semiological seizure classification are stressed.

The paraneoplastic amphiphysin(+) stiff-person syndrome (SPS) has so far only been described in women with breast adenocarcinoma. Here, we describe the rare case of a female patient with antiamphiphysin(+) SPS due to small cell cancer of the lung.

The clinical and neurophysiologic features of 14 patients with chronic posthypoxic myoclonus are presented. Patients were first seen a mean of 2.5 years (range, 2 to 105 months) after the hypoxic event and followed up for 3.7 years (range, 7 to 84 months) thereafter. All patients had had a cardiorespiratory arrest, most caused by an acute asthmatic attack (11 cases). All patients had multifocal action myoclonus. Eleven patients had additional stimulus-sensitive myoclonus. There was late improvement in the myoclonic syndrome and the level of disability in all but one patient. Three patients were eventually able to discontinue antimyoclonic medication, and five patients were able to walk unaided. Cognitive deficits were found in seven patients and were usually mild. Other neurologic deficits were rare. Electrophysiologic investigation confirmed cortical action myoclonus in every case, although this could be combined with cortical reflex myoclonus, an exaggerated startle response, or brainstem reticular reflex myoclonus. We conclude that posthypoxic myoclonus typically consists of multifocal cortical action myoclonus that improves with time. It is only rarely associated with severe additional neurologic deficit.

Summary Purpose Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16–70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. Methods This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs). Key Findings Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. Significance In this study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20–100 mg/day was well tolerated without up-titration, with a high completion rate.

There have been conflicting reports over whether it is possible to stimulate the human cerebellum through the intact scalp using transcranial magnetic stimulation. Here we attempt to clarify the situation in normal subjects by comparing the various methods which have been used. EMG responses evoked by magnetic stimulation over the motor cortex could be suppressed by a prior magnetic stimulus over the cerebellum but the onset latency of the effect varied according to the type of magnetic coil used. Inhibition began at a latency which ranged from 5 to 9 msec in different subjects if conditioning stimuli were given through a flat figure-of-eight coil held horizontally over the basal occiput. The effect lasted a further 6-10 msec. With a larger double cone coil, held vertically over the basal occiput, inhibition began earlier and at a more constant latency of 5 msec. It lasted only 3 msec. Stimulation of the C6/7 nerve roots in the brachial plexus with either an electrical or magnetic stimulus also could suppress EMG responses evoked by cortical stimulation. This began at a conditioning-test interval of 7 or 8 msec and lasted for some 5 msec. We suggest that two types of motor cortical suppression may be elicited from stimulation over the posterior neck/skull: a cerebellar effect starting at 5 msec, and a peripheral nerve effect starting later at 7/8 msec. Stimulation with a horizontal large figure-of-eight coil may produce a mixture of effects because the lower wing of the coil overlaps the posterior neck and can activate peripheral nerve fibres in the brachial plexus.

Objective: To perform a controlled trial of transcranial magnetic stimulation (TMS). Methods: Twenty-four patients with localization-related epilepsy were randomized to blinded active or placebo stimulation. Weekly seizure frequency was compared for 8 weeks before and after 1 week of 1-Hz TMS for 15 minutes twice daily. Results: When the 8-week baseline and post-stimulation periods were compared, active patients had a mean seizure frequency reduction of 0.045 ± 0.13 and sham-stimulated control subjects −0.004 ± 0.20. Over 2 weeks, actively treated patients had a mean reduction in weekly seizure frequency of 0.16 ± 0.18 and sham-stimulated control subjects 0.01 ± 0.24. Neither difference was significant. Conclusion: The effect of TMS on seizure frequency was mild and short lived.

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (0.3 μM) attenuated epileptiform activity, whereas3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.

Postictal motor deficits may occur in patients following partial and generalized tonic-clonic seizures. Frequency is unclear, epidemiology being hampered by heterogeneous populations and variable methods of detection. Postictal paresis may affect any body part, may be bilateral, and may occur more frequently in seizures involving the sensorimotor cortex. Duration varies depending on the precise mode of testing from a few minutes to 36 hours. Sensory deficits following seizures have been rarely reported but may be missed if not specifically tested for. The lateralizing value of postical paresis is high (>90%), pointing to a seizure origin in the opposite frontal lobe. Postictal paresis often is lesion associated and should encourage MRI, particularly in new-onset epilepsy. Etiology is unclear, neuronal exhaustion and hyperinhibition being the main pathophysiological theories discussed. As disability from seizures may be increased, postictal paresis should more systematically be asked and tested for and should also be included when evaluating the success of anticonvulsive treatment.

To quantify extrastriatal and striatal D2/D3 receptor binding in patients with juvenile myoclonic epilepsy (JME) using the high-affinity dopamine D2/D3 receptor positron emission tomography (PET) ligand (18) F-Fallypride ([(18) F]FP).Twelve patients with JME and 21 age-matched control subjects were studied. Dynamic images (180 min) were acquired after injection of [(18) F]FP. Patients had been seizure-free of all seizure types for at least 10 days before scanning. Parametric images of binding potential (BP) were created using the simplified reference tissue model. The images were stereotactically normalized using a ligand-specific template. We performed a voxel-based analysis with statistical parametric mapping (SPM2). Region of interest (ROI) analysis was done comparing the BP of the thalamus, caudate nucleus, anterior (ventral) and posterior (dorsal) putamen, ventral striatum, and temporal lobe.Compared to controls, patients with JME showed a significant decrease in [(18) F]FP BP (SPM analysis corr. p0.001 at cluster level) restricted to the bilateral posterior putamen. There was no significant alteration of [(18) F]FP binding in other brains regions. ROI analysis revealed a significant (p0.05) decrease of [(18) F]FP BP in the left (mean -14.8%) and right (mean -16.9%) posterior putamen, but not in the anterior putamen, caudate, ventral striatum, thalamus, or temporal lobe.Patients with JME showed a reduction in D2/3 receptor binding restricted to the bilateral posterior putamen, suggesting a specific alteration of the dopaminergic system. Whether these changes can be regarded as merely functional or whether they relate to the pathophysiology of juvenile myoclonic epilepsy still remains unclear.

Epilepsy is the third most common disease affecting the brain in the elderly. Current demographic trends will lead to an increased prevalence of epilepsy in the general population.A selective literature search revealed 102 relevant publications as of September 2008, 50 of which were original articles.The level of evidence was found to be very low. No guidelines, systematic reviews or meta-analyses are available, and there have been only three randomized, double-blind trials of treatment for epilepsy in the elderly. The seizures often escape clinical attention, because premonitory symptoms (aura) and secondary generalization into tonic-clonic seizures are both rarer in older patients. On the other hand, sudden loss of consciousness from various causes becomes more common with increasing age, presenting a challenge in differential diagnosis. Treatment is often more complex because of comorbidities and multiple other drugs, and requires a cautious approach. Drug interactions, in particular, require special attention. On the positive side, epileptic seizures in the elderly seem to be more easily controlled by medications than they are in young adults.Epilepsy is often more difficult to recognize in old age. The treatment is hampered by side effects and drug interactions. Thus, certainty about the diagnosis is indispensable, and the treatment often requires the use of newer-generation antiepileptic drugs.

Intracortical disinhibitory mechanisms play a crucial role in epilepsy. Therefore, the recruitment of motor cortical excitability was evaluated to distinct between focal and generalized epileptic syndromes. Twenty-five untreated patients with epilepsy and 20 controls were enrolled. Classification into focal (FE, n=10) or idiopathic generalized (IGE, n=15) epilepsy was based on seizure semiology, EEG and MRI. The recruitment of motor cortical inhibition and facilitation was measured by varying the stimulus intensity (SI) of the first conditioning stimulus in a paired-pulse transcranial magnetic stimulation (TMS) paradigm producing stimulus-response (S-R) curves of intracortical excitability. S-R curves were then compared with other commonly used TMS measures of cortical excitability [cortical silent period (CSP) and motor threshold (MT)]. In patients with IGE, inhibition occurred only at higher conditioning SIs compared to patients with focal epilepsy and controls. Recruitment of inhibition was unchanged in patients with focal epilepsy compared to controls. Recruitment of facilitation (ICF), CSP duration and MT, were not different between patients with FE or IGE or between patients and controls. These results suggest that the recruitment for motor cortical inhibition in patients with IGE is less effective. This may reflect a disturbed access to or an increased threshold of inhibitory neurons within the motor cortex. Impaired recruitment of inhibition might be a helpful parameter to access cortical excitability in newly diagnosed patients with generalized or focal epilepsy.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Oral administration of zolmitriptan, a novel 5-hydroxytriptamine receptor agonist, to eight healthy volunteers significantly reduced motor cortical excitability as tested by paired transcranial magnetic stimulation (TMS) at short interstimulus intervals. Zolmitriptan did not change motor thresholds to TMS or electromyographic silent period durations. We conclude that zolmitriptan acts centrally by reducing the inhibition within the motor cortex. The results suggest that the action of zolmitriptan on motor cortical excitability does not result from changes at the level of the cell membrane but from the influence on GABAergic inhibitory interneurons.